Effects of Drugs (Papers)

ABSTRACT

Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.

KEYWORDS: Cannabis, sperm, DNA methylation, autism, heritability

Introduction

Cannabis sativa is the most commonly used illicit psychoactive drug in the United States (U.S.) and Europe [1]. In the U.S., 11 states and Washington D.C. have legalized the recreational use of cannabis and 33 states have legalized the use of medicinal cannabis [2,3]. Since 1995, cannabis potency (defined as the concentration of the psychoactive cannabis component delta-9-tetrahydrocannabinol, or THC, in the sample [4]) has consistently risen from ~4% to as high as 32% in some states [2,5,6]. Changes in cannabis potency have been accompanied by changes in attitudes about cannabis and patterns of cannabis use. Between 2002 and 2014, the percentage of adults in the U.S. who perceived cannabis use as risky declined from 50% to 33% [6]. During this same period, the percentage of U.S. adults who believed cannabis to have no risk rose from 6% to 15% [6]. According to a 2015 Survey on Drug Use and Health, 52.5% of men in the U.S. of reproductive age (≥18) have reported cannabis use at some point in their lives, making cannabis exposure especially relevant for potential future fathers [7–11].

Given the increased prevalence of cannabis use in the U.S., studies are beginning to focus on the effects of use on the health and development of offspring. Prenatal cannabis exposure via maternal use during pregnancy is associated with decreased infant birth weight, an increased likelihood to require the neonatal intensive care unit, and the potential for an impaired fetal immune system compared to those infants who are not exposed during gestation [1,12]. In rodent studies, rat pups born to parents who were both exposed to THC during adolescence had increased heroin-seeking behaviour later in life, a phenotype that was accompanied by epigenetic changes in the nucleus accumbens [13–15]. These studies and others have begun to highlight the potential for intergenerational consequences of cannabis exposure [16]. Identifying the mechanism that underlies these changes is critical as cannabis use continues to increase across the U.S.

The environment impacts the integrity and maintenance of the epigenome such that it is now viewed as a molecular archive of past exposures [17]. While the majority of environmental epigenetic studies are focused on the impact of the inutero environment on the epigenome and health of the child, it has become apparent that the exposure history of the father must also be considered – specifically the impact of his exposures on the sperm epigenome. Studies have shown that exposure to phthalates, pesticides, nutritional deficiencies, and obesity can all induce potentially heritable changes in the sperm epigenome [18–24]. It is likely that other common and emerging exposures, including cannabis, may also contribute to disruption of sperm DNA methylation in a similar fashion, and that such changes could be transmitted to the subsequent generation.

Using reduced representation bisulphite sequencing (RRBS) our group recently demonstrated that cannabis use in humans, and THC exposure in rats, is associated with decreased sperm concentrations and widespread changes in sperm DNA methylation [25]. Of the regions identified in humans, Discs-Large Associated Protein 2 (DLGAP2) exhibited significant hypomethylation in the sperm of cannabis-exposed men compared to controls (p < 0.05). DLGAP2, a membrane-associated protein located in the post-synaptic density of neurons, plays a key role in synapse organization and neuronal signaling [26]. Dysregulation of DLGAP2 is associated with various neurological and psychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia [26–29]. In our prior screen, we identified 17 differentially methylated CpG sites within DLGAP2 in the sperm of cannabis-exposed men compared to controls. DLGAP2 was just one of 46 genes with greater than 10 CpG sites showing significantly altered DNA methylation in the sperm of cannabis users compared to controls, out of the 2,077 genes we identified as having altered DNA methylation. The first objective of this study was to validate our preliminary RRBS findings for DLGAP2 using quantitative bisulphite pyrosequencing. Our second objective was to determine the functional association between DNA methylation and gene expression of DLGAP2 to better understand how cannabis use might affect this relationship. To determine the possible intergenerational effects of paternal cannabis use, our third objective was to determine if Dlgap2 was differentially methylated in the sperm of rats exposed to THC versus controls, and if so, whether or not these changes were intergenerationally heritable.

Results

DLGAP2 is hypomethylated in sperm from cannabis users versus controls by Reduced Representation Bisulphite Sequencing (RRBS)

Our prior study [25] revealed 17 differentially methylated sites by RRBS in the sperm of cannabis users compared to controls for the DLGAP2 gene. Table S1 lists all 17 of these sites and their genomic coordinates. Figure 1a graphically demonstrates the significant hypomethylation of nine of these sites that are clustered together in the seventh intron of this gene. DLGAP2 is schematically shown in Figure 1b, including the exon-intron structure, position of CpG islands, transcription start site and the region of interest in intron 7 within the context of the gene body, with an inset showing the nucleotide sequence analysed in this study.

Validation of DLGAP2 RRBS methylation data

To confirm the methylation differences that were initially detected using RRBS, we designed a bisulphite pyrosequencing assay for the DLGAP2 intron 7 region (see Figure 1b) which captures 10 CpG sites, nine of which were identified as significantly differentially methylated using RRBS. We first validated pyrosequencing assay performance using defined mixtures of fully methylated and unmethylated human genomic DNAs. The measured levels of methylation by pyrosequencing showed good agreement between the amount of input methylation levels and the amount of methylation detected (r2 = 0.99 and p = 0.0003) (Figure 1c). These results confirmed the linearity of the assay in the ability to detect increasing amounts of DNA methylation at this region across the full range of possible methylation values, and indicate that the assay is suitable for use with biological specimens.

The DLGAP2 intron 7 region is not an imprinting control region (ICR)

DLGAP2 is paternally expressed in the testis, biallelically expressed in the brain, and has low expression elsewhere in the body [30]. Since DLGAP2 is known to be genomically imprinted in testis [30], and since the imprint control region for this gene has not yet been defined, we sought to determine if the region of interest in intron 7 is part of the DLGAP2 imprint control region (ICR). The methylation at ICRs is established during epigenome reprogramming in the primordial germ cells in embryonic development. Male and female gametes exhibit divergent methylation at ICRs, and this methylation profile is maintained through subsequent post-fertilization epigenetic reprogramming and in somatic cells throughout the life course. Therefore, we expected that if the DLGAP2 intron 7 region is an ICR, the diploid testis tissues from human conceptuses would exhibit approximately 50% methylation due to the complete methylation of one allele at this region and the complete lack of methylation at the other allele. Human conceptal testes tissues (n = 3) showed an average of 72.5% methylation at the DLGAP2 intron 7 region (Figure 1d). This finding, of higher than anticipated and variable levels of methylation, is inconsistent with ICR status.

Bisulphite pyrosequencing validates the RRBS methylation data in human sperm

We next performed quantitative bisulphite pyrosequencing on the same sperm DNA samples from cannabis users and controls as those used to generate the RRBS data to confirm the loss of methylation present at the intron 7 region of DLGAP2. All nine CpG sites that were hypomethylated in the cannabis users by RRBS were also found to be hypomethylated by bisulphite pyrosequencing, as well as an additional CpG site that was captured in the assay design (p < 0.05 for all 10 sites) (Figure 2). Following Bonferroni correction of the p value to adjust for multiple comparisons (p < 0.005), CpG sites 1,2,3,5,7,8,9, and 10 remained significant. From this pyrosequencing assay we observed methylation differences of 7–15% between the sperm of the cannabis users (n = 8) compared to controls (n = 7). Correlation of the RRBS and pyrosequencing data for each individual CpG site showed significant agreement at all sites analysed (p < 0.02 for all sites; Figure S1). All CpG sites showed a significant loss of methylation in accordance with the direction of change observed by RRBS for these same CpG sites.

Methylation of DLGAP2 intron 7 is inversely correlated with DLGAP2 expression

Given that we observed significant loss of intron 7 DLGAP2 DNA methylation in sperm of cannabis users relative to non-users, we next examined the relationship between DNA methylation and gene expression in the brain, where this gene’s function is critical. We used 28 conceptal brain tissues to examine the relationship between DNA methylation and mRNA expression. Expression levels were normalized to the lowest expressing sample, and the relationship between DNA methylation and mRNA expression was calculated with a Pearson correlation. We found that as methylation increased in this region, mRNA expression decreased significantly (p < 0.05) (Figure 3a). Knowing that there are sex differences in autism spectrum disorder (ASD), and that dysregulation of DLGAP2 is associated with ASD [26], we sought to determine if there were any sex differences in the methylation-expression relationship in these tissues. To investigate this, we ran the correlation for males (n = 15) and females (n = 13) independently. The inverse relationship between methylation and expression was evident for both males and females, but this relationship was significant only in females (p = 0.006) (Figure 3b, c).

Intergenerational inheritance of altered Dlgap2 DNA methylation

We next sought to investigate Dlgap2 using data obtained from our prior study [25] to determine if there was any differential methylation of Dlgap2 in THC versus control rats that was not initially identified using the imposed thresholds of that study. We were particularly interested in the potential for intergenerational transmission and to determine if route of THC exposure affected DNA methylation at this gene. The pilot study rats [25] were given THC via oral gavage (to mimic oral ingestion of drug) while subsequent studies dosed rats via intraperitoneal injection (to mimic inhalation of drug). From the rats administered THC via oral gavage versus controls, we identified a region of Dlgap2 that showed differential methylation by the RRBS analysis that contains eight CpG sites. This region is in the first intron of Dlgap2, in a CpG island that spans the first exon of this gene as well (schematic of the gene structure and sequence of this region shown in Figure 4a). We validated the rat Dlgap2 pyrosequencing assay using commercially available rat DNA of defined methylation status. The results showed good agreement between the input methylation and the amount of methylation detected by pyrosequencing (r2 = 0.92, p = 0.01) (Figure 4b).

We were able to demonstrate intergenerational inheritance of an altered DNA methylation pattern in Dlgap2. Comparing the average methylation for exposed and unexposed sperm for each CpG site revealed that sites 2,3,4 and 6 of the eight CpG sites analysed were significantly hypomethylated in the sperm of rats exposed via injection to 4mg/kg THC compared to controls (p = 0.03 to p = 0.005) (Figure 4c). CpG site 6 remained significant after Bonferroni correction (p < 0.006). The same region of Dlgap2 was then analysed in the hippocampus and nucleus accumbens of rats whose fathers were exposed to control or 4mg/kg THC. While CpG site 7 was significantly hypomethylated (p < 0.05) in the hippocampus of the offspring (Figure 5a), this site was not identified as differentially methylated in the sperm of THC exposed rats, and therefore we could not conclude that this change was transmitted as the result of changes present in the exposed sperm. In the nucleus accumbens, however, significant hypomethylation (p = 0.02) at CpG site 2 was detected in the offspring (Figure 5b), one of the same sites identified in the sperm of THC exposed rats. We also found that there was an inverse relationship between DNA methylation and expression of Dlgap2 in the nucleus accumbens, though not statistically significant likely due to the small sample size available in this study (n = 6 exposed, n = 8 unexposed; Figure S2).

Discussion

In this study, we examined the effects of regular male cannabis use on human sperm DNA methylation, at DLGAP2. Our RRBS study initially identified 17 CpG sites in DLGAP2 that were differentially methylated in the sperm of cannabis users compared to controls. Of the sites that were initially identified, nine of them all reside together in the seventh intron of this gene, though not in a defined CpG island. To first confirm the RRBS data, we performed quantitative bisulphite pyrosequencing for the nine clustered CpG sites. We were able to capture an additional CpG site with careful assay design for a total of ten CpG sites analysed via bisulphite pyrosequencing. We successfully validated the RRBS findings, confirming that there was significant hypomethylation among these ten sites with cannabis use. We confirmed a significant inverse correlation between methylation and expression at this region in human conceptal brain tissues.

To begin to determine whether or not the effects of cannabis on sperm are heritable, we analysed sperm from THC exposed and control male rats, as well as the hippocampus and nucleus accumbens from offspring of THC exposed and control males for changes in DNA methylation at Dlgap2. Rats exposed to THC were given a dose (4mg/kg THC for 28 days) that is pharmacodynamically equivalent to daily cannabis use to resemble frequent use in humans. We identified significant hypomethylation at Dlgap2 in the sperm of exposed rats as compared to controls. This hypomethylated state was also detected in the nucleus accumbens of rats born to THC exposed fathers compared to controls, supporting the potential for intergenerational inheritance of an altered sperm DNA methylation pattern. While the changes in the degree of methylation are small in the rats (0.5–0.7%), we previously reported that fractional changes in methylation can significantly influence the degree to which the gene’s expression is altered [31].

DLGAP2 is a member of the DLGAP family of scaffolding proteins located in the post-synaptic density (PSD) of neurons. The PSD is a protein-dense web that lies under the postsynaptic membrane of neurons and facilitates excitatory glutamatergic signaling in the central nervous system [26,32]. DLGAP2 functions to transmit neuronal signals across synaptic junctions and helps control downstream signaling events [26,32]. Due to its important role in PSD signaling, even small changes in the expression of DLGAP2 can have severe consequences [26,32]. Of particular relevance, DLGAP2 has been linked to schizophrenia and importantly, has been identified as an autism candidate gene [27,28,33,34]. Differential methylation of DLGAP2 is reported in the brain of individuals with autism, and has been linked to post-traumatic stress disorder in rats [27,35]. Knockout of Dlgap2 in mice results in abnormal social behaviour, increased aggressive behaviour, and learning deficits [36].

Studies are increasingly showing associations between cannabis use and various neuropsychiatric and behavioural disorders including anxiety, depression, cognitive deficits, autism, psychosis, and addiction [2,6,7,9,14,37–39]. Research looking into the effects of THC exposure found that rat pups born to parents who were exposed to THC during adolescence showed increased effort to self-administer heroin compared to those born to unexposed parents [13]. This increase in addictive behaviour was driven by THC-induced changes in DNA methylation, occurring in the striatum, including the nucleus accumbens [14,15]. One of the genes whose methylation was altered by parental THC exposure was Dlgap2 [15]. Recently, a group from Australia analysed datasets from two independent cohorts to examine the relationship between cannabis legalization in the U.S. and ASD incidence. They determined there was a strikingly significant positive association between cannabis legalization and increased ASD incidence. Further, the study authors predicted that there will be a 60% increase in excess ASD cases in states with legal cannabis by 2030, and deemed ASD the most common form of cannabis-associated clinical teratology [40].

It is estimated that the ratio of boys with ASD to girls with ASD is 4:1 which led us to stratify our analysis looking at the relationship between DNA methylation and gene expression by sex [41,42]. The results of our methylation-expression analyses demonstrated a significant association in females but not males. While we don’t know the ASD status of these samples, there are several reasons why this may be the case. First, there are certain genes that confer a stronger ASD phenotype in girls compared to boys [41,42]. Thus, while we see the trend in both sexes, it is possible that dysregulation of this gene may manifest phenotypically more in girls. Alternatively, it may be that the regulatory relationship between methylation and expression is retained in females while altered methylation further exacerbates an already fragile relationship in males. Overall, this data confirms that the region of DNA methylation within DLGAP2 that was differentially methylated in the sperm of cannabis users compared to controls is functionally important in the brain.

DLGAP2 is an imprinted gene that exhibits paternal expression in the testis, biallelic expression in the brain, and low expression elsewhere in the body [30]. Because the methylation established at imprinted genes resists post-fertilization epigenetic reprogramming [43–45], this supports the possibility that changes in methylation at DLGAP2 in sperm could be transmitted to the next generation. However, given that the region in intron 7 is not an ICR, it is unlikely that this would be a potential mechanism for intergenerational inheritance of an altered methylation pattern at this region. However, it has recently been discovered that a subset of genes termed ‘escapees’ are able to escape primordial germ cell (PGC) and post-fertilization reprogramming events [46,47], providing a mechanism for epigenetic changes incurred by sperm to be passed on to the subsequent generation.

Processes in the PSD are sensitive to endocannabinoids [26,48–51], which suggests that these processes are potentially sensitive to exogenous cannabinoids, such as THC and cannabis. This is especially important as cannabis legalization and use are increasing dramatically across the U.S. It is estimated that 22% of American adults currently use cannabis, of which 63% are regular users (≥1–2 times per month) [7–10]. Among regular users 55% are males and over half of all men over 18 have reported cannabis use in their lifetime [7–10]. Importantly, this age range includes individuals of reproductive age. Since almost half of all pregnancies in the U.S. are unplanned, there is concern that many pregnancies may occur during a time when one, or both, parents are using or are exposed to cannabis [52].

Our results provide novel findings about the effects of paternal cannabis use on the methylation status of an ASD candidate gene, a disorder whose rates continue to climb, but whose precise aetiologies remain unknown. Studies are beginning to show that there is a potential for paternal intergenerational inheritance. In particular, epigenetic changes in umbilical cord blood of babies born to obese fathers were also found in the sperm of obese men. This study is the first to demonstrate that there are changes present in the sperm epigenome of cannabis users at a gene involved in ASD.

The results of this study have several limitations. The sample size was small, which might limit generalization of the study findings. However, even though our sample size was small, we were able to identify common pathways that were differentially methylated in both human and rat sperm, highlighting the potential specificity of these effects [25]. We did not account for a wide variety of potential confounders such as various lifestyle habits, sleep, diet/nutrition, exercise, etc, given that their influence on the sperm DNA methylome is largely unknown. Larger studies are required to confirm these findings. In the conceptal tissues we were only able to analyse whole brain, rather than the areas where DLGAP2 is most highly expressed such as the hippocampus and the striatum, which could have diluted the strength of the results.

Strengths of the study included that we used a highly quantitative method to confirm the methylation status that was measured by RRBS. This study was the first demonstration of the association between cannabis use and substantial hypomethylation of DLGAP2 in human sperm. Additionally, we are able to confirm a functional relationship between methylation and expression in a relevant target tissue, and have shown that the relationship between methylation and expression is weakened in males, which could bear relevance to the sexual dimorphism in the prevalence of autism. This is the first demonstration of potential heritability of altered methylation resulting from preconceptional paternal THC exposure. Given the increasing legalization and use of cannabis in the U.S., our results underscore a need for larger studies to determine the potential for heritability of DLGAP2 methylation changes in the human F1 generation and beyond. It will also be important to examine how cannabis-associated methylation changes relate to neurobehavioral phenotypes

Source:   Epigenetics. 2020; 15(1-2): 161–173.

Published online 2019 Aug 26. doi: 10.1080/15592294.2019.1656158

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers) :

(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified.

The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki=1.2nM) resulted similar to that of CP55940 (Ki=0.9nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity.
The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.

Cannabis sativa has always been a controversial plant as it can be considered as a lifesaver for several pathologies including glaucoma and epilepsy, an invaluable source of nutrients, an environmentally friendly raw material for manufacturing and textiles, but it is also the most widely spread illicit drug in the world, especially among young adults
.
Its peculiarity is its ability to produce a class of organic molecules called phytocannabinoids, which derive from an enzymatic reaction between a resorcinol and an isoprenoid group. The modularity of these two parts is the key for the extreme variability of the resulting product that has led to almost 150 different known phytocannabinoids. The precursors for the most commonly naturally occurring phytocannabinoids are olivetolic acid and geranyl pyrophosphate, which take part to a condensation reaction leading to the formation of cannabigerolic acid (CBGA). CBGA can be then converted into either tetrahydrocannabinolic acid (THCA) or cannabidiolic acid (CBDA) or cannabichromenic acid (CBCA) by the action of a specific cyclase enzyme. All phytocannabinoids are biosynthesized in the carboxylated form, which can be converted into the corresponding decarboxylated (or neutral) form by heat.

The best known neutral cannabinoids are undoubtedly Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the former being responsible for the intoxicant properties of the cannabis plant, and the latter being active as antioxidant, anti-inflammatory, anti-convulsant, but also as antagonist of THC negative effects.
All these cannabinoids are characterized by the presence of an alkyl side chain on the resorcinol moiety made of five carbon atoms. However, other phytocannabinoids with a different number of carbon atoms on the side chain are known and they have been called varinoids (with three carbon atoms), such as cannabidivarin (CBDV) and Δ9-tetrahydrocannabivarin (Δ9 -THCV), and orcinoids (with one carbon atom), such as cannabidiorcol (CBD-C1) and tetrahydrocannabiorcol (THC-C1)7. Both series are biosynthesized in the plant as the specific ketide synthases have been identified.
Our research group has recently reported the presence of a butyl phytocannabinoid series with a four-term alkyl chain, in particular cannabidibutol (CBDB) and Δ9-tetrahydrocannabutol (Δ9-THCB), in CBD samples derived from hemp and in a medicinal cannabis variety. Since no evidence has been provided for the presence of plant enzymes responsible for the biosynthesis of these butyl phytocannabinoids, it has been suggested that they might derive from microbial ω-oxidation and decarboxylation of their corresponding five-term homolog.
The length of the alkyl side chain has indeed proved to be the key parameter, the pharmacophore, for the biological activity exerted by Δ9-THC on the human cannabinoid receptor CB1 as evidenced by structure-activity relationship (SAR) studies collected by Bow and Rimondi. In particular, a minimum of three carbons is necessary to bind the receptor, then the highest activity has been registered with an eight-carbon side chain to finally decrease with a higher number of carbon atoms. Δ8-THC homologs with more than five carbon atoms on the side chain have been synthetically produced and tested in order to have molecules several times more potent than Δ9-THC.
To the best of our knowledge, a phytocannabinoid with a linear alkyl side chain containing more than five carbon atoms has never been reported as naturally occurring. However, our research group disclosed for the first time the presence of seven-term homologs of CBD and Δ9-THC in a medicinal cannabis variety, the Italian FM2, provided by the Military Chemical Pharmaceutical Institute in Florence.

The two new phytocannabinoids were isolated and fully characterized and their absolute configuration was confirmed by a stereoselective synthesis. According to the International Non-proprietary Name (INN), we suggested for these CBD and THC analogues the name “cannabidiphorol” (CBDP) and “tetrahydrocannabiphorol” (THCP), respectively. The suffix “-phorol” comes from “sphaerophorol”, common name for 5-heptyl-benzen-1,3-diol, which constitutes the resorcinol moiety of these two new phytocannabinoids.
A number of clinical trials and a growing body of literature provide real evidence of the pharmacological potential of cannabis and cannabinoids on a wide range of disorders from sleep to anxiety, multiple sclerosis, autism and neuropathic pain20–23. In particular, being the most potent psychotropic cannabinoid, Δ9-THC is the main focus of such studies.

In light of the above and of the results of the SAR studies, we expected that THCP is endowed of an even higher binding affinity for CB1 receptor and a greater cannabimimetic activity than THC itself. In order to investigate these pharmacological aspects of THCP, its binding affinity for CB1 receptor was tested by a radioligand in vitro assay and its cannabimimetic activity was assessed by the tetrad behavioral tests
in mice.
Results
Identifcation of cannabidiphorol (CBDP) and Δ9-tetrahydrocannabiphorol (Δ9-THCP) by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS).

The FM2 ethanolic extract was analyzed by an analytical method recently developed for the cannabinoid profiling of this medicinal cannabis variety. As the native extract contains mainly the carboxylated forms of phytocannabinoids as a consequence of a cold extraction25, part of the plant material was heated to achieve decarboxylation where the predominant forms are neutral phytocannabinoids.

The advanced analytical platform of ultra-high performance liquid chromatography coupled to high resolution Orbitrap mass spectrometry was employed to analyze the FM2 extracts and study the fragmentation spectra of the analytes under investigation. The precursor ions of the neutral derivatives cannabidiphorol (CBDP) and Δ9-tetrahydrocannabiphorol (Δ9-THCP), 341.2486 for the [M-H]− and 343.2632 for the [M+H]+, showed an elution time of 19.4 min for CBDP and 21.3 min for Δ9-THCP (Fig. 1a).
Their identification was confirmed by the injection of a mixture (5 ng/mL) of the two chemically synthesized CBDP and Δ9-THCP (Fig. 1b) as it will be described later. As for their carboxylated counterpart, the precursor ions of the neutral forms CBDP and Δ9-THCP break in the same way in ESI+mode, but they show a different fragmentation pattern in ESI− mode. Whilst Δ9-THCP shows only the precursor ion [M-H]− (Fig. 1d), CBDP molecule generates the fragments at m/z 273.1858 corresponding to a retro Diels-Alder reaction, and 207.1381
corresponding to the resorcinol moiety after the break of the bond with the terpenoid group (Fig. 1c). It is noteworthy that for both molecules, CBDP and Δ9-THCP, each fragment in both ionization modes differ exactly by an ethylene unit (CH2)2 from the corresponding five-termed homologs CBD and THC.

Moreover, the longer elution time corroborates the hypothesis of the seven-termed phytocannabinoids considering the higher lipophilicity of the latter.

Source: https://www.nature.com/articles/s41598-019-56785-1 December 2019

Filed under: Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers) :

Abstract

The molecular composition of the cannabinoid type 1 (CB1) receptor complex beyond the classical G-protein signaling components is not known. Using proteomics on mouse cortex in vivo, we pulled down proteins interacting with CB1 in neurons and show that the CB1 receptor assembles with multiple members of the WAVE1 complex and the RhoGTPase Rac1 and modulates their activity. Activation levels of CB1 receptor directly impacted on actin polymerization and stability via WAVE1 in growth cones of developing neurons, leading to their collapse, as well as in synaptic spines of mature neurons, leading to their retraction. In adult mice, CB1 receptor agonists attenuated activity-dependent remodeling of dendritic spines in spinal cord neurons in vivo and suppressed inflammatory pain by regulating the WAVE1 complex. This study reports novel signaling mechanisms for cannabinoidergic modulation of the nervous system and demonstrates a previously unreported role for the WAVE1 complex in therapeutic applications of cannabinoids.

Filed under: Brain and Behaviour,Cannabis/Marijuana,Effects of Drugs (Papers),Marijuana and Medicine :

Abstract

Background

Whilst cannabis commercialization is occurring rapidly guided by highly individualistic public narratives, evidence that all congenital anomalies (CA) increase alongside cannabis use in Canada, a link with 21 CA’s in Hawaii, and rising CA’s in Colorado indicate that transgenerational effects can be significant and impact public health. It was therefore important to study Northern New South Wales (NNSW) where cannabis use is high.

Methods

Design: Cohort. 2008–2015. Setting: NNSW and Queensland (QLD), Australia. Participants. Whole populations. Exposures. Tobacco, alcohol, cannabis. Source: National Drug Strategy Household Surveys 2010, 2013. Main Outcomes. CA Rates. NNSW-QLD comparisons. Geospatial and causal regression.

Results

Cardiovascular, respiratory and gastrointestinal anomalies rose with falling tobacco and alcohol but rising cannabis use rates across Queensland. Maternal age NNSW-QLD was not different (2008–2015: 4265/22084 v. 96,473/490514 > 35 years/total, Chi.Sq. = 1.687, P = 0.194). A higher rate of NNSW cannabis-related than cannabis-unrelated defects occurred (prevalence ratio (PR) = 2.13, 95%C.I. 1.80–2.52, P = 3.24 × 10− 19). CA’s rose more potently with rising cannabis than with rising tobacco or alcohol use. Exomphalos and gastroschisis had the highest NNSW:QLD PR (6.29(2.94–13.48) and 5.85(3.54–9.67)) and attributable fraction in the exposed (84.11%(65.95–92.58%) and 82.91%(71.75–89.66%), P = 2.83 × 10− 8 and P = 5.62 × 10− 15). In multivariable geospatial models cannabis was significantly linked with cardiovascular (atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus), genetic (chromosomal defects, Downs syndrome), gastrointestinal (small intestinal atresia), body wall (gastroschisis, diaphragmatic hernia) and other (hypospadias) (AVTPCDSGDH) CA’s. In linear modelling cannabis use was significantly linked with anal stenosis, congenital hydrocephalus and Turner syndrome (ACT) and was significantly linked in borderline significant models (model P < 0.1) with microtia, microphthalmia, and transposition of the great vessels. At robust and mixed effects inverse probability weighted multivariable regression cannabis was related to 18 defects. 16/17 E-Values in spatial models were > 1.25 ranging up to 5.2 × 1013 making uncontrolled confounding unlikely.

Conclusions

These results suggest that population level CA’s react more strongly to small rises in cannabis use than tobacco or alcohol; cardiovascular, chromosomal, body wall and gastrointestinal CA’s rise significantly with small increases in cannabis use; that cannabis is a bivariate correlate of AVTPCDSGDH and ACT anomalies, is robust to adjustment for other substances; and is causal.

Source: Broad Spectrum Epidemiological Contribution of Cannabis, Tobacco and Alcohol to the Teratological Profile of Northern New South Wales: Geospatial and Causal Inference Analysis | Research Square November 2020

Filed under: Australia,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers) :

Cancer is a word that conjures up many images. It is a varied disease that affects many people and can leave families distraught. There are fortunately treatments for a large number of these cancers, which work by restricting tumour growth and inducing cell death. However, there are cancers which pose more of a challenge, and so finding new drugs that can fight these ones becomes even more important.

The methods for discovering and developing new drugs, or chemotherapies, simply fall into two camps. The more recent approach has been the design of drugs with a particular molecular target in mind. This is arguably best exemplified by the drug imatinib, notably used to eat leukaemia. After scientists understood that the BCR-ABL hybrid gene was the cause of a certain type of leukaemia it allowed them to develop pharmacological ways to specifically counteract it – by inhibiting the signals inside the cancer cell used to grow and divide. The drug that was born to much fanfare and arguably revolutionised drug development.

Continued improvements in the understanding of the mechanisms inside cells that are hijacked by cancer have helped to improve the way that compounds are designed and then tested clinically. Those that are able to restore the normal function of the signalling pathways disrupted by cancer are an attractive target for drug development.

At least three major pharmaceutical players are in a fight to negate the cancer-supporting action of AKT, for example. This protein kinase – a key regulator of cell function – is a central player in determining cell proliferation and growth, and is intimately linked with a number of other cell communications systems that all work in unison to support a cancer developing. Its level is over-expressed in a number of cancers, and is linked to a poorer prognosis. Consequently, therapeutic interventions to counteract its effects are particularly attractive and potentially lucrative.

Isolating the compound

It was however, never like this. Before the mystery of cancer was opened up, drug discovery was empirical in nature. Through antiquity, a range of flora were said to cure ailments and, using these anecdotes as guides, active ingredients have been extracted, purified and improved. This has been successful, and a number of drugs now form normal members of the pharmacopeia, including aspirin, which was isolated from the white willow, and less familiar anti-cancer drugs such as etoposide, irinotecan and taxol, which were derived from mayapples, camptotheca trees and Pacific yews. There is no doubt of their value in treatment and they’ve been used successfully for over 40 years.

Then there is the cannabis plant. The putative medicinal property of cannabis has been known for some time; indeed, history records show they were used to ease symptoms of gout, malaria and even childbirth. However, the fundamental issue with using cannabis in its whole form as a medicine is its psychoactive properties, so it would make sense to identify the important anti-cancer parts and remove the psychoactive components. Cannabinoids are these. They number around 80, with cannabidiol (CBD) and tetrahydrocannabinol (THC) the two lead medicinal candidates. However, unlike the mayapple and Pacific yew, their development has been seriously curtailed.

Cannabis. M a n u e l, CC BY

It’s likely that the widespread use of cannabis as a recreational drug has affected research into the potential in cannabis – and the result was death by association. I wonder how the early development of CBD and THC would have progressed if it was known by any other name.

Chequered pasts

Drugs with chequered pasts have found redemption; take the thalidomide story. This drug was infamously linked to babies born with deformations; however, serendipitous observations of improvements in leprosy in a patient taking thalidomide in 1965 led to the discovery that it also had important effects on the immune system. Refinements to the chemistry of the drug were made and the result was a new family of drugs that are valuable tools in anti-cancer research and treatment.

The story emphasises the point that medicinal potential of drugs should be seen objectively and guided scientifically. Cannabinoids and cannabis are not the same thing – it’s just that cannabinoids are derived from cannabis. Cannabinoids possess anti-cancer properties, which they achieve through their fundamental interactions with proteins embedded in the signalling pathways in cells that are now seen as particularly interesting for research.

In addition to this direct anti-cancer action, cannabinoids also have the capacity to disrupt the ability of cancer to feed itself by a process called angiogenesis as well as being able to modulate the immune system to make it more hostile towards cancer. Furthermore, CBD and THC appear to support the activity and efficacy of other chemotherapy drugs. Indeed, we recently showed that the cancer-killing property of radiotherapy was dramatically enhanced when cannabinoids were used in combination with this treatment – certain forms of brain cancer were reduced to sizes that were difficult to detect. Taken together, all of these features show a profile with great anti-cancer potential.

However slow things have been, a sea-change has been occurring; there is a palpable sense that legislators are becoming open to the scientific evidence that suggests cannabinoids may possess medicinal quality. Clinical trials using various forms of cannabinoids are now taking place in a number of countries, and we all await the results of these studies.

I hope to be able to change the answer that I give to patients who contact me to ask: “do you think I should be using cannabinoids for my cancer?” from the negative to the affirmative. My frustrating answer has always been it is too early to say, as promising laboratory data has not yet been confirmed by objective clinical studies. This is not a criticism of the drug development system, as convincing clinical trials are needed to ensure patients are given drugs that have been thoroughly tested to ensure the best chance of them fighting their disease.

The flip side of those who passionately shout for the “legalisation of cannabis” is that their call may inadvertently hamper the medical development of cannabinoids, which is a shame. My aim is to deliver a drug that can be used in patients with cancer. And for a headache, no one would suggest you chew on a white willow plant, especially when you could be taking an aspirin. The same is true of cannabis and cannabinoids.

Source:    https://theconversation.com/profiles/wai-liu-144882 

Senior Research Fellow, St George’s, University of London

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Medical Studies :

ABSTRACT

Recent data from the Kollins lab (‘Cannabinoid exposure and altered DNA methylation in rat and human sperm’ Epigenetics 2018; 13: 1208–1221) indicated epigenetic effects of cannabis use on sperm in man parallel those in rats and showed substantial shifts in both hypo- and hyper-DNA methylation with the latter predominating. This provides one likely mechanism for the transgenerational transmission of epigenomic instability with sperm as the vector. It therefore contributes important pathophysiological insights into the probable mechanisms underlying the epidemiology of prenatal cannabis exposure potentially explaining diverse features of cannabis-related teratology including effects on the neuraxis, cardiovasculature, immune stimulation, secondary genomic instability and carcinogenesis related to both adult and pediatric cancers.

The potentially inheritable and therefore multigenerational nature of these defects needs to be carefully considered in the light of recent teratological and neurobehavioural trends in diverse jurisdictions such as the USA nationally, Hawaii, Colorado, Canada, France and Australia, particularly relating to mental retardation, age-related morbidity and oncogenesis including inheritable cancerogenesis. Increasing demonstrations that the epigenome can respond directly and in real time and retain memories of environmental exposures of many kinds implies that the genome-epigenome is much more sensitive to environmental toxicants than has been generally realized. Issues of long-term multigenerational inheritance amplify these concerns. Further research particularly on the epigenomic toxicology of many cannabinoids is also required.

Introduction

Physiology and pathobiology of the epigenome and its complex interactions with the genome, metabolome and immunometabolome, and cannabinoid physiopharmacology represents some of the most exciting areas of modern biological research. Type 1 and 2 cannabinoid receptors (CB1R and CB2R) are involved in a host of endogenous processes with potential therapeutic applications in numerous fields as diverse as pain, nausea, temperature regulation and weight control amongst others. Several recent detailed structural descriptions of the CB1R and CB2R complexed with high affinity agonists and antagonists, and pathways for the bulk biological synthesis of cannabinoids open the way to the rational design of high affinity molecules to differentially modulate these key receptors which are involved in a host of endogenous processes with diverse potential therapeutic applications. The use of exogenous cannabinoid compounds that bind to CB1R and CB2R may however also produce unwanted side effects including through modulation of DNA methylation states.

Within each nucleated cell, 2 m of DNA is normally stored coiled around four histones known as a nucleosome. A total of 147 bases of DNA are wrapped twice around two sets of H2A, H2B, H3 and H4 which together form the histone octamer. The bases of DNA itself may have a methyl group (CH3-) attached to them, usually to cytosine-phosphate-guanine (CpG), which when it occurs in the region of the gene promoter, blocks the transcription machinery and prevents the gene from becoming activated. The tails of the four histone proteins protrude from the central globular core and normally bind by electrostatic forces to the coiled DNA. Addition of an acetyl group to these histone tails, particularly on H3 and H4, disrupts the salt bridges opening up the DNA code for active transcription. Histone tails can also be methylated or indeed be modified by many groups (mono-, di- and trimethyl, acetyl, phosphoryl, crotonyl, citrulline, ubiquitin and ADP-ribosyl, etc.) which control gene transcription . DNA is transcribed into RNA some of which is made into the many proteins from which our bodies are made. However, much of the RNA also has purely informatic roles, and short and long non-coding RNA’s (ncRNA) controls DNA availability and transcription, RNA processing and splicing and can form a scaffold upon which layers of DNA regulation can be built. These various mechanisms, DNA methylation, post-translational modification of histone tails, nucleosome positioning, histone replacement, nuclear positioning and ncRNA’s form the basis of epigenetic regulation and appear to undergo an ‘epigenetic conversation’ amongst these different layers.

Chromatin loops are extruded through cohesin rings giving rise to transcription factories (topologically active domains) where different regions of the DNA including proximal promoters and distal enhancers are brought into close proximity to control transcription either on the same chromosome (in cis) or sometimes on nearby chromosomes (in trans). Super-enhancers, enhancer cross-talk, and extensive 3D remodelling of euchromatin looping during development are also described.

Moreover, a variety of studies in animals and several epidemiological studies in humans show that the epigenetic code can form a mechanism for inheritable changes across generations from both father and mother to subsequent generations which do not involve changes in the genetic code itself. Such epigenetic inheritance has been shown clinically for starvation, obesity, bariatric surgery and for tobacco and alcohol consumption. It has also been demonstrated in rodents for alcohol, cocaine and opioids, and in rodents’ immune system, nucleus accumbens and sperm following cannabinoid exposure in the parents.

If DNA is thought of as the cells’ bioinformatic ‘hardware’ then the epigenome can be considered its programming ‘software’. The epigenome controls gene expression and is key to cell differentiation into different tissue fates, different states of cellular differentiation, to cellular reprogramming into induced pluripotential stem cell states, cancer, numerous neuropsychiatric diseases including addiction, immune, metabolic and brain memory, aging, and the response of the cell to changes in its environment by way of gene-environment interactions including the development of so-called ‘epigenetic scars’.

This powerful informatic system has recently been shown to have a host of unforeseen capabilities. It has been shown that histone tails sense oxygen tension rapidly within 1 h with resulting modification of gene expression cassettes. Lysine (K) demethylase 5A (KDM5A) is a Jumanji-C domain containing molecular dioxygenase which is inactivated by hypoxia in a hypoxia-inducible factor-independent manner, controls H3K4me3 and H3K36me3 histone trimethylations and governs the transcriptome expression several hours after brief hypoxia. Similarly, KDM6A is also an oxygen sensitive dioxygenase and histone demethylase which controls H3K27me3. Its blockade by hypoxia interferes with cell differentiation and maintains cells in an undifferentiated state. Since the ten eleven translocase enzymes and are key demethylators of DNA and are dioxygenases also sensitive to profound hypoxia, and since hypoxia exists in most stem cell niches and at the centre of many tumours, such histone- and DNA-centred mechanisms are likely to be important in stem cell, aging, cellular differentiation and cancer biology.

Epigenomic regulation of tumour immunometabolome

Similarly, one of the great paradoxes of cancer biology is the presence within tumours of numerous effector T-cells which are able to expand and eradicate large metastatic tumours effectively, but do not do so within clinical cancers. It was recently shown that this effect is due to the very elevated nucleocytosolic potassium level within tumour lymphocytes which stalls metabolism and runs down acetyl-coenzyme A levels, the main acetyl donor for histone acetylation and induces a form of calorie restriction (like starvation) including autophagy and mitophagy and impairs the normal mTOR (mammalian target of rapamycin)-dependent T-cell receptor-mediated activation response. This program was mediated by reduced levels of H3K9 and H3K27 acetylation. Hence, tumour lymphocyte anergy and stemness were both mediated epigenetically and were shown to be reversible when the immunometabolic defect was corrected either genetically or by substrate supplementation. This work elegantly demonstrates the close relationship between the metabolic state of cells, cell differentiation state and starvation response, the control of cell fate by the epigenetic landscape and disease outcome.

Metabolomic supply of epigenetic substrate

Several studies similarly link the supply of metabolic intermediates required as inputs by the epigenetic machinery to epigenetic state and downstream gene control. Indeed, the well-known supplementation of staple foods by folic acid is believed to act because of the central role played by this vitamin in the methyl cycle and the supply of single carbon units to the methylation machinery for DNA and histones. A moments reflection shows that expression of the DNA of the mitochondria and the DNA of the nucleus need to be tightly coordinated to supply the correct number of subunits for the complex machineries of the mitochondrion including electron transport. This mitonuclear balance acts at several levels including RNA transfer, metabolic substrate (acetyl-coenzyme A, nicotinamide mononucleotide) transfer and the control of the epigenetic regulators PARP (polyadenosineribosyl polymerase) and Sirt1 (a major histone deacetylase).

Cannabinoid signalling impacts mitochondria

As noted above the identification of CB1R and CB2R on the plasma membrane has been a major milestone in cellular cannabinoid physiology. It is less well known that CB1R’s also exist on the mitochondrial outer membrane, and that the inner and outer leaflet of the mitochondria, together with the intermembrane space host the same cannabinoid transduction machinery as the plasmalemma. Neuronal mitochondrial CB1R’s have been implicated in memory and several critical neural processes. Hence, the well-substantiated findings that diverse cannabinoids generally suppress mitochondrial activity (in neurons, lung, liver and sperm), lower the mitochondrial transmembrane potential and interfere with oxidative phosphorylation carry major epigenetic implications not only for mitonuclear balance and trafficking including the mitochondrial stress response, but also for the supply of the requisite metabolic intermediates in terms of acetyl-coenzyme A which is an absolute requirement for histone acetylation and normal gene activation.

Histone serotonylation and dopaminylation

Serotonin, which has long been implicated in mood dysregulation and drug addiction was recently shown to act as a novel post-translational modification of the tail of H3 at lysine 4 via serotonylation where it increases the binding of the transcription machinery and allows correct cell differentiation. It is likely that dopamine will soon be similarly implicated.

Almost accompanying the modern bioinformatic explosion of knowledge related to the sequencing of the human genome has been a parallel increase in knowledge of the complexities and intricacies of epigenomic regulation. Nowhere is this more evident than in cancer. Indeed, it has become apparent that there are numerous forms of cross-talk, interaction and cross-regulation between the genome and the epigenome and the two are in fact highly inter-related. This is of particular relevance to chromosomal integrity and cancerogenic mechanisms. Several mechanisms have been described for such interactions including alterations of DNA methylation, altered cytosine hydroxymethylation, alteration of TERT function which is a key catalytic component of the telomerase enzyme which protects chromosome ends and altered architecture of enhancers and their looping interactions with promoters which control gene expression. Indeed, pharmacological modulation of the bromodomain ‘readers’ of epigenomic information has become a very exciting area within modern cancer therapeutic research , and forms an area into which large pharmaceutical companies are presently investing several billion dollars.

Gamete cannabinoid epigenomics – Murphy et. al

In this powerful context, the masterful epigenetic work from the Kollins laboratory of Murphy and colleagues was situated. These workers studied 12 control men who self-reported no psychoactive drug use in the last 6 months, and 12 subjects who reported more than weekly use of cannabis only, with all results confirmed by urine toxicology and ultra performance liquid chromatography/tandem mass spectrometry and enzyme immunoassay. In parallel two groups of 9-week-old male rats were administered solvent or 2 mg/kg THC by gastric lavage for 12 days prior to sacrifice and the epididymis was harvested. Sperm were assayed by the ‘swim out’ method where sperm swam out into normal saline bath solution. Cannabis exposed men had lower sperm counts, and it was found that there was differential sperm DNA methylation at 6,640 CpG sites including at 3,979 CpG islands in gene promoters where methylation was changed by more than 10% (which is alot). Significant changes were in both the hypomethylation and hypermethylation direction were noted with the changes in the hypomethylation group being more marked across the genome and at gene promoters. Pathways in cancer (including the BRAF, PRCACA, APC2 PIK3R2, LAMA1, LAMB1, AKT1 and FGF genes), hippo pathways (which are also important in cancer and in embryonic body pattern formation), the MAP kinase pathway (also involved in growth and cancer), AMPA, NMDA and kainate glutamate receptor subunits, and the Wnt genes 3A, 5A, 9A, 10A (involved in cancer and in body patterning and morphogensis) were found to be particularly affected. A dose–response effect was demonstrated at 183 CpG sites on 177 genes including the PTG1R gene which encodes the prostacyclin (a powerful vasodilator and antithrombotic agent) receptor which was down-regulated.

Twenty-three genes involved in platelet activation and 21 genes involved in glutamate metabolism were also modulated. LAMB1, whose gene product laminin B has been implicated in progeria and is increasingly implicated in genetic ageing pathways through its role in nuclear positioning of chromatin and the maintenance of heterochromatin (including female X-chromosome inactivation) in an inactive state inside the nuclear membrane, and its role in establishing integrity of the nuclear envelope, was also identified.

Results in the rats closely paralleled those found in humans. Fifty-five genes were found to overlap between altered sperm methylation patterns and a previous study of brain Nuclear Accumbens DNA methylation in prenatally cannaboid exposed rats which showing increased heroin self-administration, a highly statistically significant result. These results support the hypothesis that the transgenerational transmission of defects following pre-conceptual exposure to cannabis found in the immune system and limbic system of the brain including increased tendency for drug use in later life in rodents may be transmitted through alterations in the DNA methylation of the male germ line. More work is clearly needed in this area with exhaustive epigenetic, transcriptomic and genomic characterization of these results with larger sample sizes and in other species.

Cannabis – cancer links

Mechanistically these results have very far-reaching implications indeed and appear to account for much of the epidemiologically documented associations of cannabis use. Cannabis has been associated with cancer of the mouth and throat, lung, bladder, leukaemia, larynx, prostate and cervix and in four out of four studies with testicular teratomas with a relative risk of three in meta-analysis. Cannabis has also been implicated with increased rates of the childhood cancers acute lymphocytic leukaemia, acute myeloid leukaemia, acute myelomonocytic leukaemia, neuroblastoma and rhabdomyosarcoma.

These are believed to be due to inheritable genetic or epigenetic problems from the parents, albeit the mechanism of such transmission was not understood in the pre-epigenomic era. Results of Murphy and colleagues may potentially explain mechanistically much of the epidemiologically documented morbidity that has in the past been associated with cannabis use. As noted, cannabis contains the same tars as tobacco and also several known genotoxic compounds, and is also immunoactive. Such actions imply several mechanisms by which cannabis may be implicated in carcinogenic mechanisms.

That cannabis is associated with heritable paediatric cancers where the parents themselves do not harbour such tumours is suggestive evidence that non-genetic and likely epigenetic mechanisms are involved in the childhood cancers which are observed. Detailed delineation of such putative pathways will require further research.

Cannabis has also been shown to be associated with increased rates of gastroschisis in seven of seven studies to examine this association. This pathology, where the bowels of the neonate protrude through the abdominal wall usually to the right of the umbilicus, is believed to be due to a disruption of blood flow to the forming abdominal wall. If cannabinoid exposure powerfully activates platelets through multiple mechanisms and disrupts major vasodilator systems such as the prostacyclin receptor then such a pathway could well damage the tiny blood vessels of the developing foetus and account for the development of gastroschisis. Cannabis use in adults has been linked with both myocardial infarction and stroke possibly by similar mechanisms. It has been shown elsewhere that cannabis use can also stimulate inflammation and be proinflammatory.

Epigenomics of foetal alcohol syndrome

Indeed, foetal alcohol syndrome disorder (FASD) is said to be mediated in part by the CB1R , to be epigenetically mediated, and to comprise amongst other features small heads, microcephaly, impaired visuospatial coordination and to be commonly associated with ventricular septal defect and atrial septal defect all of which have been described in association with prenatal cannabis exposure. However, the facial features of FASD are not described in the congenital cannabis literature.

Cannabis and congenital anomalies

Indeed, one Hawaiian statewide epidemiological report found elevated rates of 21 congenital defects in prenatally cannabis exposed infants. Whilst this paper is unique in the literature it helps explain much about the presently reported patterns of congenital anomalies across USA in relation to atrial septal defect, Downs’ syndrome, Trisomy 18, ventricular septal defect, limb reduction defects, anotia, gastroschisis and autism, all of which crude rates are more common in states with liberal cannabis policies. Similar morbidity patterns were observed in Canada with crude rates of all congenital defects, gastroschisis, total cardiovascular defects and orofacial clefts more common in areas with higher cannabis use. The Colorado birth defects registry has also reported a three-fold increase in the crude (unadjusted) rate of atrial septal defects 2000–2014 spanning the period of cannabis legalization together with increases of 30% or more over the same period in crude rates of total cardiovascular defects, ventricular septal defects, Down’s syndrome and anencephaly. This is highly significant as atrial septal defect has only been found to be linked with cannabis in the Hawaiian study, suggesting that our list of cannabis-related defects is as yet incomplete. As mentioned above the putative link between atrial septal defect and cannabis use has also been found in the generality of states across the USA. It should also be noted that according to a major nationally representative recurrent survey the use of all other drugs in Colorado fell during this period, making cannabis the most likely pharmacological suspect for the surge in congenital anomalies.

These findings are also consistent with data arising from France, wherein three separate regions which have permitted cannabis to be used as feed for the dairy industry calves are born without legs, and an increase in the rate of phocomelia (no arms) in human infants has similarly been observed. In the French northeast region of Ain which is adjacent to Switzerland, the crude rate of phocomelia is said to be elevated 58 times above background, whilst in nearby Switzerland which has not permitted cannabis to be used as a feed crop no such anomalies are observed.

Neuroteratogenesis and beyond

The above comments in relation to epigenetic modulation of the glutamate system have been shown in recent studies to be related to many neuropsychiatric disorders. However, the recent demonstration at least in insects that glutamate could also act as a key morphogen in body patterning processes and major organ formation may have much wider implications well beyond the neuraxis Cannabis and epigenetic ageing.

The finding of overall DNA hypomethylation by Murphy’s group carries particular significance especially in the context of disordered lamin B metabolism. Chronic inflammation is known to be a major risk factor for carcinogenesis in humans in many organs including the skin, oropharynx, bronchi, lungs, oesophagus, stomach, pancreas, liver, biliary tree, colon, bladder and prostate. Inflammatory conditions are invariably strongly pro-oxidative and damage to DNA is not unusual. Because CpGs in gene promoters are more often largely unmethylated and therefore exposed the guanine in these positions is a common target for oxidative damage. Oxo-guanine is strongly mutagenic. This form of DNA damage recruits the maintenance DNA methyltransferase DNMT1 from the gene body to the gene promoter. There DNMT1 recruits Sirt1, a histone deacetylase which tends to epigenetically silence gene expression, and also EZH2 part of the polycomb repressive complexes 2 and 4 which epigenetically silences gene expression and tends to spread the silencing of chromatin. Hence, one of the end results of this form of oxidative DNA damage is to move the DNA methylation from the gene bodies to the gene promoters, thereby hypermethylating the promoters, the CpG Island Methylator Phenotype (CIMP) and hypomethylating the gene bodies and intergenic regions. By this epigenetic means chronic inflammation and tobacco smoke have been shown to induce widespread epigenomic field change right across tissues such as colon, bronchi or bone marrow. Furthermore, this mechanism moves gene expression from the control of histone modification to DNA methylation which tends to be more fixed and less plastic than histone alterations. Such findings are consistent with a previous demonstration of accelerated ageing in cannabis exposed clinical populations.

Epigenomic control of mobile transposable genetic elements

Reducing the global level of DNA methylation also has the effect of reducing the control of mobile transposable repeat elements in the genome. Forty-two per cent of the human genome has been shown to be comprised of these mobile elements of various varieties. Long Interspersed Repeat Elements (LINE-1) are believed to be retroviral repeat elements which long ago became incorporated in the genome and are able when expressed to induce their own reverse transcription back into the genome via endogenous reverse transcriptases. For this reason, they are also called ‘jumping genes.’ Because they become randomly incorporated into the genome after reverse transcription their activity is very damaging to genetic integrity. Whilst retrotransposon mobility is normally controlled by three mechanisms these defences can be overcome in advanced cellular senescence. The presence of double-stranded DNA (dsDNA) in the cytoplasm is strongly stimulating for the immune system and stimulates a type-1 interferon proinflammatory response, which further exacerbates the cycle and directly drives the Senescence Associated Secretory Phenotype (SASP) of advanced senescence and the ‘inflamm-aging’ which is well described in advanced age. Accelerated ageing in patients exposed clinically to cannabis has previously been described using a well validated metric of arterial stiffness. Whilst neither Murphy nor Watson found evidence following cannabinoid exposure for altered methylation of repeat elements the presence of chronic inflammation in the context of widespread preneoplastic change and documented neoplasia suggest that this newly described ageing mechanism might well merit further investigation.

These changes are likely exacerbated by several classical descriptions that cannabinoids reduce the overall level of histone protein synthesis. Since the overall length of DNA does not change this is likely to further open up the genome to dysregulated transcription. Severe morphological abnormalities of human and rodent sperm have been reported.

Similarly classical descriptions exist of grossly disrupted mitoses, particularly in oocytes, which are said to be seriously deficient in DNA repair machinery. Morishima reported as long ago as 1984, evidence of nuclear blebs and bridges due to deranged meiotic divisions in cannabinoid-exposed rodent oocytes . Similar blebs and bridges have been reported by others. It has since been shown that these nuclear blebs represent areas of weakness of the nuclear membrane which are often disrupted spilling their contents into the cytoplasm. They are also a sign of nuclear ageing.

Cannabinoids and micronuclei

Cannabis has long been known to test positive in the micronuclear assay due to interference with the function of the mitotic spindle. This is a major cause of chromosomal disruption and downstream severe genetic damage in surviving cells, has previously been linked with teratogenesis and carcinogenesis, and which is also potently proinflammatory by releasing dsDNA into the cytoplasm and stimulating cGAS-STING (Cyclic GMP-AMP synthase – STimulator of INterferon Gamma) signalling and downstream innate immune pathways.

Cytoplasmic dsDNA has also been shown to be an important factor driving the lethal process of cancer metastasis.

Cannabis and wnt signalling

The findings of Murphy in relation to Wnt signalling are also of great interest. It has been found by several investigators that prenatal cannabis exposure is related to encephalocoele or anencephaly defects. Non-canonical Wnt signalling has been shown to control the closure of the anterior neuropore providing a mechanistic underpinning for this fascinating finding. Wnt signalling has also been implicated in cancer development in numerous studies and in controlling limb development which have been previously linked with cannabis exposure (as noted above).

Cannabis and autism

It was recently demonstrated that the rising use of cannabis parallels the rising incidence of autism in 50 of 51 US states and territories including Washington D.C., and that cannabis legalization was associated with increased rates of autism in legal states. Several cannabinoids in addition to Δ9-tetrahydrocannabinol (THC) were implicated in such actions including cannabidiol, cannabinol, cannabichromene, cannabigerol and tetrahydrocannabivarin. A rich literature demonstrates the impacts of epigenomics on brain development and its involvement in autistic spectrum disorders. Whether cannabis is acting by epigenetic or other routes including those outlined above remains to be demonstrated. Further research is indicated.

Cannabidiol and other cannabinoids

These findings raise the larger issue of the extent to which the described changes reflect the involvement of THC as compared to other cannabinoids in the more general genotoxicity and epigenotoxicity of both oral (edible) and inhaled (smoked) cannabis. THC, cannabidiol, cannabidivarin, and cannabinol have previously been shown to be genotoxic to chromosomes and associated with micronucleus development. American cannabis has been selectively bred for its THC content and the ratio of THC to cannabidiol (CBD) was noted to have increased from 14:1 to 80:1 1998–2018. However in more recent times, cannabidiol is being widely used across the USA for numerous (nonmedical) recommendations.

Cannabidiol is known to inhibit mitochondrial oxidative phosphorylation including calcium metabolism which is known to have a negative effect on genome maintenance and is believed to secondarily restrict the supply of acetyl and other groups for epigenetic modifications. Cannabidiol is known to act via CB1R’s particularly at higher doses. Cannabidiol acts via PPARγ (Peroxisome Proliferator Activator Receptor) which is a nuclear receptor which is implicated in various physiological and pathological states including adipogenesis, obesity, diabetes, atherogenesis, neurodegenerative disease, fertility and cancer. In a human skin cell culture experiment, cannabidiol was shown to act via CB1R’s as a transcriptional repressor by increasing the level of global DNA methylation by enhancing the expression of the maintenance DNA methylase DNMT1 which in turn suppressed the expression of skin differentiation genes and returned the cells to a less differentiated state. One notes, importantly, that this DNA hypermethylation paralleled exactly the changes reported by Murphy for THC hypermethylation. The de-differentiation reported or implied in both studies is clearly a more proliferative and proto-oncogenic state. Hence, while more research is clearly required to carefully delineate the epigenetic actions of cannabidiol, its activity at CB1R’s, its mitochondrial inhibitory action, its implication of PPARγ and particularly its THC-like induction of epigenetic and cellular de-differentiation, together with its implication in chromosomal fragmentation and micronucleus induction would suggest that caution is prudent whilst the results of further research are awaited.

Other cannabinoid receptors and notch signalling

The above discussion is intended to be indicative and suggestive rather than exhaustive as the cannabinoids’ pharmacological effects are very pleiotropic, partly because CB1R’s, CB2R’s – and six other cannabinoid sensing receptors are widely distributed across most tissues. One notes that the mechanisms described above do not obviously account for very important finding that in both Colorado and Canada increasing rates of cannabis use were associated with higher rates of total congenital cardiovascular disease. One observes that in both cases the cited rise in rates refers to an elevation of crude rates unadjusted for other covariates. This finding is important for several reasons not the least of which is that cardiovascular disease is the commonest class of congenital disorders. It may be that this action is related to the effects of cannabinoids binding high-density endovascular CB1R’s from early in foetal life and interacting with the notch signalling system. Notch is a key morphogen involved in the patterning particularly of the brain, heart, vasculature and haemopoietic systems and also in many cancers. Notch signalling both acts upon the epigenome and is acted upon by the epigenome both in benign (atherosclerotic and haemopoietic) and cancerous (ovarian, biliary, colonic, leukaemic) diseases. Clearly in view of their salience, the interactions between cannabinoids and both notch and Wnt signalling pathways constitute fertile areas for ongoing research.

Conclusion

In short the timely paper by Murphy and colleagues nicely fills the gap between extant studies documenting that pre-conception exposure to cannabis is related to widespread changes in epigenetic regulation of the immune and central nervous systems and confirms that male germ cells are a key vector of this inheritance and has given new gravity to epidemiological data on the downstream teratological manifestations of prenatal cannabinoid exposure. The reasonably close parallels in findings between rats and man confirm the usefulness of this experimental model. Since guinea pigs and white rabbits are known to form the most predictive preclinical models for human teratogenicity studies it would be prudent to investigate how epigenomic results in these species compared to those identified in man and rodents. Finally the considerable and significant clinical teratogenicity of cannabis, including its very substantial neurobehavioural teratogenicity imply that such studies need to be prioritized by the research community and the research resourcing community alike, particularly if the alarming findings of recent European experience in terms of cannabinoids allowed in the food chain is not to be repeated elsewhere. Indeed, the recent passage of the nearly $USD1trillion USA Farm Act which encourages hemp to be widely grown for general use together with the advent in some US cafés of ‘hempburgers’ and ‘cannabis cookies’ would appear to have ushered in just such an era. Hemp oil has recently been marketed in Australian supermarkets completely unsupervised. Meanwhile, the rapidly accumulating and stellar discoveries relating to the pathobiology of the epigenome and its remarkable bioinformatical secrets continue to be of general medical and community importance. In some areas, particularly relating to the epigenotoxicology of the non-THC cannabinoids, further research is clearly indicated, especially in view of the widespread use and relatively innocuous reputation of cannabis derivates including particularly cannabidiol.

Such issues suggest that in the pharmacologically exciting era of the development of novel intelligently designed cannabinoids intended for human therapeutics, considerations of genomic and epigenomic toxicity including mutagenicity, teratogenicity, carcinogenicity, pro-ageing and heritable multigenerational effects warrant special caution and attention prior to the widespread exposure of whole populations either to phytocannabinoids or to their synthetic derivatives. Equally, the possibility of locus-specific epigenetic medication development as modifiers of the epigenetic reading, writing and erasing machinery suggests that very exciting developments are also beginning in this area.

Author Note

While this paper was in review our paper examining the epidemiological pattern and trends of Colorado birth defects of 2000-2014 and entitled “Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends” was accepted by the journal Clinical Pediatrics. It provides further details and confirmation on some of the issues discussed in the present paper. It also contains a detailed ecological investigation of the role of cannabidiol at the epidemiological level which confirms and extends the mechanistic observations and the quantitative remarks relating to the epidemiology of birth defects in Colorado made in the present manuscript. The interested reader may also wish to consult this resource.

Source: https://www.tandfonline.com/doi/full/10.1080/15592294.2019.1633868 July 2019

Filed under: Cannabis/Marijuana,Drug use-various effects,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Medical Studies :

 

Source:

http://www.pnas.org/content/109/40/E2657

July 2012

Filed under: Brain and Behaviour,Cannabis/Marijuana,Effects of Drugs (Papers),Health,Medical Studies :
By William Ross Perlman, Ph.D., CMPP, NIDA Notes Contributing Writer

This research:

  • Identified a gene variant that promotes impulsive behavior and enhanced responses to heroin in rats.
  • Linked the corresponding human gene variant to increased risk for impulsivity and drug use.

People who are highly impulsive and those diagnosed with ADHD are at increased risk for substance use disorders (SUD). Recent research implicates a variant of the gene for a protein called cAMP-response element modulator (CREM) in these associations. Drs. Michael L. Miller and Yasmin L. Hurd from the Icahn School of Medicine at Mount Sinai in New York, with colleagues from several other institutions, showed that the gene variant promotes impulsive and hyperactive behavior in both animals and humans, and can contribute to a person’s risk for developing SUD.

Of Rats…

The Icahn researchers began their investigations with a strain of rats that exhibit impulsive behaviors resembling human attention-deficit/hyperactivity disorder (ADHD). Initial experiments confirmed that, compared with a strain (Western Kyoto) of rats that are not known for impulsivity, these “spontaneously hypertensive” (SH) rats:

  • Were more impatient to receive rewards, fidgeted more while waiting to receive rewards, ran around more, and were more attracted to novel experiences.
  • Self-administered more heroin and, when it was made unavailable, gave up seeking it less readily.  
  • Had enhanced elevation of dopamine levels in response to heroin.

The researchers screened the rats’ DNA for genetic differences that might contribute to these behavioral differences. The results revealed that the two strains carried different variants of the gene for CREM. As a result, the SH rats had lower concentrations of CREM in the core of the nucleus accumbens—a key brain region governing reward and movement.

…And People

 

Figure 1. A CREM Gene Variant Increases HyperactivityHyperactivity scores were higher in ADHD subjects than in control subjects. In addition, ADHD subjects who carried at least one copy of the less highly expressed A variant (i.e., with the G/A or A/A CREM genotype) reported significantly higher hyperactivity than did those carrying only the more highly expressed G variant (i.e., with the G/G genotype). Genotype had no effect on hyperactivity in non-ADHD control subjects

The researchers used genetic and behavioral evidence from previous studies conducted by other researchers to demonstrate that the corresponding variant in the human CREM gene similarly predisposes people to impulsivity. This variant occupies approximately the same position on the human gene that the rodent variant occupies on the rodent gene. At this site, known as rs12765063, the CREM gene exists in two versions—called A and G—and the A variant dials down CREM production. In one study, preschool children with the A variant were found to be more distractible and to engage in more dangerous activities than peers with only the G variant (Figure 1). In another, among adolescents with ADHD, those who carried the A variant reported more symptomatic hyperactivity than those who did not.

The researchers further found that by promoting impulsivity, the variant raises the risk of drug use. Thus, in two studies of adolescents, neither the A variant alone nor ADHD alone increased the risk for drug use, but the two together did. The first analysis looked at adolescents with ADHD, and found higher rates of drug use among those with the A variant than among those with only the G variant. The second analysis looked at adolescents who had the A variant of rs12765063 and histories of childhood ADHD. It found that those whose childhood ADHD still persisted reported more use of alcohol, tobacco, marijuana, and prescription stimulants than those who had outgrown their ADHD (Figure 2). Moreover, those who no longer had ADHD reported no more drug use than a comparison group who did not carry the A variant.

 

Figure 2. The A Variant of the CREM Gene Is Associated With Increased Drug Use in People With Persistent ADHD Among a cohort whose childhood ADHD persisted through adolescence, those with the CREM A variant reported more drug use than those with only the G variant. Genotype was not linked to risk for drug use in people without ADHD (i.e., those who never had ADHD or those with remitted ADHD).

A Key to Prevention and Treatment?

Dr. Hurd suggests that CREM may be a key link between impulsivity and vulnerability to addiction. Understanding these relationships may help identify new ways of treating or preventing SUD. The protein is known to regulate multiple gene networks and their biological functions, and to influence the growth of structures that neurons use to communicate with each other.

Dr. Hurd says, “These results highlight that CREM is a mediating factor between impulsivity and substance abuse vulnerability. It brings attention to CREM in the nucleus accumbens as a regulator of impulsive action and structural plasticity.”

The study was supported by NIH grants DA015446, DA030359, DA006470, DA038954, DA031559, and DA007135.

Source: https://www.drugabuse.gov/news-events/nida-notes/2018/06/gene-links-impulsivity-drug-use-vulnerability June 2018

Filed under: Addiction,Addiction (Papers),Brain and Behaviour,Effects of Drugs (Papers),Medical Studies :

Introduction by Theodore M. Pinkert, M.D., J.D.

The study of the consequences of maternal drug abuse represents one of the most compelling areas of research in the drug abuse field. The potential victims of this problem have no say in the maternal behaviors, which may place them at risk. Therefore, it is incumbent upon the research community to attempt to delineate the potential hazards to the fetus, the newborn, the infant, and the child, so that deficits may be identified in sufficient time to compensate, where possible, with specific treatment interventions.

The purpose of this volume is to focus attention on recent studies of the effects of maternal substance abuse on offspring. The material presented includes reviews of animal data, as well as the results of large interdisciplinary clinical studies, which were originally presented on September 24th and 25th, 1984, at a National Institute on Drug Abuse Technical Review sponsored by the Divisions of Preclinical and Clinical Research. (The papers presented in the preclinical portion of this meeting will be published in a separate volume, entitled Prenatal Drug Exposure: Kinetics and Dynamics.)

     In the opening chapter of this monograph, Dr. Donald Hutchings defines the field of study known as behavioral teratology and provides a conceptual and historical framework that facilitates an understanding of what inferences may reasonably be drawn from both the animal and clinical literature. His studies in behavioral teratology integrate developmental toxicology and teratology with developmental psychology and focus on a variety of neurobehavioral changes that are crucial to the development and maturation of the individual.

The next chapter, by Dr. Ernest Abel, elaborates on the difficulties inherent in attempting to understand the interactive nature of the maternal and fetoplacental units. Through a careful review of his own work, and that of others, he provides important insights into the limitations and strengths of both epidemiological and clinical studies. He also points out the value of animal studies in providing the methodological rigor necessary (in combination with the human studies) to establish the most convincing demonstration of causality when adverse pregnancy outcomes are suspected from one or more chemical agents. Then he reviews the effects of marijuana (A5—THC) on pregnant animals and their offspring and discusses both the results and the methodological pitfalls to be avoided in these studies.

     In the following chapter, Dr. Nancy Day and her colleagues analyze the problems faced by clinical researchers in obtaining reliable and valid results using the instruments and techniques currently employed in prenatal research. The two major challenges identified are: (1) When questionnaire formats are used, do subjects understand the questions and report accurately? and (2) How does one obtain accurate measures of complex and changing events (substance abuse patterns) for specific time periods which coincide with different stages of fetal vulnerability, so that the prediction of biological effects can be made with a high degree of probability?

In the same chapter, the authors suggest techniques for eliciting accurate patterns of maternal drug intake and describe how these techniques are implemented in their current research on the effects of maternal marijuana and alcohol use during pregnancy. The value of the assessment instruments they have developed is that they measure both the quantity and frequency of drug intake in a manner that more closely resembles the way subjects naturally organize their own memory of substance use——in terms of both language and sequence. The authors also elaborate other techniques which are designed to overcome accuracy problems created either by the patient’s deliberate misrepresentation of past drug intake or by their flawed recall of remote events. These techniques include the bogus pipeline, which attempts to overcome misrepresentation of drug use, and the breakdown of prepregnancy and first trimester events into specific time intervals to aid in more accurate recall of the quantity and frequency of drug use.

     The next chapter, by Katherine Tennes and colleagues, describes the results of a large clinical study on the effects of prenatal marijuana exposure. Participating women responded to structured questionnaires about themselves, their habits (substance abuse, nutritional, etc.), and the habits of the father, if known. After delivery, infants were examined for birth measurements, physical anomalies, and muscle tone, and the Brazelton Neonatal Behavioral Assessment Scale was administered. At 1 year of age, the infant’s physical parameters were reexamined and they were evaluated on the Bayley Infant Scale of Mental and Motor Development and Behavior Checklist. One finding of this study is that maternal marijuana use decreased from previous levels of consumption as the pregnancy advanced. At delivery, no significant differences in 12 indices of obstetrical complications were detected that could not be attributed to parity, or to the amount of pain—relieving medication administered (although users of marijuana required more pain—relieving medication than nonusers). Heavy marijuana use was found to be associated with an increase in male over female offspring, but with a decrease in infant length at birth. No increase in teratogenicity, or decrease in APGAR or Brazelton scores, was associated with prenatal marijuana use. No significant differences were detected in physical measurements or Bayley scores at 1 year. The authors point out that some of their outcome data are in disagreement with previous clinical studies, and they explore possible reasons for the difference in results. In addition, the authors caution that studies examining the effects of maternal marijuana use on more complex cognitive functioning in offspring have yet to be performed.

     In the next chapter, Dr. Peter Fried reports on another major clinical study of maternal marijuana use, but in a population with significantly different demographics than the previous study. Among his findings were that gestation was shortened by maternal marijuana use and that there were neurobehavioral effects, as measured by altered visual responses and changes in state regulation (heightened tremors and startles), in the newborn. Although not yet completed, studies employing neuro- opthalmological and electrophysiological testing suggested that prenatal exposure to marijuana might delay maturation of the visual system. In agreement with the Tennes study, there were no differences in rates of miscarriage, obstetrical complications. APGAR scores, or teratological effects between the marijuana—using population and the comparison group. (Studies of both animal and human populations which suggest different results are presented and discussed.)

In addition, data collected from developmental tests administered to the infants at 6—month intervals after birth failed to discriminate infants of marijuana—using mothers from either matched controls or the general population. Dr. Fried cautions that it is not at all clear whether neurological findings present at birth are transient, or compensated for by maturation. He suggests the possibility that the tests currently used to measure developmental neurological disturbances in the newborn and neonate may not have
sufficient discriminatory sensitivity to detect subtle differences that may remain in the older, marijuana—exposed infant or child.

     In the next chapter, Drs. Rosen and Johnson review their findings on the prenatal effects and postnatal consequences to the offspring of methadone—maintained mothers. Their results include analyses of methadone’s effects upon the neonatal and infant periods of development, and they present recent data from their oldest cohorts of children, who are now in the 4— to 7—year—old age range. Among the effects on offspring of methadone—maintained mothers was a higher incidence of small—for—gestational—age infants, and infants below the third percentile in head circumference.

In addition, the maternal methadone dose and the length of time on methadone had a positive correlation with a higher incidence of obstetrical complications, decreased birth weight, and decreased infant performance on certain Brazelton measures. Neurological and developmental testing continued to reveal significant differences between methadone—exposed children and a comparison group through the 36—month evaluations. These differences included an increased incidence of abnormal reflexes, nystagmus, infections, abnormal muscle tone, and delayed developmental milestones among the methadone—exposed infants. As the children reached school age, those who did poorly neuro— developmentally at earlier evaluations continued to do poorly. A trend toward lower scores in receptive language evaluations was evident among the methadone—exposed children.

Their neurological evaluations demonstrated a higher prevalence of abnormalities of fine and gross motor coordination, poor balance, decreased attention span, hyperactivity, and speech and language delays. There was also a higher incidence of referrals for behavioral and academic problems. However, as the comparison group of children (a population selected from women in a low socioeconomic status similar to that of the methadone—maintained mothers) approached school age, they too began to show poor performance in testing. This raises important questions about the interaction between prenatal environments and the socioeconomic status of the child in the postnatal environment.

     In the following chapter, Dr. Ira Chasnoff compares the effects on offspring of the maternal use of narcotic versus nonnarcotic substances. Unique in this group of reports, his study is an attempt to distinguish the in utero effects of narcotic use (methadone and pentazocine/tripelennamine groups), from non— narcotic drug use (including a small group of women whose primary drug of abuse was phencyclidine EPCPJ, and another group with mixed sedative/hypnotic exposure, including marijuana). Although the number of subjects in each group was small, infants exposed in utero to narcotic substances showed fairly consistent decreases in birth weight, length, and head circumference from both the sedative/hypnotic group and the comparison group.

The methadone—exposed group of neonates also demonstrated deficits in auditory orientation and motor maturity. Infants exposed to both narcotic and nonnarcotic drugs showed decrements in state regulation, and infants exposed to PCP showed increased state liability and poor consolability when compared to all other drug—exposed groups. As was manifested in the preceding Rosen and Johnson material, the scores of the comparison group of infants began to fall away from the normal range toward that of the drug—exposed infants by 24 months of age.

     In the last chapter, Dr. Barry Zuckerman reviews the developmental consequences of maternal drug use. He describes the features compatible with the fetal alcohol syndrome and discusses research which suggests that these features may reflect a final common pathway of numerous agents (Including drugs of abuse), rather than a specific teratogenic effect of alcohol.

In addition, the author stresses the importance to developmental outcome studies of repeated assessments over time, and he suggests the application of newer physiologic techniques such as evoked responses, Brain Electrical Activity Mapping (BEAM),
Positron Emission Tomography (PET Scan), and Nuclear Magnetic Resonance (NMR), to enhance our understanding of the effects of prenatal drug exposure.

     In summary, much remains to be learned about the specific developmental effects of a variety of commonly used and abused drugs. The research community has not yet exhausted the potential for the development and application of new testing techniques and Instruments that will help us to identify the scope of subtle cognitive and motor effects caused by prenatal drug exposure.

Beyond these refinements lies the possibility of understanding the particular mechanisms through which these drugs exert their effects. It is the hope of those who participated in the conference that what lies herein will stimulate research into the many unanswered questions In this area.

Source and link to full articles:

https://archives.drugabuse.gov/sites/default/files/monograph59_0.pdf

Filed under: Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers) :

Introduction by Cora Lee Wetherington, Vincent L. Smeriglio, and Loretta P. Finnegan

For several years the use of drugs during pregnancy, particularly cocaine, has been a major public health issue because of the concern about possible adverse behavioral effects on the neonate and the developing child. While many popular press publications have warned of the severe adverse effects of prenatal drug exposure, the scientific literature has been less clear on this issue, in part because of complex methodological issues that confront research in this field.
    On July 12 and 13, 1993, the National Institute on Drug Abuse conducted a technical review at which researchers reviewed the state of the art regarding behavioral assessments of offspring prenatally exposed to abused drugs. Presenters identified and addressed the complex methodological issues that abound in both human and animal studies designed to assess behavioral effects of prenatal drug exposure, and they stressed the caveats involved in drawing causal conclusions from associations between maternal drug abuse and adverse behavioral outcomes in the offspring. This research monograph is based upon revisions of presentations made at that technical review. The fundamental aim of this research monograph is to clarify the methodological issues for future research in this field, to provide caution in the interpretation of research findings, and to suggest future research directions.

Link to source and full articles:

https://archives.drugabuse.gov/sites/default/files/monograph164_0.pdf  1996

Filed under: Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Medical Studies :

Sydney Parliament House, 09.07.2018

Cannabis has been greatly oversold by a left leaning press controlled by globalist and centralist forces while its real and known dangers have not been given appropriate weight in the popular press. In particular its genotoxic and teratogenic potential on an unborn generation for the next hundred years has not been aired or properly weighed in popular forums.

These weighty considerations clearly take cannabis out of the realm of personal choice or individual freedoms and place it squarely in the realm of the public good and a matter with which the whole community is rightly concerned and properly involved.

Cannabinoids are a group of 400 substances which occur only in the leaves of the Cannabis sativa plant where they are used by the plants as toxins and poisons in natural defence against other plants and against herbivores.

Major leading world experts such as Dr Nora Volkow, Director of the National Institute of Drug Abuse at NIH 1, Professor Wayne Hall, Previous Director of the Sydney Based National Drug and Alcohol Research Centre at UNSW 2, and Health Canada 3 – amongst many others – are agreed that cannabis is linked with the following impressive lists of toxicities:

1) Cannabis is addictive, particularly when used by teenagers

2) Cannabis affects brain development

3) Cannabis is a gateway to other harder drug use

4) Cannabis is linked with many mental health disorders including anxiety, depression,

psychosis, schizophrenia and bipolar disorder

5) Cannabis alters and greatly impairs the normal developmental trajectory – getting a

job, finishing a course and forming a long term stable relationship 4-11

6) Cannabis impairs driving ability 12

7) Cannabis damages the lungs

8) Cannabis is immunosuppressive

9) Cannabis is linked with heart attack, stroke and cardiovascular disease

10) Cannabis is commonly more potent in recent years, with forms up to 30% being widely available in many parts of USA, and oils up to 100% THC also widely available.

Serious questions have also been raised about its involvement in 12 different cancers, increased Emergency Room presentations and exposures of developing babies during pregnancy. It is with this latter group that the present address is mainly concerned.

Basic Physiology and Embryology Cells make energy in dedicated organelles called mitochondria. Mitochondrial energy, in the form of ATP, is known to be involved in both DNA protection and control of the immune system. This means that when the cell’s ATP is high DNA maintenance is good and the genome is intact. When cellular ATP drops DNA maintenance is impaired, DNA breaks remain unsealed, and cancers can form. Also immunity is triggered by low ATP.

As organisms age ATP falls by half each 20 years after the age of 20. Mitochondria signal and shuttle to the cell nucleus via several pathways. Not only do cells carry cannabinoid receptors on their surface, but they also exist, along with their signalling machinery, at high density on mitochondria themselves 13-19. Cannabis, and indeed all addictive drugs, are known to impair this cellular energy generation and thus promote the biochemical aging process 14-16,19,20. Most addictions are associated with increased cancers, increased infections and increased clinical signs of ageing 21-34.

The foetal heart forms very early inside the mother with a heartbeat present from day 21 of human gestation. The heart forms by complicated pathways, and arises from more than six groups of cells inside the embryo 35,36. First two arteries come together, they fold, then flex and twist to give the final shape of the adult heart. Structures in the centre of the heart mass called endocardial cushions grow out to form the heart valves between the atria and ventricles and parts of the septum which grows between the two atria and ventricles. These cardiac cushions, and their associated conoventricular ridges which grow into and divide the cardiac outflow tract into left and right halves, all carry high density cannabinoid type 1 receptors (CB1R’s) and cannabis is known to be able to interfere with their growth and development.CB1R’s appear on foetal arteries from week nine of human gestation 37.

The developing brain grows out in a complex way in the head section 35,36. Newborn brain cells are born centrally in the area adjacent to the central ventricles of the brain and then migrate along pathways into the remainder of the brain, and grow to populate the cortex, parietal lobes, olfactory lobes, limbic system, hypothalamus and hippocampus which is an important area deep in the centre of the temporal lobes where memories first form.

Developing bipolar neuroblasts migrate along pathways and then climb out along 200 million guide cells, called radial glia cells, to the cortex of the brain where they sprout dendrites and a major central axon which are then wired in to the electrical network in a “use it or lose it”, “cells that fire together wire together” manner.

The brain continues to grow and mature into the 20’s as new neurons are born and surplus dendrites are pruned by the immune system. Cannabinoids interfere with cellular migration, cellular division, the generation of newborn neurons and all the classes of glia, axonal pathfinding, dendrite sprouting, myelin formation around axons and axon tracts and the firing of both inhibitory and stimulatory synapses 14-16,19,20,38-40. Cannabinoids interfere with gene expression directly, via numerous epigenetic means, and via immune perturbation.

Cannabinoids also disrupt the mechanics of cell division by disrupting the mitotic spindle on which chromosomal separation occurs, causing severe genetic damage and frank chromosomal mis-segregation, disruption, rupture and pulverization 41-43.

Cannabis was found to be a human carcinogen by the California Environmental Protection agency in 2009 44. This makes it a likely human teratogen (deforms babies). Importantly, while discussion continues over some cancers, it bears repeating that a positive association between cannabis and testicular cancer was found in all four studies which investigated this question 45-49.

Cannabis Teratogenesis

The best animal models for human malformations are hamsters and rabbits. In rabbits cannabis exhibits a severe spectrum of foetal abnormalities when applied at high dose including shortened limbs, bowels hanging out, spina bifida and exencephaly (brain hanging out). There is also impaired foetal growth and increased foetal loss and resorption 50,51.

Many of these features have been noted in human studies 52. In 2014 Centres for Disease Control Atlanta Georgia reported increased rates of anencephaly (no brain, usually rapid death) gastroschisis (bowels hanging out), diaphragmatic hernia, and oesophageal narrowing 53,54. The American Heart Association and the American Academy of Pediatrics reported in 2007 an increased rate of ventricular septal defect and an abnormality of the tricuspid valve (Ebstein’s anomaly) 55. Strikingly, a number of studies have shown that cannabis exposure of the father is worse than that of the mother 56. In Colorado atrial septal defect is noted to have risen by over 260% from 2000-2013 (see Figure 1; note close correlation (correlation coefficient R = 0.95, P value = 0.000066) between teenage cannabis use and rising rate of major congenital anomalies in Colorado to 12.7%, or 1 in 8 live births, a rate four times higher than the USA national average !) 57.

And three longitudinal studies following children exposed to cannabis in utero have consistently noted abnormalities of brain growth with smaller brains and heads – persisting into adult life – and deficits of cortical and executive functioning persistent throughout primary, middle and high schools and into young adult life in the early 20’s 58-63. An Australian MRI neuroimaging study noted 88% disconnection of cortical wiring from the splenium to precuneus which are key integrating and computing centres in the cerebral cortex 38,39,64. Chromosomal defects were also found to be elevated in Colorado (rose 30%) 57, in Hawaii 52 in our recent analysis of cannabis use and congenital anomalies across USA, and in infants presenting from Northern New South Wales to Queensland hospitals 65. And gastroschisis shows a uniform pattern of elevation in all recent studies which have examined it (our univariate meta-analysis) 52,54,66-71.

Interestingly the gastroschisis rate doubled in North Carolina in just three years 1997-2001 72, but rose 24 times in Mexico 73 which for a long time formed a principal supply source for Southern USA 74. Within North Carolina gastroschisis and congenital heart defects closely followed cannabis distribution routes 74-76. In Canada a remarkable geographical analysis by the Canadian Government has shown repeatedly that the highest incidence of all anomalies – including chromosomal anomalies – occurs in those northern parts where most cannabis is smoked 77,78.

Congenital anomalies forms the largest cause of death of babies in the first year of life. The biggest group of them is cardiovascular defects. Since cannabis affects several major classes
of congenital defects it is obviously a major human teratogen. Its heavy epigenetic footprint,
by which it controls gene expression by controlling DNA methylation and histone modifications 79-81, imply that its effects will be felt for the next three to four generations – that is the next 100 years 82,83. Equally obviously it is presently being marketed globally as a major commodity apparently for commercial – or ideological – reasons. Since cannabis is clearly contraindicated in several groups of people including:

1) Babies

2) Children

3) Adolescents

4) Car drivers

5) Commercial Drivers – Taxis, Buses, Trains,

6) Pilots of Aeroplanes

7) Workers – Manual Tools, Construction, Concentration Jobs

8) Children

9) Adolescents

10) Males of Reproductive age

11) Females of Reproductive age

12) Pregnancy

13) Lactation

14) Workers

15) Older People – Mental Illness

16) Immunosuppressed

17) Asthmatics – 80% Population after severe chest infection

18) People with Personal History of Cancer

19) People with Family History of Cancer

20) People with Personal History of Mental Illness

21) People with Family History of Mental Illness

22) Anyone or any population concerned about ageing effects 34

… cannabis legalization is not likely to be in the best interests of public health.

Concluding Remarks

In 1854 Dr John Snow achieved lasting public health fame by taking the handle off the Broad Street pump and saving east London from its cholera epidemic, based upon the maps he drew of where the cholera cases were occurring – in the local vicinity of the Broad Street pump.

Looking across the broad spectrum of the above evidence one notices a trulyremarkable concordance of the evidence between:

1) Preclinical studies in

i) Rabbits and

ii) Hamsters

2) Cellular and biological mechanisms, particularly relating to:

i) Brain development

ii) Heart development

iii) Blood vessel development

iv) Genetic development

v) Abnormalities of chromosomal segregation

i. Downs syndrome

ii. Turners syndrome

iii. Trisomy 18

iv. Trisomy 13

vi) Cell division / mitotic poison / micronucleus formation

vii) Epigenetic change

viii) Growth inhibition

3) 84Cross-sectional Epidemiological studies, especially from:

i) Canada 77,85

ii) USA 86,87

iii) Northern New South Wales 65,88 4) Longitudinal studies from 58:

i) Ottawa 59-63

ii) Pittsburgh

iii) Netherlands

Our studies of congenital defects in USA have also shown a close concordance of congenital anomaly rates for 23 defects with the cannabis use rate indexed for the rising cannabis concentration in USA, and mostly in the three major classes of brain defects, cardiovascular defects and chromosomal defects, just as found by previous investigators in Hawaii 52.

Of no other toxin to our knowledge can it be said that it interferes with brain growth and development to the point where the brain is permanently shrunken in size or does not form at all. The demonstration by CDC twice that the incidence of anencephaly (no brain) is doubled by cannabis 53,54 implies that anencephaly is the most severe end of the neurobehavioural teratogenicity of cannabis and forms one end of a continuum with all the other impairments which are implied by the above commentary.

(Actually when blighted ova, foetal resorptions and spontaneous abortion are included in the teratological profile anencephaly is not the most severe end of the teratological spectrum – that is foetal death). It is our view that with the recent advent of high dose potent forms of cannabis reaching the foetus through both maternal and paternal lines major and clinically significant neurobehavioural teratological presentations will become commonplace, and might well become all but universal in infants experiencing significant gestational exposure.

One can only wonder if the community has been prepared for such a holocaust and tsunami amongst its children?

It is the view of myself and my collaborators that these matters are significant and salient and should be achieving greater airplay in the public discussion proceeding around the world at this time on this subject.

Whilst cannabis legalization may line the pockets of the few it will clearly not be in the public interest in any sense; and indeed the public will be picking up the bill for this unpremeditated move for generations to come. Oddly – financial gain seems to be one of the primary drivers of the present transnational push. When the above described public health message gets out amongst ambitious legal fraternities, financial gain and the threat of major medico-legal settlements for congenital defects – will quickly become be the worst reason for cannabis legalization.

Indeed it can be argued that the legalization lobby is well aware of all of the above concerns – and their controlled media pretend debate does not allow such issues to air in the public forum. The awareness of these concerns is then the likely direct reason that cannabis requires its own legislation. As noted in the patient information leaflet for the recently approved Epidiolex (cannabidiol oil for paediatric fits) the US Food and Drug Administration (FDA) is well aware of the genotoxicity of cannabinoids.

The only possible conclusion therefore is that the public is deliberately being duped. To which our only defence will be to publicize the truth.

Source: Summary of Address to Sydney Parliament House, 09.07.2018 by Professor Dr. Stuart Reece, Clinical Associate Professor, UWA Medical School. University of Western Australia

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60 Smith, A., Fried, P., Hogan, M. & Cameron, I. The effects of prenatal and current marijuana exposure on response inhibition: a functional magnetic resonance imaging study. Brain Cogn 54, 147-149 (2004).

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62 Smith, A. M., Longo, C. A., Fried, P. A., Hogan, M. J. & Cameron, I. Effects of marijuana on visuospatial working memory: an fMRI study in young adults. Psychopharmacology (Berl) 210, 429-438, doi:10.1007/s00213-010-1841-8 (2010).

63 Smith, A. M. et al. Prenatal marijuana exposure impacts executive functioning into young adulthood: An fMRI study. Neurotoxicol Teratol 58, 53-59, doi:10.1016/j.ntt.2016.05.010 (2016).

64 Zalesky, A. et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain 135, 2245-2255, doi:aws136 [pii] 10.1093/brain/aws136 (2012).

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69 Skarsgard, E. D. et al. Maternal risk factors for gastroschisis in Canada. Birth Defects Res A Clin Mol Teratol 103, 111-118, doi:10.1002/bdra.23349 (2015).

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Filed under: Australia,Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Global Drug Legalisation Efforts,Health :

Authors: Mücke M, Weier M, Carter C, Copeland J, Degenhardt L, Cuhls H, Radbruch L, Häuser W, Conrad R.

Abstract

We provide a systematic review and meta-analysis on the efficacy, tolerability, and safety of cannabinoids in palliative medicine. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus, and http://clinicaltrials.gov, and a selection of cancer journals were searched up until 15th of March 2017.

     Of the 108 screened studies, nine studies with a total of 1561 participants were included. Overall, the nine studies were at moderate risk of bias. The quality of evidence comparing cannabinoids with placebo was rated according to Grading of Recommendations Assessment, Development, and Evaluation as low or very low because of indirectness, imprecision, and potential reporting bias.

     In cancer patients, there were no significant differences between cannabinoids and placebo for improving caloric intake (standardized mean differences [SMD]:

0.2 95% confidence interval [CI]: [-0.66, 1.06] P = 0.65),

appetite (SMD: 0.81 95% CI: [-1.14, 2.75]; P = 0.42),

nausea/vomiting (SMD: 0.21 [-0.10, 0.52] P = 0.19),

>30% decrease in pain (risk differences [RD]: 0.07 95% CI: [-0.01, 0.16]; P = 0.07),

or sleep problems (SMD: -0.09 95% CI: [-0.62, 0.43] P = 0.72).

     In human immunodeficiency virus (HIV) patients, cannabinoids were superior to placebo for weight gain (SMD: 0.57 [0.22; 0.92]; P = 0.001) and appetite (SMD: 0.57 [0.11; 1.03]; P = 0.02) but not for nausea/vomiting (SMD: 0.20 [-0.15, 0.54]; P = 0.26).

     Regarding side effects in cancer patients, there were no differences between cannabinoids and placebo in symptoms of dizziness (RD: 0.03 [-0.02; 0.08]; P = 0.23) or poor mental health (RD: -0.01 [-0.04; 0.03]; P = 0.69), whereas in HIV patients, there was a significant increase in mental health symptoms (RD: 0.05 [0.00; 0.11]; P = 0.05).

     Tolerability (measured by the number of withdrawals because of adverse events) did not differ significantly in cancer (RD: 1.15 [0.80; 1.66]; P = 0.46) and HIV patients (RD: 1.87 [0.60; 5.84]; P = 0.28). Safety did not differ in cancer (RD: 1.12 [0.86; 1.46]; P = 0.39) or HIV patients (4.51 [0.54; 37.45]; P = 0.32) although there was large uncertainty about the latter reflected in the width of the CI. In one moderate quality study of 469 cancer patients with cancer-associated anorexia, megestrol was superior to cannabinoids in improving appetite, producing >10% weight gain and tolerability.

     In another study comparing megestrol to dronabinol in HIV patients, megestrol treatment led to higher weight gain without any differences in tolerability and safety. We found no convincing, unbiased, high quality evidence suggesting that cannabinoids are of value for anorexia or cachexia in cancer or HIV patients.

Source: https://www.ncbi.nlm.nih.gov/pubmed/29400010  February 2018

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Health,Medicine and Marijuana :

Abstract
Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning.

This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors—Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048207/

Filed under: Brain and Behaviour,Cannabis/Marijuana,Effects of Drugs (Papers),Health,Medical Studies :

by Kerstin Iffland and Franjo Grotenhermen

Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.

Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.

Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.

Keywords: : cannabidiol, cannabinoids, medical uses, safety, side effects, toxicity

Introduction

Since several years, other pharmacologically relevant constituents of the Cannabis plant, apart from Δ9-THC, have come into the focus of research and legislation. The most prominent of those is cannabidiol (CBD). In contrast to Δ9-THC, it is nonintoxicating, but exerts a number of beneficial pharmacological effects. For instance, it is anxiolytic, anti-inflammatory, antiemetic, and antipsychotic. Moreover, neuroprotective properties have been shown.1,2 Consequently, it could be used at high doses for the treatment of a variety of conditions ranging in psychiatric disorders such as schizophrenia and dementia, as well as diabetes and nausea.1,2

At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne.3,4

The comprehensive review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells. Chronic use and high doses of up to 1500 mg per day have been repeatedly shown to be well tolerated by humans.1

Nonetheless, some side effects have been reported for CBD, but mainly in vitro or in animal studies. They include alterations of cell viability, reduced fertilization capacity, and inhibition of hepatic drug metabolism and drug transporters (e.g., p-glycoprotein).1Consequently, more human studies have to be conducted to see if these effects also occur in humans. In these studies, a large enough number of subjects have to be enrolled to analyze long-term safety aspects and CBD possible interactions with other substances.

This review will build on the clinical studies mentioned by Bergamaschi et al. and will update their survey with new studies published until September 2016.

Relevant Preclinical Studies

Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. First, CBD has been studied in humans using oral administration or inhalation. Administration in rodents often occures either via intraperitoneal injection or via the oral route. Second, the plasma levels reached via oral administration in rodents and humans can differ. Both these observations can lead to differing active blood concentrations of CBD.1,5,6

In addition, it is possible that CBD targets differ between humans and animals. Therefore, the same blood concentration might still lead to different effects. Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.

The following study, which showed a positive effect of CBD on obsessive compulsive behavior in mice and reported no side effects, exemplifies the existing pharmacokinetic differences.5 When mice and humans are given the same CBD dose, more of the compound becomes available in the mouse organism. This higher bioavailability, in turn, can cause larger CBD effects.

Deiana et al. administered 120 mg/kg CBD either orally or intraperitoneally and measured peak plasma levels.5 The group of mice, which received oral CBD, had plasma levels of 2.2 μg/ml CBD. In contrast, i.p. injections resulted in peak plasma levels of 14.3 μg/ml. Administering 10 mg/kg oral CBD to humans leads to blood levels of 0.01 μg/ml.6 This corresponds to human blood levels of 0.12 μg/ml, when 120 mg/kg CBD was given to humans. This calculation was performed assuming the pharmacokinetics of a hydrophilic compound, for simplicity’s sake. We are aware that the actual levels of the lipophilic CBD will vary.

A second caveat of preclinical studies is that supraphysiological concentrations of compounds are often used. This means that the observed effects, for instance, are not caused by a specific binding of CBD to one of its receptors but are due to unspecific binding following the high compound concentration, which can inactivate the receptor or transporter.

The following example and calculations will demonstrate this. In vitro studies have shown that CBD inhibits the ABC transporters P-gp (P glycoprotein also referred to as ATP-binding cassette subfamily B member 1=ABCB1; 3–100 μM CBD) and Bcrp (Breast Cancer Resistance Protein; also referred to as ABCG2=ATP-binding cassette subfamily G member 2).7 After 3 days, the P-gp protein expression was altered in leukemia cells. This can have several implications because various anticancer drugs also bind to these membrane-bound, energy-dependent efflux transporters.1 The used CBD concentrations are supraphysiological, however, 3 μM CBD approximately corresponds to plasma concentrations of 1 μg/ml. On the contrary, a 700 mg CBD oral dose reached a plasma level of 10 ng/ml.6 This means that to reach a 1 μg/ml plasma concentration, one would need to administer considerably higher doses of oral CBD. The highest ever applied CBD dose was 1500 mg.1Consequently, more research is warranted, where the CBD effect on ABC transporters is analyzed using CBD concentrations of, for example, 0.03–0.06 μM. The rationale behind suggesting these concentrations is that studies summarized by Bih et al. on CBD effect on ABCC1 and ABCG2 in SF9 human cells showed that a CBD concentration of 0.08 μM elicited the first effect.7

Using the pharmacokinetic relationships mentioned above, one would need to administer an oral CBD dose of 2100 mg CBD to affect ABCC1 and ABCG2. We used 10 ng/ml for these calculations and the ones in Table 1,6,8 based on a 6-week trial using a daily oral administration of 700 mg CBD, leading to mean plasma levels of 6–11 ng/ml, which reflects the most realistic scenario of CBD administration in patients.6 That these levels seem to be reproducible, and that chronic CBD administration does not lead to elevated mean blood concentrations, was shown by another study. A single dose of 600 mg led to reduced anxiety and mean CBD blood concentrations of 4.7–17 ng/ml.9

Table 1.

Inhibition of Human Metabolic Enzymes by Exogenous Cannabinoids In Vitro and the Extrapolated Levels of Oral Daily CBD Administration in Humans Needed to Reach These In Vitro Concentrations (Adapted)6,8

CYP-450 isoform 1A1 1A2 1B1 2A6 2B6 2C9 2D6 3A4 3A5 3A7
CBD (in μM) 0.2 2.7 3.6 55.0 0.7 0.9–9.9 1.2–2.7 1.0 0.2 12.3
aExtrapolated oral daily CBD doses to reach the levels above (in mg) 4900 63,000 84,000 1.28 Mio. Ca. 16,000 21,000–231,000 28,000–63,000 Ca. 23,000 4900 0.29 Mio.
aThe calculations made here are based on the assumption that the CBD distribution in the blood follows the pharmacokinetics of a hydrophilic substance such as alcohol. The reality is more complex, because CBD is lipophilic and, for example, will consequently accumulate in fat tissue. These calculations were made with the intention to give the reader an impression and an approximation of the supraphysiological levels used in in vitro studies.

It also seems warranted to assume that the mean plasma concentration exerts the total of observed CBD effects, compared to using peak plasma levels, which only prevail for a short amount of time. This is not withstanding, that a recent study measured Cmax values for CBD of 221 ng/ml, 3 h after administration of 1 mg/kg fentanyl concomitantly with a single oral dose of 800 mg CBD.10

CBD-drug interactions

Cytochrome P450-complex enzymes

This paragraph describes CBD interaction with general (drug)-metabolizing enzymes, such as those belonging to the cytochrome P450 family. This might have an effect for coadministration of CBD with other drugs.7 For instance, CBD is metabolized, among others, via the CYP3A4 enzyme. Various drugs such as ketoconazol, itraconazol, ritonavir, and clarithromycin inhibit this enzyme.11 This leads to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active. In contrast, phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, causing reduced CBD bioavailability.11 Approximately 60% of clinically prescribed drugs are metabolized via CYP3A4.1 Table 1 shows an overview of the cytochrome inhibiting potential of CBD. It has to be pointed out though, that the in vitro studies used supraphysiological CBD concentrations.

Studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short term, but can induce them after repeated administration. This is similar to their induction by phenobarbital, thereby implying the 2b subfamily of isozymes.1 Another study showed this effect to be mediated by upregulation of mRNA for CYP3A, 2C, and 2B10, after repeated CBD administration.1

Hexobarbital is a CYP2C19 substrate, which is an enzyme that can be inhibited by CBD and can consequently increase hexobarbital availability in the organism.12,13 Studies also propose that this effect might be caused in vivo by one of CBD metabolites.14,15Generally, the metabolite 6a-OH-CBD was already demonstrated to be an inducer of CYP2B10. Recorcinol was also found to be involved in CYP450 induction. The enzymes CYP3A and CYP2B10 were induced after prolonged CBD administration in mice livers, as well as for human CYP1A1 in vitro.14,15 On the contrary, CBD induces CYP1A1, which is responsible for degradation of cancerogenic substances such as benzopyrene. CYP1A1 can be found in the intestine and CBD-induced higher activity could therefore prevent absorption of cancerogenic substances into the bloodstream and thereby help to protect DNA.2

Effects on P-glycoprotein activity and other drug transporters

A recent study with P-gp, Bcrp, and P-gp/Bcrp knockout mice, where 10 mg/kg was injected subcutaneously, showed that CBD is not a substrate of these transporters itself. This means that they do not reduce CBD transport to the brain.16 This phenomenon also occurs with paracetamol and haloperidol, which both inhibit P-gp, but are not actively transported substrates. The same goes for gefitinib inhibition of Bcrp.

These proteins are also expressed at the blood–brain barrier, where they can pump out drugs such as risperidone. This is hypothesized to be a cause of treatment resistance.16 In addition, polymorphisms in these genes, making transport more efficient, have been implied in interindividual differences in pharmacoresistance.10 Moreover, the CBD metabolite 7-COOH CBD might be a potent anticonvulsant itself.14 It will be interesting to see whether it is a P-gp substrate and alters pharmacokinetics of coadministered P-gp-substrate drugs.

An in vitro study using three types of trophoblast cell lines and ex vivo placenta, perfused with 15 μM CBD, found BCRP inhibition leading to accumulation of xenobiotics in the fetal compartment.17BCRP is expressed at the apical side of the syncytiotrophoblast and removes a wide variety of compounds forming a part of the placental barrier. Seventy-two hours of chronic incubation with 25 μM CBD also led to morphological changes in the cell lines, but not to a direct cytotoxic effect. In contrast, 1 μM CBD did not affect cell and placenta viability.17 The authors consider this effect cytostatic. Nicardipine was used as the BCRP substrate in the in vitro studies, where the Jar cell line showed the largest increase in BCRP expression correlating with the highest level of transport.17,and references therein

The ex vivo study used the antidiabetic drug and BCRP substrate glyburide.17 After 2 h of CBD perfusion, the largest difference between the CBD and the placebo placentas (n=8 each) was observed. CBD inhibition of the BCRP efflux function in the placental cotyledon warrants further research of coadministration of CBD with known BCRP substrates such as nitrofurantoin, cimetidine, and sulfasalazine. In this study, a dose–response curve should be established in male and female subjects (CBD absorption was shown to be higher in women) because the concentrations used here are usually not reached by oral or inhaled CBD administration. Nonetheless, CBD could accumulate in organs physiologically restricted via a blood barrier.17

Physiological effects

CBD treatment of up to 14 days (3–30 mg/kg b.w. i.p.) did not affect blood pressure, heart rate, body temperature, glucose levels, pH, pCO2, pO2, hematocrit, K+ or Na+ levels, gastrointestinal transit, emesis, or rectal temperature in a study with rodents.1

Mice treated with 60 mg/kg b.w. CBD i.p. for 12 weeks (three times per week) did not show ataxia, kyphosis, generalized tremor, swaying gait, tail stiffness, changes in vocalization behavior or open-field physiological activity (urination, defecation).1

Neurological and neurospychiatric effects

Anxiety and depression

Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated 14-day administration of CBD.2 However, this finding might depend on the used animal model of anxiety or depression. This is supported by a study, where CBD was administered in an acute and “chronic” (2 weeks) regimen, which measured anxiolytic/antidepressant effects, using behavioral and operative models (OBX=olfactory bulbectomy as model for depression).18 The only observed side effects were reduced sucrose preference, reduced food consumption and body weight in the nonoperated animals treated with CBD (50 mg/kg). Nonetheless, the behavioral tests (for OBX-induced hyperactivity and anhedonia related to depression and open field test for anxiety) in the CBD-treated OBX animals showed an improved emotional response. Using microdialysis, the researchers could also show elevated 5-HT and glutamate levels in the prefrontal cortex of OBX animals only. This area was previously described to be involved in maladaptive behavioral regulation in depressed patients and is a feature of the OBX animal model of depression. The fact that serotonin levels were only elevated in the OBX mice is similar to CBD differential action under physiological and pathological conditions.

A similar effect was previously described in anxiety experiments, where CBD proved to be only anxiolytic in subjects where stress had been induced before CBD administration. Elevated glutamate levels have been proposed to be responsible for ketamine’s fast antidepressant function and its dysregulation has been described in OBX mice and depressed patients. Chronic CBD treatment did not elicit behavioral changes in the nonoperated mice. In contrast, CBD was able to alleviate the affected functionality of 5HT1A receptors in limbic brain areas of OBX mice.18 and references therein

Schiavon et al. cite three studies that used chronic CBD administration to demonstrate its anxiolytic effects in chronically stressed rats, which were mostly mediated via hippocampal neurogenesis.19 and references therein For instance, animals received daily i.p. injections of 5 mg/kg CBD. Applying a 5HT1A receptor antagonist in the DPAG (dorsal periaqueductal gray area), it was implied that CBD exerts its antipanic effects via these serotonin receptors. No adverse effects were reported in this study.

Psychosis and bipolar disorder

Various studies on CBD and psychosis have been conducted.20 For instance, an animal model of psychosis can be created in mice by using the NMDAR antagonist MK-801. The behavioral changes (tested with the prepulse inhibition [PPI] test) were concomitant with decreased mRNA expression of the NMDAR GluN1 subunit gene (GRN1) in the hippocampus, decreased parvalbumin expression (=a calcium-binding protein expressed in a subclass of GABAergic interneurons), and higher FosB/ΔFosB expression (=markers for neuronal activity). After 6 days of MK-801 treatment, various CBD doses were injected intraperitoneally (15, 30, 60 mg/kg) for 22 days. The two higher CBD doses had beneficial effects comparable to the atypical antipsychotic drug clozapine and also attenuated the MK-801 effects on the three markers mentioned above. The publication did not record any side effects.21

One of the theories trying to explain the etiology of bipolar disorder (BD) is that oxidative stress is crucial in its development. Valvassori et al. therefore used an animal model of amphetamine-induced hyperactivity to model one of the symptoms of mania. Rats were treated for 14 days with various CBD concentrations (15, 30, 60 mg/kg daily i.p.). Whereas CBD did not have an effect on locomotion, it did increase brain-derived neurotrophic factor (BDNF) levels and could protect against amphetamine-induced oxidative damage in proteins of the hippocampus and striatum. No adverse effects were recorded in this study.22

Another model for BD and schizophrenia is PPI of the startle reflex both in humans and animals, which is disrupted in these diseases. Peres et al., list five animal studies, where mostly 30 mg/kg CBD was administered and had a positive effect on PPI.20 Nonetheless, some inconsistencies in explaining CBD effects on PPI as model for BD exist. For example, CBD sometimes did not alter MK-801-induced PPI disruption, but disrupted PPI on its own.20 If this effect can be observed in future experiments, it could be considered to be a possible side effect.

Addiction

CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. This was shown in an animal heroin self-administration study, where mice received 5 mg/kg CBD i.p. injections. The observed effect lasted for 2 weeks after CBD administration and could normalize the changes seen after stimulus cue-induced heroin seeking (expression of AMPA, GluR1, and CB1R). In addition, the described study was able to replicate previous findings showing no CBD side effects on locomotor behavior.23

Neuroprotection and neurogenesis

There are various mechanisms underlying neuroprotection, for example, energy metabolism (whose alteration has been implied in several psychiatric disorders) and proper mitochondrial functioning.24 An early study from 1976 found no side effects and no effect of 0.3–300 μg/mg protein CBD after 1 h of incubation on mitochondrial monoamine oxidase activity in porcine brains.25 In hypoischemic newborn pigs, CBD elicited a neuroprotective effect, caused no side effects, and even led to beneficial effects on ventilatory, cardiac, and hemodynamic functions.26

A study comparing acute and chronic CBD administration in rats suggests an additional mechanism of CBD neuroprotection: Animals received i.p. CBD (15, 30, 60 mg/kg b.w.) or vehicle daily, for 14 days. Mitochondrial activity was measured in the striatum, hippocampus, and the prefrontal cortex.27 Acute and chronic CBD injections led to increased mitochondrial activity (complexes I-V) and creatine kinase, whereas no side effects were documented. Chronic CBD treatment and the higher CBD doses tended to affect more brain regions. The authors hypothesized that CBD changed the intracellular Ca2+ flux to cause these effects. Since the mitochondrial complexes I and II have been implied in various neurodegenerative diseases and also altered ROS (reactive oxygen species) levels, which have also been shown to be altered by CBD, this might be an additional mechanism of CBD-mediated neuroprotection.1,27

Interestingly, it has recently been shown that the higher ROS levels observed after CBD treatment were concomitant with higher mRNA and protein levels of heat shock proteins (HSPs). In healthy cells, this can be interpreted as a way to protect against the higher ROS levels resulting from more mitochondrial activity. In addition, it was shown that HSP inhibitors increase the CBD anticancer effect in vitro.28 This is in line with the studies described by Bergamaschi et al., which also imply ROS in CBD effect on (cancer) cell viability in addition to, for example, proapoptotic pathways such as via caspase-8/9 and inhibition of the procarcinogenic lipoxygenase pathway.1

Another publication studied the difference of acute and chronic administration of two doses of CBD in nonstressed mice on anxiety. Already an acute i.p. administration of 3 mg/kg was anxiolytic to a degree comparable to 20 mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3 mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus. Interestingly, the repeated administration of 30 mg/kg also led to anxiolytic effects. However, the higher dose caused a decrease in neurogenesis and cell proliferation, indicating dissociation of behavioral and proliferative effects of chronic CBD treatment. The study does not mention adverse effects.19

Immune system

Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes. These animal and human ex vivo studies have been reviewed extensively elsewhere, but studies with pure CBD are still lacking. Often combinations of THC and CBD were used. It would be especially interesting to study when CBD is proinflammatory and under which circumstances it is anti-inflammatory and whether this leads to side effects (Burstein, 2015: Table 1 shows a summary of its anti-inflammatory actions; McAllister et al. give an extensive overview in Table 1 of the interplay between CBD anticancer effects and inflammation signaling).29,30

In case of Alzheimer’s disease (AD), studies in mice and rats showed reduced amyloid beta neuroinflammation (linked to reduced interleukin [IL]-6 and microglial activation) after CBD treatment. This led to amelioration of learning effects in a pharmacological model of AD. The chronic study we want to describe in more detail here used a transgenic mouse model of AD, where 2.5-month-old mice were treated with either placebo or daily oral CBD doses of 20 mg/kg for 8 months (mice are relatively old at this point). CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.

Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment. Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. Also, CBD increased cholesterol levels in WT mice but not in CBD-treated transgenic mice. This was probably due to already elevated cholesterol in the transgenic mice. The study observed no side effects.31 and references within

In nonobese diabetes-prone female mice (NOD), CBD was administered i.p. for 4 weeks (5 days a week) at a dose of 5 mg/kg per day. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD treatment lead to considerable reduction of diabetes development (32% developed glucosuria in the CBD group compared to 100% in untreated controls) and to more intact islet of Langerhans cells. CBD increased IL-10 levels, which is thought to act as an anti-inflammatory cytokine in this context. The IL-12 production of splenocytes was reduced in the CBD group and no side effects were recorded.32

After inducing arthritis in rats using Freund’s adjuvant, various CBD doses (0.6, 3.1, 6.2, or 62.3 mg/day) were applied daily in a gel for transdermal administration for 4 days. CBD reduced joint swelling, immune cell infiltration. thickening of the synovial membrane, and nociceptive sensitization/spontaneous pain in a dose-dependent manner, after four consecutive days of CBD treatment. Proinflammatory biomarkers were also reduced in a dose-dependent manner in the dorsal root ganglia (TNF alpha) and spinal cord (CGRP, OX42). No side effects were evident and exploratory behavior was not altered (in contrast to Δ9-THC, which caused hypolocomotion).33

Cell migration

Embryogenesis

CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis.1 For instance, it was recently shown that CBD inhibits Id-1. Helix-loop-helix Id proteins play a role in embryogenesis and normal development via regulation of cell differentiation. High Id1-levels were also found in breast, prostate, brain, and head and neck tumor cells, which were highly aggressive. In contrast, Id1 expression was low in noninvasive tumor cells. Id1 seems to influence the tumor cell phenotype by regulation of invasion, epithelial to mesenchymal transition, angiogenesis, and cell proliferation.34

There only seems to exist one study that could not show an adverse CBD effect on embryogenesis. An in vitro study could show that the development of two-cell embryos was not arrested at CBD concentrations of 6.4, 32, and 160 nM.35

Cancer

Various studies have been performed to study CBD anticancer effects. CBD anti-invasive actions seem to be mediated by its TRPV1 stimulation and its action on the CB receptors. Intraperitoneal application of 5 mg/kg b.w. CBD every 3 days for a total of 28 weeks, almost completely reduced the development of metastatic nodules caused by injection of human lung carcinoma cells (A549) in nude mice.36 This effect was mediated by upregulation of ICAM1 and TIMP1. This, in turn, was caused by upstream regulation of p38 and p42/44 MAPK pathways. The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies. Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs’ adverse muscoskeletal effects.37,38

Two studies showed in various cell lines and in tumor-bearing mice that CBD was able to reduce tumor metastasis.34,39 Unfortunately, the in vivo study was only described in a conference abstract and no route of administration or CBD doses were mentioned.36 However, an earlier study used 0.1, 1.0, or 1.5 μmol/L CBD for 3 days in the aggressive breast cancer cells MDA-MB231. CBD downregulated Id1 at promoter level and reduced tumor aggressiveness.40

Another study used xenografts to study the proapoptotic effect of CBD, this time in LNCaP prostate carcinoma cells.36 In this 5-week study, 100 mg/kg CBD was administered daily i.p. Tumor volume was reduced by 60% and no adverse effects of treatment were described in the study. The authors assumed that the observed antitumor effects were mediated via TRPM8 together with ROS release and p53 activation.41 It has to be pointed out though, that xenograft studies only have limited predictive validity to results with humans. Moreover, to carry out these experiments, animals are often immunologically compromised, to avoid immunogenic reactions as a result to implantation of human cells into the animals, which in turn can also affect the results.42

Another approach was chosen by Aviello et al.43 They used the carcinogen azoxymethane to induce colon cancer in mice. Treatment occurred using IP injections of 1 or 5 mg/kg CBD, three times a week for 3 weeks (including 1 week before carcinogen administration). After 3 months, the number of aberrant crypt foci, polyps, and tumors was analyzed. The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt (elevation caused by the carcinogen).42 No adverse effects were mentioned in the described study.43

Food intake and glycemic effects

Animal studies summarized by Bergamaschi et al. showed inconclusive effects of CBD on food intake1: i.p. administration of 3–100 mg/kg b.w. had no effect on food intake in mice and rats. On the contrary, the induction of hyperphagia by CB1 and 5HT1A agonists in rats could be decreased with CBD (20 mg/kg b.w. i.p.). Chronic administration (14 days, 2.5 or 5 mg/kg i.p.) reduced the weight gain in rats. This effect could be inhibited by coadministration of a CB2R antagonist.1

The positive effects of CBD on hyperglycemia seem to be mainly mediated via CBD anti-inflammatory and antioxidant effects. For instance, in ob/ob mice (an animal model of obesity), 4-week treatment with 3 mg/kg (route of administration was not mentioned) increased the HDL-C concentration by 55% and reduced total cholesterol levels by more than 25%. In addition, treatment increased adiponectin and liver glycogen concentrations.44 and references therein

Endocrine effects

High CBD concentrations (1 mM) inhibited progesterone 17-hydroxylase, which creates precursors for sex steroid and glucocorticoid synthesis, whereas 100 μM CBD did not in an in vitro experiment with primary testis microsomes.45 Rats treated with 10 mg/kg i.p. b.w. CBD showed inhibition of testosterone oxidation in the liver.46

Genotoxicity and mutagenicity

Jones et al. mention that 120 mg/kg CBD delivered intraperetonially to Wistar Kyoto rats showed no mutagenicity and genotoxicity based on personal communication with GW Pharmaceuticals47,48These data are yet to be published. The 2012 study with an epilepsy mouse model could also show that CBD did not influence grip strength, which the study describes as a “putative test for functional neurotoxicity.”48

Motor function was also tested on a rotarod, which was also not affected by CBD administration. Static beam performance, as an indicator of sensorimotor coordination, showed more footslips in the CBD group, but CBD treatment did not interfere with the animals’ speed and ability to complete the test. Compared to other anticonvulsant drugs, this effect was minimal.48 Unfortunately, we could not find more studies solely focusing on genotoxicity by other research groups neither in animals nor in humans.

Acute Clinical Data

Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD. Already in the 1970s, it was shown that oral CBD (15–160 mg), iv injection (5–30 mg), and inhalation of 0.15 mg/kg b.w. CBD did not lead to adverse effects. In addition, psychomotor function and psychological functions were not disturbed. Treatment with up to 600 mg CBD neither influenced physiological parameters (blood pressure, heart rate) nor performance on a verbal paired-associate learning test.1

Fasinu et al. created a table with an overview of clinical studies currently underway, registered in Clinical Trials. gov.49 In the following chapter, we highlight recent, acute clinical studies with CBD.

CBD-drug interactions

CBD can inhibit CYP2D6, which is also targeted by omeprazole and risperidone.2,14 There are also indications that CBD inhibits the hepatic enzyme CYP2C9, reducing the metabolization of warfarin and diclofenac.2,14 More clinical studies are needed, to check whether this interaction warrants an adaption of the used doses of the coadministered drugs.

The antibiotic rifampicin induces CYP3A4, leading to reduced CBD peak plasma concentrations.14 In contrast, the CYP3A4 inhibitor ketoconazole, an antifungal drug, almost doubles CBD peak plasma concentration. Interestingly, the CYP2C19 inhibitor omeprazole, used to treat gastroesophageal reflux, could not significantly affect the pharmacokinetics of CBD.14

A study, where a regimen of 6×100 mg CBD daily was coadministered with hexobarbital in 10 subjects, found that CBD increased the bioavailability and elimination half-time of the latter. Unfortunately, it was not mentioned whether this effect was mediated via the cytochrome P450 complex.16

Another aspect, which has not been thoroughly looked at, to our knowledge, is that several cytochrome isozymes are not only expressed in the liver but also in the brain. It might be interesting to research organ-specific differences in the level of CBD inhibition of various isozymes. Apart from altering the bioavailability in the overall plasma of the patient, this interaction might alter therapeutic outcomes on another level. Dopamine and tyramine are metabolized by CYP2D6, and neurosteroid metabolism also occurs via the isozymes of the CYP3A subgroup.50,51 Studying CBD interaction with neurovascular cytochrome P450 enzymes might also offer new mechanisms of action. It could be possible that CBD-mediated CYP2D6 inhibition increases dopamine levels in the brain, which could help to explain the positive CBD effects in addiction/withdrawal scenarios and might support its 5HT (=serotonin) elevating effect in depression.

Also, CBD can be a substrate of UDP glucuronosyltransferase.14Whether this enzyme is indeed involved in the glucuronidation of CBD and also causes clinically relevant drug interactions in humans is yet to be determined in clinical studies. Generally, more human studies, which monitor CBD-drug interactions, are needed.

Physiological effects

In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects.10Blood samples were obtained before and after 400 mg CBD (previously demonstrated to decrease blood flow to (para)limbic areas related to drug craving) or 800 mg CBD pretreatment. This was followed by a single 0.5 (Session 1) or 1.0μg/kg (Session 2, after 1 week of first administration to allow for sufficient drug washout) intravenous fentanyl dose. Adverse effects and safety were evaluated with both forms of the Systematic Assessment for Treatment Emergent Events (SAFTEE). This extensive tool tests, for example, 78 adverse effects divided into 23 categories corresponding to organ systems or body parts. The SAFTEE outcomes were similar between groups. No respiratory depression or cardiovascular complications were recorded during any test session.

The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows. Peak CBD plasma concentrations of the 400 and 800 mg group were measured after 4 h in the first session (CBD administration 2 h after light breakfast). Peak urinary CBD and its metabolite concentrations occurred after 6 h in the low CBD group and after 4 h in the high CBD group. No effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose, in which CBD clearance was reduced. Importantly, fentanyl coadministration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl’s effects. No correlation was found between CBD dose and plasma cortisol levels.

Various vital signs were also measured (blood pressure, respiratory/heart rate, oxygen saturation, EKG, respiratory function): CBD did not worsen the adverse effects (e.g., cardiovascular compromise, respiratory depression) of iv fentanyl. Coadministration was safe and well tolerated, paving the way to use CBD as a potential treatment for opioid addiction. The validated subjective measures scales Anxiety (visual analog scale [VAS]), PANAS (positive and negative subscores), and OVAS (specific opiate VAS) were administered across eight time points for each session without any significant main effects for CBD for any of the subjective effects on mood.10

A Dutch study compared subjective adverse effects of three different strains of medicinal cannabis, distributed via pharmacies, using VAS. “Visual analog scale is one of the most frequently used psychometric instruments to measure the extent and nature of subjective effects and adverse effects. The 12 adjectives used for this study were as follows: alertness, tranquility, confidence, dejection, dizziness, confusion/disorientation, fatigue, anxiety, irritability, appetite, creative stimulation, and sociability.” The high CBD strain contained the following concentrations: 6% Δ9-THC/7.5% CBD (n=25). This strain showed significantly lower levels of anxiety and dejection. Moreover, appetite increased less in the high CBD strain. The biggest observed adverse effect was “fatigue” with a score of 7 (out of 10), which did not differ between the three strains.52

Neurological and neurospychiatric effects

Anxiety

Forty-eight participants received subanxiolytic levels (32 mg) of CBD, either before or after the extinction phase in a double-blind, placebo-controlled design of a Pavlovian fear-conditioning experiment (recall with conditioned stimulus and context after 48 h and exposure to unconditioned stimulus after reinstatement). Skin conductance (=autonomic response to conditioning) and shock expectancy measures (=explicit aspects) of conditioned responding were recorded throughout. Among other scales, the Mood Rating Scale (MRS) and the Bond and Bodily Symptoms Scale were used to assess anxiety, current mood, and physical symptoms. “CBD given postextinction (active after consolidation phase) enhanced consolidation of extinction learning as assessed by shock expectancy.” Apart from the extinction-enhancing effects of CBD in human aversive conditioned memory, CBD showed a trend toward some protection against reinstatement of contextual memory. No side/adverse effects were reported.53

Psychosis

The review by Bergamaschi et al. mentions three acute human studies that have demonstrated the CBD antipsychotic effect without any adverse effects being observed. This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.1

Fifteen male, healthy subjects with minimal prior Δ9-THC exposure (<15 times) were tested for CBD affecting Δ9-THC propsychotic effects using functional magnetic resonance imaging (fMRI) and various questionnaires on three occasions, at 1-month intervals, following administration of 10 mg delta-9-Δ9-THC, 600 mg CBD, or placebo. Order of drug administration was pseudorandomized across subjects, so that an equal number of subjects received any of the drugs during the first, second, or third session in a double-blind, repeated-measures, within-subject design.54 No CBD effect on psychotic symptoms as measured with PANSS positive symptoms subscale, anxiety as indexed by the State Trait Anxiety Inventory (STAI) state, and Visual Analogue Mood Scale (VAMS) tranquilization or calming subscale, compared to the placebo group, was observed. The same is true for a verbal learning task (=behavioral performance of the verbal memory).

Moreover, pretreatment with CBD and subsequent Δ9-THC administration could reduce the latter’s psychotic and anxiety symptoms, as measured using a standardized scale. This effect was caused by opposite neural activation of relevant brain areas. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured.54

A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. Oral Δ9-THC=10 mg, CBD=600 mg, or placebo was administered in three consecutive sessions at 1-month intervals. The doses were selected to only evoke neurocognitive effects without causing severe toxic, physical, or psychiatric reactions. The 600 mg CBD corresponded to mean (standard deviation) whole blood levels of 0.36 (0.64), 1.62 (2.98), and 3.4 (6.42) ng/mL, 1, 2, and 3 h after administration, respectively.

Physiological measures and symptomatic effects were assessed before, and at 1, 2, and 3 h postdrug administration using PANSS (a 30-item rating instrument used to assess psychotic symptoms, with ratings based on a semistructured clinical interview yielding subscores for positive, negative, and general psychopathology domains), the self-administered VAMS with 16 items (e.g., mental sedation or intellectual impairment, physical sedation or bodily impairments, anxiety effects and other types of feelings or attitudes), the ARCI (Addiction Research Center Inventory; containing empirically derived drug-induced euphoria; stimulant-like effects; intellectual efficiency and energy; sedation; dysphoria; and somatic effects) to assess drug effects and the STAI-T/S, where subjects were evaluated on their current mood and their feelings in general.

There were no significant differences between the effects of CBD and placebo on positive and negative psychotic symptoms, general psychopathology (PANSS), anxiety (STAI-S), dysphoria (ARCI), sedation (VAMS, ARCI), and the level of subjective intoxication (ASI, ARCI), where Δ9-THC did have a pronounced effect. The physiological parameters, heart rate and blood pressure, were also monitored and no significant difference between the placebo and the CBD group was observed.55

Addiction

A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: “treated with oral 300 mg on Day 1; CBD 600 mg on Days 2–10 (divided into two doses of 300 mg), and CBD 300 mg on Day 11.” CBD treatment resulted in a fast and progressive reduction in withdrawal, dissociative and anxiety symptoms, as measured with the Withdrawal Discomfort Score, the Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory (BDI). Hepatic enzymes were also measured daily, but no effect was reported.56

Naturalistic studies with smokers inhaling cannabis with varying amounts of CBD showed that the CBD levels were not altering psychomimetic symptoms.1 Interestingly, CBD was able to reduce the “wanting/liking”=implicit attentional bias caused by exposure to cannabis and food-related stimuli. CBD might work to alleviate disorders of addiction, by altering the attentive salience of drug cues. The study did not further measure side effects.57

CBD can also reduce heroin-seeking behaviors (e.g., induced by a conditioned cue). This was shown in the preclinical data mentioned earlier and was also replicated in a small double-blind pilot study with individuals addicted to opioids, who have been abstinent for 7 days.52,53 They either received placebo or 400 or 800 mg oral CBD on three consecutive days. Craving was induced with a cue-induced reinstatement paradigm (1 h after CBD administration). One hour after the video session, subjective craving was already reduced after a single CBD administration. The effect persisted for 7 days after the last CBD treatment. Interestingly, anxiety measures were also reduced after treatment, whereas no adverse effects were described.23,58

A pilot study with 24 subjects was conducted in a randomized, double-blind, placebo-controlled design to evaluate the impact of the ad hoc use of CBD in smokers, who wished to stop smoking. Pre- and post-testing for mood and craving of the participants was executed. These tests included the Behaviour Impulsivity Scale, BDI, STAI, and the Severity of Dependence Scale. During the week of CBD inhalator use, subjects used a diary to log their craving (on a scale from 1 to 100=VAS measuring momentary subjective craving), the cigarettes smoked, and the number of times they used the inhaler. Craving was assessed using the Tiffany Craving Questionnaire (11). On day 1 and 7, exhaled CO was measured to test smoking status. Sedation, depression, and anxiety were evaluated with the MRS.

Over the course of 1 week, participants used the inhaler when they felt the urge to smoke and received a dose of 400 μg CBD via the inhaler (leading to >65% bioavailability); this significantly reduced the number of cigarettes smoked by ca. 40%, while craving was not significantly different in the groups post-test. At day 7, the anxiety levels for placebo and CBD group did not differ. CBD did not increase depression (in contract to the selective CB1 antagonist rimonabant). CBD might weaken the attentional bias to smoking cues or could have disrupted reconsolidation, thereby destabilizing drug-related memories.59

Cell migration

According to our literature survey, there currently are no studies about CBD role in embryogenesis/cell migration in humans, even though cell migration does play a role in embryogenesis and CBD was shown to be able to at least influence migratory behavior in cancer.1

Endocrine effects and glycemic (including appetite) effects

To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. In this study, the strain high in CBD elicited less appetite increase compared to the THC-only strain.52

Eleven healthy volunteers were treated with 300 mg (seven patients) and 600 mg (four patients) oral CBD in a double-blind, placebo-controlled study. Growth hormone and prolactin levels were unchanged. In contrast, the normal decrease of cortisol levels in the morning (basal measurement=11.0±3.7 μg/dl; 120 min after placebo=7.1±3.9 μg/dl) was inhibited by CBD treatment (basal measurement=10.5±4.9 μg/dl; 120 min after 300 mg CBD=9.9±6.2 μg/dl; 120 min after 600 mg CBD=11.6±11.6 μg/dl).60

A more recent study also used 600 mg oral CBD for a week and compared 24 healthy subjects to people at risk for psychosis (n=32; 16 received placebo and 16 CBD). Serum cortisol levels were taken before the TSST (Trier Social Stress Test), immediately after, as well as 10 and 20 min after the test. Compared to the healthy individuals, the cortisol levels increased less after TSST in the 32 at-risk individuals. The CBD group showed less reduced cortisol levels but differences were not significant.61 It has to be mentioned that these data were presented at a conference and are not yet published (to our knowledge) in a peer-reviewed journal.

Chronic CBD Studies in Humans

Truly chronic studies with CBD are still scarce. One can often argue that what the studies call “chronic” CBD administration only differs to acute treatment, because of repeated administration of CBD. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.

CBD-drug interactions

An 8-week-long clinical study, including 13 children who were treated for epilepsy with clobazam (initial average dose of 1 mg/kg b.w.) and CBD (oral; starting dose of 5 mg/kg b.w. raised to maximum of 25 mg/kg b.w.), showed the following. The CBD interaction with isozymes CYP3A4 and CYP2C19 caused increased clobazam bioavailability, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its side effects.62

These results are supported by another study described in the review by Grotenhermen et al.63 In this study, 33 children were treated with a daily dose of 5 mg/kg CBD, which was increased every week by 5 mg/kg increments, up to a maximum level of 25 mg/kg. CBD was administered on average with three other drugs, including clobazam (54.5%), valproic acid (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%), and zonisamide (18.2%). The coadministration led to an alteration of blood levels of several antiepileptic drugs. In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study.

Physiological effects

A first pilot study in healthy volunteers in 1973 by Mincis et al. administering 10 mg oral CBD for 21 days did not find any neurological and clinical changes (EEG; EKG).64 The same holds true for psychiatry and blood and urine examinations. A similar testing battery was performed in 1980, at weekly intervals for 30 days with daily oral CBD administration of 3 mg/kg b.w., which had the same result.65

Neurological and neuropsychiatric effects

Anxiety

Clinical chronic (lasting longer than a couple of weeks) studies in humans are crucial here but were mostly still lacking at the time of writing this review. They hopefully will shed light on the inconsistencies observerd in animal studies. Chronic studies in humans may, for instance, help to test whether, for example, an anxiolytic effect always prevails after chronic CBD treatment or whether this was an artifact of using different animal models of anxiety or depression.2,18

Psychosis and bipolar disorder

In a 4-week open trial, CBD was tested on Parkinson’s patients with psychotic symptoms. Oral doses of 150–400 mg/day CBD (in the last week) were administered. This led to a reduction of their psychotic symptoms. Moreover, no serious side effects or cognitive and motor symptoms were reported.66

Bergamaschi et al. describe a chronic study, where a teenager with severe side effects of traditional antipsychotics was treated with up to 1500 mg/day of CBD for 4 weeks. No adverse effects were observed and her symptoms improved. The same positive outcome was registered in another study described by Bergamaschi et al., where three patients were treated with a starting dose of CBD of 40 mg, which was ramped up to 1280 mg/day for 4 weeks.1 A double-blind, randomized clinical trial of CBD versus amisulpride, a potent antipsychotic in acute schizophrenia, was performed on a total of 42 subjects, who were treated for 28 days starting with 200 mg CBD per day each.67 The dose was increased stepwise by 200 mg per day to 4×200 mg CBD daily (total 800 mg per day) within the first week. The respective treatment was maintained for three additional weeks. A reduction of each treatment to 600 mg per day was allowed for clinical reasons, such as unwanted side effects after week 2. This was the case for three patients in the CBD group and five patients in the amisulpride group. While both treatments were effective (no significant difference in PANSS total score), CBD showed the better side effect profile. Amisulpride, working as a dopamine D2/D3-receptor antagonist, is one of the most effective treatment options for schizophrenia. CBD treatment was accompanied by a substantial increase in serum anandamide levels, which was significantly associated with clinical improvement, suggesting inhibition of anandamide deactivation via reduced FAAH activity.

In addition, the FAAH substrates palmitoylethanolamide and linoleoyl-ethanolamide (both lipid mediators) were also elevated in the CBD group. CBD showed less serum prolactin increase (predictor of galactorrhoea and sexual dysfunction), fewer extrapyramidal symptoms measured with the Extrapyramidal Symptom Scale, and less weight gain. Moreover, electrocardiograms as well as routine blood parameters were other parameters whose effects were measured but not reported in the study. CBD better safety profile might improve acute compliance and long-term treatment adherence.67,68

A press release by GW Pharmaceuticals of September 15th, 2015, described 88 patients with treatment-resistant schizophrenic psychosis, treated either with CBD (in addition to their regular medication) or placebo. Important clinical parameters improved in the CBD group and the number of mild side effects was comparable to the placebo group.2 Table 2 shows an overview of studies with CBD for the treatment of psychotic symptoms and its positive effect on symptomatology and the absence of side effects.69

Table 2.

Studies with CBD with Patients with Psychotic Symptoms (Adapted)69

Assessment Oral CBD administration Total number of study participants Main findings
BPRS (brief psychiatric rating scale) Up to 1500 mg/day for 26 days 1 Improvement of symptomatology, no side effects
BPRS Up to 1280 mg/day for 4 weeks 3 Mild improvement of symptomatology of 1 patient, no side effects
BPRS, Parkinson Psychosis Questionnaire (PPQ) Up to 600 mg/day for 4 weeks 6 Improvement of symptomatology, no side effects
Stroop Color Word Test, BPRS, PANSS (positive and negative symptom scale) Single doses of 300 or 600 mg 28 Performance after placebo and CBD 300 mg compared to CBD 600 mg; no effects on symptomatology
BPRS, PANSS Up to 800 mg/day for 4 weeks 39 CBD as effective as amisulpride in terms of improvement of symptomatology; CBD displayed superior side effect profile

Treatment of two patients for 24 days with 600–1200 mg/day CBD, who were suffering from BD, did not lead to side effects.70 Apart from the study with two patients mentioned above, CBD has not been tested systematically in acute or chronic administration scenarios in humans for BD according to our own literature search.71

Epilepsy

Epileptic patients were treated for 135 days with 200–300 mg oral CBD daily and evaluated every week for changes in urine and blood. Moreover, neurological and physiological examinations were performed, which neither showed signs of CBD toxicity nor severe side effects. The study also illustrated that CBD was well tolerated.65

A review by Grotenhermen and Müller-Vahl describes several clinical studies with CBD2: 23 patients with therapy-resistant epilepsy (e.g., Dravet syndrome) were treated for 3 months with increasing doses of up to 25 mg/kg b.w. CBD in addition to their regular epilepsy medication. Apart from reducing the seizure frequency in 39% of the patients, the side effects were only mild to moderate and included reduced/increased appetite, weight gain/loss, and tiredness.

Another clinical study lasting at least 3 months with 137 children and young adults with various forms of epilepsy, who were treated with the CBD drug Epidiolex, was presented at the American Academy for Neurology in 2015. The patients were suffering from Dravet syndrome (16%), Lennox–Gastaut syndrome (16%), and 10 other forms of epilepsy (some among them were very rare conditions). In this study, almost 50% of the patients experienced a reduction of seizure frequency. The reported side effects were 21% experienced tiredness, 17% diarrhea, and 16% reduced appetite. In a few cases, severe side effects occurred, but it is not clear, if these were caused by Epidiolex. These were status epilepticus (n=10), diarrhea (n=3), weight loss (n=2), and liver damage in one case.

The largest CBD study conducted thus far was an open-label study with Epidiolex in 261 patients (mainly children, the average age of the participants was 11) suffering from severe epilepsy, who could not be treated sufficiently with standard medication. After 3 months of treatment, where patients received CBD together with their regular medication, a median reduction of seizure frequency of 45% was observed. Ten percent of the patients reported side effects (tiredness, diarrhea, and exhaustion).2

After extensive literature study of the available trials performed until September 2016, CBD side effects were generally mild and infrequent. The only exception seems to be a multicenter open-label study with a total of 162 patients aged 1–30 years, with treatment-resistant epilepsy. Subjects were treated for 1 year with a maximum of 25 mg/kg (in some clinics 50 mg/kg) oral CBD, in addition to their standard medication.

This led to a reduction in seizure frequency. In this study, 79% of the cohort experienced side effects. The three most common adverse effects were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), and diarrhea (n=31 [19%]).72 It has to be pointed out that no control group existed in this study (e.g., placebo or another drug). It is therefore difficult to put the side effect frequency into perspective. Attributing the side effects to CBD is also not straightforward in severely sick patients. Thus, it is not possible to draw reliable conclusions on the causation of the observed side effects in this study.

Parkinson’s disease

In a study with a total of 21 Parkinson’s patients (without comorbid psychiatric conditions or dementia) who were treated with either placebo, 75 mg/day CBD or 300 mg/day CBD in an exploratory double-blind trial for 6 weeks, the higher CBD dose showed significant improvement of quality of life, as measured with PDQ-39. This rating instrument comprised the following factors: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. For the factor, “activities of daily living,” a possible dose-dependent relationship could exist between the low and high CBD group—the two CBD groups scored significantly different here. Side effects were evaluated with the UKU (Udvalg for Kliniske Undersøgelser). This assessment instrument analyzes adverse medication effects, including psychic, neurologic, autonomic, and other manifestations. Using the UKU and verbal reports, no significant side effects were recognized in any of the CBD groups.73

Huntington’s disease

Fifteen neuroleptic-free patients with Huntington’s disease were treated with either placebo or oral CBD (10 mg/kg b.w. per day) for 6 weeks in a double-blind, randomized, crossover study design. Using various safety outcome variables, clinical tests, and the cannabis side effect inventory, it was shown that there were no differences between the placebo group and the CBD group in the observed side effects.6

Immune system

Forty-eight patients were treated with 300 mg/kg oral CBD, 7 days before and until 30 days after the transplantation of allogeneic hematopoietic cells from an unrelated donor to treat acute leukemia or myelodysplastic syndrome in combination with standard measures to avoid GVHD (graft vs. host disease; cyclosporine and short course of MTX). The occurrence of various degrees of GVHD was compared with historical data from 108 patients, who had only received the standard treatment. Patients treated with CBD did not develop acute GVHD. In the 16 months after transplantation, the incidence of GHVD was significantly reduced in the CBD group. Side effects were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) classification, which did not detect severe adverse effects.74

Endocrine and glycemic (including appetite, weight gain) effects

In a placebo-controlled, randomized, double-blind study with 62 subjects with noninsulin-treated type 2 diabetes, 13 patients were treated with twice-daily oral doses of 100 mg CBD for 13 weeks. This resulted in lower resistin levels compared to baseline. The hormone resistin is associated with obesity and insulin resistance. Compared to baseline, glucose-dependent insulinotropic peptide levels were elevated after CBD treatment. This incretin hormone is produced in the proximal duodenum by K cells and has insulinotropic and pancreatic b cell preserving effects. CBD was well tolerated in the patients. However, with the comparatively low CBD concentrations used in this phase-2-trial, no overall improvement of glycemic control was observed.40

When weight and appetite were measured as part of a measurement battery for side effects, results were inconclusive. For instance, the study mentioned above, where 23 children with Dravet syndrome were treated, increases as well as decreases in appetite and weight were observed as side effects.2 An open-label trial with 214 patients suffering from treatment-resistant epilepsy showed decreased appetite in 32 cases. However, in the safety analysis group, consisting of 162 subjects, 10 showed decreased weight and 12 had gained weight.52 This could be either due to the fact that CBD only has a small effect on these factors, or appetite and weight are complex endpoints influenced by multiple factors such as diet and genetic predisposition. Both these factors were not controlled for in the reviewed studies.

Conclusion

This review could substantiate and expand the findings of Bergamaschi et al. about CBD favorable safety profile.1Nonetheless, various areas of CBD research should be extended. First, more studies researching CBD side effects after real chronic administration need to be conducted. Many so-called chronic administration studies, cited here were only a couple of weeks long. Second, many trials were conducted with a small number of individuals only. To perform a throrough general safety evaluation, more individuals have to be recruited into future clinical trials. Third, several aspects of a toxicological evaluation of a compound such as genotoxicity studies and research evaluating CBD effect on hormones are still scarce. Especially, chronic studies on CBD effect on, for example, genotoxicity and the immune system are still missing. Last, studies that evaluate whether CBD-drug interactions occur in clinical trials have to be performed.

In conclusion, CBD safety profile is already established in a plethora of ways. However, some knowledge gaps detailed above should be closed by additional clinical trials to have a completely well-tested pharmaceutical compound.

Abbreviations Used

AD Alzheimer’s disease
ARCI Addiction Research Center Inventory
BD bipolar disorder
BDI Beck Depression Inventory
CBD cannabidiol
HSP heat shock protein
IL interleukin
MRS Mood Rating Scale
PPI prepulse inhibition
ROS reactive oxygen species
SAFTEE Systematic Assessment for Treatment Emergent Events
STAI State Trait Anxiety Inventory
TSST Trier Social Stress Test
UKU Udvalg for Kliniske Undersøgelser
VAMS Visual Analogue Mood Scale
VAS Visual Analog Scales

Acknowledgments

The study was commissioned by the European Industrial Hemp Association. The authors thank Michal Carus, Executive Director of the EIHA, for making this review possible, for his encouragement, and helpful hints.

Author Disclosure Statement

EIHA paid nova-Institute for the review. F.G. is Executive Director of IACM.#

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62. Geffrey AL, Pollack SF, Bruno PL, et al. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–1251 [PubMed]
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64. Mincis M, Pfeferman A, Guimarães RX. Chronic administration of cannabidiol in man. Pilot study. AMB Rev Assoc Med Bras.1973;19:185–190 [PubMed]
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569602/
June 2017
Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Medical Studies,Medicine and Marijuana :

The following letter was submitted to the US government Food and Drug Adminstration by Australian Professor Dr. Stuart Reece as evidence against the suggested re-scheduling of cannabinoids in the USA. This item can be found online where a full list of carefully researched references is included. Professor Reece has produced an extraordinary article which should be widely read.

We cannot recommend this article highly enough.

NDPA April 2018

http://GordonDrugAbusePrevention.com

This website has been created as a public service to help address the problem of the use of marijuana and other mood- and mind-altering substances in the United States and around the world. A purpose is help inform the public, the media, and those in positions of public responsibility of the challenges facing the nation as a result of the widespread use of psychoactive and mood-altering substances, particularly marijuana and designer drugs. The harmful effects of these substances have not been well understood. In fact, there is great ignorance of the harmful effects of marijuana and other drugs that are being used for experimental or recreational purposes. The implications that the harmful effects that these drugs have for the health and wellbeing of individuals, families, and society are legion. * * * * * * *

Federal Register Submission
Food and Drug Administration,
10903 New Hampshire Ave.,
Silver Spring,
MD, 20993-0002, USA.

Re: Re-Scheduling of Cannabinoids in USA – Tetrahydrocannabinol and Cannabidiol Related Arteriopathy, Genotoxicity and Teratogenesis

I am very concerned about the potential for increased cannabis availability in USA implied by full drug legalization; however, a comprehensive and authoritative submission of the evidence would take weeks and months to prepare. Knowing what we know now and indeed, what has been available in the scientific literature for a growing number of years concerning a myriad of harmful effects of marijuana, marijuana containing THC should not be reclassified.

These effects that are now well documented in the scientific literature include, alarmingly, harm involving reproductive function and birth anomalies as a result of exposure to or use of marijuana with THC. In addition to all of the usual concerns which you will have heard from many sources including the following I have further particular concerns:

1) Effect on developing brains

2) Effect on driving

3) Effect as a Gateway drug to other drug use including the opioid epidemic

4) Effect on developmental trajectory and failure to attain normal adult goals(stable relationship, work, education)

5) Effect on IQ and IQ regression

6) Effect to increase numerous psychiatric and psychological disorders

7) Effect on respiratory system

8) Effect on reproductive system

9) Effect in relation to immunity and immunosuppression

10) Effect of now very concentrated forms of cannabis, THC and CBD which are widely available

11) Outdated epidemiological studies which apply only to the era before cannabis became so potent and so concentrated

12) Cannabis is now known to have an important arteriopathic effect and cardiovascular toxic effect .

These issues are all well covered by a rich recent literature including reviews from such major international authorities as Dr Nora Volkow Director of NIDA, Professor Wayne Hall and others .

Cannabinoid Therapeutics

In my view the therapeutic effects of cannabinoids have been wildly inflated by the press. Moreover, with over 1,000 studies listed for cannabinoids on clinicaltrials.gov, the chance of a type I experimental error, or studies being falsely reported to be positive when in fact they are not, is at last 25/1,000 at the 0.05 level.

THC as dronabinol is actually a failed drug from USA which has such a high incidence of side effects that it was rarely used as superior agents are readily available for virtually all of its touted and alleged therapeutic applications. My American liaisons advise that dronabinol sales have climbed in recent times as patients use it as a ruse to avoid detection of cannabinoid use at work in states where it is not yet legal. So when I call it a failed therapeutic I mean in a traditional sense, not in the novel way it is now applied for flagrantly flouting the law.

In considering the alleged benefits of cannabis one has to be particularly mindful of cannabis addiction in which cannabinoids will alleviate the effect of drug withdrawal as they do in any other addiction. Moreover, the fact that cannabis itself is known to cause both pain and nausea, greatly complicates the interpretation of many studies.

I also have the following concerns which relate in sum to the arteriopathy and vasculopathy and the genotoxicity of cannabis, tetrahydrocannabinol and likely including cannabidiol and various other cannabinoids:

Cannabinoid Arteriopathy

Particularly noteworthy amongst these various reports are two reports by Dr Nora Volkow in 2014, the Director of the National Institute of Drug Abuse at NIH to the New England Journal of Medicine which together document the adverse cardiovascular and cerebrovascular effects of cannabis at the epidemiological level ; a report from our own increase cardiovascular aging to BMJ Open ; a series of reports showing a fivefold

increase in the rate of heart attack within one hour after cannabis smoking ; several reports of cannabis related arteritis ; other reports of the cerebrovascular actions of cannabis ; documentation that cannabis exposure increases arterial stiffness and cardiovascular and organismal aging ; and a recent report showing that human endothelial vascular function – vasodilation – is substantially inhibited within just one minute of cannabis exposure .

It is also relevant that a synthetic cannabinoid was recently shown to directly induce both thromboxane synthase and lipoxygenase, and so be directly vasoconstrictive, prothrombotic and proinflammatory .

Vascular aging, including both macrovascular and microvascular aging is a major pathological feature not only because most adults in western nations die from myocardial infarction or cerebrovascular accidents, but also because local blood flow and microvascular function is a key determinant of stem cell niche activity in many stem cell beds. This has given rise to the vascular theory of aging which has been produced by some of the leading researchers at the National Health Lung and Blood Institute at NIH, amongst many others .

It can thus be said not only that “You are as old as your (macrovascular) arteries”, but also that “you are as old as your (microvascular) stem cells.” Hence the now compelling evidence for the little known arteriopathic complications of cannabis and cannabinoids, carry very far reaching implications indeed. This was confirmed directly in the clinical study of arterial stiffness from my clinic mentioned above .

Whilst aging, myocardial infarction and cerebrovascular accidents are all highly significant outcomes and major public health endpoints, these effects assume added significance in the context of congenital anomalies. Some congenital defects, such as gastroschisis, are thought to be due to a failure of vascular supply of part of the anterior abdominal wall . Hence in one recent study the unadjusted odds ratio of having a gastroschisis pregnancy amongst cannabis users (O.R.=8.03, 95%C.I. 5.63-11.46) was almost as high as that for heroin, cocaine and amphetamine users (O.R.= 9.35, 95%C.I.
6.64-13.15), and the adjusted odds ratio for any illicit drug use (of which was 84% cannabis) was O.R.=3.54 (95%C.I. 2.22-5.63) and for cannabis alone was said by these Canadian authors to be O.R.=3.0. Hence cannabis related vasculopathy – arteriopathy beyond its very serious implications in adults also carries implications for paediatric and congenital disorders and may also constitute a major teratogenic mechanism.

Cannabinoid Genotoxicity and Teratogenesis

Cannabis is associated with 11 cancers (lung, throat, bladder, airways, testes, prostate,

cervix, larynx) including;

Four congenital and thus inherited cancers (rhabdomyosarcoma, neuroblastoma,ALL,

AML and AMML);

Sativex product insert in many nations carries standard warning against its use by

males or females who might be having a baby.

Cannabis – and likely also CBD – is known to be associated with epigenetic changes

some of which are believed to be inheritable for at least four generations.

Cannabis is known to interfere with tubulin synthesis and binding and it also

acts via Stathmin so that microtubule function is impeded . This leads directly to

micronucleus formation. Cannabis has been known to test positive in the

micronucleus assay for over fifty years. This is a major and standard test for

genotoxicity. Micronucleus formation is known to lead directly to major chromosomal toxicity including chromosomal shattering – so-called chromothripsis –and is known to be associated with cell death, cancerogenesis and major foetal abnormalities.

Cannabis has also been linked definitively with congenital heart disease is a statement

by the American Heart Association and the American Academy of Pediatrics in 2007, on the basis of just three epidemiological studies, all done in the days before cannabis became so concentrated. Congenital heart defects have also been linked with

the father’s cannabis use . Indeed, one study showed that paternal cannabis use was

the strongest risk factor of all for preventable congenital cardiac defects.

Cannabis has also been linked with gastroschisis in at least seven cohort and case

control studies some of which are summarized in a Canadian Government

Report 200. In that report the geographic incidence of most major congenital anomalies

closely paralleled the use of cannabis as described in other major Canadian reports.

The overall adjusted odds ratio for cannabis induction of gastroschisis was

quoted by these authors as 3.0. Moreover, outbreaks of both congenital heart disease and gastroschisis in North Carolina also paralleled the local use of cannabis in that state as described by Department of Justice Reports . The incidence of gastroschisis was noted to double in North Carolina 1999-2001 in the same period the cannabis trade there was rising.

Figures of cannabis use in pregnant women in California by age were also

recently reported to JAMA 229, age group trend lines by age group which closely

approximate those reported by CDC for the age incidence of gastroschisis in the USA

Importantly much of the cannabis coming into both North Carolina and Florida is said to originate in Mexico. An eight-fold rise in the rate of gastroschisis has been reported from Mexico . Gastroschisis has also risen in Washington state. Cannabis has also been associated with 17 other major congenital defects by major Hawaiian epidemiological study reported by Forrester in 2007 when it was used alone

When considered in association with other drug use – which in many cases cannabis leads to – cannabis use was associated with a further 19 major congenital defects. In addition to the effect of cannabinoids on the epigenome and microtubules, cannabinoids have been firmly linked to a reduction of the ability of the cell to produce energy from their mitochondria. An extensive and robust evidence base now links cellular energy generation to the maintenance and care of cellular DNA .

Moreover, as the cellular energy charge falls so too DNA maintenance collapses, and indeed, the cell can spiral where its remaining energy resources, particularly as NAD+, are routed into failing and futile DNA repair, the cell slips into pseudohypoxic metabolism like the Warburg effect well known in cancerogenesis , NAD+ falls below the level required for further energy generation and cellular metabolism collapses. Hence this well-established collapse of the mitochondrial energy charge and transmembrane potential forms a potent engine of continuing and accelerating genotoxicity .

Moreover, the well documented decline in mitochondrial respiration induced by cannabinoids, including tetrahydrocannabinol, cannabidiol and anandamide achieves particular significance in the light of the robustly documented decline in cellular energetics including NAD+ which not only occurs with age but indeed, has now been shown to be one of the primary drivers of cellular and whole organismal aging. It follows therefore that cannabinoid administration (including THC andCBD) necessarily phenocopies cellular aging. This implies of course that cannabinoid dependent patients are old at the cellular level. Indeed, normal human aging is phenocopied in the clinical syndrome of cannabinoid dependence which includes:

1) Neurological deficits in:

i) attention,

ii) learning and

iii) memory;

iv) social withdrawal and disengagement and

v) academic and

vi) occupational underachievement

2) Psychiatric disorders including

i) Anxiety,

ii) Depression,

iii) Mixed Psychosis

iv) Bipolar Affective disorder and

v) Schizophrenia,

3) Respiratory disorders including:

i) Asthma

ii) Chronic Bronchitis (increased sputum production)

iii) Emphysema (Increased residual volume)

iv) Probably increased carcinomas of the aerodigestive tract

4) Immune suppression which generally implies

i) segmental immunostimulation in some parts of the immune system since the innate and adaptive immune systems exert profound homeostatic mechanisms in response to suppression of one of its parts. A Substantial literature on immunostimulation

5) Reproductive effects generally characterized by reduced

i) Male and

ii) Female fertility

6) Cardiovascular toxicity with elevated rates of

i) Myocardial infarction

ii) Cerebrovascular accident

iii) Arteritis

iv) Vascular age – vascular stiffness

7) Genotoxicity in

i) Respiratory epithelium and

ii) Gonadal tissues.

8) Osteoporosis

9) Cancers of the

i) Head and neck

ii) Larynx

iii) Lung

iv) Leukaemia

v) Prostate

vi) Cervix

vii) Testes

viii) Bladder

ix) Childhood neuroblastoma

x) Childhood acute lymphoblastic leukaemia

xi) Childhood Acuter Myeloid and myelomonocytic leukaemia

xii) Childhood rhabdomyosarcoma 201,202.

The issue here of course is that cannabinoid dependence therefore copies without exception all of the major disorders of old age, each of which is also faithfully phenocopied by cannabis dependence.

The most prominent disorders of older age include:

1) Alzheimer’s disease

2) Cardiovascular and cerebrovascular disease

3) Osteoporosis

4) Systemic inflammatory syndrome

5) Changes in lung volume and the mechanics of breathing

6) Cancers

Hence this provides one powerful pathway by which cannabinoid exposure can replicate and phenocopy the disorders of old age. This is not of course to suggest that this is the only such pathway. Obviously changes of the general level of immune activity, or alterations of the level of DNA repair occurring directly or indirectly associated with cannabis use can form similar such pathways: both are well documented in cannabis use and also in the aging literature as major pathways implicated in systemic aging.

Nevertheless, the decline in mitochondrial energetics together with its inherent genotoxic implications does seem to be a particularly well substantiated and robustly demonstrated pathway which must give serious pause to cannabinoid advocates if the sustainability of the health and welfare systems is to be factored in together with any consideration of individual patient, advocate and industrial-complex rights.

The genotoxicity of THC, CBD and CBN has been noted against sperm since at least 1999 (Zimmerman and Zimmerman in Nahas “Marijuana and Medicine” 1999, Springer). This is clearly highly significant as sperm go directly into the formation of the zygote and the new human individual. CB1R receptors are known to exist intracellularly on both the membranes of endoplasmic reticulum and mitochondria. In both locations they can induce organellar stress and major cell toxicity including disruption of DNA maintenance. Interestingly mitochondrial outer membrane CB1R’s signal via a complex signalling chain involving the G-protein transduction machinery, protein kinase A and cyclic-AMP across the intermembrane space to the inner membrane and cristae, in a fashion replicating much of the G-protein signalling occurring at the cell membrane. This machinery is also implicated in mitonuclear signalling, and the mitonuclear DNA balance between mitochondrial DNA and nuclear DNA transcriptional control, which has long been implicated in inducing the mitochondrial unfolded protein cellular stress response cell aging, stem cell behaviour and DNA genotoxic mechanisms.

You are no doubt aware that human sperm are structured like express outboard motors behind DNA packets with layers of mitochondria densely coiled around the rotating flagellum which powers their progress in the female reproductive tract. These mitochondria also carry CB1R’s and are significantly inhibited even at 100 nanomolar THC. The acrosome reaction is also inhibited .

Cannabidiol is known to act via the PPARγ system 101,302-308. PPARγ is known to have a major effect on gene expression, reproductive and embryonic and zygote function during development 309-332 so that significant genotoxic and / or teratogenic effects seem inevitable via this route. Drugs which act in this class, known as the thiazolidinediones, are classed as category B3 in pregnancy and caution is indicated in their use in pregnancy and lactation.

The Report of the Reproductive and Cancer Hazard Assessment Branch of the Office of Environmental Health Hazard Assessment of the Health Department of California was mentioned above in connection with the carcinogenicity of marijuana smoke . Since virtually all mutagens are also teratogens it follows therefore from the basic tenets of mutagenesis that if cannabis is unsafe as a known carcinogen it must also be at the very least a putative teratogen.

CBD has also been noted to be a genotoxic in other studies . All of which points to major teratogenic activity for both THC and CBD. Some of the quotations from Professor James Graham’s classical book on the effects of THC in hamsters and white rabbits, the best animal models for human genotoxicity, bear repeating:

a) “The concentration of THC was relatively low and the malignancy severe.”

b) “40-100μg resin/ml there occurred marked inhibition of cell division.

c) “large total dose, Hamsters, 25-300mg/kg …“oedema,phocomelia,omphalocoele, spina bifida, exencephaly, multiple malformations and myelocoele. This is a formidable list.”

d) “It is to this anti-mitotic action that the authors attribute the embryotoxic action of cannabis.”

e) “By such criteria resin or extract of cannabis would be forbidden to women

during the first three months of pregnancy.”

Indeed, even from the other side of the world I have heard many exceedingly adverse reports from US states in which cannabis has been legalized including Colorado, Washington, Oregon, Florida and California. Taken together the above evidence suggests that these negative reports stem directly from the now known actions of cannabis and cannabinoids, and are by no means incidental epiphenomena somehow related to social constructs surrounding cannabis use or the product forms, dosages, or routes of administration involved.

Cannabis that contains increasingly high levels of THC is now widely available, particularly in the jurisdictions where the use of cannabis has been legalized. This means that another major genotoxin, akin to Thalidomide, is being unleashed on the USA and the world. This is clearly a very grave, and. indeed, an entirely preventable occurrence.

Dr Frances Kelsey of FDA is said to have the public servant based at FDA who saved American from the thalidomide scandal which devastated so many other English-speaking nations including my own . This occurred because the genotoxicity section of the file application with FDA was blank. It was blank because thalidomide tested positive in various white rabbit and guinea pig assays. It is these same tests which cannabis is known to have failed. Dr Kelsey’s photograph has been published in the medical press with President Kennedy for her service to the nation. The challenge to FDA at this time seems whether Science can triumph over agenda driven populism, its primary vehicle, the mass media, and its primary proximate driver the burgeoning cannabis industry. Since FDA is the Federal agency par excellence where Health Science is weighed, commissioned and thoughtfully considered the challenge in our time would appear to be no less.

Evidence to date does not suggest that major congenital malformations are as common after prenatal cannabis exposure as they are after prenatal thalidomide exposure. Nevertheless the qualitative similarities remain and indeed are prominent. It is yet to be seen whether the rate of congenital anomalies after cannabis are quantitatively as common: epidemiological studies in a high potency era have not been undertaken; and even the birth defects rates from most birth defects registers in western nations including that held by CDC, Atlanta appear to be seriously out of date at the time of writing. Moreover the non-linear dose response curve in many cannabis genotoxicity studies which includes a sharp knee bend upwards beyond a certain threshold level which suggests that we could well be in for a very unpleasant quantitative surprise. At the time of writing this remains to be formally determined.

Dr Bertha Madras, Professor of Addiction Psychiatry at Harvard Medical School has recently argued against re-scheduling of cannabis. Her comments include the following:

“Why do nations schedule drugs? …… Nations schedule psychoactive drugs because we revere this three-pound organ (of our brain) differently than any other part of our body. It is the repository of our humanity. It is the place that enables us to write poetry and to do theater, to conjure up calculus and send rockets to Pluto three billion miles away, and to create I Phones and 3 D computer printing. And that is the magnificence of the human brain. Drugs can influence (the brain) adversely. So, this is not a war on drugs. This is a defense of our brains, the ultimate source of our humanity” .

I look forward to seeing the comments that you post concerning the reasons why the classification for marijuana should not be changed and that, indeed, the public should be alerted to the very harmful effects of marijuana with THC, especially in light of the wide range of marijuana’s harmful effects and the high potency of THC in today’s marijuana and in light of the idiosyncratic effects of marijuana of even low doses of THC and owing to the certain risk of harm to progeny and babies born to users of marijuana.

Please feel free to call on me if you would like further information concerning the research to which I have referred herein.

Yours sincerely,

Professor Dr. Stuart Reece, MBBS (Hons.), FRCS(Ed.), FRCS(Glas.), FRACGP, MD(UNSW). School of Psychiatry and Clinical Neurosciences Edith Cowan University and University of Western Australia, Perth, WA stuart.reece@uwa.edu.au

Source: http://GordonDrugAbusePrevention.com.

Filed under: Australia,Effects of Drugs (Papers),Political Sector,Social Affairs (Papers),USA :

EXECUTIVE SUMMARY

The objectives of this risk assessment were to:

· ascertain the state of the science in research into the potential health effects of low levels of tetrahydrocannabinol (THC) and other cannabinoids found in Cannabis sativa;

· identify key health hazards that may be associated with the presence of THC and other cannabinoids in consumer products made with industrial hemp (C. sativa cultivars with <0.3% (w/w) THC);

· assess the human health safety of the Canadian limit of 10 ug/g THC for raw materials and products made from industrial hemp; and

· to identify uncertainties and critical data gaps in the risk assessment.

Of the more than 60 cannabinoids identified in C. sativa, the toxicity of THC is the best characterized. Limited toxicity data have been reported for two other cannabinoids, cannabidiol (CBD) and cannabinol (CBN), but there are no toxicity data on the remaining cannabinoids.

Two key hazards of cannabinoid exposure are neuroendocrine disruption and neurological impairment. Neuroendocrine disruption by low levels of cannabinoids during developmental stages (perinatal, prepubertal, pubertal) leads to permanent adverse effects on brain and reproductive system development in animals. The lowest observed effect level (LOEL) for neuroendocrine disruption by THC was 1 ug/kg/d derived from a study in rats (no suitable human studies were available). Such effects could occur in humans. Similarities in the types of adverse effects, the cannabinoid receptor distribution in the brain, and the pharmacokinetics and metabolism of cannabinoids among humans and animal species support the extrapolation from animal data to humans for the purposes of risk assessment. Neurological impairment is manifested as deficits in performance with respect to cognitive and motor skills. The LOEL for neurological impairment by THC was 70 ug/kg based on data from a dose-response study in which human subjects who had a history of marihuana use received a single oral dose of THC, and cognitive and motor skills and perception of psychoactive effects were measured.

It was not deemed possible to develop a tolerable daily intake (TDI) due to the lack of a no observed effect level (NOEL), lack of data on chronic exposure and lack of data on the potential contribution of other cannabinoids to the adverse effects. Potential health risks of foods made with industrial hemp ingredients were characterized by estimating the amount of food from various food categories that would need to be eaten to reach a dose of THC equal to the LOELs for neurological impairment in humans and neuroendocrine effects in animals. Potential health risks from use of cosmetics and personal care products and nutraceuticals made with industrial hemp oil were characterized by comparing exposure to

THC through product use with the LOELs for neurological impairment in humans and neuroendocrine effects in animals. These exposure estimates were based on the assumption that the THC concentration in industrial hemp-based in ingredients was 10 ug/g, the current Canadian guideline.

The direct comparison of exposure results with the LOELs does not address:

· the bioaccumulative potential of THC with repeated dosing or consumer use;

· the lack of an identified NOELfor THC for neuroendocrine disruption or neurological impairment;

· the potential that some individuals may be more sensitive to THC than the adults with a history of marihuana use for which the LOEL of 70 ug/g for neurological impairment was observed;

· the possibility that humans could be more sensitive to THC than the rats in the study used to derive the LOEL of 1 ug/kg for neuroendocrine disruption; and,

· the potential for neuroendocrine disruption or neurological impairment by other cannabinoids (i.e. CBD, CBN and others) that would be present in industrial hemp-based products (concentrations of these have not been measured).

In consideration of the above uncertainties, the conclusions from the risk characterization were as follows:
Food: Risk of neuroendocrine disruption: Likely.

Risk of neurological impairment and psychoactivity: Likely, particularly for children.

With respect to neurological impairment, the amount of each food type that would need to be consumed to deliver a dose of THC equal to the LOEL exceeded the mean daily intake and "serving size" which may suggest an absence of risk. In the case of the child; however, some foods (dairy substitutes and candy) were identified that could be consumed in sufficient quantities on occasion in a single day or a single sitting to cause neurological impairment, or even psychoactive effects. For example 2.3 ice cream bars could deliver a dose of THC of 70 ug/kg (the LOEL for neurological impairment) and 4.6 ice cream bars could deliver a dose of 140 ug/kg (the LOEL for psychoactivity) for a 33.9 kg child.

Cosmetics: Risk of neuroendocrine disruption: Possible

Risk of neurological impairment: Unlikely

The risk of neurological impairment cannot be excluded entirely, particularly in the case of children without further information on the relative sensitivities of children vs adults, the relative sensitivities of marihuana users vs non users, the effects of repeated exposure over a long time period, the effects and concentrations of cannabinoids other than THC and the extent of dermal penetration and systemic exposure of topically applied cannabinoids under conditions of actual product use.

Nutraceuticals: Risk of neuroendocrine disruption: Likely

Risk of neurological impairment: Possible, particularly in children.

Major shortcomings related to key data gaps identified in the assessment that preclude the development of definitive conclusions regarding the degree of potential risk are:

· the inability to consider the potential contribution of cannabinoids other than THC (limited toxicity data for other cannabinoids indicate their ability to cause neuroendocrine disruption) to the overall health risks;

· the inability to consider the long term effects of bioaccumulation of THC over time from repeated low dose exposure due to lack of chronic low level toxicity studies and lack of data on the steady-state pharmacokinetics of THC;

· the inability to consider the effects of THC and other cannabinoids after multi-generation long term exposure;

· the inability to determine the degree of exposure to the developing fetus and nursing infant; and

· the lack of analytical data for THC and other cannabinoid concentrations, at detectable levels, in raw materials and finished products made from industrial hemp.

Filed under: Effects of Drugs (Papers) :

Abstract

Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route.

Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated.

In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels.

Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility.

In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not.

In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour.

Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications.

Source:  https://pubmed.ncbi.nlm.nih.gov/29129557/ Eur Neuropsychopharmacol. 2017 Dec;27(12):1223-1237. doi: 10.1016/j.euroneuro.2017.10.037. Epub 2017 Nov 10.

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers) :

Cannabis is the most widely used illicit drug in the United States, and trends show increasing use in the general population. As cannabis consumption rises, there has been significant emerging evidence for cannabis-related risks to health.1

Numerous lines of evidence suggest a correlation between cannabis consumption and a variety of psychiatric conditions, including cannabis-induced psychosis (CIP). While it can be difficult to differentiate CIP from other psychoses, CIP holds distinguishing characteristics, which may aid in its diagnosis. Given the increasing push toward cannabis legalization, assessing CIP and employing timely treatments is critical.

Specifically in youth, there is a direct relationship between cannabis use and its risks. The lack of knowledge surrounding its detrimental effects, combined with misunderstandings related to its therapeutic effects, has potential for catastrophic results.

CASE VIGNETTE

Ms. J, a 19-year-old college sophomore, was admitted to the Early Psychosis Unit at the Centre for Addiction and Mental Health (CAMH) displaying signs of agitation and acute psychosis. Her roommates had noted that her behavior had become increasingly bizarre, and she had isolated herself over the past month. She began smoking marijuana at the age of 17 and since starting college used it daily.

Ms. J exhibited signs of paranoia, believing other students in her dorm were stealing from her and trying to poison her. She remained adamant that all her problems were rooted in the competitive environment of the university and that smoking marijuana aided in keeping her sanity. In a sense, she was self-medicating. Her clinical presentation was consistent with a diagnosis of CIP.

After the hospitalization, she received outpatient case management services in the Early Psychosis Program at CAMH, which included motivational interviewing to raise her awareness about the importance of abstaining from cannabis use. She has been abstinent from cannabis for more than a year with no evidence of psychosis; she recently returned to school to finish her degree.

Epidemiology of CIP

Reports have shown a staggering increase in cannabis-related emergency department (ED) visits in recent years. In 2011, the Substance Abuse and Mental Health Services Administration (SAMHSA) and Drug Abuse Warning Network (DAWN) estimated a total of 1.25 million illicit-drug–related ED visits across the US, of which 455,668 were marijuana related.2 A similar report published in 2015 by the Washington Poison Center Toxic Trends Report showed a dramatic increase in cannabis-related ED visits.3 In states with recent legalization of recreational cannabis, similar trends were seen.4

States with medicinal marijuana have also shown a dramatic rise in cannabis-related ED visits. Moreover, states where marijuana is still illegal also showed increases.5 This widespread increase is postulated to be in part due to the easy accessibility of the drug, which contributes to over-intoxication and subsequent symptoms. Overall, from 2005 to 2011, there has been a dramatic rise in cannabis-related ED visits among all age groups and genders.

Neurobiology of CIP

Cannabis is considered an environmental risk factor that increases the odds of psychotic episodes, and longer exposure is associated with greater risk of psychosis in a dose-

dependent fashion. The drug acts as a stressor that leads to the emergence and persistence of psychosis. While a number of factors play a role in the mechanism by which consumption produces psychosis, the primary psychoactive ingredient is considered to be delta 9-tetrahydrocannabinol (delta9-THC). Properties of delta9-THC include a long half-life (up to 30 days to eliminate the long-acting THC metabolite carboxy-THC from urine) and high lipophilicity, which may contribute to CIP.

During acute consumption, cannabis causes an increase in the synthesis and release of dopamine as well as increased reuptake inhibition, similar to the process that occurs during stimulant use. Consequently, patients with CIP are found to have elevated peripheral dopamine metabolite products.

Findings from a study that examined presynaptic dopaminergic function in patients who have experienced CIP indicate that dopamine synthesis in the striatum has an inverse relationship with cannabis use. Long-term users had reduced dopamine synthesis, although no association was seen between dopaminergic function and CIP.6 This observation may provide insight into a future treatment hypothesis for CIP because it implies a different mechanism of psychosis compared with schizophrenia. As cannabis may not induce the same dopaminergic alterations seen in schizophrenia, CIP may require alternative approaches—most notably addressing associated cannabis use disorder.

Polymorphisms at several genes linked to dopamine metabolism may moderate the effects of CIP. The catechol-o-methyltransferase (COMT Val 158Met) genotype has been linked to increased hallucinations in cannabis users.7Homozygous and heterozygous genetic compositions (Met/Met, Val/Met, Val/Val) for COMT Val 158Met have been studied in patients with CIP and suggest that the presence of Val/Val and Val/Met genotypes produces a substantial increase in psychosis in relation to cannabis use. This suggests that carriers of the Val allele are most vulnerable to CIP attacks.

There has been much controversy surrounding the validity of a CIP diagnosis and whether it is a distinct clinical entity or an early manifestation of schizophrenia. In patients being treated for schizophrenia, those with a history of CIP had an earlier onset of schizophrenia than patients who never used cannabis.8Evidence suggests an association between patients who have received treatment for CIP and later development of schizophrenia spectrum disorder. However, it has been difficult to distinguish whether CIP is an early manifestation of schizophrenia or a catalyst. Nonetheless, there is a clear association between the 2 disorders.

Assessment of CIP

DSM-5 categorizes cannabis-induced psychotic disorder as a substance-induced psychotic disorder. However, there are distinguishing characteristics of CIP that differentiate it from other psychotic disorders such as schizophrenia. Clear features of CIP are sudden onset of mood lability and paranoid symptoms, within 1 week of use but as early as 24 hours after use. CIP is commonly precipitated by a sudden increase in potency (eg, percent of THC content or quantity of cannabis consumption; typically, heavy users of cannabis consume more than 2 g/d). Criteria for CIP must exclude primary psychosis, and symptoms should be in excess of expected intoxication and withdrawal effects. A comparison of the clinical features of idiopathic psychosis versus CIP is provided in the Table.

When assessing for CIP, careful history taking is critical. Time of last drug ingestion will indicate if a patient’s psychotic symptoms are closely related to cannabis intoxication/withdrawal effects. While acute cannabis intoxication presents with a range of transient positive symptoms (paranoia, grandiosity, perceptual alterations), mood symptoms (anxiety), and cognitive deficits (working memory, verbal recall, attention), symptoms that persist beyond the effects of intoxication and withdrawal are better categorized as CIP, regardless of the route of administration (smoke inhalation, oral, intravenous). CIP has historically been associated with fewer negative symptoms than schizophrenia; however, without a clear timeline of use, distinguishing schizophrenia from CIP may prove difficult.

A diagnosis of primary psychosis (eg, schizophrenia) is warranted in the absence of heavy cannabis use or withdrawal (for at least 4 weeks), or if symptoms preceded onset of heavy use. The age at which psychotic symptoms emerge has not proved to be a helpful indicator; different studies show a conflicting median age of onset.

Clinical features of schizophrenia and CIP share many overlapping characteristics. However, compared with primary psychoses with concurrent cannabis abuse, CIP has been established to show more mood symptoms than primary psychosis. The mood symptom profile includes obsessive ideation, interpersonal sensitivity, depression, and anxiety. Of significance is the presence of social phobia: 20% of patients with CIP demonstrate phobic anxiety compared with only 3.8% of patients with primary psychosis with cannabis abuse.

Hypomania and agitation have also been found to be more pronounced in cases of CIP.9 Visual hallucinations are more common and more distinct in CIP than in other psychoses such as schizophrenia. Perhaps the most discriminating characteristic of CIP is awareness of the clinical condition, greater disease insight, and the ability to identify symptoms as a manifestation of a mental disorder or substance use. The presence of much more rapidly declining positive symptoms is another distinctive factor of CIP.

Finally, family history may help distinguish CIP from primary psychosis. Primary psychosis has a strong association with schizophrenia and other psychotic disorders in first- or second-degree relatives, whereas CIP has a weaker family association with psychosis.

Treatment of CIP

As with all substance-induced psychotic states, abstinence from cannabis may be the definitive measure to prevent recurrence. With limited research surrounding CIP, achieving symptomatic treatment during acute phases of CIP has proved to be difficult. The Figure suggests possible treatment progression for CIP.

Pharmacotherapeutic interventions include the second-generation antipsychotic drug olanzapine and haloperidol. While both are equally effective, their different adverse- effect profiles should be taken into consideration when treating a patient; olanzapine is associated with significantly fewer extrapyramidal adverse effects.

One report indicates that antipsychotics worsened the condition in some patients.10 Conventional antipsychotics failed to abate the symptoms of CIP in one 20-year old man. Trials of olanzapine, lithium, and haloperidol had little to no effect on his psychosis. Risperidone was tried but elicited temporal lobe epilepsy with auditory, somatic, and olfactory hallucinations. However, the use of valproate sodium markedly improved his symptoms and cognition, returning him to baseline.

Carbamazepine has also been shown to have rapid effects when used as an adjunct to antipsychotics.11 Use of anti-seizure medication in CIP treatment has been hypothesized to reduce neuroleptic adverse effects, resulting in better tolerance of antipsychotics.10,11 These results suggest the use of adjunctive anti-epileptics should be considered in CIP treatment strategies, although further studies in a broad range of patients with CIP are needed.

Abstaining from cannabis is the most beneficial and effective measure for preventing future CIP events; however, it is likely to be the most difficult to implement.

Psychosocial intervention has a significant impact on early-phase psychosis, and when the intervention is initiated plays a role in disease outcomes. A delay in providing intensive psychosocial treatment has been associated with more negative symptoms compared with a delay in administrating antipsychotic medication.12 Employing cannabis- focused interventions with dependent patients who present with first-episode psychosis can decrease use in a clinically meaningful way and subjectively improve patient quality of life.

Compared with the standard of care, motivational interviewing significantly increases number of days abstinent from cannabis and aids in decreasing short-term consumption.13 Patients who are treated with motivational interviewing in addition to standard of care (combination of antipsychotic medication, regular office-based psychiatric contact, psychoeducation) are reported to also have more confidence and willingness to reduce cannabis use.

Patients with CIP who are unwilling or unable to decrease cannabis consumption may be protected from psychotic relapse with aripiprazole (10 mg/d). Its use suppresses the re-emergence of psychosis without altering cannabis levels. However, no direct comparison has been made with aripiprazole and other antipsychotics in treating CIP. Clearly, well-controlled large studies of putative treatments for CIP are needed.

Conclusions

As more countries and states approve legalization, and marijuana becomes more accessible, CIP and other cannabis-related disorders are expected to increase. Efforts should be made by physicians to educate patients and discourage cannabis use. Just as there was an era of ignorance concerning the damaging effects of tobacco, today’s conceptions about cannabis may in fact be judged similarly in the future. The onus is on psychiatrists to take an evidence-based approach to this increasing problem.

Source:  http://www.psychiatrictimes.com/substance-use-disorder/cannabis-induced-psychosis-review  14th July

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers),Health,Medical Studies :

Investigating the proposition that cannabis is worth bothering with, this hot topic looks at reports that stronger cannabis on the market is increasing harms to users, prospects of recovery from disorders and dependence, and the emerging response to synthetic forms of cannabis like ‘spice’.

CANNABIS IN THE LAW

A controlled ‘Class B’ substance, cannabis carries legal penalties for possession, supply, and production. Between 2004–2009 cannabis was reclassified as a ‘Class C’ substance, meaning for a brief period of time it carried lesser penalties for possession. In 2009, the Association of Chief Police Officers issued new guidance, advising officers to take an escalating approach to the policing of cannabis possession for personal use: • A warning • A penalty notice for disorder (PND) • Arrest

This three-tiered approach was designed to be “ethical and non-discriminatory”, but also reinforce the “national message that cannabis is harmful and remains illegal”.

In 1990s Britain a common reaction to allocating resources to treating cannabis users was, ‘Why bother? We have more than enough patients with problems with serious drugs like heroin.’ The typically calming use of the drug by adults was seen as preferable to the main alternative – alcohol and its associated violence and disorder. Calls for a treatment response were seen as pathologising what in many societies is both normal and in some ways desirable youth development: trying new experiences, challenging conventions, and exposing the hypocrisy of alcohol-drinking adults. In 1997 the Independent on Sunday launched a campaign to decriminalise cannabis, culminating in a mass ‘roll-up’, and 16,000-strong pro-cannabis march from Hyde Park to Trafalgar Square. Its Editor Rosie Boycott wrote in the paper about her own coming-of-age experience smoking cannabis, telling readers:

“I Rolled my first joint on a hot June day in Hyde Park. Summer of ’68. Just 17. Desperate to be grown-up. … My first smoke, a mildly giggly intoxication, was wholly anti-climatic. The soggy joint fell apart. I didn’t feel changed. But that act turned me – literally – into an outlaw. I was on the other side of the fence from the police – or the fuzz, as we used to call them. So were a great many of my generation.”

The campaign was explosive, but short-lived, apparently subsiding when Boycott left to take up her role as Editor of the Daily Express. A decade later, the Independent issued an apology for the campaign. ‘If only they had known then, what they knew now’, was the message of the article, referring to the reportedly damaging impact of the more potent strains of cannabis and its links to “mental health problems and psychosis for thousands of teenagers”.

Are stronger strains creating more problems?

There has been a long-standing, but controversial, association between cannabis strength and harm. Reading newspaper articles on the subject, it wouldn’t be unusual to see a headline drawing a straight line between ‘super-strength skunk’ and addiction, violence, deaths, or psychosis. In 2008, then Prime Minister Gordon Brown spoke in a similar vein, telling a breakfast-television viewing audience:

I have always been worried about cannabis, with this new skunk, this more lethal part of cannabis.

I don’t think that the previous studies took into account that so much of the cannabis on the streets is now of a lethal quality and we really have got to send out a message to young people – this is not acceptable.

Brown was warning of a dangerous new strain of cannabis on the market, that caused very severe harms to users – contrasting starkly with the common perception of cannabis as a ‘low harm’ or ‘no harm’ drug. The strength or potency of cannabis is determined by the amount of ‘THC’ it contains. THC produces the ‘high’ associated with cannabis, and another major component ‘CBD’ produces the sedative and anti-anxiety effects. As well as potency, the relative amounts of THC and CBD are important for understanding the effects of cannabis – something explored in a University College London study during the programme Drugs Live: Cannabis on Trial. The research team compared two different types of cannabis: the first had high levels of THC (approx. 13%) but virtually no CBD; and the second had a lower level of THC (approx. 6.5%) and substantial amounts of CBD (approx. 8%). They found that CBD had a moderating or protective effect on some of the negative effects of THC, and that “many of the effects that people enjoy are still present in low-potency varieties without some of the harms associated with the high-potency varieties”. At least in the US over the last two decades (between 1995–2014), potency has increased from around 4% to 12%, and the protective CBD content of cannabis has decreased, from around 28% to less than 15%, significantly affecting the ratio of THC to CBD, and with it, the nature and strength of the psychoactive effect of cannabis. Until the 1990s, herbal cannabis sold in the UK was predominantly imported from the Caribbean, West Africa, and Asia. After this time, it was increasingly produced in the UK, being grown indoors using intensive means (artificial lighting, heating, and control of day-length). A study funded by the Home Office analysed samples of cannabis confiscated by 23 police forces in England and Wales in 2008, and found that over 97% of herbal cannabis had been grown by intensive methods; its average potency of 16% compared with just 8% for traditional imported herbal cannabis. This matched other reports of home-grown cannabis being consistently (around 2–3 times) stronger than imported herbal cannabis and cannabis resin.

In 2015, observing a decrease in the use of cannabis in England and Wales, but parallel increase in demand for treatment, a UK study examined whether the trend could be explained by an increase in the availability of higher-potency cannabis. Over 2500 adults were surveyed about their use of different types of cannabis, severity of dependence, and cannabis-related concerns. The researchers found that higher potency cannabis was associated with a greater severity of dependence, especially in young people, and was rated by participants as causing more memory impairment and paranoia than lower potency types. However at the same time, it was reported to produce the best ‘high’, and to be the preferred type.

By definition cannabis is a psychoactive substance, which means it can change people’s perceptions, mood, and behaviour. Higher potency cannabis contains more of the psychoactive component, so it makes sense that higher potency cannabis could increase the risk of temporary or longer-term (adverse) problems with perceptions, mood, and behaviour. However, there is a particular concern that cannabis use could be linked to ‘psychosis’, a term describing a mental illness where a person perceives or interprets reality in a very different way to those around them, which can include hallucinations or delusions.

Whether cannabis causes psychosis, precipitates an existing predisposition, aggravates an existing condition, or has no impact at all on psychotic symptoms, has for decades been hotly contested. With our focus on evaluations of interventions, Drug and Alcohol Findings is in no position to pronounce on this issue, nor on the possibility that the drug might sometimes improve mental health, but some examples of research informing this debate are included below. A 2009 UK study examined whether daily use of high-potency cannabis was linked to an elevated risk of psychosis, comparing 280 patients in London presenting with a first episode of psychosis with a healthy control group. The patients were found to be more likely to smoke cannabis on a daily basis than the control group, and to have smoked for more than five years. Among those who used cannabis, 78% of the patients who had experienced psychosis used higher-potency cannabis, compared with 37% of those in the control group. The findings indicated that the risk of psychosis was indeed greater among the people who were using high potency cannabis on a frequent basis, but couldn’t show that the cannabis use caused the psychosis, or even that the cannabis use made the group more susceptible to psychosis. The wider literature on mental health and substance use would suggest that the association is more complex than this. A recently published paper from the University of York has demonstrated the complications of attributing any association between cannabis use and psychosis to a causal effect of cannabis use rather than other factors or a reverse causal effect. A calculation based on data from England and Wales helped to put this into perspective, indicating that even if cannabis did cause psychosis more than 20,000 people would need to be stopped using cannabis to prevent just one case of psychosis. The apparent steady increase in cannabis potency in the UK since the 1990s is important context for further research. Where higher potency cannabis is increasingly becoming the norm, and is the preference for cannabis users, it would be relevant to generate more evidence of the health-related problems with high potency cannabis, and the treatment and harm reduction solutions based around these health-related problems.

Cannabis accounts for half of all new drug treatment patients

The most widely used illegal drug in Europe, many seemingly enjoy cannabis without it leading to any significant negative social or health effects. However, numbers entering treatment for cannabis use problems have been on the rise (both in the UK, and the rest of Europe), while heroin treatment numbers have fallen  chart. According to Public Health England, this is not because more people are using cannabis, but perhaps because services relieved of some of the recent pressure of opiate user numbers are giving more priority to cannabis, because they are making themselves more amenable to cannabis users, and because of emerging issues with stronger strains of the drug. Whatever the causes, across the UK figures submitted to the European drug misuse monitoring centre show that the proportion of patients starting treatment for drug problems who did so primarily due to their cannabis use rose steadily from 11% in 2003/04 to 22% in 2011/12. With the caveat that data from 2013 onwards is not directly comparabledue to changes in methodology, in 2014 and 2015 the proportion of patients who entered treatment primarily because of a cannabis issue hovered above previous years at 26% (25,278 and 26,295 respectively). Among first ever treatment presentations, the increase from 2003/04 was more pronounced, from 19% to 37%. By 2013, cannabis use had become the main prompt for half the patients who sought treatment for the first time (at 49%), and stayed relatively constant at 47% in 2014, and 48% in 2015.

Showing that more users was not the reason for more starting treatment, over about the same period, in England and Wales the proportion of 16–59-year-olds who in a survey said they had used cannabis in the past year fell from about 11% to 7% in 2013/14, then stayed at that level in 2014/15 and 2015/16. The treatment figures largely reflect trends in England, where in 2013/14 the number of patients starting treatment with cannabis use problems had risen to 30,422, 21% of all treatment starters, up from 23,018 and 19% in 2005/06. Subsequently the number dropped to 27,965 in 2015/16, still around a fifth of all treatment starters. Among the total treatment population – starting or continuing in treatment – cannabis numbers rose from 40,240 in 2005/06 to peak at 64,407 in 2013/14 before falling back to 59,918 in 2015/16; corresponding proportions again hovered around a fifth. As a primary problem substance among under-18s cannabis dominated, accounting for three-quarters of all patients in treatment in 2015/16 and in numbers, 12,863. The dominance of cannabis increased from 2008/09 as numbers primarily in treatment for drinking problems fell.

‘All treatments appear to work’

According to the two main diagnostic manuals used in Europe and the USA, problem cannabis use can develop into a cannabis use disorder or cannabis dependence, identifiable by a cluster of symptoms including: loss of control; inability to cut down or stop; preoccupation with use; neglecting activities unrelated to use; continued use despite experiencing problems; and the development of tolerance and withdrawal. This level of clinical appreciation for cannabis use problems didn’t exist when researcher and writer William L. White entered the addictions field half a century ago:

“When I first entered the rising addiction treatment system in the United States nearly half a century ago, there existed no clinical concept of cannabis dependence and thus no concept of recovery from this condition. In early treatment settings, cannabis was not consider[ed] a “real” drug, the idea of cannabis addiction was scoffed at as remnants of “Reefer Madness,” and casual cannabis use was not uncommon among early staff working in addiction treatment programs of the 1960s. Many in the field remain sceptical of the idea of cannabis dependence, specifically whether problem users at the severe end experience physiological withdrawal. However, reviewing what they believe is mounting evidence, these authors suggest there can be confidence in the existence of a “true withdrawal syndrome” – albeit one that differs qualitatively from the “significant medical or psychiatric problems as observed in some cases of opioid, alcohol, or benzodiazepine withdrawals”. In the case of cannabis, the main symptoms are primarily emotional and behavioural, although appetite change, weight loss, and some physical discomfort are reported. A brief review aimed at practitioners in UK primary care provides guidance on how to manage symptoms of withdrawal among patients trying to stop or reduce their cannabis use.

Research has come a long way, says William L. White, with now “clear data supporting the dependency producing properties of cannabis, a clear conceptualization of cannabis use disorders (CUD) and cannabis dependence (CD)”, but until recently, very little evidence about the prospects of long-term recovery. Yet, key papers – found here and here – indicate that:

• Full remission from cannabis use disorders is not only possible, but probable.

• Stable remission takes time – an average of 33 months.

• Abstinence may not be initially realistic for heavy cannabis users – but those in  remission are usually able to reduce the intensity of their use and its  consequences.

At least in the United States, it seems dependence is more quickly overcome from cannabis than the main legal drugs. A survey of the US general adult population found that within a year of first becoming dependent, 3% each of smokers and drinkers were in remission and remained so until they were surveyed. For cannabis the figure was nearly 5% and for cocaine, nearly 9%. After ten years the proportions in remission had risen to 18% for nicotine, 37% for alcohol, 66% for cannabis and 76% for cocaine. About 26 years after first becoming dependent, half the people at some time dependent on nicotine were in remission, a milestone reached for alcohol after 14 years, for cannabis six years, and for cocaine, five.

Specialised treatment programmes for cannabis users in European countries

Generally for people with cannabis use problems, the European Monitoring Centre for Drugs and Drug Addiction concluded in 2015, and before that in 2008, that “all treatments appear to work”. For adults, effective treatments include motivational interviewing, motivational enhancement therapy and cognitive-behavioural therapy, and for younger people, family-based therapies seem most beneficial. Less important than the type of treatment is the treatment context and the individual’s determination to overcome their problems through treatment. And there is “no firm basis for a conclusion” that cannabis-specific interventions (designed around the risks and harms associated with cannabis) are more effective than general substance use treatment tailored to the individual needs of the cannabis user seeking treatment chart. In some studies brief interventions have been found to work just as well as more intensive treatment, but when the patients are heavily dependent, and the most difficult cases are not filtered out by the research, longer and more individualised therapies can have the advantage. When the World Health Organization trialled its ASSIST substance use screening and brief advice programme in Australia, India, the United States, and Brazil, just over half the identified patients (all had to be at moderate risk of harm but probably not dependent) were primarily problem cannabis users. Among these, risk reduction in relation to this drug was significantly greater among patients allocated to a brief advice session than among those placed on a three-month waiting list for advice. In each country too, risk reduction was greater among intervention patients, except for the USA, where the order was reversed. Suggesting that severity of use was not a barrier to reacting well to brief intervention, only patients at the higher end of the moderate risk spectrum further reduced their cannabis use/risk scores following intervention. The ASSIST study was confined to adults, but young people in secondary schools in the USA whose problem substance use focused mainly on cannabis also reacted well to brief advice.

The relative persistence of opiate use problems versus the transitory nature of those primarily related to cannabis seemed reflected in an analysis of treatment entrants in England from 1 April 2005 to the end of 2013/14, the last time this particular analysis was published. At the end of this period just 7% of primary cannabis users were still in or back in treatment compared to the 30% overall figure and 36% for primary opiate users. The figure peaked at 43% for users of opiates and crack. Over half – 53% – of primary cannabis users had left treatment as planned, apparently having overcome their cannabis problems, compared to 27% of primary opiate users and just 20% with dual opiates and crack use problems. Another 40% of cannabis users had left treatment in an unplanned manner, a slightly higher proportion than among opiate users. The figures tell a tale of relatively high level of success which enables cannabis users to leave treatment, though even in the absence of recorded success, few stay long-term.

However, the forms patients in England complete with their keyworkers while in treatment seem to tell a different story. Compared to how they started treatment, around six months later 45% of primary cannabis users were assessed as using just as often (including a few using more), compared to 30% of opiate users and 42% whose main problem drugs were both opiates and crack, suggesting more rapid and/or more complete remission for opiate users than for cannabis users. One interpretation is that the widespread use of substitute drugs like methadone more reliably reduced the illegal opiate use of opiate users and also helped retain them in treatment, while cannabis users tended quickly to leave treatment, having done well or not. However, these figures relate only to patients who completed the forms at their six-month review, which in practice could have happened anywhere from about one to six months after their assessment for treatment. What proportion of primary cannabis users were still in treatment at that point and available to complete the forms is not clear, but they may have been the patients whose problems were deep seated enough to require extended treatment.

Enjoyable and trouble-free for many, but not without harms Harm reduction – the “set of practical strategies and ideas aimed at reducing negative consequences associated with drug use” – is mostly associated with ‘harder’ drugs like heroin, for which blood-borne viruses and drug-related deaths are clear and severe risks. Yet while “many people experience cannabis as enjoyable and trouble free”, there are also varying degrees of harm with this drug depending on the characteristics of the person using, the type of the cannabis, and the way they consume it. Many formal cannabis harm reduction programmes borrow from the fields of alcohol and tobacco. Advice includes:

• safer modes of administration (eg, on the use of vaporisers, on rolling safer joints, on less risky modes of inhaling) Many people experience cannabis as enjoyable and trouble free … some people require help to reduce or stop

• skills to prevent confrontation with those who disapprove of use

• encouraging users to moderate their use

 

• discouraging mixing cannabis with other drugs

• drug driving prevention and controls

• reducing third-party exposure to second-hand smoke

• education about spotting signs of problematic use

• self-screening for problematic use

In some parts of the UK, National Health Service tobacco smoking cessation services incorporated cannabis into their interventions with adults; and Health Scotland, also addressing the risks of tobacco and cannabis smoking, published a booklet for young people titled Fags ‘n’ Hash: the essential guide to cutting down the risks of using tobacco and cannabis.

Vaporising or swallowing cannabis offers a way to avoid respiratory risks, but only a minority of cannabis do this, most choosing to smoke cannabis joints (or cannabis and tobacco joints). While not all will know about the different health risks, cannabis users may choose against safer consumption methods anyway for a range of reasons (including their own thoughts about safe use):

• Users may find it easier to control the effects (eg, severity, length of effect) of cannabis when inhaling in the form of a joint or spliff

• Preparing and sharing joints can be an enjoyable part of the routine, or part of a person’s social activities

• Alternative methods of smoking (eg, bongs and vaporisers) may be inconvenient to use, or expensive to buy

 

Most harm reduction advice is delivered informally long before users come into contact with drugs professionals – for example through cannabis magazines, websites, and headshops – highlighting the importance of official sources engaging with non-official sources to promote the delivery of accurate, evidence-based harm reduction messages.

A new high

In May 2016 the Psychoactive Substances Act placed a ‘blanket ban’ on new psychoactive substances (previously known as ‘legal highs’), including synthetic cannabinoids (synthetic forms of cannabis). Prior to this, in 2014, there had been 163 reported deaths from new psychoactive substances in the UK, and 204 the year after. The average age was around 28, younger than the average age for other drug misuse deaths of around 38. The fact that these psychoactive substances – which produced similar effects to illicit drugs like cannabis, cocaine, and ecstasy – could be bought so easily online or on the high street, appeared inconsistent; and each fatality prompted “an outcry for something to be done to prevent further tragedies”. This was the context (and arguably the political trigger) for the introduction of the Psychoactive Substances Act. While possession of a psychoactive substance as such wasn’t criminalised;, production, supply, offer to supply, possession with intent to supply, import or export were – with a maximum penalty of seven years’ imprisonment.

Just seven months after the Act came into effect, the Home Office labelled it a success, with a press release stating that nearly 500 people had been arrested, 332 shops around the UK had been stopped from selling the substances, and four people had been sent to prison. But did the Psychoactive Substances Act have the presumably desired effect of limiting access to psychoactive substances (and reducing deaths), or did it just push the drugs the way of dealers? It is perhaps too early to tell, but former chair of the Advisory Council on the Misuse of Drugs Professor Nutt had warned before the Act came into effect that the ‘blanket ban’ would make it harder (not easier) to control drugs. And while Chief executive of DrugWise Harry Shapiro had said the new law would make new psychoactive substances harder to obtain, he also agreed that sale of the drugs would not cease, but merely be diverted to the illicit market: “The same people selling heroin and crack will simply add this to their repertoire.” The paper “From niche to stigma” examined the changing face of the new psychoactive substance user between 2009 and 2016, focusing on people using the synthetic cannabis known as ‘spice’. It looked at the transition of (then) ‘legal highs’ from an “experimental and recreational” scene associated with a “niche middle class demographic”, to “those with degrees of stigma”, especially homeless, prison, and socially vulnerable youth populations (including looked after children, those involved in or at risk of offending, and those excluded or at risk of exclusion from mainstream education). In 2014, the DrugScope Street Drug Survey also observed a problem among these particular groups, recording a “rapid rise in the use of synthetic cannabinoids such as Black Mamba and Exodus Damnation by opiate users, the street homeless, socially excluded teenagers and by people in prison”.

‘SPICE’ AND OTHER SYNTHETICS

Cannabis contains two key components:

• ‘THC’ (tetrahydrocannabinol), which produces the ‘high’

• ‘CBD’ (cannabidiol), which produces the sedative and anti-anxiety effects

Synthetic forms of cannabis contain chemicals that aim to copy the effects of ‘THC’ in cannabis. But the effects of synthetic cannabis can be quite different (and often stronger): firstly, because synthetic production makes it easier to manipulate the amount of the THC-like chemical; and secondly, because of the absence of the moderating equivalent of ‘CBD’. Some synthetics are purposely designed to resemble herbal cannabis, and can be consumed in the same ways (eg, smoked or inhaled). The names also often have deliberate cannabis connotations. The risk of this is that people wishing to take cannabis may be initially unaware that they have been sold the synthetic form, or may believe from the look of it that it will produce similar sought-after effects. The greater intensity of synthetic cannabis at lower dose levels ( box) ensures that it has an appeal in terms of potency and affordability, but may put those with fewer resources at greater harm.

In 2014, the prison inspectorate for England and Wales raised concerns about the rise in the use of psychoactive substances in prisons, in particular synthetic cannabis. A study set in an English adult male prison found that the nature of the market was posing significant challenges to the management of offenders. There, the primary motivation for consumption was being able to take a substance without it being detected. Given this motivation, and the greater likelihood of harms from synthetic versus natural cannabis, the researchers concluded that it was imperative for mandatory drug-testing policies to be revised, and instead rooted in harm reduction – something which would also apply to people on probation subject to mandatory drug-testing.

Cannabis throws up a range of issues rather different from those associated with the drugs treatment in the UK has normally focused on. If current trends continue, understanding the findings will become yet more important to British treatment services.

Source:   http://findings.org.uk/PHP/dl.php?file=cannabis_treat.    Last revised 10 July 2017. 

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers),Health,Intervention (including testing) (Papers) :

ABSTRACT

PURPOSE:

Nationwide data have been lacking on drug abuse (DA)-associated mortality. We do not know the degree to which this excess mortality results from the characteristics of drug-abusing individuals or from the effects of DA itself.

METHOD:

DA was assessed from medical, criminal, and prescribed drug registries. Relative pairs discordant for DA were obtained from the Multi-Generation and Twin Registers. Mortality was obtained from the Swedish Mortality registry.

RESULTS:

We examined all individuals born in Sweden 1955-1980 (n = 2,696,253), 75,061 of whom developed DA. The mortality hazard ratio (mHR) (95% CIs) for DA was 11.36 (95% CIs, 11.07-11.66), substantially higher in non-medical (18.15, 17.51-18.82) than medical causes (8.05, 7.77-8.35) and stronger in women (12.13, 11.52-12.77) than in men (11.14, 10.82-11.47). Comorbid smoking and alcohol use disorder explained only a small proportion of the excess DA-associated mortality.

Co-relative analyses demonstrated substantial familial confounding in the DA-mortality association with the strongest direct effects seen in middle and late-middle ages. The mHR was highest for opiate abusers (24.57, 23.46-25.73), followed by sedatives (14.19, 13.11-15.36), cocaine/stimulants (12.01, 11.36-12.69), and cannabis (10.93, 9.94-12.03).

CONCLUSION:

The association between registry-ascertained DA and premature mortality is very strong and results from both non-medical and medical causes. This excess mortality arises both indirectly-from characteristics of drug-abusing persons-and directly from the effects of DA. Excess mortality of opiate abuse was substantially higher than that observed for all other drug classes. These results have implications for interventions seeking to reduce the large burden of DA-associated premature mortality.

Source:  https://www.ncbi.nlm.nih.gov/pubmed/28550519   May 2017

Filed under: Effects of Drugs (Papers),Europe,Medical Studies :

HUNTINGTON, W.Va. — Officer Sean Brinegar arrived at the house first — “People are coming here and dying,” the 911 caller had said — and found a man and a woman panicking. Two people were dead inside, they told him.

Brinegar, 25, has been on the force in this Appalachian city for less than three years, but as heroin use has surged, he has seen more than his fair share of overdoses. So last Monday, he grabbed a double pack of naloxone from his gear bag and headed inside.

A man was on the dining room floor, his thin body bluish-purple and skin abscesses betraying a history of drug use. He was dead, Brinegar thought, so the officer turned his attention to the woman on a bed. He could see her chest rising but didn’t get a response when he dug his knuckle into her sternum.

Brinegar gave the woman a dose of injected naloxone, the antidote that can jumpstart the breathing of someone who has overdosed on opioids, and returned to the man. The man sat up in response to Brinegar’s knuckle in his sternum — he was alive after all — but started to pass out again. Brinegar gave him the second dose of naloxone.

Maybe on an average day, when this Ohio River city of about 50,000 people sees two or three overdoses, that would have been it. But on this day, the calls kept coming.

Two more heroin overdoses at that house, three people found in surrounding yards. Three overdoses at the nearby public housing complex, another two up the hill from the complex.

From about 3:30 p.m. to 7 p.m., 26 people overdosed in Huntington, half of them in and around the Marcum Terrace apartment complex. The barrage occupied all the ambulances in the city and more than a shift’s worth of police officers.

By the end of it, though, all 26 people were alive. Authorities attributed that success to the cooperation among local agencies and the sad reality that they are well-practiced at responding to overdoses. Many officials did not seem surprised by the concentrated spike.

“It was kind of like any other day, just more of it,” said Dr. Clay Young, an emergency medicine doctor at Cabell Huntington Hospital.

But tragic news was coming. Around 8 p.m., paramedics responded to a report of cardiac arrest. The man later died at the hospital, and only then were officials told he had overdosed. On Wednesday, authorities found a person dead of an overdose elsewhere in Cabell County and think the death could have happened Monday. They are investigating whether those overdoses are tied to the others, potentially making them Nos. 27 and 28.

It’s possible that the rash of overdoses was caused by a particularly powerful batch of heroin or that a dearth of the drug in the days beforehand weakened people’s tolerance. But police suspect the heroin here was mixed with fentanyl, a synthetic opioid that is many times more potent than heroin. A wave of fatal overdoses signaled fentanyl’s arrival in Huntington in early 2015, and now some stashes aren’t heroin laced with fentanyl, but “fentanyl laced with heroin,” said Police Chief Joe Ciccarelli. Another possibility is carfentanil, another synthetic opioid, this one used to sedate elephants. Police didn’t recover drugs from any of the overdoses, but toxicology tests from the deaths could provide answers.

A battle-scarred city

In some ways, what happened in Huntington was as unremarkable as the spurts in overdoses that have occurred in other cities. This year, fentanyl or carfentanil killed a dozen people in Sacramento, nine people in Florida, and 23 people in about a month in Akron, Ohio. The list of cities goes on: New Haven, Conn.; Columbus, Ohio; Barre, Vt.

But what happened in Huntington stands out in other ways. It underlines the potential of a mysterious substance to unleash wide-scale trauma and overwhelm a city’s emergency response. And it suggests that a community that is doing all the right things to combat a worsening scourge can still get knocked back by it.

“From a policy perspective, we’re throwing everything we know at the problem,” said Dr. James Becker, the vice dean for governmental affairs and health care policy at the medical school at Marshall University here. “And yet the problem is one of those that takes a long time to change, and probably isn’t going to change for quite a while.”

Surrounded by rolling hills packed with lush trees, Huntington is one of the many fronts in the fight against an opioid epidemic that is killing almost 30,000 Americans a year. But this city, state, and region are among the most battle-scarred. West Virginia has the highest rate of fatal drug overdoses of any state and the highest rate of babies born dependent on opioids among the 28 states that report data. But even compared with other communities in West Virginia, Huntington sees above-average rates of heroin use, overdose deaths, and drug-dependent newborns. Local officials estimate up to 10 percent of residents use opioids improperly.

The heroin problem emerged about five years ago when authorities around the country cracked down on “pill mills” that sent pain medications into communities; officials here specifically point to a 2011 Florida law that arrested the flow of pills into the Huntington area.

As the pills became harder to obtain and harder to abuse, people turned to heroin. It has devoured many communities in Appalachia and beyond.

In Huntington, law enforcement initially took the lead, with police arresting hundreds of people. They seized thousands of grams of heroin. But it wasn’t making a dent. So in November 2014, local leaders established an office of drug control policy.

“As far as numbers of arrests and seizures, we were ahead of the game, but our problem was getting worse,” said Jim Johnson, director of the office and a former Huntington police officer. “It became very obvious that if we did not work on the demand side just as hard as the supply side, we were never going to see any success.”

The office brought together law enforcement, health officials, community and faith leaders, and experts from Marshall to try to tackle the problem together.

Changes in state law have opened naloxone dissemination to the public and protected people who report overdoses. But the city and its partners have gone further, rolling out programs through the municipal court system to encourage people to seek treatment. One program is designed to help women who work as prostitutes to feed their addiction. Huntington has eight of the state’s 28 medically assisted detox beds, and they’re always full.

Also, in 2014, a center called Lily’s Place opened in Huntington to wean babies from drugs. Last year, the local health department launched this conservative state’s first syringe exchange. The county, health officials know, is at risk for outbreaks of HIV and hepatitis C because of shared needles, so they are trying to get ahead of crises seen in other communities afflicted by addiction.

“Huntington just happens to have taken ownership of the problem, and very courageously started some programs … that have been models for the rest of the state,” said Kenneth Burner, the West Virginia coordinator for the Appalachia High Intensity Drug Trafficking Areas program.

‘A revolving door’

While paramedics in the area have carried naloxone for years, it was this spring that Huntington police officers were equipped with it. Just a few officers have administered it, but Monday was Brinegar’s third time reviving overdose victims with naloxone.

Paramedics, who first try reviving victims by pumping air with a bag through a mask, had to administer another 10 doses of naloxone Monday. Three doses went to one person, said Gordon Merry, the director of Cabell County Emergency Services. During the response, ambulances from stations outside Huntington were called into the city to assist the eight or so response teams already deployed.

Merry was clearly proud of the response, but also frustrated. He was tired, he said, of people whom emergency crews revived going back to drugs. Because of the power of their disease, saving their lives didn’t get at the root of their addiction.

“It’s a revolving door. We’re not solving the problem past reviving them,” he said. “We gave 26 people another chance on life, and hopefully one of those 26 will seek help.”

In the part of town where half the overdoses happened, some homes are well-kept, with gardens, bird feeders, and American flags billowing. “Home Sweet Home,” read an engraved piece of wood above one front door; in another front yard, a wooden sculpture presented a bear holding a fish with “WELCOME” written across its body.

But many structures are decrepit and have their windows blacked out with cardboard and sheets. At one boarded-up house, the metal slats that once made up an overhang for the front porch split apart and warped as they collapsed, like gnarled teeth. On the plywood that covered a window frame was a message spelled out in green dots: GIRL SCOUTS RULE.

In and around the public housing complex, which is made up of squat two-story brick buildings sloping up a hill, people either said they did not know what had happened Monday, or that “lowlifes” in another part of the complex sparked the problem. Even as paramedics were responding to the overdoses, police started raiding residences as part of their investigation, including apartments at the complex, the chief said.

Just up the hill, a man named Bill was sitting on a recliner on his front porch with his cat. He said he saw the police out in the area Monday, but doesn’t pay much attention to overdoses anymore. They are so frequent.

Bill, who is retired, asked to be identified only by his first name because he said he has a son in law enforcement. He has lived in that house for five decades and started locking his door only in recent years. His neighbors’ house had been broken into, and he had seen people using drugs in cars across the street from his house. He called the police sometimes, he said, but the users were always gone by the time the police arrived.

“I hate to say this, but you know, I’d let them die,” Bill said. “If they knew that no one was going to revive them, maybe they wouldn’t overdose.”

Even here, where addiction had touched so many lives, it’s not an uncommon sentiment. Addiction is still viewed by some as a bad personal choice made by bad people.

“Some folks in the community just didn’t care” that 26 of their fellow residents almost died, said Matt Boggs, the executive director of Recovery Point.  Recovery Point is a long-term recovery program that teaches “clients” to live a life without drugs or alcohol. Boggs himself is a graduate of the program, funded by the state and donations and grants.

The clients live in bunk rooms at the facility for an average of more than seven months before graduating. The program says that about two-thirds of graduates stay sober in the first year after graduation, and about 85 percent of those people are sober after two years.

Local officials praise Recovery Point, but like many other recovery programs, it is limited in what it can do. It has 100 beds for men at its location in Huntington, and is expanding at other sites in the state, but Boggs said there’s a waiting list of a couple hundred people.

Mike Thomas, 30, graduated from the main part of the program a month ago and is working as a peer mentor there as he transitions out of the facility. Thomas has been clean since Oct. 15, 2015, but has dreams about getting high or catches himself thinking he could spare $100 from his bank account for drugs.

Thomas hopes to find a full-time job helping addicts. His own recovery will be a lifelong process, one that can be torn apart by a single bad decision, he said. He will always be in recovery, never recovered.    “I’m not cured,” he said.

 

A killer that doesn’t discriminate

As heroin has bled into communities across the country, it has spread beyond the regular drug hotbeds in cities. On a 2004 map of drug use in Huntington — back then, mostly crack cocaine — a few blocks of the city glow red. Almost the entire city glows in yellows and reds on the 2014 map.

In 2015, there were more than 700 drug overdose calls in Huntington, ranging from kids in their early teens to seniors in their late 70s. In 2014, it was 272 calls; in 2012, 146. One bright spot: fatal overdoses, which stood at 58 in 2015, have ticked down so far this year.

“I used to be able to say, ‘We need to focus here,’” said Scott Lemley, a criminal intelligence analyst at the police department. “I can’t do that anymore.”

Heroin hasn’t just dismantled geographic barriers. It has infiltrated every demographic “It doesn’t discriminate.   Prominent businessmen, their child. Police officers, their child. Doctors, their child,” Merry said. “The businessman and police officer do not have their child anymore.”

The businessman is Teddy Johnson. His son, Adam, died in 2007 when he was 22, one of a dozen people who died in a five-month period because of an influx of black-tar heroin. The drug hadn’t made its full resurgence into the region yet, but now, Johnson sees the drug that killed his son everywhere.

 

Teddy Johnson lost his son, Adam, in 2007 to a heroin overdose. He has several tattoos dedicated to Adam’s memory.  He runs a plumbing, heating, and kitchen fixture and remodelling business. From his storefront, he has witnessed deals across the street.

Adam, who was a student at Marshall, was a musician and artist who hosted radio shows. He was the life of any party, his dad said.

Johnson was describing Adam as he sat at the marble countertop of a model kitchen in his business last week. With the photos of his kids on the counter, it felt like a family’s home. Johnson explained how he still kept Adam’s bed made, how he kept his son’s room the same, and then he began to cry.

“The biggest star in the sky we say is Adam’s star,” he said. “When we’re in the car — and it can’t be this way — but it always seems to be in front of us, guiding us.”

Adam’s grave is at the top of a hill near the memorial to the 75 people — Marshall football players, staff, and fans — who died in a 1970 plane crash. It’s a beautiful spot that Johnson visits a few times each week, bringing flowers and cutting the grass around his son’s grave himself. Recently a note was left there from a couple Johnson knows who

just lost their son to an overdose; they were asking Adam to look out for their son in heaven.

But even here, at what should be a respite, Johnson can’t escape what took his son. He said he has seen deals happen in the cemetery, and he recently found a burnt spoon not more than 20 feet from his son’s grave.

Johnson keeps fresh flowers on his son’s grave and cuts the grass around the grave himself.

“I’ve just seen too much of it,” he said.

If Huntington doesn’t have a handle on heroin, at least the initiatives are helping officials understand the scale of the problem. More than 1,700 people have come through the syringe exchange since it opened, where they receive a medical assessment and learn about recovery options. The exchange is open one day a week, and in less than a year, it has distributed 150,000 clean syringes and received 125,000 used syringes.

But to grow and sustain its programs, Huntington needs money, officials say. The community has received federal grants, and state officials know they have a problem. But economic losses and the collapse of the coal industry that fueled the drug epidemic have also depleted state coffers.

“We have programs ready to launch, and we have no resources to launch them with,” said Dr. Michael Kilkenny, the physician director of the Cabell-Huntington Health Department. “We’re launching them without resources, because our people are dying, and we can’t tolerate that.”

In some ways, Huntington is fortunate. It has a university with medical and pharmacy schools enlisted to help, and a mayor’s office and police department collaborating with public health officials. But what does that herald then for other communities?

“If I feel anxious about what happens in Huntington and in Cabell County, I cannot imagine what it must be like to live in one of these other at-risk counties in the United States, where they don’t have all those resources, they don’t have people thinking about it,” said Dr. Kevin Yingling, the dean of the Marshall University School of Pharmacy.

Yingling, Kilkenny, and others were gathered on Friday afternoon to talk about the situation in Huntington, including the rash of overdoses. But by then, there was already a different incident to discuss.

A car had crashed into a tree earlier that afternoon in Huntington. A man in the driver seat and a woman in the passenger seat had both overdosed and needed naloxone to be revived. A preschool-age girl was in the back seat.

Source:    https://www.statnews.com/2016/08/22/heroin-huntington-west-virginia-overdoses/ 22.08.16

Filed under: Addiction (Papers),Effects of Drugs,Effects of Drugs (Papers),Political Sector,USA :

In this guest blog, Kate Fleming, Senior Lecturer, Public Health Institute, Liverpool John Moores University, and Raja Mukherjee, Consultant Psychiatrist, Lead Clinician UK National FASD clinic, Surrey and Borders Partnership NHS Foundation Trust consider the context and future for Foetal Alcohol Spectrum Disorders in the UK.

A recent opinion piece in The Guardian entitled Nothing prepared me for pregnancy- apart from the never ending hangover of my 20s took a, presumably, humorous take on the tiredness, vomiting, dehydration, and secrecy that so many women live through in early pregnancy, likening this to days spent hungover after excessive drinking in the author’s early 20s.

In an article that was entirely about alcohol and pregnancy there was reassuringly no mention of the author consuming alcohol during pregnancy, indeed quite the reverse “I don’t actually want booze in my body”.  But neither was there explicit reference to the harms that alcohol can cause in pregnancy.

The harms caused by consuming alcohol in pregnancy

Foetal Alcohol Spectrum Disorders (FASD) is an umbrella term that encompasses the broad range of conditions that are related to maternal alcohol consumption.  The most severe end of the spectrum is Foetal Alcohol Syndrome (FAS) associated with distinct facial characteristics, growth restriction and permanent brain damage.  However, the spectrum includes conditions displaying mental, behavioural and physical effects on a child which can be difficult to diagnose.  Confusingly, these conditions also go under several other names including Neuro-developmental Disorder associated with Prenatal Alcohol Exposure (ND-PAE) the preferred term by the American Psychiatric Association’s fifth version of its Diagnostic and Statistical Manual (APA DSM-V), alcohol-related birth defects, alcohol-related neuro-developmental disorder, and partial foetal alcohol syndrome.

How common is FASD? A recent study which brought together information from over 300 studies estimates the prevalence of drinking in pregnancy to be close to 10%, and around 1 in 4 women in Europe drinking during pregnancy. Their estimates of FAS (the most severe end of the spectrum) were 14.6 per 10000 people worldwide or 37.4 per 10000 people in Europe, corresponding to 1 child in every 67 women who drank being born with FAS.

Given the figure for alcohol consumption in pregnancy is even higher in the UK, with some studies suggesting up to 75% of women drink at some point in their pregnancy, conservatively in the UK we might expect a prevalence of FASD of at least 1%.  We also know that it is highly unlikely that anything close to this number of individuals have formally had a diagnosis.  This lack of knowledge of the prevalence in the UK is hampering efforts to ensure the required multi-sector support for those affected by FASD and their families.

Current policy

For some time a significant focus of alcohol in pregnancy research was to try and identify a safe threshold of consumption, without demonstrable success.  No evidence of harm at low levels does not however equate to evidence of no harm and as such in 2016 the Chief Medical Officer revised guidance on alcohol consumption in pregnancy to recommend that women should avoid alcohol when trying to conceive or when pregnant.  Though this clarity of guidelines has been well received by the overwhelming majority of health professionals there are barriers to its implementation with few professionals “very prepared to deal with the subject”.  In addition, knowledge of the guideline amongst the general public has yet to be evaluated.

As part of the 2011 public health responsibility deal a commitment to 80% of products having labels which include warnings about drinking when pregnant forms part of the alcohol pledges. A study in 2014 showed that 90% of all labels did indeed include this information. However, it has also been shown that this form of education is amongst the least effective in terms of alcohol interventions, and the pledge is no longer in effect.

Pregnancy is recognised as a good time for the initiation of behaviour change yet in the context of alcohol consumption it is arguably too late. An estimated half of all pregnancies are unplanned and there remains therefore a window of early pregnancy before a woman is likely to have had contact with a health professional and before the guidelines can be explained during which unintentional damage to her unborn baby could occur.  The same argument can be used when considering the suggestion of banning the sale of alcohol to pregnant women – visible identification of pregnancy tends only to be possible at the very latest stages.

How then to address consumption of alcohol during pregnancy? 

Consumption of alcohol is doubtless shaped by the culture and context of the society in which one is living.  Highest levels of alcohol consumption in pregnancy are, unsurprisingly, seen in countries where the population consumption of alcohol is also highest.  Current UK policy that is directed to reducing population consumption of alcohol will likely have a knock-on effect of reducing alcohol consumption in pregnancy.

Many women will however be familiar with the barrage of questions that they encounter when not drinking on a night out.  From the not-so-subtle “Not drinking, eh… Wonder why that is? <nudge, nudge, wink, wink>” to the more overt “Are you pregnant?”.  The road to conception and pregnancy is littered with enough stumbling blocks and pressures that the additional unintentional announcement of either fact of conception or intention to conceive is an unnecessary cause of potential further anxiety. Until society accepts that not drinking is an acceptable choice, without any need for clarification or explanation, then pregnant women or those hoping to conceive who are adhering to guidelines will continue to identify themselves, perhaps before they want to.

What next?

The UK’s All Party Parliamentary Group for FASD had its inaugural meeting in June 2015.  This group calls for an increased awareness of FASD particularly regarding looked

after children and individuals within the criminal justice system, sectors where the prevalence of FASD is particularly high. Concerted efforts need to be made to identify children with FASD to ensure that the appropriate support pathways are in place. Alongside this, efforts to ensure the best mechanisms for education of the dangers of alcohol consumption in pregnancy need to be increased, including training for midwives, and other health professionals who may be able to offer brief intervention and advice to women both before and after conception.

The views expressed by the authors are theirs alone and do not represent the views of Liverpool John Moores University, the UK National FASD clinic at Surrey and Borders Partnership NHS Foundation Trust. NOFAS run a national FASD helpline on on 020 8458 5951 as do the FASD Trust on 01608 811 599.

Source:  http://www.alcoholpolicy.net/2017/05/drinking-in-pregnancy-where-next-for-fasd-in-the-uk.html

Filed under: Alcohol,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Health :

In Southern Ohio, the number of drug-exposed babies in child protection custody has jumped over 200%.  The problem is so dire that workers agreed to break protocol to invite a reporter to hear their stories.  Foster care placements are at record levels, and the number of drug-exposed newborns in their custody has jumped over 200% in the past decade

Inside the Clinton County child protection office, the week has been tougher than most.

Caseworkers in this thinly populated region of southern Ohio, east of Cincinnati, have grown battle-weary from an opioid epidemic that’s leaving behind a generation of traumatized children. Drugs now account for nearly 80% of their cases. Foster-care placements are at record levels, and the number of drug-exposed newborns in their custody has jumped over 200% in the past decade. Funding, meanwhile, hasn’t budged in years.

“Many of our children have experienced such high levels of trauma that they can’t go into traditional foster homes,” said Kathi Spirk, director of Clinton County job and family services. “They need more specialized care, which is very expensive.”

The problem is so dire that workers agreed to break protocol and invite a reporter to camp out in a conference room and hear their stories. For three days, they relived their worst cases and unloaded their frustrations, in scenes that played out like marathon group therapy, for which they have no time. Many agreed that talking about it only made them feel worse, yet still they continued, one after another.

Hence the bad week.

Given the small size of their community, they asked that their names be changed out of concern for their own safety and the privacy of the children.

The caseworkers, like most, are seasoned in despair. Many worked in the 1990s when crack cocaine first arrived, followed by crystal meth in the early 2000s. In 2008, after the shipping giant DHL shuttered its domestic hub here in Wilmington and shed more than 7,000 jobs, prescription pill mills flourished while the economy staggered. Back then, a typical month saw 30 open cases, only a few of them drug-related. But the flood of cheap heroin and fentanyl, now at its highest point yet, has changed everything. A typical month now brings four times as many cases, while institutional knowledge has been flipped on its head.

“At least with meth and cocaine, there was a fight,” said Laura, a supervisor with over 20 years of experience. “Parents used to challenge you to not take their kids. And now you have them say: ‘Here’s their stuff. Here’s their formula and clothes.’ They’re just done. They’re not going to fight you any more.”

Heroin has changed how they approach every step of their jobs, they said, from the first intake calls to that painstaking decision to place a child into temporary foster care or permanent custody. Intake workers now fear what used to be routine.

“Occasionally, we’d get thrown a dirty house, something easy to close and with little trauma to the child,” said Leslie, another worker. “We’re not getting those any more.

Now they’re all serious, and most of them have a drug component. So you may get a dirty house, but it’s never just a dirty house.”

‘I had a four-year old whose mom had died in front of her and she described it like it was nothing’ Children come into the system in two ways. The first is through a court order after caseworkers deem their environment unsafe, and if no friends or family can be found.

Because of the added trauma, removing a child is always the last option, caseworkers said. But in a county with only 42,000 people spread out over 400 square miles, the magnitude of the epidemic has compromised an already delicate safety net. Relatives are overwhelmed financially. Multiple generations are now addicted, along with cousins, uncles, and neighbors. In many cases, a safe house with a grandparent or other relative will eventually attract drug activity.

Law enforcement will also bring children in, usually after parents overdose. These cases often reveal the most horrendous neglect: a three-year old who needed every tooth pulled because he’d never been made to brush them, or kids found sleeping on bug-infested mattresses, going to the toilet in buckets because the water had been shut off. Children are coming in more hardened, they said, older than their years.

“I had a four-year-old whose mom had died in front of her and she described it like it was nothing,” said Bridgette, another caseworker. “She knew how to roll up a dollar bill and snort white powder off the counter. That’s what she thought dollar bills were for.” She added that many of the children could detail how to cook heroin. One foster family had a five-year-old boy who put his medicine dropper in his shoe. “Because that’s where daddy hid his needles,” she said.

“The kids are used to surviving in that mess,” added Carole, another veteran. “Now all the sudden the system is going in and saying it’s not safe. All their survival instincts are taken away and they go ballistic. They don’t know what to do.”

During the first weeks of foster care, meltdowns, tantrums, and violence are common as children navigate new landscapes and begin to process what they’ve experienced.

One afternoon, the caseworkers brought in a foster couple who’d taken in two sisters, an infant born drug-exposed, and her four-year old sister. The baby had to be weaned off opioids and now suffered chronic respiratory problems. Part of her withdrawal had included non-stop hiccups. The older girl had lived with her parents in a drug house and displayed clear signs of post-traumatic stress. Once, a family friend sitting next to her in a car had overdosed and turned purple. She’d witnessed domestic abuse, and one day a neighbor shot and killed her dog while she watched (she’d let the dog out). After a meltdown at a classmate’s pool party, over a year after entering foster care, she revealed having seen a toddler drown in a pond while adults got high. Through therapy, she’d also revealed sexual assault. The foster mother described how the girl suffered flashbacks, triggered by stress and certain anniversaries, like the day of her removal, and other seemingly random events. When this happened, she slipped into catatonic seizures.

“Her eyes are closed and you can’t wake her,” she said. “It’s like narcolepsy, a deep, unconscious sleep. We later discovered it was a coping mechanism she’d developed in order to survive.”

Despite what they’ve endured, most children wish desperately to return to their parents. Many come to see themselves as their parents’ caretakers and feel guilty for being taken away, especially if they were the ones to report an overdose, as in the case of a four-year-old girl who climbed out of a window to alert a neighbor. “She asked me: if I took her away, who was going to take care of mommy?” Bridgette remembered.

For caseworkers, reunification is the endgame. After children enter temporary foster care, the agency spends up to two years working closely with the family while the parents try to stay sober. The only contact with their children comes in the form of twice-weekly visits held in designated rooms here at the office. Each contains a tattered sofa and some second-hand toys. Currently, the agency runs about 200 visits each week. The encounters are monitored through closed-circuit cameras. For everyone involved, it can be the most trying period.

Many parents use the time to build trust and re-establish bonds. “During those first four years, a child gets such good stuff from their parents,” said Sherry, the caseworker who monitors the visits. “The kids are just trying to get that back.” Some parents bring doughnuts and pictures, while others need more guidance. Caseworkers hold parenting classes. Some moms lost newborns at the hospital after they tested positive for drugs; workers teach them how to feed and hold the child, and encourage them to bring outfits to dress their babies.

For other children, the visits trigger a storm of emotion that churns up the trauma of removal. “We had one girl who’d scream and wail at the end of every visit,” Laura, the supervisor, remembered. “Each time she thought she’d never see her mother again. We’d have to pry her out of mom’s arms and carry her down the hallway.”

“We’d sit in our offices and just sob,” added another worker. “But that girl’s cries weren’t enough to keep Mom off heroin.”

The number of available foster families is dwindling, while the cost of supporting them has never been higher

Perhaps the greatest difference with heroin and opioids, caseworkers said, is their iron grasp. Staying sober is a herculean task, especially in this rural community short on resources, where the nearest treatment facilities are over 30 miles away in Dayton, Cincinnati, or Columbus. At some point, nearly every parent falls off the wagon. They disappear and miss visits, leaving children to wait. One of the hardest parts of the job is telling a child that mom or dad isn’t coming, or that they can’t even be found.

“You see the hurt in their eyes,” Sherry said. “It’s a look of defeat, and it just breaks your heart.” She remembered a mother who’d failed to show up for months, then made it for her twin boys’ birthday. “The next day she overdosed and died.”

A tally sheet is used to track how many times prospective clients waiting to enter the program call a detox center, in Huntington, West Virginia. Photograph: Brendan Smialowski/AFP/Getty Images

When parents fail drug screenings during the 18-month period, caseworkers use discretion. Parents might be doing better in other areas like landing a job, or finding secure housing, so workers help them to get back on the wagon. “It’s all about showing progress,” Laura said. Some parents make it 16, 17 months sober and fully engaged. “And they’re the toughest cases, because we’ve been rooting for them this whole time and helping them. We’re giving kids pep talks, saying: ‘Mom’s doing great, she’s getting it together!’ They’re so happy to be going home. And then it all falls apart.”

With heroin, defeat is something the workers have learned to reckon with. Lately they’ve started snapping photos of parents and children during their first visit together, getting medical histories and other vital information – something they used to do much later. “Because we know the parents probably aren’t going to make it,” Laura admitted. “And if we never see them again, this is the info we need.” When asked how many opioid cases had ended in reunification, only two workers raised their hands.

The repeated disappointments come as resources and morale have reached their tipping point. The number of available foster families is dwindling, they said, while the cost of supporting them – over $1.5m a year – has never been higher.

Spirk, the agency’s director, said that all the agency’s budget was paid for with federal dollars and a county tax levy, although they’ve been flat-funded for nearly 10 years. The state contributes just 10%. When it comes to investing in child protection, Ohio ranks last in the country – despite having spent nearly $1bn fighting its opioid problem in 2016 alone.

The Ohio house of representatives recently passed a new state budget with an additional $15m for child protective services, but the state senate has yet to pass its own version. The only bit of hope came in March, when the Ohio attorney general’s office announced a pilot program that will give Clinton County, along with others, additional resources to help treat children for trauma, and to assist with drug treatment. It starts in October.

The epidemic’s unrelenting barrage has also taken a toll on mental health. “Our caseworkers are experiencing secondary trauma and frustration at not being able to reunify children with their parents because of relapses,” Spirk said.

Almost every caseworker said they had experienced depression or some form of PTSD, although no one had sought professional help. The privacy of their cases also means that few can speak openly with friends or family members. Some chose to drink, while others leaned on their faiths. But most said coping mechanisms they once relied on had failed.

“I used to have a routine on my drive home,” Laura said. “I’d stop in front of a church, roll down my window, and throw out all the day’s problems. The next morning I’d pick them back up. These days, I can’t do that anymore.”

“There’s no more outlet,” added Shelly, another supervisor. “You think you’re able to separate but you can’t let it go anymore. You try to eat healthy, do yoga, whatever they tell you to do. But it’s just so horrific now, and it keeps getting worse.”

At some point, the inevitable happens. When a parent can’t stay sober, or stops showing progress, the decision is made to place the child into permanent custody and put them up for adoption. For everyone, including caseworkers, it’s the most wrenching day.

The final act of every case is the “goodbye visit”, held in one of the nicer conference rooms. It’s a chance for parents to let their children know they love them and will miss them, and that it’s time to move on. Adoptive parents can choose to stay in contact, but it isn’t mandatory.

To make the time less stressful, Sherry, the worker who monitors the visits, has them draw pictures together, which she scans and gives to them as mementoes. She also tapes the meetings for them to keep. Watching from her tiny room full of TV screens, she can’t help but cry. “What people don’t realize is that when a baby comes into our custody, they’re still in a carrier seat. By the time the case is over, we’ve helped to potty train them. Two years is a very long time with a child. So in a way, it’s like my goodbye visit, too.”

Caseworkers have started making “life books” for kids once they come into the system. It’s where they put the photos they’ve taken, plus any pictures of birth parents or relatives they can find, report cards, ribbons and medals – the souvenirs of any childhood.  “It’s their history,” Sherry said, “so that one day they can make sense of their lives.”   She noted that one kid, after turning 18, tore his to pieces, taking with him only the good memories.

Source:  https://www.theguardian.com/us-news/2017/may/17/ohio-drugs-child-protection-workers

Filed under: Addiction,Addiction (Papers),Drug use-various effects on foetus, babies, children and youth,Effects of Drugs,Effects of Drugs (Papers),Social Affairs,Social Affairs (Papers),USA :

Abstract

Childhood maltreatment increases the risk of subsequent depression, anxiety and alcohol abuse, but the rate of resilient victims is unknown. Here, we investigated the rate of victims that do not suffer from clinical levels of these problems after severe maltreatment in a population-based sample of 10980 adult participants.

Compared to men, women reported more severe emotional and sexual abuse, as well as more severe emotional neglect. For both genders, severe emotional abuse (OR = 3.80 [2.22, 6.52]); severe physical abuse (OR = 3.97 [1.72, 9.16]); severe emotional neglect (OR = 3.36 [1.73, 6.54]); and severe physical neglect (OR = 11.90 [2.66, 53.22]) were associated with depression and anxiety while only severe physical abuse (OR = 3.40 [1.28, 9.03]) was associated with alcohol abuse.

Looking at men and women separately, severe emotional abuse (OR = 6.05 [1.62, 22.60] in men; OR = 3.74 [2.06, 6.81] in women) and severe physical abuse (OR = 6.05 [1.62, 22.60] in men; OR = 3.03 [0.99, 9.33] in women) were associated with clinical levels of depression and anxiety. In addition, in women, severe sexual abuse (OR = 2.40 [1.10, 5.21]), emotional neglect (OR = 4.78 [2.40, 9.56]), and severe physical neglect (OR = 9.86 [1.99, 48.93]) were associated with clinical levels of depression and anxiety.

Severe emotional abuse in men (OR = 3.86 [0.96, 15.48]) and severe physical abuse in women (OR = 5.18 [1.48, 18.12]) were associated with alcohol abuse. Concerning resilience, the majority of severely maltreated participants did not report clinically significant levels of depression or anxiety (72%), or alcohol abuse (93%) in adulthood. Although the majority of severely abused or neglected individuals did not show clinical levels of depression, anxiety or alcohol use, severe childhood maltreatment increased the risk for showing clinical levels of psychopathology in adulthood.

Introduction

Severe child maltreatment is conventionally defined within child protection practice as severe physical, emotional, sexual abuse and/or severe physical and emotional neglect by adults [1]. Severity can be defined on the basis of the type of maltreatment, its frequency, if the child was subjected to multiple forms of maltreatment, if a weapon had been used, if the maltreatment resulted in an injury, and if the abuse was considered severe by the victim. For sexual abuse, even a single experience is often considered to be severe [1].

Childhood maltreatment and its psychosocial consequences

There are annually over one million victims of childhood maltreatment in the USA alone and childhood maltreatment has a large public health impact [2]. Several studies show that childhood physical, emotional, and sexual abuse are all related to an increased risk of depression and anxiety disorders in adulthood [3–9]. Other studies have found that the severity of abuse and neglect is associated with increased depression and anxiety symptoms in adulthood [10–12]. This means that as a general rule, the more severe the abuse and neglect, the more likely the abused individuals are to show symptoms of depression and anxiety.

There is also a robust relationship between childhood maltreatment and later alcohol abuse [13–16]. For example, Young-Wolff et al. [17] found that men who had experienced childhood maltreatment were 1.7 times more likely to suffer from alcohol abuse in adulthood than men who did not report experiences of childhood maltreatment. Similar findings have been made when investigating the consequences of abuse and neglect in women (e.g., [18]). Findings from a study by Schwandt et al. [19] suggested that the severity of emotional and physical abuse plays a prominent role in the development of alcohol abuse. In line with these results suggesting a role of the severity of childhood abuse on later substance misuse, Hyman et al. [20] found that the severity of abuse was predictive of cocaine use after having been discharged from an inpatient treatment for cocaine addiction.  This was true for women but not for men. Kendler et al. [21] showed that women who had experienced child sexual abuse reported higher incidences of alcohol abuse. Twin studies have also shown that childhood sexual abuse increases the risk of alcohol abuse and addiction later in life [21–24]. To summarize, there is a strong, robust relationship between childhood maltreatment and mental disorders in adulthood. These associations include associations between childhood experiences of physical abuse, emotional abuse, and neglect, respectively, and mental disorders such as depression and anxiety disorders, and alcohol abuse [25–26]. Moreover, multi-type maltreatment in childhood is associated with greater impairment in adulthood, and this association also includes a range of psychological and behavioral problems, such as depression, anxiety, and alcohol abuse [27].

However, not all victims of childhood maltreatment develop symptoms of substance abuse or psychopathology in adulthood. Meta-analyses suggest that many (but not all) children who have experienced abuse succeed in overcoming some of the possible negative outcomes [28]. For example, Klika and Herrenkohl [28] found that some individuals who have experiences of abuse in childhood do not suffer long-term negative sequelae. Collishaw et al. [29] reported that despite serious experiences of childhood sexual or physical abuse, some individuals did not develop psychiatric problems during adulthood. Moreover, Hamilton et al. [30] reported that emotional neglect did not significantly predict increases in depressive or anxiety symptoms later in life. It has been estimated that 12–22% of maltreated individuals are functioning well despite experiencing childhood maltreatment [31].

The current study

Several studies have focused on only experiencing one type of maltreatment (e.g., sexual abuse) or one type of outcome (e.g., depression). Moreover, most previous studies have relied on either convenience samples or samples from health care services, and especially samples of the latter kind might bias the results and show less resilience than is actually the case.

In the present study, we used a large, population-based sample of Finnish men and women. The types of maltreatment included emotional, physical, and sexual abuse as well as emotional and physical neglect.   Thus, the aims of the present study were to:

1. Investigate gender differences in severe experiences of different types of childhood abuse;

2. Compare if and how individuals reporting severe experiences of different types of childhood abuse differ from individuals who did not report experiencing childhood abuse, in terms of presence of clinically significant symptoms of depression and anxiety in adulthood; and

3. Compare if and how individuals reporting severe experiences of different types of childhood abuse differ from individuals who did not report experiencing childhood abuse in terms of presence of alcohol abuse symptoms in adulthood.

Results

Descriptive results

The proportion of participants with severe experiences of emotional abuse was 0.6% (n = 64). The corresponding proportion for severe experiences of physical abuse was 0.2% (n = 26) while the proportions for severe experiences of sexual abuse was 0.4% (n = 43). For severe experiences of emotional neglect, the proportion was 0.4% (n = 44) and for severe experiences of physical neglect 0.1% (n = 7).  With regard to gender differences in the different types of severe experiences of abuse, Table 2 shows that there were statistically significant differences between men and women in the proportion of individuals with severe experiences of emotional abuse, sexual abuse and emotional neglect. All of these were more prevalent in women. There were no statistical differences between men and women in terms of having severe experiences of physical abuse and physical neglect.

We then investigated whether the proportion of individuals having clinical levels of depression and anxiety was higher in individuals with severe experiences of abuse and neglect compared to individuals with less severe (or no) experiences of abuse and neglect. Table 3 shows that, for both genders, severe experiences of emotional and physical abuse and emotional and physical neglect increased the likelihood of suffering from clinical depression or anxiety compared to less severe experiences of the said forms of childhood maltreatment.

In men, severe abuse experiences were significantly associated with increases in the prevalence of clinical depression or anxiety when it came to experiences of severe emotional and physical abuse and physical neglect. No association was observed for severe sexual abuse and severe emotional neglect. For women, severe experiences of all childhood maltreatment types increased the likelihood of suffering from clinical depression or anxiety compared to other lower experiences of maltreatment.

Next, we explored the proportions of both men and women who were resilient to severe experiences of childhood maltreatment with regards to not suffering from clinical levels of depression or anxiety in adulthood. Depending on the abuse type, 55.6% to 100% of men with experiences of severe abuse did not show clinically significant levels of depression or anxiety. For women, 50% to 80.5% did not show clinically significant levels of depression or anxiety.

Discussion

The present study investigated five types of maltreatment: emotional, physical and sexual abuse, and physical and emotional neglect; and their relationships to depression, anxiety and alcohol abuse. The study used a population-based sample of 10980 participants and used validated measures of experiences of childhood maltreatment, current depression and anxiety, and current alcohol abuse.

More particularly, our aim was to investigate gender differences in victims of severe childhood maltreatment, as well as to compare if and how individuals reporting severe experiences of different types of childhood abuse differ from individuals without such severe experiences in terms of presence of clinically significant symptoms of depression, anxiety and alcohol abuse in adulthood.

The present study found that women reported more childhood experiences of severe emotional, sexual abuse and emotional neglect than men. Our findings are inconsistent with the results of those of previous studies indicating that men reported more childhood experiences of abuse than women [3, 38]. However, our results are consistent with findings suggesting that women are more sensitive than men to the effects of experiences abuse in childhood [29].

Compared to another Finnish population based sample, the frequencies of severe abuse were relatively low in our sample. This could be due to samples being obtained at different times, as abuse in Finland has been decreasing [39], or that in the present study the complete CTQ was used: in the study by Albrecht’s et al. [33], only one item per factor was used. The decrease in measurement reliability that follows from removing 80% of the original items might have inflated the estimates in Albrecht’s study [33].

More specifically, our results revealed that, in men, severe experiences of emotional and physical abuse as well as physical neglect were significantly associated with increases in the prevalence of depression and anxiety symptoms. For women, there was an association between all types of severe childhood maltreatment (emotional, physical and sexual abuse, and physical and emotional neglect) with depression and anxiety symptoms in adulthood.

These results were consistent with previous literature indicating that physical abuse and/or emotional abuse are related to depression and anxiety disorders [4–5, 40–41]. These findings also corroborate findings from meta-analyses and extend previous reports of severe experiences of abuse or neglect being associated with greater risk of developing depressive and anxiety disorders in adulthood [26].

When we examined each type of maltreatment for associations with alcohol abuse, the results showed that severe emotional abuse was associated with alcohol abuse in men. For women, severe physical abuse emerged as a predictor for problematic alcohol use. This is consistent with research suggesting that childhood experiences of emotional and physical abuse were found to be the primary predictor of alcohol abuse [19, 42].

It is intriguing, however, that there appears to be a gender difference in response to abuse type, with men having a considerably more severe response to emotional abuse in terms of propensity to develop alcoholism later in life. For example, an explanation for why women appear to suffer greater consequences in terms of abusing alcohol later in life could be that boys are more likely to engage in rough-and-tumble play and play fights [43], and are thus desensitized to physical abuse to a higher extent than women. It is also, however, possible that measurement invariance could explain the perceived gender differences.

Our current findings suggest that, fortunately, more than half of the participants who have severe experiences of abuse and neglect in childhood seem to succeed in overcoming some of the possible consequences with regards to depression and anxiety symptoms and alcohol abuse in adulthood. While the present study did not investigate mediators of resilience, many studies have considered successful psychosocial adjustment as a mediator of psychological resilience following adverse events [44–45]. It should also be mentioned that some individuals likely have heritable factors that have been shown to protect against adverse effects of maltreatment, by means of gene–environment interaction (i.e., the concept that individuals respond differently to environmental stressors depending on their genotype) [46].

Limitations of the research

Despite the strengths of the present study, it is also characterized by some limitations worth mentioning. First, memories are usually influenced by later experiences, and since the questionnaire was about events that happened during childhood, the obtained information might be somewhat biased. Second, we did not consider the possible overlap between experiences of maltreatment types. Because experiencing one type of abuse or form of neglect is associated with experiencing also another type of abuse or form of neglect [10, 47], it is possible that also severe forms of abuse and neglect are correlated across types or maltreatment. This could, for example, mean that several of the individuals with clinical cases of depression and anxiety or alcohol abuse, not only had experienced one form of severe abuse, but several. Should this be the case, the additive effect of multiple types of abuse could influence the results.

In the present study, it is possible that the true prevalence of anxiety, depressive symptoms or alcohol abuse has been underestimated, as we have only one cross-sectional assessment of the above mentioned indicators (i.e., some individuals may have experienced clinically significant symptoms before study participation, or may experience symptoms in the future, but did not do so at the time of assessment). A longitudinal assessment of adulthood symptoms would thus arguable have been more appropriate than a single, cross-sectional measure.

Also, some of our results and group comparisons were based on very few individuals. This might both influence the estimated prevalence of depression and anxiety or problematic alcohol use and undermines the statistical power to detect differences. Finally, we only included three known consequences of experiencing childhood maltreatment: Depression and anxiety and problematic alcohol use. It is possible that individuals showing resilience on these possible consequences of maltreatment are not resilient with respect to other negative outcomes, such as social functioning or health-risk behavior.

Conclusions  

To our knowledge, this is the first study that has looked at the effects of severe experiences of abuse in childhood on depression and anxiety symptoms and alcohol abuse in adulthood in a relatively large sample.

We found that a majority of individuals with severe experiences of childhood maltreatment did not meet the criteria for clinical of levels depression and anxiety or clinical significant levels of alcohol abuse. Although this is a positive message, it is important to remember that experiences of child maltreatment increase the risk of psychosocial problems in adulthood and several of the victims of severe maltreatment included in our study may have had increased, but non-clinical significant levels of depression, anxiety, and alcohol abuse.

Source: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177252

Filed under: Alcohol,Effects of Drugs (Papers),Social Affairs (Papers) :

Kuei Y. Tseng was awarded $1.95 million by NIH for a five-year study of “Adolescent Maturation of the Prefrontal Cortex: Modulation by Cannabinoids.” Regular marijuana use by teens can stop the brain from maturing, according to a new study by scientists at Rosalind Franklin University of Medicine and Science, North Chicago, IL. Published March 4 in the journal Molecular Psychiatry, the study is the first to establish a causal link between repeated cannabinoid exposure during adolescence and an interruption of the normal maturation processes in the prefrontal cortex, a region in the brain’s frontal lobe, which regulates decision making and working memory and undergoes critical development during adolescence.

The findings apply to natural cannabinoids, including those in marijuana, and a new generation of more potent, synthetic cannabinoid products. THC, the compound in marijuana that produces feelings of euphoria, is of particular concern. The chemical can be manipulated, resulting in varying concentrations between marijuana strains – from 2 to 28 percent. A higher concentration of THC and increasing use by younger teens poses a greater risk for long term negative effects, the study finds. Kuei Y. Tseng, MD, PhD, associate professor of cellular and molecular pharmacology at the Chicago Medical School at RFUMS and principal investigator of the study, blames the CB1 cannabinoid receptor, which governs neuronal communication, for the drug’s long -lasting effect.

Tseng and his team of researchers used rat models in testing the effect of cannabinoid exposure during narrow age windows and analyzed the way information is later processed by the adult prefrontal cortex. They discovered that when CB1 receptors are repeatedly activated by cannabinoids during early adolescence, development of the prefrontal cortex stalls in that phase. The window of vulnerability represents two thirds of the span of adolescence. Test animals showed no such effect when exposure occurred in late adolescence or adulthood.

“We have conclusively demonstrated that an over activation of the CB1 receptor during the window equivalent to age 11 to 17 in humans, when the prefrontal cortex is still developing, will inhibit its maturation and have a long lasting effect on its functions,” Tseng said.

The study shows how chronic cannabis use by teens can cause persistent behavioral deficits in adulthood, including problems with attention span and impulse control. The findings also add to prior research that draws a correlation between adolescent marijuana abuse and the development of schizophrenia.

The discovery, which comes as a growing number of states are considering legalization of marijuana for both medicinal and recreational use, calls for the attention of physicians who prescribe medical marijuana and policy makers who, according to Tseng, “will have to establish regulations to take advantage of the beneficial effects of marijuana while minimizing its detrimental potential.”

Researchers are focusing on developing outcome measures to reveal the degree of frontal lobe maturation and history of drug exposure. The challenge now, Tseng said, is to find ways to return the frontal lobe back to a normal state either through pharmacological or cognitive interventions.

“Future research will tell us what other mechanisms can be triggered to avoid this type of impairment of the frontal lobe,” Tseng said. “Ultimately, we want to restore the prefrontal cortex.”

Supported by RFUMS, the research was funded primarily through NIH Grant R01-MH086507 to Tseng and also by a 2012 seed grant from the Brain Research Foundation.

Source:  https://www.rosalindfranklin.edu/news/profiles/study-shows-marijuana-use-interrupts-adolescent-brain-development/   4th March 2017

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Youth :

Chairman Murphy, Ranking Member DeGette, and Members of the Committee: thank you for inviting the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH), to participate in this important hearing to provide an overview of what we know about the role of fentanyl in the ongoing opioid overdose epidemic and how scientific research can help us address this crisis.

The misuse of and addiction to opioids – including prescription pain medicines, heroin, and synthetic opioids such as fentanyl – is a serious national problem that affects public health as well as social and economic welfare.  The Centers for Disease Control and Prevention (CDC) recently estimated that the total “economic burden” of prescription opioid misuse alone in the United States is $78.5 billion a year, including the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.1  In 2015, over 33,000 Americans died as a result of an opioid overdose.2  That year, an estimated 2 million people in the United States suffered from substance use disorders related to prescription opioid pain medicines (including fentanyl), and 591,000 suffered from a heroin use disorder (not mutually exclusive).3

This issue has become a public health epidemic with devastating consequences including not just increases in opioid abuse and related fatalities from overdoses, but also the rising incidence of neonatal abstinence syndrome due to opioid use during pregnancy, and the increased spread of infectious diseases, including HIV and hepatitis C.4-6  Recent research has also found a significant increase in mid-life mortality in the United States particularly among white Americans with less education.  Increasing death rates from drug and alcohol poisonings are believed to have played a significant role in this change.7

The Pharmacology of Fentanyl and Other Synthetic Opioids

Prescription opioids, heroin, and synthetic opioid drugs all work through the same mechanism of action.  Opioids reduce the perception of pain by binding to opioid receptors, which are found on cells in the brain and in other organs in the body.  The binding of these drugs to opioid receptors in reward regions in the brain produces a sense of well-being, while stimulation of opioid receptors in deeper brain regions results in drowsiness and respiratory depression, which can lead to overdose deaths.  The presence of opioid receptors in other tissues can lead to side effects such as constipation and cardiac arrhythmias through the same mechanisms that support the use of opioid medications to treat diarrhea and to reduce blood pressure after a heart attack.  The effects of opioids typically are mediated by specific subtypes of opioid receptors (mu, delta, and kappa) that are activated by the body’s own (endogenous) opioid chemicals (endorphins, enkephalins).  With repeated administration of opioid drugs (prescription or illicit), the production of endogenous opioids decreases, which accounts in part for the discomfort that ensues when the drugs are discontinued (i.e., withdrawal).8

The rewarding effects of opioids – whether they are medications, heroin, or illicitly produced synthetic opioids – are increased when they are delivered rapidly into the brain, which is why non-medical users often inject them directly into the bloodstream.9 Fentanyl, in particular, is highly fat-soluble, which allows it to rapidly enter the brain, leading to a fast onset of effects. This high potency and rapid onset are likely to increase the risk for both addiction and overdose, as well as withdrawal symptoms.10  In addition, injection use increases the risk for infections and infectious diseases.  Another important property of opioid drugs is their tendency, when used repeatedly over time, to induce tolerance.  Tolerance occurs when the person no longer responds to the drug as strongly as he or she initially did, thus necessitating a higher dose to achieve the same effect.  The establishment of tolerance results from the desensitization of the brain’s natural opioid system, making it less responsive over time.11  Furthermore, the lack of sufficient tolerance contributes to the high risk of overdose during a relapse to opioid use after a period of abstinence whether it is intentional – for example, when a person tries to quit using – or situational – for example, if a person cannot obtain opioid drugs while incarcerated or hospitalized.  Users no longer know what dose of the drug they can safely tolerate, resulting in overdoses.

While all of these opioids belong to a single class of drugs, each is associated with distinct risks. The risk of overdose and negative consequences is generally greater with illicit opioids due to the lack of control over the purity of the drug and its potential adulteration with other drugs.  All of these factors increase the risk for overdose, since users have no way of assessing the potency of the drug before taking it.  In the case of adulteration with highly potent opioids such as fentanyl or carfentanil, this can be particularly deadly.12-14  Another contributing factor to the risk of opioid-related mortality is the combined use with benzodiazepines or other respiratory depressants, like some sleeping pills or alcohol.15

The Role of Fentanyl in the Opioid Crisis

The emergence of illicitly manufactured synthetic opioids including fentanyl, carfentanil, and their analogues represents an escalation of the ongoing opioid overdose epidemic.  Fentanyl is a µ-opioid receptor agonist that is 80 times more potent than morphine in vivo. While fentanyl is available as a prescription – primarily used for anesthesia, treating post-surgical pain, and for the management of pain in opioid-tolerant patients – it is the illicitly manufactured versions that have been largely responsible for the tripling of overdose deaths related to synthetic opioids in just two years – from 3,105 in 2013 to 9,580 in 2015.2  A variety of fentanyl analogues and synthetic opioids are also included in these numbers, such as carfentanil (approximately 10,000 times more potent than morphine), acetyl-fentanyl (about 15 times more potent than morphine), butyrfentanyl (more than 30 times more potent than morphine), U-47700 (about 12 times more potent than morphine), and MT-45 (roughly equivalent potency to morphine), among others.17

The opioid crisis began in the mid-to late 1990’s, following a confluence of events that led to a dramatic increase in opioid prescribing, including: a regulatory, policy and practice focus on opioid medications as the primary treatment for all types of pain;18 an unfounded concept that opioids prescribed for pain would not lead to addiction;19 the release of guidelines from the American Pain Society in 1996 encouraging providers to assess pain as “the 5th vital sign” at each clinical encounter; and the initiation of aggressive marketing campaigns by pharmaceutical companies promoting the notion that opioids do not pose significant risk for misuse or addiction and promoting their use as “first-line” treatments for chronic pain.19-21

The sale of prescription opioids more than tripled between 1999 and 2011, and this was paralleled by a more than four-fold increase in treatment admissions for opioid abuse and a nearly four-fold increase in overdose deaths related to prescription opioids.22  Federal and state efforts to curb opioid prescribing resulted in a leveling off of prescriptions starting in 2012;23 however, heroin-related overdose deaths had already begun to rise in 2007 and sharply increased from just over 3,000 in 2010 to nearly 13,000 in 2015.2  We now know prescription opioid misuse is a significant risk factor for heroin use; 80 percent of heroin users first misuse prescription opioids.24  While only about four percent of people who misuse prescription opioids initiate heroin use within 5 years,24,25 for this subset of people the use of the cheaper, often easier to obtain street opioid is part of the progression of an opioid addiction.26

The opioid overdose epidemic has now further escalated, with the rise in deaths related to illicitly manufactured synthetic opioids.  Often, the population of people using and overdosing on fentanyl looks very similar to the population using heroin. However, the drivers of fentanyl use can be complicated as the drug is often sold in counterfeit pills – designed to look like common prescription opioids or benzodiazepines (e.g. Xanax) – or is added as an adulterant to heroin or other drugs, unbeknownst to the user.14  And there are also market forces supporting the proliferation of higher-potency opioids, as people with opioid addictions develop increasing tolerance to these drugs.27

History of Fentanyl Misuse

The first fentanyl formulation (Sublimaze) received approval by the Food and Drug Administration (FDA) as an intravenous anesthetic in the 1960s.  Other formulations, including a transdermal patch, a quick acting lozenge or “lollipop” for breakthrough pain, and dissolving tablet and film, have since received FDA approval.28  Misuse of prescription fentanyl was first described in the mid-1970s among clinicians,29 and continues to be reported among the people misusing prescription opioids.3  More recently, between April 2005 and March 2007 there was an uptick in deaths related to illicitly manufactured fentanyl that was traced to a single laboratory in Mexico. Once the laboratory shut down the rate of overdose declined.30  However, over the last few years there has been a growing production of illicitly manufactured fentanyl, much of which is imported from China, Mexico, and Canada.14  The increase in illicitly manufactured fentanyl availability in the U.S. is reflected by the substantial increase in seizures of fentanyl by law enforcement which jumped from under 1,000 seizures in 2013 to over 13,000 in 2015.31 Research shows that the increasing availability of illicitly manufactured fentanyl closely parallels the increase in synthetic opioid overdose deaths in the U.S.32

HHS Response and NIDA-Supported Research Related to Fentanyl

Within HHS, the Office of the Assistant Secretary for Planning and Evaluation (ASPE) has been leading a targeted and coordinated policy and programmatic effort to reduce opioid abuse and overdose, including fentanyl use and overdose. The effort focuses on strengthening surveillance, improving opioid prescribing practices and the treatment of pain, increasing access to treatment for opioid addiction, expanding use of naloxone to reverse opioid overdose, and funding and conducting research to better understand the epidemic and identify effective interventions. Under this effort, NIDA is engaged in number critical activities.

NIDA supports the National Drug Early Warning System (NDEWS), which monitors emerging drug use trends to enable health experts, researchers and others to respond quickly to potential outbreaks of illicit drugs.  In partnership with the NDEWS, the Northeast Node of the NIDA’s Clinical Trials Network (CTN) has been funded to complete a Fentanyl Hot Spot Study in New Hampshire.  In 2015, New Hampshire had the highest rate of fentanyl-related deaths in the country and this study is investigating the causes of increased fentanyl use and related deaths in this region.

In the first phase of the study, multiple stakeholders throughout the state, including treatment providers, medical responders, law enforcement, state authorities and policymakers were interviewed about their perspectives on the fentanyl crisis.33  Many expressed that better user-level data was imperative to answer pointed questions to more accurately inform policy, such as the trajectory of fentanyl use, supply chain, fentanyl-seeking behavior versus accidental ingestion, value of testing kits, treatment preferences, etc. The researchers reported that, “Some may seek out a certain dealer or product when they hear about overdoses because they think that it must be good stuff.”  According to the group leader, only approximately a third of users knowingly use fentanyl, but the number of users is slowly increasing.

The second phase of the study is conducting a rapid epidemiological investigation of fentanyl users’ and first responders’ perspectives, so that real-time data can inform policy in tackling the fentanyl overdose crisis.

Another ongoing NIDA funded study is characterizing the fentanyl crisis in Montgomery County, Ohio – an area experiencing one of the largest surges of illicitly manufactured fentanyl in the country. This study will explore the scope of the fentanyl crisis in this area, collecting data from postmortem toxicology and crime laboratories, and will explore active user knowledge and experiences with fentanyl.  Other NIDA funded research is working to develop faster methods for screening for fentanyl and other synthetic opioids to track overdoses through emergency department screening and improve surveillance of the fentanyl threat across the country.

NIDA-supported research is also working to develop new treatments for opioid addiction, including treatments targeting fentanyl specifically. One ongoing NIDA-funded study is in the early stages of developing a vaccine for fentanyl that could prevent this drug from reaching the brain.34

Evidence-Based Approaches

With the emergence of very high potency opioids addressing supply becomes increasingly difficult because the quantities transported may be much lower.  Thus, it is critical to address demand reduction through the deployment of evidence-based prevention and treatment strategies to reduce the number of people developing an opioid addiction and treating the population of Americans who already suffer from this addiction.

Evidence-Based Treatments for Opioid Addiction

Three classes of medications have been approved for the treatment of opioid addiction : (1) agonists, e.g. methadone , which activate opioid receptors; (2) partial agonists, e.g. buprenorphine, which also activate opioid receptors but produce a diminished response; and (3) antagonists, e.g. naltrexone, which block the opioid receptor and interfere with the rewarding effects of opioids.35  These medications represent the first-line treatments for opioid addiction.

The evidence strongly demonstrates that methadone, buprenorphine, and injectable naltrexone (e.g., Vivitrol) all effectively help maintain abstinence from other opioids and reduce opioid abuse-related symptoms.  These medications have also been shown to reduce injection drug use and HIV transmission and to be protective against overdose.36-40  These medications should be administered in the context of behavioral counseling and psychosocial supports to improve outcomes and reduce relapse.  Two comprehensive Cochrane reviews, one analyzing data from 11 randomized clinical trials that compared the effectiveness of methadone to placebo, and another analyzing data from 31 trials comparing buprenorphine or methadone treatment to placebo, found that38,39:

* Patients on methadone were over four times more likely to stay in treatment and had 33 percent fewer opioid-positive drug tests compared to patients treated with placebo;

* Methadone treatment significantly improves treatment outcomes alone and when added to counseling; long-term (beyond six months) outcomes are better for patients receiving methadone, regardless of counseling received;

* Buprenorphine treatment significantly decreased the number of opioid-positive drug tests; multiple studies found a 75-80 percent reduction in the number of patients testing positive for opioid use;

* Methadone and buprenorphine are equally effective at reducing symptoms of opioid addiction; no differences were found in opioid-positive drug tests or self-reported heroin use when treating with these medications.

To be clear, the evidence supports long-term maintenance with these medicines in the context of behavioral treatment and recovery support, not short-term detoxification programs aimed at abstinence.41  Abstinence from all medicines may be a particular patient’s goal, and that goal should be discussed between patients and providers.  However, the scientific evidence suggests the relapse rates are extremely high when tapering off of these medications, and treatment programs with an abstinence focus generally do not facilitate patients’ long-term, stable recovery.42,43

Treatment Challenges

Unfortunately, medications approved for the treatment of opioid abuse are underutilized and often not delivered in an evidence based manner.44,45  Fewer than half of private-sector treatment programs offer these medications; and of patients in those programs who might benefit, only a third actually receive it.45  Further, many people suffering with opioid addiction do not seek treatment. Identifying the need for and engaging them in treatment is an essential element of addressing the opioid crisis. For example, recent research suggests that initiating patients on buprenorphine following an opioid overdose can increase treatment retention and improve outcomes.46  Overcoming the misunderstandings and other barriers that prevent wider adoption of these treatments is crucial for tackling the opioid crisis.

In addition, to achieve positive outcomes, treatments must be delivered with fidelity. To be effective, methadone and buprenorphine must be given at a sufficiently high dose.38,39  Some treatment providers wary of using methadone or buprenorphine have prescribed lower doses for short treatment durations, leading to treatment failure and the mistaken conclusion that the medication is ineffective.38,47

As of 2011, more than 22 percent of patients in a methadone treatment programs were receiving less than the minimum recommended dose of methadone.48  Interestingly, a recent study identified a genetic variant near the mu opioid receptor gene associated with a higher required dose of methadone (corresponding to a need for about an additional 20 mg per day) in African American patients but not European Americans with this gene variant.49  This highlights the need for dosing flexibility to achieve the effective dose for an individual patient.  The NIH Precision Medicine Initiative and other ongoing research projects are working to define the genetic, biological, and clinical factors that influence the efficacy of treatment to help clinicians deliver care precisely tailored for a specific patient to improve outcomes.

Research has also shown that tapering off of buprenorphine can present significant risks for relapse.43,50  A recent analysis of five studies that examined outcomes following buprenorphine taper found that on average only 18 percent (a range of 10 to 50 percent) of patients remained abstinent one to two months after tapering off of buprenorphine.50  In addition, some state programs and insurance providers limit the duration of treatment a patient may receive.  There is no evidence base to support this practice, and the available evidence suggests that it poses a significant risk for patient relapse.  This is also an important consideration in the context of the two years of funding for the opioid crisis authorized through the 21st Century Cures Act. This funding will be critical for helping states address the ongoing opioid epidemic, however, opioid addiction is a chronic condition and many patients will need ongoing treatment for many years.  It will be important to develop sustainability strategies to ensure that patients do not lose access to these life-saving medications when a particular funding program is discontinued.

While users seeking treatment are on a wait list they generally continue to engage in opioid use and this may contribute to failure to enter treatment when a slot becomes available.  Research has shown that providing interim treatment with medications while patients are awaiting admission to a treatment program increases the likelihood that they will engage in treatment.  In one study, over 64 percent of study participants receiving interim methadone entered comprehensive care within six months, compared with only 27 percent in the control group, and the group receiving methadone had lower rates of heroin use and criminal behavior.51 One model for interim treatment with buprenorphine would use urine testing call backs and a special medicine dispensing device to prevent diversion.52  Implementation would require a regulatory change because take home buprenorphine is not allowed under interim regulations currently. When this model was tested, patients showed strong adherence to the interim treatment plan and reported strong satisfaction with the treatment. State regulations and payment system issues (bundled payment that does not accommodate billing for interim treatment) are often barriers to this type of program and they are not frequently used.

Fentanyl specific challenges

While specific data on treatment outcomes for patients addicted to fentanyl or other high potency synthetic opioids are not available, the same principles of treatment still apply.  In addition, patients regularly using these substances and surviving would be expected to have a strong opioid dependency. At this time we are not sure how many people fit this clinical picture. In this scenario the withdrawal symptoms are likely to be severe, and could lead to life threatening cardiac arrhythmias and seizures if untreated or if extreme opioid withdrawal is potentiated during overdose reversal.53 There is an urgent need for more research to determine if people using fentanyl or other high potency opioids respond differently to medications for overdose reversal as well as treatment and to determine the most effective approaches for utilizing medications and psychosocial supports in this population.

In general outcomes are better predicted by the strength of the psychosocial supports around patients to support their recovery – educational or job opportunities, supportive friends and family, stable housing, access to child care – than the severity of their addiction.  Providing behavioral counseling and wrap around services to address these needs is important for achieving the best outcomes.

Prevention of Opioid Misuse and Addiction

Since the majority of people who develop an opioid addiction begin by misusing prescription opioids, the Department of Health and Human Services (HHS) continues to focus efforts on improving opioid prescribing and preventing the misuse of prescription drugs as the long-run strategy to stop the opioid epidemic.  NIDA supports research to understand the impact of federal and state policy changes on rates of opioid abuse and related public health outcomes.  This and other federally supported research has demonstrated the efficacy of multiple types of interventions, including:

* Educational initiatives delivered in school and community settings (primary prevention)54

* Supporting consistent use of prescription drug monitoring programs (PDMPs)

* Aggressive law enforcement efforts to address doctor shopping and pill mills56,57

* Providing healthcare practitioners with tools for managing pain, including prescribing guidelines and enhanced warnings on drug labels with expanded information for prescribers58-61

In states with the most comprehensive initiatives to reduce opioid overprescribing, the results have been encouraging.  Washington State’s implementation of evidence-based dosing and best-practice guidelines, as well as enhanced funding for the state’s PDMP, helped reduce opioid deaths by 27 percent between 2008 and 2012.58  In Florida, new restrictions were imposed on pain clinics, new policies were implemented requiring more consistent use of the state PDMP, and the Drug Enforcement Administration (DEA) worked with state law enforcement to conduct widespread raids on pill mills, which resulted in a dramatic decrease in overdose deaths between 2010 and 2012.62  These examples show that state and Federal policies can reduce the availability of prescription opioids and related overdose deaths.  However, the increasing supply of heroin and illicit fentanyl in the United States is undermining the effects of these improvements. While we have seen a leveling off of overdose deaths related to commonly prescribed opioids over the last few years, overdose deaths related to illicit opioids have risen dramatically during this time.

In early 2016 CDC released guidelines for prescribing opioids for chronic pain.60  We believe they represent an important step for improving prescriber education and pain prescribing practices in our nation.  NIDA is advancing addiction awareness, prevention, and treatment in primary care practices through seven Centers of Excellence for Pain Education.63  Intended to serve as national models, these centers target physicians-in-training, including medical students and resident physicians in primary care specialties (e.g. internal medicine, family practice, and pediatrics).

Addressing the Public Health Consequences of Opioid Misuse

Other evidence-based strategies can be used to reduce the health harms associated with opioid use, including increasing access to the opioid-overdose-reversal drug naloxone.

Preventing Overdoses with Naloxone

The opioid overdose-reversal drug naloxone can rapidly restore normal respiration to a person who has stopped breathing as a result of an overdose from heroin or prescription opioids.  Naloxone is widely used by emergency medical personnel and some other first responders.  Beyond first responders, a growing number of communities have established overdose education and naloxone distribution programs that make naloxone more accessible to opioid users and their friends or loved ones, or other potential bystanders, along with brief training in how to use these emergency kits.  Such programs have been shown to be effective, as well as cost-effective, ways of saving lives.64,65  CDC reported that, as of 2014, more than 152,000 naloxone kits had been distributed to laypersons and more than 26,000 overdoses had been reversed since 1996.66  In addition, the majority of states now allow individuals to obtain naloxone from retail pharmacies without a patient-specific prescription.67

Two naloxone formulations specifically designed to be administered by family members or caregivers have recently been developed.  In 2014 the FDA approved a handheld auto-injector of naloxone, and in late 2015 the FDA approved a user-friendly intranasal formulation that was developed through a NIDA partnership with Lightlake Therapeutics, Inc. (a partner of Adapt Pharma Limited).68

The availability of naloxone is critical to reduce opioid-related fatalities.69  However, research examining past fentanyl outbreaks shows that higher than typical naloxone doses were required to reverse fentanyl overdose.70  As the use of fentanyl and other highly potent opioids is increasing, it would be prudent to promote the use of naloxone while recognizing that multiple doses may be needed to revive someone experiencing a fentanyl overdose.71  It is also important for first responders to know that, while fentanyl has a short duration of action (30-90 minutes), it can stay in fat deposits for hours, and patients should be monitored for up to 12 hours after resuscitation.72  More research may be needed to develop new naloxone formulations tailored to higher-potency opioids.

Ongoing Opioid-Related Research: Implementation Science

Despite the availability of evidence based treatments for opioid abuse, we have a significant and ongoing treatment gap in our Nation.  Among those who need treatment for an addiction, few receive it.  In 2014, less than 12 percent of the 21.5 million Americans suffering with addiction received specialty treatment.3   Further, many specialty treatment programs do not provide current evidence based treatments – fewer than half provide access to MAT for opioid use disorders.45  In addition, it is clear that preventing drug use before it begins—particularly among young people—is the most cost-effective way to reduce drug use and its consequences.73  Evidence based prevention interventions also remain highly underutilized.

Ongoing NIDA research is working to better understand the barriers to successful and sustainable implementation of evidence based practices and to develop implementation strategies that effectively overcome these barriers.  This work also seeks to understand the role environment—be it social, familial, structural, or geographic—plays in preventing opioid use and in the success of prevention and treatment interventions, as well as how to tailor prevention and treatment interventions to individuals with unique needs, including those in the criminal justice system or with HIV.

Other NIDA supported research is looking at how to improve access to treatment among other high risk populations.  For example, patients with opioid addiction are at increased risk of adverse health consequences and often seek medical care in emergency departments (EDs). NIDA is also collaborating with the Baltimore County Health Department on a pilot study to explore the possibility of providing methadone through pharmacies to increase access to treatment in underserved parts of the city. In the pilot, pharmacies would be considered satellite locations of licensed methadone treatment facilities; this model has been used in Pennsylvania and New York. Discussions are underway to explore whether regulatory exceptions can be granted to make this possible. Similarly, ongoing research is examining on the impact of providing opioid addiction treatment within infectious disease clinics.  This type of research is essential for translating evidence based strategies into real-world interventions that will reach the greatest number of people and get the most out of limited prevention and treatment resources.

Implementation Research to Address the Opioid Crisis in Rural Communities

Our efforts are also focused on addressing the opioid crisis in the epicenter of the epidemic – Appalachia.  NIDA is partnering with the Appalachian Regional Commission (ARC) to fund one-year services planning and needs assessment research grants to provide the foundation for future intervention programs and larger scale research efforts to test interventions to address opioid misuse in rural Appalachia.  Four grants were awarded in FY 2016 that will address issues related to injection drug use and associated transmission of infectious disease as well as the coordination of care for prisoners with opioid addiction as they re-enter the community.

A second funding opportunity announcement in partnership with the Substance Abuse and Mental Health Services Administration (SAMHSA), CDC, and ARC was released in October 2016 to support comprehensive, integrated approaches to prevent opioid injection and its consequences, including addiction, overdose, HIV and hepatitis C, as well as sexually transmitted diseases.  High rates of injection drug use in Appalachia has led to a rapid increase in the transmission of hepatitis C, raising concern about an outbreak of HIV.6 These projects will work with state and local communities to develop best practices that can be implemented by public health systems in the Nation’s rural communities including opioid abuse treatment  and other strategies to increase the testing and treatment for HIV.

HIV Testing and Treatment

NIDA supported research has helped to develop the seek, test, treat, and retain model of care (STTR) that involves reaching out to high-risk, hard-to-reach drug users who have not been recently tested for HIV; engaging them in HIV testing; engaging those testing positive in antiretroviral therapy; and retaining patients in care. Research has shown that implementation of STTR has the potential to decrease the rate of HIV transmission by half.75

Ongoing Opioid-Related Research: Development of Pain Treatments with Reduced Potential for Misuse

NIDA is one of multiple institutes of the NIH supporting research into novel pain treatments with reduced potential for misuse and diversion, including abuse resistant opioid analgesics, non-opioid medication targets, and non-pharmacological treatments. Some of the most promising potential therapies include:

* Abuse Resistant Opioid Analgesics: Efforts are underway to identify new opioid pain medicines with reduced misuse, tolerance, and dependence risk, as well as alternative delivery systems and formulations for existing drugs that minimize diversion and misuse (e.g., by preventing tampering) and reduce the risk of overdose deaths.  Multiple recent NIH-funded studies have reported progress in the discovery of opioid compounds with selective analgesic effects with reduced respiratory depressive effects and reduced abuse liability.76-78

* Non-Opioid Medications: Some non-opioid targets with promising preliminary data include fatty acid binding proteins, the G-protein receptor 55, cannabinoids, and transient receptor potential cation channel A1.

* Nervous Stimulation Therapies: Several non-invasive nervous stimulation therapies – including transcranial magnetic stimulation and transcranial direct current stimulation, as well as electrical deep brain stimulation, spinal cord stimulation, and peripheral nerves/tissues stimulation – have shown promise for the treatment of intractable chronic pain.  These devises have been approved by the FDA for treatment of other conditions but more research is needed on their effectiveness for pain.

* Neurofeedback: Neurofeedback is a novel treatment modality in which patients learn to regulate the activity of specific brain regions by getting feedback from real-time brain imaging.  This technique shows promise for altering the perception of pain in healthy adults and chronic pain patients and may also be effective for the treatment of addiction.

*

Ongoing Opioid-Related Research: Accelerating Development of New Treatments for Addiction

While the three available medications have represented significant advances in the ability to treat opioid use disorders the efficacy of these medications is far from ideal.  NIDA is funding research to accelerate development of new treatments.  This includes development of non-pharmacological interventions including biologics – such as vaccines, monoclonal antibodies, and bioengineered enzymes designed to prevent a drug from entering the brain – and novel brain stimulation techniques – such as TMS and transcranial direct current stimulation (tDCS), that target brain circuits impaired in addiction with improved specificity and temporal and spatial resolutions, and thus, with less adverse effects.  One ongoing NIDA-funded study is in the early stages of developing a vaccine for fentanyl that could prevent this drug from reaching the brain.34

Since the pharmaceutical industry has traditionally made limited investment in the development of medications to treat SUDs, NIDA has focused on forming alliances between strategic partners (pharmaceutical and biotechnology companies as well as academic institutions) with the common goal of advancing medications through the

development pipeline toward FDA approval.  NIDA conducts research to decrease the risks associated with medications development to make it more appealing for pharmaceutical companies to complete costly phase IIb and III clinical studies.  An example of such a project is a partnership with US World Meds, is in late stage development of lofexidine, a medication for the treatment of opioid withdrawal symptoms that might also hold promise for the treatment of other addictions.

Conclusion

NIDA will continue to closely collaborate with other federal agencies and community partners with a strong interest in preserving public health to address the interrelated challenges posed by misuse of prescription opioids, heroin, and synthetic opioids such as fentanyl.  We commend the committee for recognizing the serious and growing challenge associated with this exceedingly complex issue.  Under the leadership of the Department of Health and Human Services and the Office of National Drug Control Policy, NIDA will continue to support the implementation of the multi-pronged, evidence-based strategies to improve opioid prescribing and pain management, reduce overdose deaths, and increase access to high quality opioid abuse treatment.

Source:https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opioids-heroin-prescription-drug-abuse 

March 2017

Filed under: Effects of Drugs (Papers),Synthetics :

‘What can we do?’ This was the question that dominated the weekend’s news and current affairs in the aftermath of the Westminster ‘terror’ attack. We still do not know if it was organised by so-called Islamic State or, as seems increasingly likely, was the savage work of a ‘lone wolf’.

The discussion I heard on Any Questions centred on rooting out radicalisation, smartening up security, or accepting ‘the new normal’ that the likes of Sadiq Khan and Dominic Grieve (the security services have done well and something was bound to happen at some point) seem resigned to – a world where increasingly frequent human sacrifices are subliminally accepted as a price worth paying to protect our democracy and ‘our way of life’.

Two factors were not considered. One, the role of family dysfunction and two, the role of drugs, in catalysing the sort of violence perpetrated in Westminster last Wednesday.

From the moment he was born to a 17-year-old lone mother, Adrian Ajao was statistically at risk. Newspapers referred to his ‘well to do’ Home Counties upbringing but of far more significance for this baby’s future life path was a birth certificate that listed only his mother. I am not asking you to weep but to accept, statistically, that Adrian didn’t get off to a very good start. The hard statistical fact is that children who live continuously with lone mothers have poorer cognitive and socio-emotional outcomes compared to children who have biological fathers as a stable part of the household and family life.

Any idea that the presence of a stepfather helps can be forgotten. It doesn’t stack up statistically either – children are no less at risk of poor outcomes in step households. Adrian adopted his stepfather’s name only symbolically to abandon it later.

While some children in Africa are named after the unfortunate circumstances they are born to, in the modern West the unfortunate circumstance is not to have a biological father to name you.

Here is where the trajectory from pain to violence begins. As the young Adrian hit his late teens, his chances of his hitting drugs too were high. From the graphic descriptions volunteered by former friends it was to prove disastrous. Cannabis, it seems likely, triggered the psychosis that was a key factor in his increasingly psychotic and violent behaviour.

Before his final horrific killing spree in Westminster last week, Khalid Masood (as he became) had gone from troubled teen to terror of his neighbourhood; once he tried to run a neighbour down and the wife he married in 2004 fled for her life. He would be jailed twice for slashing people with knives.

For anyone in a culture of denial about cannabis, schizophrenia and violence let me refer them to the epidemiological evidence in the public domain. It not only identifies cannabis use as a risk factor for schizophrenia, but in individuals with a predisposition for schizophrenia, it results in an exacerbation of symptoms and worsening of the schizophrenic prognosis (Simona A. Stilo,MD; Robin M. Murray RM. Translational Research 2010: The epidemiology of schizophrenia: replacing dogma with knowledge. Dialogues Clin Neurosci. 2010 Sep;12(3):305–315). A recently published Cambridge Study in Delinquent Development – a 50-year cohort study – has categorically found that cannabis caused a seven-fold increase in a violent behaviour and that continued use of cannabis over the lifetime of the study was strongest predictor of violent convictions, even when all other factors that contributed to violent behaviour were accounted for. A study of Norwegian youths similarly found an association between cannabis use and violence and that frequency of cannabis use relates to frequency of incidents of violent behaviour. The preliminary findings of another study have found the changes in brain function that suggest the mechanism for cannabis-induced violence.

Ajao is not the only young British drug user to become prone to sudden bursts of violence, to dream about killing someone or to harbour a blood lust. Our NHS psychiatric wards are full of them on anti-psychotic medication to stop them hearing voices while they yet still abuse cannabis.

An analysis of hospital episode statistics I investigated a few years ago revealed the extent of the cannabis mental health crisis in the UK, despite an overall fall in use. Between 1998 and 2011, mental and behavioural disorders due to cannabis use increased overall by 54 per cent. This included an 108 per cent increase in harmful use episodes, a 51 per cent increase in dependence, a 61.8 per cent increase in psychotic disorders, and a 450 per cent increase in ‘other mental and behavioural disorders. Drug-related hospital admissions have reached record highs too in recent years. Most, 70 per cent are men and most of these are young men. The science is there for the behavioural unit in the Home Office to investigate, as Amber Rudd promised would be the case last year when she was asked.

Since Wednesday police have been searching for explanations for Khalid Masood’s violence. They are checking all possible contacts with ISIL cells and the influence of Islamist radicals, quite rightly. Masood, I have no doubt, was ripe for radicalisation in his own unhappy quest for personal ‘justice’.

Like Lee Rigby’s killers before him, I suspect the drugs came first and the conversion followed, giving a purpose to the violent impulses lurking within. Newspaper columnist Peter Hitchens has been right to ask what violent killers have in common and to ask whether it is dope that may be the real mind-blowing terror threat in our midst and where dysfunctional families abound. For the fact is that mental illness, triggered by cannabis, increases the risk of aggressive behaviour, crime and violence.

British longitudinal data on cannabis use and schizophrenia shows that the incidence of schizophrenia in South London doubled between 1965 and 1999. The study uniquely allowed for the examination of trends in cannabis use prior to first presentation with schizophrenia. The greatest increase was found in people under 35. Its author Professor Sir Robin Murray has suggested that up to 20 per cent of schizophrenia cases could be cannabis attributable.

Despite all this, the Government in the UK has kept its head in the sand over this public health and safety time bomb. It has never fulfilled its pledge to run a major public health education campaign.

The evidence should tell Amber Rudd’s Home Office ‘behaviour unit’ that it is overdue, as is committed policing to protect young men at risk.  This has to be part of any prevention strategy in response to the carnage in Westminster last week. The link between cannabis and violence, as I argued before, can no longer be ignored.

Source:  http://www.conservativewoman.co.uk/kathy-gyngell-did-cannabis-trigger-westminster-killers-madness/   28th March 2017 

Filed under: Effects of Drugs (Papers),Social Affairs (Papers) :

Abstract

Background Amphetamine abuse is becoming more widespread internationally. The possibility that its many cardiovascular complications are associated with a prematurely aged cardiovascular system, and indeed biological organism systemically, has not been addressed.

Methods

Radial arterial pulse tonometry was performed using the SphygmoCor system (Sydney). 55 amphetamine exposed patients were compared with 107 tobacco smokers, 483 non-smokers and 68 methadone patients (total=713 patients) from 2006 to 2011. A cardiovascular-biological age (VA) was determined.

Results

The age of the patient groups was 30.03±0.51–40.45±1.15 years. This was controlled for with linear regression. The sex ratio was the same in all groups. 94% of amphetamine exposed patients had used amphetamine in the previous week. When the (log) VA was regressed against the chronological age (CA) and a substance-type group in both cross-sectional and longitudinal models, models quadratic in CA were superior to linear models (both p<0.02). When log VA/CA was regressed in a mixed effects model against time, body mass index, CA and drug type, the cubic model was superior to the linear model (p=0.001). Interactions between CA, (CA)2 and (CA)3 on the one hand and exposure type were significant from p=0.0120. The effects of amphetamine exposure persisted after adjustment for all known cardiovascular risk factors (p<0.0001).

Conclusions

These results show that subacute exposure to amphetamines is associated with an advancement of cardiovascular-organismal age both over age and over time, and is robust to adjustment. That this is associated with power functions of age implies a feed-forward positively reinforcing exacerbation of the underlying ageing process.

To read the whole research study log on to:

Source:    http://dx.doi.org/10.1136/heartasia-2016-010832

Filed under: Drug use-various effects,Effects of Drugs (Papers),Health :

Once you drop, you can’t stop – sometimes for up to 15 hours. Images revealing how LSD interacts with receptors in the brain could explain why a trip lasts so long, while another study involving a similar receptor unpicks how the drug makes these experiences feel meaningful.

LSD acts on with a number of different receptors in the brain, including ones for the chemicals serotonin and dopamine, but it’s not known exactly which receptors are responsible for its various effects. Daniel Wacker and his colleagues at the University of North Carolina, Chapel Hill, used crystallography to look at the structure of LSD when it binds to a receptor in the brain that normally detects serotonin. They discovered that part of this serotonin 2B receptor acts as a lid, closing around the LSD molecule and trapping it.

This could explain the extended trips the drug produces. “It takes LSD very long to get into the receptor, and once it’s stuck it doesn’t go away,” says Wacker.

However, there is conflicting evidence. Other studies have shown that LSD hangs around in the blood for a long time. “No prolonged action at the receptor is needed to explain the duration of action,” says Matthias Liechti at the University of Basel, Switzerland.

But if Wacker is right, the fact that LSD seems to get stuck inside the receptor might mean it can have effects at very low doses. In recent years, there have been reports of some people taking LSD in amounts too small to cause hallucinations, in an attempt to boost creativity or general well-being.

There’s little hard evidence about whether this microdosing works, but Wacker says psychoactive effects at low doses are plausible. “Our study suggests even very low amounts of LSD may be enough to cause psychoactive effects.” Scientific interest in LSD’s clinical use has revived in recent years – notably to relieve severe psychiatric conditions such as PTSD and anxiety. There are also signs that LSD has helpful non-psychoactive effects on other ailments, such as cluster headaches.

Suppressing bliss

A second study finds evidence that LSD affect the brain by binding to serotonin receptors, and hints at possible ways to harness some of its effects therapeutically. Katrin Preller and her colleagues at the University of Zurich, Switzerland, gave 22 volunteers 100 micrograms of LSD each to determine the role of the serotonin 2A receptor, which is similar to the one studied by Wacker’s team.

In some of the tests, subjects were also given ketanserin, a drug that blocks the serotonin 2A receptor. In those tests, the trippy effects of LSD – including hallucinations, feeling separate from the body, and feelings of bliss – were completely blocked, showing that this receptor must be responsible for them.

The researchers also played songs to the participants. Some of the songs were ones the volunteers had chosen as meaningful beforehand, while others were not. While on LSD, they rated what had been non-meaningful songs as highly meaningful – an effect that, once again, ketanserin blocked.

Preller thinks these findings suggest that the serotonin 2A receptor is important for how we decide which things are relevant to us. “This is something that’s incredibly important for our everyday life,” she says. “We do it constantly, for example if you see a familiar face.”

Some psychiatric conditions, such as schizophrenia and phobias, are associated with paying too much attention to unimportant stimuli. Preller speculates that LSD might help people refocus their attention in a different direction.

“If you have a depressed patient ruminating about negative thoughts, LSD might facilitate a process where you attribute meaning to other things,” says Preller.

Alternatively, people with these conditions might benefit from drugs that reduce the action of the serotonin 2A receptor, like ketanserin.

Source: Journal reference: Current Biology, DOI: 10.1016/j.cub.2016.12.030 Journal reference: Cell, DOI: 10.1016/j.cell.2016.12.033

Filed under: Brain and Behaviour,Drug use-various effects,Effects of Drugs (Papers),Methamphetamine/GHB/Hallucinogens/Oxycodone :

Currently, 29 states and Washington, DC, have passed laws to legalize medical marijuana. Although evidence for the effectiveness of marijuana or its extracts for most medical indications is limited and in many cases completely lacking, there are a handful of exceptions. For example, there is increasing evidence for the efficacy of marijuana in treating some forms of pain and spasticity, and 2 cannabinoid medications (dronabinol and nabilone) are approved by the US Food and Drug Administration for alleviating nausea induced by cancer chemotherapy.

A systematic review and meta-analysis by Whiting et al1 found evidence, although of low quality, for the effectiveness of cannabinoid drugs in the latter indication. The anti -nausea effects of tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, are mediated by the interactions of THC with type cannabinoid (CB1) receptors in the dorsal vagal complex. Cannabidiol, another cannabinoid in marijuana, exerts antiemetic properties through other mechanisms. Nausea is a medically approved indication for marijuana in all states where medical use of this drug has been legalized. However, some sources on the internet are touting marijuana as a solution for the nausea that commonly accompanies pregnancy, including the severe condition hyperemesis gravidarum.

Although research on the prevalence of marijuana use by pregnant women is limited, some data suggest that this population is turning to marijuana for its antiemetic properties, particularly during the first trimester of pregnancy, which is the period of greatest risk for the deleterious effects of drug exposure to the foetus. Marijuana is the most widely used illicit drug during pregnancy, and its use is increasing. Using data from the National Survey of Drug Use and Health, Brown et al report in this issue of JAMA that 3.85%of pregnant women between the ages of 18 and 44 years reported past-month marijuana use in 2014, compared with 2.37%in 2002. In addition, an analysis of pregnancy data from Hawaii reported that women with severe nausea during pregnancy, compared with other pregnant women, were significantly more likely to use marijuana (3.7%vs 2.3%, respectively).

Although the evidence for the effects of marijuana on human prenatal development is limited at this point, research does suggest that there is cause for concern. A recent review and a meta-analysis found that infants of women who used marijuana during pregnancy were more likely to be anaemic, have lower birth weight, and require placement in neonatal intensive care than infants of mothers who did not use marijuana. Studies have also shown links between prenatal marijuana exposure and impaired higher-order executive functions such as impulse control, visual memory, and attention during the school years.

The potential for marijuana to interfere with neurodevelopment has substantial theoretical justification. The endocannabinoid system is present from the beginning of central nervous system development, around day 16 of human gestation, and is increasingly thought to play a significant role in the proper formation of neural circuitry early in brain development, including the genesis and migration of neurons, the outgrowth of their axons and dendrites, and axonal pathfinding. Substances that interfere with this system could affect foetal brain growth and structural and functional neurodevelopment.

An ongoing prospective study, for example, found an association between prenatal cannabis exposure and foetal growth restriction during pregnancy and increased frontal cortical thickness among school-aged children. Some synthetic cannabinoids, such as those found in “K2/Spice” products, interact with cannabinoid receptors even more strongly than THC and have been shown to be teratogenic in animals.

A recent study in mice found brain abnormalities, eye deformations, and facial disfigurement (cleft palate) in mouse foetuses exposed at day 8 of gestation to a potent full cannabinoid agonist, CP-55,940. The percentage of mouse foetuses with birth defects increased in a linear fashion with dose. (The eighth day of mouse gestation is roughly equivalent to the third or fourth week of embryonic development in humans, which is before many mothers know they are pregnant.) It is unknown whether these kinds of effects translate to humans; thus far, use of synthetic cannabinoids has not been linked to human birth defects, although use of these substances is still relatively new.

THC is only a partial agonist at the CB1 receptor, but the marijuana being used both medicinally and recreationally today has much higher THC content than in previous generations (12% in 2014 vs 4% in 1995), when many of the existing studies of the teratogenicity of marijuana were performed. Marijuana is also being used in new ways that have the potential to expose the user to much higher THC concentrations—such as the practice of using concentrated extracts (eg, hash oil). More research is needed to clarify the neurodevelopmental effects of prenatal exposure to marijuana, especially high-potency formulations, and synthetic cannabinoids.

One challenge is separating these effects from those of alcohol, tobacco, and other drugs, because many users of marijuana or K2/Spice also use other substances. In women who use drugs during pregnancy, there are often other confounding variables related to nutrition, prenatal care, and failure to disclose substance use because of concerns about adverse legal consequences.    Even with the current level of uncertainty about the influence of marijuana on human neurodevelopment, physicians and other health care providers in a position to recommend medical marijuana must be mindful of the possible risks and err on the side of caution by not recommending this drug for patients who are pregnant. Although no states specifically list pregnancy-related conditions among the allowed recommendations for medical marijuana, neither do any states currently prohibit or include warnings about the possible harms of marijuana to the foetus when the drug is used during pregnancy. (Only 1 state, Connecticut, currently includes an exception to the medical marijuana exemption in cases in which medical marijuana use could harm another individual, although potential harm to a foetus is not specifically listed.)

In 2015, the American College of Obstetricians and Gynecologists issued a committee opinion discouraging physicians from suggesting use of marijuana during preconception, pregnancy, and lactation. Pregnant women and those considering becoming pregnant should be advised to avoid using marijuana or other cannabinoids either recreationally or to treat their nausea.

Source:  http://jamanetwork.com/ on 12/21/2016

Filed under: Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Global Drug Legalisation Efforts,Marijuana and Medicine,Medicine and Marijuana :

Robert J. Tait, et al

Abstract

Context: Synthetic cannabinoids (SCs) such as “Spice”, “K2”, etc. are widely available via the internet despite increasing legal restrictions. Currently, the prevalence of use is typically low in the general community (<1%) although it is higher among students and some niche groups subject to drug testing. Early evidence suggests that adverse outcomes associated with the use of SCs may be more prevalent and severe than those arising from cannabis consumption.

Objectives: To identify systematically the scientific reports of adverse events associated with the consumption of SCs in the medical literature and poison centre data.

Method: We searched online databases  and manually searched reference lists up to December 2014. To be eligible for inclusion, data had to be from hospital, emergency department, drug rehabilitation services or poison centre records of adverse events involving SCs and included both self-reported and/or analytically confirmed consumption.

Results: From 256 reports, we identified 106 eligible studies including 37 conference abstracts on about 4000 cases involving at least 26 deaths. Major complications include cardiovascular events (myocardial infarction, ischemic stroke and emboli), acute kidney injury (AKI), generalized tonic-clonic seizures, psychiatric presentations (including first episode psychosis, paranoia, self-harm/suicide ideation) and hyperemesis. However, most presentations were not serious, typically involved young males with tachycardia (≈37–77%), agitation (≈16–41%) and nausea (≈13–94%) requiring only symptomatic care with a length of stay of less than 8 hours.

Conclusions: SCs most frequently result in tachycardia, agitation and nausea. These symptoms typically resolve with symptomatic care, including intravenous fluids, benzodiazepines and anti-emetics, and may not require inpatient care. Severe adverse events (stroke, seizure, myocardial infarction, rhabdomyolysis, AKI, psychosis and hyperemesis) and associated deaths manifest less commonly. Precise estimates of their

incidence are difficult to calculate due to the lack of widely available, rapid laboratory confirmation, the variety of SC compounds and the unknown number of exposed individuals. Long-term consequences of SCs use are currently unknown. Keywords: Emergency medical services, street drugs, drug overdose, mental disorders, drug-related side effects and adverse reactions

Discussion

The prevalence of SC consumption is low in the general population.   However, the risk of requiring medical attention following use of SC seems to be greater than that for cannabis consumption.  Our systematic review of adverse events found that typically events were not severe, only required symptomatic or supportive care and were of short duration.

Nevertheless, a number of deaths have been attributed either directly or indirectly to SC consumption, together with other major adverse sequelae, including a significant number with persistent effects including new on-set psychosis with no family history of psychosis

We did not include popular media reports or the grey literature in the search, which would probably reveal further cases but would be less likely to contain reliable medical information. We were unable to determine the exact number of cases in the scientific literature due to the potential overlap between poison centre data and hospital reports. We could not even definitively establish the number of deaths attributed to SC consumption. Of the 28 531 ED visits in 2011 recorded in the DAWN database, 119 (0.4%) led to death potentially related to SC use

Our review of published cases identified only 22 fatal cases in the USA through to the end of 2014. As not all presentations especially for psychiatric problems or palpitations will include assessment of SC use, SC presentations may currently be seriously underreported. This suggests that the magnitude of the health burden due to SC use is considerably greater than that currently documented. Most of the data were based on self-reported consumption of SC, with no simple screening test available yet for clinicians.

Some of the information on adverse effects of SCs arises from poison centre data. Wood et al. outlined the strengths and weakness of poison centre data for novel psychoactive substances.  In brief, poison centres may detect new and unfamiliar exposures, but the rates of detection may decline with familiarity with the substances involved. In addition, the data depend upon voluntary reporting, often lack analytical confirmation, and may not discern which symptoms to attribute to a given substance, in cases of poly-drug exposure. Similarly, novel adverse events and events involving new SCs are more likely to be reported or published in the medical literature.

The consumption of cannabis affects the cardiovascular system and increases the risk of myocardial infarction.  Similarly, cannabis has been implicated in ischemic stroke, especially multifocal intracranial stenosis among young adults.   Cannabis use, ischemic stroke, and multifocal intracranial vasoconstriction, a prospective study in 48 consecutive young patients. The potential mechanisms include cardiac ischemia due to increased heart rate, postural hypotension, impaired oxygen supply arising from raised carboxyhemoglobin levels, especially in conjunction with tobacco smoking, and catecholamine-mediated pro-arrhythmic effects.  Marijuana as a trigger of cardiovascular events: speculation or scientific certainty? It is thus perhaps unsurprising that similar adverse outcomes have occurred following the use of SCs given their increased potency at CB1 receptors. Whether these compounds have significant direct effects on other receptors is still unknown.

The comparatively short period for which SC have been available and used in the general community means that long-term outcomes are currently unknown. However, the occurrence of AKI has implications for future health with a meta-analysis estimating a nearly nine-fold increase in the risk of developing chronic kidney disease, and a three-fold increase in the risk of end stage renal disease, compared to those who have not had AKI.   Thus, even low prevalence events with apparently limited duration, like AKI, have the potential to result in significant health costs following the resolution of acute symptoms. The other effects with long-term potential health consequences are initiation or exacerbation of psychiatric disorders, particularly psychosis. These are extremely debilitating and disabling conditions with large societal and health impacts for patients, families and the health system.

Clinical implications

SC intoxication appears to be a distinct and novel clinical entity. Use of SCs can cause more significant clinical effects than marijuana. There also appear to be qualitative differences in the nature of the symptoms with which patients present. The sheer number of SCs available and the rate at which they continue to change confound examinations of the scale and extent of the problem.   More recent formulations (in the UK termed “Third Generation”) are typically more potent that earlier SCs and seem to be associated with greater harms.  Trecki and colleagues report that the incidence of clusters and severity of adverse events involving SCs appears to be increasing.   This increase could be due to greater familiarity with presentations, better coordination between public health authorities and laboratories or the characteristics of newer SCs.   The overall effects of SC can resemble those of cannabis, but other than anxiety and paranoia these are not usually the symptoms associated with acute hospital presentation. Instead, patients seem to present in EDs because of behavioural abnormalities (agitated behaviour, psychosis, anxiety) or symptoms associated with acute critical illness. The latter includes seizures (which if prolonged can lead to rhabdomyolysis and hyperthermia), AKI, myocardial ischaemia and infarction in demographic groups where this would be most unusual. The majority of mild intoxications only require symptomatic treatment and generally do not require hospital admission. Severe intoxications, involving seizures, severe agitation or mental health disturbances, arrhythmias and significant chest pain, should be admitted to hospital for further investigation.

The lack of an antidote to SCs, analogous to that for opioid overdose, complicates management, as does the unpredictable effects and lack of a clear toxidrome to distinguish SCs from other recreational drugs.   The differential diagnosis requires the elimination of diverse conditions including hypoglycaemia, CNS infection, thyroid hyperactivity, head trauma and mental illness.  Benzodiazepines are usually sufficient to control agitation: while the use of haloperidol has also been described.  Caution is advised in undifferentiated agitation. Benzodiazepine failure should prompt consideration of definitive airway control. In addition to intravenous fluids for dehydration, the primary goals are protecting the airway, preventing rhabdomyolysis and to monitor for either cardiac or cerebral ischemia.

Traditionally, most recreational drug overdoses have been easily explicable based on clinical presentation alone. From an epidemiological perspective, this position should be revisited. Both the Welsh Emerging Drugs and Identification of Novel Substances (WEDINOS) and the Australian Capital Territory Novel Substances (ACTINOS) projects, routinely analyse raw product samples in the possession of patients, associated with severe or unusual presentations. This protocol has been able to characterize novel products well before their identification by law enforcement, arguably generating important information, not just for the patient concerned but also for population health services.

Conclusions

Data from poison centres and drug monitoring systems in Europe, the UK, the USA, and Australia illustrate trends of increased use of SCs. The number of unique SCs appears to continue growing, but the SCs seem to share common characteristics within the class. The most common effects include tachycardia, agitation and nausea; these generally respond to supportive care. However, physicians should be aware of the severe cardiovascular, cerebrovascular, neurological, psychiatric and renal effects, which occur in a minority of cases.

Differences among compounds in the class are difficult to assess. Methods to detect, identify and confirm new SCs lag behind the appearance of these drugs. Further, many of the cases depend upon self-report of the patients, whose information may be unreliable or inaccurate. Improving the availability of advanced laboratory resources will improve our ability to recognize SCs with higher risk of severe toxicity.

Source:  Extracts from Clinical Toxicology  Volume 54, 2016 – Issue 1  Nov.2015

Filed under: Effects of Drugs (Papers),Synthetics :

A recognized deficiency: Inadequate protective protocols

An evaluation of risk applied to marijuana products for medical purposes concludes that advanced mitigation strategies and new protective delivery protocols are necessary to adequately protect the public from harm. The Risk Evaluation and Mitigation Strategies (REMS) program is already an approved protocol in the United States (US) by the US Food and Drug Administration and in Canada a similar controlled distribution program is in place including RevAid®.1,2    These programs are intended to assure patients are monitored to prevent or minimize major side effects and or reactions.   There are a number of medications that fall into existing REMS restrictions include thalidomide, clozapine, isotretinoin, and lenilidomide.  In both of these programs only prescribers and pharmacists who are registered or patients who are enrolled and who have agreed to meet all the conditions of the program are given access to these drugs.1,2

Current Government-approved Cannabinoid Products

Dronabinol (Marinol®, generic), nabilone (Cesamet®, generic) are synthetic cannabinoids to mimic delta-9-THC and nabiximols (Sativex®) is a combination of delta-9-THC and cannabidiol. They all lack the pesticides, herbicides and fungicides placed on marijuana plants during growth.

The longest approved agents, dronabinol and nabilone are indicated for short term use in nausea and vomiting due to chemotherapy and appetite stimulation.3,4  Nabiximols is used as a buccal spray for multiple sclerosis and as an adjunct for cancer pain.5  The maximum delta-9-THC strengths available are 10 mg for dronabinol and 2.7 mg/spray of nabiximols.3,5  Cannabidiol (CBD), a non-psychoactive compound, is one of many cannabinoids found in marijuana.   CBD is currently available for free from the U.S. National Institute of Health in government-sponsored clinical trials as potential treatment of resistant seizures (Dravet’s Syndrome and Lennox-Gastaut Syndrome).6

‘Medical’ Marijuana products

All marijuana products, including marijuana for medical purposes, fit the prerequisites for a REMS program. The average potency of marijuana more than doubled between 1998 and 2009.7 In 2015 common leaf marijuana averaged 17.1% THC in Colorado.8  Examples of oral marijuana products contain 80 mg of THC in chocolates, cookies and drinks and even 420 mg of THC in a “Dank Grasshopper” bar.9  Butane hash oil (BHO) is a concentrated THC product used in water bongs and/or e- cigarettes and contains upwards of 50 – 90% THC with a Colorado average of 71.7 % THC.8   One “dab” (280 mg) of 62.1% BHO is equal to 1 gram of 17% THC in marijuana leaf form.8  These extremely elevated levels of THC make true scientific research with these products incapable of passing Patient Safety Committee standards.10

The Thalidomide Parallel

The risks are so severe for thalidomide, in terms of use in pregnancy that a special protocol that educates, evaluates, mitigates and monitors has been made obligatory.11

Thalidomide (Contergan®) was developed by a German company, Chemie Gruenenthal, in 1954 and approved for the consumer market in 1957.12 It was available as an over-the-counter drug for the relief of “anxiety, insomnia, gastritis, and tension” and later it was used to alleviate nausea and to help with morning sickness by pregnant women. Thalidomide was present in at least 46 countries under a variety of brand names and was available in “sample tablet form” in Canada by 1959 and licensed for prescription on December 2, 1961. Although thalidomide was withdrawn from the market in West Germany and the UK by December 2, 1961, it remained legally available in Canada until March of 1962. It was still available in some Canadian pharmacies until mid-May of 1962.12

Canada had permitted the drug onto the Canadian market when many warnings were already available

An association was being made in 1958 of phocomelia (limb malformation) in babies of mother’s using thalidomide.  A trial conducted in Germany against Gruenenthal, for causing intentional and negligent bodily injury and death, began in 1968 ending in 1970 with a claim of insufficient evidence.  Later, the victims and Gruenenthal settled the case for 100 million dollars.11

In 1962 the American pharmaceutical laws were increased by the Kefauver-Harris Drug Amendment of 1962 and proof for the therapeutic efficiency through suitable and controlled studies would be required for any government approved medication.13 According to paragraph 25 of the Contergan foundation law, every 2 years a new report is required to determine if further development of these regulations are necessary.13

In 1987 the War Amputations of Canada established The Thalidomide Task Force, to seek compensation for Canadian-born thalidomide victims from the government of Canada.12

In 1991, the Ministry of National Health and Welfare (the current Health Canada) awarded Canadian-born thalidomide survivors a small lump-sum payment.12

In 2015 the Canadian government agreed on a settlement of $180 million dollars to 100 survivors of thalidomide drug exposure and damage.14 Through Rona Ambrose, in her capacity as the Health Minister for the government of Canada at the time of the negotiations, an attempt was made to involve the drug companies related to the thalidomide issue in the survivor’s settlement agreement. Negotiations with the drug companies failed.  The Canadian taxpayer alone paid to amend the survivors by way of monetary award.

Thalidomide continues to be sold under the brand name of Immunoprin®, among others in a REMS program. It is an immunomodulatory drug and today, it is used mainly as a treatment of certain cancers (multiple myeloma) and leprosy.11

Question: If the drug thalidomide included psychotropic properties and offered the “high” of marijuana would it be prudent or responsible to allow it to be legally sold and marketed for non-medical purposes – acknowledging thalidomide’s record for toxicity in pregnancy?

Marijuana Risk Assessment and Government Acknowledgement

Risks demonstrated in the scientific literature include genetic and chromosomal damage.15, 16

When exposure occurs in utero, there is an association with many congenital abnormalities including cardiac septal defects, anotia, anophthalmos, and gastroschisis. Marijuana use can disrupt foetal growth and the development of organs and limbs and may result in mutagenic alterations in DNA. Cannabis has also been associated with foetal abnormalities in many studies including low birth weight, foetal growth restriction, preterm birth spontaneous miscarriage, spina bifida and others.15

Phocomelia has been shown in testing in a similar preclinical model (hamster) to that which revealed the teratogenicity of thalidomide.15

THC has the ability to interfere with the first stages in the formation of the brain of the fetus; this event occurs two weeks after conception.  Exposure to today’s high potency marijuana in early pregnancy is associated with anencephaly, a devastating birth defect in which infants are born with large parts of the brain or skull missing.15

The existence of specific health risks associated with marijuana products are acknowledged by national and various local governments and a plethora of elected officials in both Canada and the United States.16, 17, 18

Warnings and the contraindications for use by specific populations and in association with identified conditions, have been publicized by the Federal Government of Canada and the Federal Government of the United States of America through their respective health agencies.16, 17, 18

A government of Canada leaflet produced by Health Canada and updated in December 2015: Consumer Information – Cannabis (Marihuana, marijuana) reads19:

“The use of this product involves risks to health, some of which may not be known or fully understood. Studies supporting the safety and efficacy of cannabis for therapeutic purposes are limited and do not meet the standard required by the Food and Drug Regulations for marketed drugs in Canada.”19

“Using cannabis or any cannabis product can impair your concentration, your ability to think and make decisions, and your reaction time and coordination. This can affect your motor skills, including your ability to drive. It can also increase anxiety and cause panic attacks, and in some cases cause paranoia and hallucinations.”19

“When the product should not be used: under the age of 25, are allergic to any cannabinoid or to smoke, have serious liver, kidney, heart or lung disease, have a personal or family history of serious mental disorders such as schizophrenia, psychosis, depression, or bipolar disorder, are pregnant, are planning to get pregnant, or are breast-feeding, are a man who wishes to start a family, have a history of alcohol or drug abuse or substance dependence.”19

“A list of health outcomes related to long term use includes the following:

Increased risk of triggering or aggravating psychiatric and/or mood disorders (schizophrenia, psychosis, anxiety, depression, bipolar disorder), decrease sperm count, concentration and motility, and increase abnormal sperm morphology. Negatively impact the behavioural and cognitive development of children born to mothers who used cannabis during pregnancy.”19

In Canada, the College of Family Physicians has issued guidelines for issuing marijuana prescriptions.20

“Dried cannabis is not appropriate for patients who: a) Are under the age of 25 (Level II) b) Have a personal history or strong family history of psychosis (Level II) c) Have a current or past cannabis use disorder (Level III) d) Have an active substance use disorder (Level III) e) Have cardiovascular disease (angina, peripheral vascular disease, cerebrovascular disease, arrhythmias) (Level III) f) Have respiratory disease (Level III) or g) Are pregnant, planning to become pregnant, or breastfeeding (Level II)”20

“Dried cannabis should be authorized with caution in those patients who: a) Have a concurrent active mood or anxiety disorder (Level II) b) Smoke tobacco (Level II) c) Have risk factors for cardiovascular disease (Level III) or d) Are heavy users of alcohol or taking high doses of opioids or benzodiazepines or other sedating medications prescribed or available over the counter (Level III)”20

In February 2013 The College of Family Physicians of Canada issued a statement advancing the position that physicians should sign a declaration rather than write a prescription as the potential liability, as well as the ethical obligations, for health professionals prescribing marijuana for medical purposes appears not to have been adequately addressed by Health Canada. 21

“In our view, Health Canada places physicians in an unfair, untenable and to a certain extent unethical position by requiring them to prescribe cannabis in order for patients to obtain it legally. If the patient suffers a cannabis-related harm, physicians can be held liable, just as they are with other prescribed medications. Physicians cannot be expected to prescribe a drug without the safeguards in place as for other medications – solid evidence supporting the effectiveness and safety of the medication, and a clear set of indications, dosing guidelines and precautions.”21

Representatives of the government of the United States held a press conference at the Office of National Drug Policy (ONDCP) in 2005. Mental health experts and scientists joined high-ranking government officials to discuss an emerging body of research that identified clear links between marijuana use and mental health disorders, including depression, suicidal thoughts and schizophrenia.22

The US Substance Abuse and Mental Health Service Administration (SAMHSA) report about the correlation between age of first marijuana use and serious mental illness; and an open letter to parents on “Marijuana and Your Teen’s Mental Health,” signed by twelve of the Nation’s leading mental health organizations, ran in major newspapers and newsweeklies across the country.23

Included were the following announcements:

“Regular use of the drug has appeared to double the risk of developing a psychotic episode or long-term schizophrenia.”23

“Research has strongly suggested that there is a clear link between early cannabis use and later mental health problems in those with a genetic vulnerability – and that there is a particular issue with the use of cannabis by adolescents.” 23

“Adolescents who used cannabis daily were five times more likely to develop depression and anxiety in later life.” 23

In 2016 the Obama Administration steadfastly opposes legalization of marijuana and other drugs because legalization would increase the availability and use of illicit drugs, and pose significant health and safety risks to all Americans, particularly young people.24 The US government still maintains marijuana is classified as a Schedule I drug, meaning it has a high potential for abuse and no currently accepted medical use in treatment in the United States.17, 18

Risk Evaluation and Mitigation Strategy for Marijuana Products

The dispensing of marijuana for medical purposes must follow a strict dispensing and monitoring protocol; no less arduous than that used for the delivery of drugs such as thalidomide.

Recommendation – The implementation of a REMS for marijuana products (REMSMP).

1. The first order for a government is to protect the public. As such, it befits a government approving marijuana for medical purposes to implement a REMS program.

2. Medical cannabis/marijuana dispensaries/stores/delivery systems will be       required to comply with all necessary components of a rigorous REMS program prior to selling and dispensing marijuana products.

3. Governmental regulatory organizations must be responsible for the cannabis/marijuana for medical purposes programs and obtain the required evaluations [(i.e. laboratory tests (pregnancy, HCG, etc.), physical and mental health examination documentation], signed patient consent, provider contract and education forms – performed in the required time frames both before initiation, during and after continued usage of marijuana products for medical purposes.

4. Quarterly audits will be performed, by the government regulatory organization, on each medical marijuana/cannabis dispensary for compliance.  Failure to comply with the REMSMP program will result in fines and other appropriate penalties to the marijuana dispensaries.

A REMS for Marijuana Product Potential Framework:

EMBRYO-FETAL TOXICITY & BREASTFEEDING

* Marijuana causes DNA damage in male and female patients.15  If marijuana is used during conception or during pregnancy, it may cause birth defects, cancer formation in the offspring, Downs Syndrome or embryo-fetal death.15, 16, 18

* Pregnancy must be ruled out before the start of marijuana treatment.  Pregnancy must be prevented by both the male and female patients during marijuana treatment by the use of two reliable methods of contraception.

* When there is no satisfactory alternative treatment, females of reproductive potential may be treated with marijuana provided adequate precautions are taken to avoid pregnancy.

* Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning marijuana therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.  Females must commit to either abstain continuously from heterosexual intercourse or use two methods or reliable birth control as mentioned.  They must have two negative pregnancy tests prior to initiating marijuana therapy and monthly pregnancy test with normal menses or two months with abnormal menses and for at least 1 month after stopping marijuana therapy.

* Males (all ages): DNA damage from marijuana is present in the semen of patients receiving marijuana.15 Therefore, males must always use a latex or synthetic condom during any sexual contacts with females of reproductive potential while using marijuana and for up to at least 28 days after discontinuing marijuana therapy, even if they have undergone a successful vasectomy.  Male patients using marijuana may not donate sperm.

* Blood Donation: Patients must not donate blood during treatment with marijuana and for at least 1 month following discontinuation of marijuana because the blood might be given to a pregnant female patient whose fetus should not be exposed to marijuana.

* Marijuana taken by any route of administration may result in drug-associated DNA damage resulting in embryo-fetal toxicity. Females of reproductive potential should avoid contact with marijuana through cutaneous absorption, smoke inhalation or orally.

* If there is contact with marijuana products topically, the exposed area should be washed with soap and water.

* If healthcare providers or other care givers are exposed to body fluids of a person on marijuana, the exposed area should be washed with soap and water.  Appropriate universal precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to marijuana.

* Several psychoactive cannabinoids in marijuana are fat soluble and are found to concentrate in breast milk.  Nursing mothers must not be receiving marijuana.16 Consult the primary care provider about how long to be off of marijuana before considering breast feeding.

NON-SEMINOMA TESTICULAR GERM CELL CARCINOMA

* Marijuana use is a known risk factor in the development of non-seminoma testicular germ cell carcinoma in males.25 – 28

* The presence of non-seminoma testicular germ cell carcinoma must be excluded before the start of marijuana treatment.  The patient’s primary care provider must perform a testicular examination and review the patient’s human chorionic gonadotropin (HCG) blood test before starting marijuana.  Male patients must perform weekly testicular self-evaluations while receiving marijuana.  They are also required to have their primary care provider perform a testicular evaluation and a HCG blood test performed every 4 months while receiving marijuana.29, 30

MENTAL HEALTH:

* Short term high dose and chronic marijuana usage is a known risk factor for the development of multiple mental health disorders.16, 18, 20, 31 – 34  Depression, paranoia, mental confusion, anxiety, addiction and suicide potential are all associated with acute and chronic exposure to marijuana.16, 18   Decline in intelligence is a potential risk of adolescent-onset marijuana exposure. 16, 18, 35

The presence of these mental health disorders must be evaluated by a licensed psychiatrist or psychologist by use of the Mini International Neuropsychiatric Interview or equivalent validated diagnostic instrument before marijuana is started.  The diagnostic mental health evaluation tool will be completed every 1month by an independent licensed psychiatrist or psychologist for a minimum of 6 months until unchanging and then every 4 months thereafter while receiving marijuana ending 4 months after the last exposure to marijuana.36

PSYCHIATRIC EVALUATIONS:

History of Substance Abuse Disorder: As the prevalence of substance use disorders amongst those patients requesting medical authorization of marijuana products is known to be extremely high the patient population must be screened prior to dispensing marijuana products for risk of a substance use disorder.  Substance use must be monitored prior to onset of marijuana with the World Health Organization, Smoking and Substance Involvement Screening Test (WHO-ASSIST, V3.0), and repeated at monthly intervals until unchanging and every 3 months thereafter while receiving marijuana, ending 6 months after the last exposure to marijuana.37

Conclusion

The evidence that thalidomide and tobacco products were harmful was known to the manufacturers/distributors before government and the populous acknowledged these dangers.

To date, there continue to be legal repercussions to said manufacturers/distributors/government for knowingly placing the public at risk.  We believe that the same will happen for marijuana products and that it is our responsibility to assist the Canadian government to protect the public from a similar outcome.

Since the government is fully aware of the marijuana harms, the  government must not be complicit in risking Canadian health/lives, but rather must mitigate any and all such risk to current and future generations.38, 39

The REMSMP program described assists in providing patient education, provider education and required patient monitoring before any marijuana products are allowed to be dispensed.  The program also requires on-going data collection and analysis, to determine the actual hazards from marijuana use and whether the program should even continue.  As the stewards of the country’s human and financial resources, it is critical that government protect the public from potential irreversible harm and itself from litigation risk by harmed individuals knowing that, in the context of marijuana use, harm is not only possible but probable.

Source:  Pamela McColl,  National Director,  Smart Approaches to Marijuana Canada and The Marijuana Victims’ Association,    Vancouver BC Canada    August  2016

Endorsements

Philip Seeman, M.D. Ph.D., O.C. Departments of Pharmacology and Psychiatry University of Toronto,   Nobel Prize nominee (Science)

Elizabeth Osuch, M.D. Associate Professor Rea Chair of Affective Disorders, University of Western Ontario Schulich School of Medicine and Denistry,  London, Ontario

Ray Baker, M.D., FCFP, FASAM, Associate Clinical Professor, University of British Columbia Faculty of Medicine,  Vancouver, British Columbia

Pamela McColl, Smart Approaches to Marijuana – Canada.  Board Member Campaign for Justice Against Tobacco Fraud

Robert L. DuPont, MD,  President, Institute for Behavior and Health, Inc. Clinical Professor of Psychiatry, Georgetown University School of Medicine,  First Director, National Institute on Drug Abuse,  Second US White House Drug Chief

Bertha K Madras, PhD Professor of Psychobiology, Department of Psychiatry,Harvard Medical School

Phillip A. Drum Pharm. D., FCSHP.    Smart Approaches to Marijuana – USA

Professor Gary Hulse, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Australia

Grainne Kenny, Dublin, Ireland Co-founder and Hon. President of EURAD ,Brussels, Belgium

Peter Stoker Director, National Drug Prevention Alliance, United Kingdom

Mary Brett, BSc (Hons), Chair of Charity Cannabis Skunk Sense (CanSS) www.cannabisskunksense.co.uk ,United Kingdom

Deidre Boyd, CEO: DB Recovery Resources, Editor: Recovery Plus UK

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9. Accessed on7/30/16: https://weedmaps.com/dispensaries/tree-house-collective-dispensary-san-marcos

10.  Personal conversation with Marilyn Huestis, NIH researcher, June 2015.

11. Accessed on 8/4/16:http://www.contergan.grunenthal.info/grt-ctg/GRT-CTG/Die_Fakten/Chronologie/152700079.jsp

12. Accessed on 7/28/16: http://www.thalidomide.ca/the-canadian-tragedy/ 13. Accessed on 7/28/16:  http://www.fda.gov/Drugs/NewsEvents/ucm320924.htm 14. Accessed on 7/29/16: http://news.gc.ca/web/article-en.do?nid=945369&tp=1

15. Reece AS, Hulse GK. Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity. Mutat Res. 2016;789:15-25. 16. Accessed on 7/28/16: http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/ infoprof-eng.php 17. Accessed on 1/8/16:  https://www.whitehouse.gov/ondcp/frequently-asked-questions-and-facts-about-marijuana#harmless 18. Accessed on 1/8/16:  https://www.whitehouse.gov/ondcp/marijuana  19. Accessed on 7/20/16: http://www.hc-sc.gc.ca/dhp-mps/marihuana/info/cons-eng.php

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21. Accessed on 3/8/16:http://www.cfpc.ca/uploadedFiles/Health_Policy/CFPC _Policy_Papers_and_Endorsements/CFPC_Policy_Papers/Medical%20Marijuana%20Position%20Statement%20CFPC.pdf 22. Accessed on 6/31/16 http://www.ovguide.com/john-p-walters-9202a8c040 00641f8000000 0003d9c0b

23. Accessed 8/1/2016: http://www.prnewswire.com/news-releases/white-house-drug-czar-research-and-mental-health-communities-warn-parents-that-marijuana-use-can-lead-to-depression-suicidal-thoughts-and-schizophrenia-54240132.html

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Filed under: Effects of Drugs (Papers),Medical Studies,Medicine and Marijuana,USA :

Thanks to advances in science, we have never known so much about the effects marijuana use has on the human body, particularly, the fragile brain. Yet, in a political era when scientific research is regularly marshalled to end public policy debates, the powerful, growing scholarship on marijuana has largely been ignored or dismissed. Indeed, marijuana use seems to be one of the glaring areas in modern life where wishful thinking reigns over rationality.

Yet, as the lesson of tobacco demonstrates, when Americans are given the scientific facts about serious threats to their health, they adjust their behavior and insist on measures to safeguard their communities. In the instance of marijuana, the public can be forgiven for not knowing the true threat. With the assistance of a sympathetic media, marijuana legalization advocates, many seeking to profit off the drug, continue to sell romantic falsehoods and outright lies. They casually dismiss the growing list of serious concerns about marijuana emerging from scientific scholarship and survey research, or just cry “reefer madness” without examining the evidence.

Amidst the current marijuana public policy discussion, more than ever, concerned citizens, community leaders, lawmakers, educators, and parents need to better understand the growing body of research about this drug. What follows is a compilation and discussion of the latest research, including reports that are beginning to come in on the effects legalization has had in Colorado and neighbouring states—including increased criminal activity even with legalization. While all research has limitations, what we do know is becoming clearer by the day, and it will make many question what they thought they knew about this drug of abuse.

Key Recent Findings:

Journal of the American Medical Association: “There is little doubt about the existence of an association between substance use and psychotic illness…studies suggest that the association between cannabis use and later psychosis might be causal, a conclusion supported by studies showing that cannabis use is associated with an earlier age at onset of psychotic disorders, particularly schizophrenia.”

Society for the Study of Addiction: “Regular cannabis use in adolescence approximately doubles the risks of early school-leaving and of cognitive impairment and psychoses in adulthood. Regular cannabis use in adolescence is also associated strongly with the use of other illicit drugs

World Psychiatric Association: “Evidence that is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high-potency cannabis and synthetic cannabinoids.”

American Academy of Paediatrics: “The adverse effects of marijuana have been well documented” and include “impaired short-term memory, decreased concentration, attention span, and problem solving” which “interfere[s] with learning.”

American Psychological Association: “Heavy marijuana use in adolescence or early adulthood has been associated with a dismal set of life outcomes including poor school performance, higher dropout rates, increased welfare dependence, greater unemployment and lower life satisfaction.”

Proceedings of the National Academy of Sciences: “Persistent adolescent-onset cannabis users” showed “an average 8-point IQ decline from childhood to adulthood.”

Clinical Psychological Science Journal: Duke University and UC Davis researchers “found that those dependent on cannabis experienced more financial difficulties, such as paying for basic living expenses and food, than those who were alcohol dependent.”

Journal of Drug and Alcohol Dependence: States that have legalized “medical” marijuana find an association with higher 12th grade drop-out rates, lessened college attainment, and increases in daily smoking. Further, there is a dose/response relationship between adverse impact and years of increased exposure under legalization.

U.S. Department of Health and Human Services, SAMHSA: Since legalizing marijuana, Colorado climbed to number one among states for both youth (12-17) and college age adults (18-25) marijuana use.

Discussion:

The further acceptance of marijuana legalization and commercialization in some states will lead to a greater availability of the drug. Greater availability and acceptance will lead to greater use of marijuana, both in the sense of more users, and likely further in the sense of more frequent and greater consumption.

In states that have legalized already there is strong evidence that adult use has surged upward. There is further evidence that use by youth will also increase.

Youth use of marijuana in states that have now commercialized sales was already more extensive than national norms, however, reports since the first commercialization began in January, 2014, indicate growing use amongst all age groups.

As marijuana use intensifies, the consequences of such use and abuse accelerates. These consequences are considerable, and will impose significant costs, both personal and economic, on health and social well-being.

Finally, and perversely, evidence is strong that the consequences will include not only continued, but intensified and entrenched criminal activity associated with drug use. Indications are clear that the criminal and violent black market capitalizes on increased marijuana availability and use. Marijuana commercialization/legalization is advancing both a public health and a public safety disaster.

We shall review recent evidence of the health-related consequences in this document. In a later accompanying document we will assess the impact on use of drugs beyond marijuana, as well as the impact on further criminal drug markets.

Though comparisons between marijuana and other substances of abuse are frequently made to the effect that marijuana is not proportionally lethal, there are nevertheless other measures of the drug’s dangers. Former National Institute on Drug Abuse Director Dr. Bob DuPont has termed marijuana “the most dangerous drug,” in part because of the sheer prevalence of what is the most widely used illegal substance in the world, and in part because the effects are not always felt or experienced by those affected. They can nevertheless be measured and are real. In some instances, research shows that they appear irreversible, even after abstinence.

Among the more troubling findings are those showing a relationship between marijuana use and psychotic episodes, diminished memory, verbal skill, and other cognitive performance, lowered life achievements, criminal and anti-social behavior, school leaving and academic failure, and even lowered life satisfaction.

Most concerning, perhaps, are the findings that heavy, early marijuana use is associated with a loss of intelligence over the life course. Specific supporting citations for other statements will be found below.

Further, Dr. Wayne Hall’s twenty-year review of the literature in the journal Addiction, as we will present in greater detail in the review, showed a clear relationship between youth marijuana use and subsequent use of other drugs. As Hall has argued:

The relationships between regular cannabis use and other illicit drug use have persisted after statistical adjustment for the effects of confounding variables in both longitudinal studies and discordant twin studies… The order of involvement with cannabis and other illicit drugs, and the increased likelihood of using other illicit drugs, are the most consistent findings in epidemiological studies of drug use in young adults.

In general, the health risks of marijuana use are reasonably well known, and based on long-standing research that now consists in multiple studies across many nations, exploring many dimensions of what is a very complex drug.

The last decade has witnessed an intensification of concern and stimulated even more studies of marijuana’s manifold impact, involving several areas of the body and the mind. The comprehensive nature of the physiological impact mirrors, to some extent, the widespread dispersal of the body’s naturally-occurring endocannabinoid receptor system.

There are additional physiological concerns, many based on smoking as the manner of consumption, focused on its effects on the cardiac and respiratory systems. These threats are real and mounting.

But the most compelling investigations regarding risk are emerging from studies of the brain, however the drug is consumed. These include both the structure and the functioning of the neurophysiology of the brain, and they further extend into discoveries regarding the consequences of brain activity, as we have mentioned, such as cognition, memory, learning, executive performance, and general behavior. Moreover, they also include examinations of drug dependency and what is termed “marijuana use disorder.”

That is, both the brain as an organ as well as “the mind,” the very personhood, of the individual are affected by the chemistry of the drug. Most concern is focused on the principle intoxicating element, THC , which shows signs of being actively toxic to the nervous system, the potency of which in modern forms is escalating dramatically under marijuana commercialization.

We must acknowledge that many studies demonstrate a risk that is emergent, and not fully known; multiple factors and confounders do coincide and must be accounted for before we argue “causation” for the effects that have been shown. Nevertheless, a substantial and repeated body of research that, taken piece by piece, showing “associations” or “correlations” or “predispositions,” must now be seen as sufficient, when taken together, to establish a clear and present danger.

In some measure, the worst effects are contingent, in the sense that not all forms of use by all individuals will produce the direst impact. But by now the evidence is compelling that certain forms of use, under certain circumstances, is deeply damaging.

Simply put, any honest observers must accept that the preponderance of evidence, as suggested by our review of recent literature which follows, demonstrates a high risk from marijuana use that is now overwhelming.

What we find is research from several related lines of inquiry, all pointing in the same direction. The risks are only worsening with time, in each line of inquiry, serving to confirm a congruence with the findings from other arena.

Studies of various marijuana disorders of behavior are being underpinned and given a basis by studies of the brain and its performance; showing consistent patterns from several interrelated domains of impact. Moreover, as over time the tools brought to bear have become more sophisticated and able to measure subtle and consequential effects, the sense of concern over what we are doing to youth is only mounting.

Though all users, even adult non-frequent users, have been shown to suffer some deficits through marijuana intoxication, and though there are further indications that even young adult casual users undergo structural brain changes, the evidence is far more robust and more worrying in other circumstances.

Danger increases, that is, when any of the following conditions are co-present with marijuana use: the existence of co-morbidities (or even predispositions), especially collateral substance dependencies or psychological deficits; certain genetic profiles that confer greater susceptibility; heavy, frequent use (daily use being the most threatening), especially of high-potency varieties; and especially exposure at a developmentally young age, during periods of highly consequential brain formation and calibration, generally ranging from prenatal or paediatric exposure up to young adulthood.

Where more than one of these factors is present, the risks escalate; where the developmentally young smoke high-potency cannabis frequently for an extended period – most markedly those with predisposing psychological deficits – the effects can be catastrophic in their lives, including dramatic “psychotic breaks.” These effects appear to be, in some cases, largely irreversible.

And it is this “worst-case scenario” that, perversely, is being fostered by state legalization and commercialization measures, thereby ensuring the greatest magnitude of damage.

A further implication of these facts concerns our emerging knowledge of the risks, given that most longitudinal studies showing long-term adult impacts were carried out without an appreciation of how the various factors above conferred greater vulnerability.

Often, studies that failed to find major impact were based on samples of adults, not adolescents, who were not exposed to heavy, frequent, newly-potent doses. Yet the commercialization of marijuana has resulted in marijuana potency that eclipses anything we have ever previously seen, in some cases by orders of magnitude. Highly potent “edibles” and concentrated cannabis extractions, like “shatter” are taking potency levels once common in the two- to three-percent range up to 80 percent. The consequence is that most everything we thought we knew about marijuana’s risks needs to be re-assessed under contemporary conditions, and most every danger, as we progressively uncover them, turns out to be heightened.

These finding are warnings of grave danger, with the promise of yet more to be discovered. Not all is “proven,” and not all establishes independent causation, but the evidence is strong enough, and growing daily, to activate in public policy a “precautionary principle.” That is, the evidence is strong enough to warrant a clear directive not to proceed further. Simply put, the pathway of legalization must not be pursued.

Recent Research and Findings: An Annotated Review

What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? (full article), Addiction, (2014).

“Regular cannabis use in adolescence approximately doubles the risks of early school-leaving and of cognitive impairment and psychoses in adulthood. Regular cannabis use in adolescence is also associated strongly with the use of other illicit drugs.”

Unintentional Pediatric Exposures to Marijuana in Colorado: 2009-2015, Pediatrics, (2016).

“Annual pediatric marijuana cases increased more than 5-fold from 2009 (9) to 2015 (47). Colorado had an average increase in cases of 34% (P < .001) per year while the remainder of the United States had an increase of 19% (P < .001).”

Wants Marijuana Products to Have Warnings Against Use in Pregnancy, National Council on Alcoholism and Drug Dependence, (2015).

The American Medical Association seeks warnings against marijuana use in pregnancy.

Cannabis Use and Earlier Onset of Psychosis, Psychiatry, (2011).

“There is little doubt about the existence of an association between substance use and psychotic illness. National mental health surveys have repeatedly found more substance use, especially cannabis use, among people with a diagnosis of a psychotic disorder. There is a high prevalence of substance use among individuals treated in mental health settings,6 and patients with schizophrenia are more likely to use substances than members of the wider community. Prospective birth cohort and population studies suggest that the association between cannabis use and later psychosis might be causal, a conclusion supported by studies showing that cannabis use is associated with an earlier age at onset of psychotic disorders, particularly schizophrenia.”

The Impact of Marijuana Policies on Youth: Clinical, Research, and Legal Update, American Academy of Pediatrics, (2015).

“The adverse effects of marijuana have been well documented, and studies have demonstrated the potential negative consequences of short- and long-term recreational use of marijuana in adolescents. These consequences include impaired short- term memory and decreased concentration, attention span, and problem solving, which clearly interfere with learning. Alterations in motor control, coordination, judgment, reaction time, and tracking ability have also been documented; these may contribute to unintentional deaths and injuries among adolescents (especially those associated with motor vehicles if adolescents drive while intoxicated by marijuana).

Negative health effects on lung function associated with smoking marijuana have also been documented, and studies linking marijuana use with higher rates of psychosis in patients with a predisposition to schizophrenia have recently been published, raising concerns about longer-term psychiatric effects. New research has also demonstrated that the adolescent brain, particularly the prefrontal cortex areas controlling judgment and decision-making, is not fully developed until the mid-20s, raising questions about how any substance use may affect the developing brain. Research has shown that the younger an adolescent begins using drugs, including marijuana, the more likely it is that drug dependence or addiction will develop in adulthood. A recent analysis of 4 large epidemiologic trials found that marijuana use during adolescence is associated with reductions in the odds of high school completion and degree attainment and increases in the use of other illicit drugs and suicide attempts in a dose-dependent fashion that suggests that marijuana use is causative.”

American Academy of Pediatrics Reaffirms Opposition to Legalizing Marijuana for Recreational or Medical Use, American Academy of Pediatrics, (2015).

The American Academy of Pediatrics () reaffirms its opposition to legalizing marijuana, citing the potential harms to children and adolescents.

Half-Baked — The Retail Promotion of Marijuana Edibles, New England Journal of Medicine, (2015).

“Edibles that resemble sugary snacks pose several clear risks. One is over-intoxication….At high doses, can produce serious anxiety attacks and psychotic-like symptoms. This problem is augmented by differences in the pharmacokinetic and metabolic effects of marijuana when it is ingested rather than smoked. In addition, case reports document respiratory insufficiency in young children who have ingested marijuana.”

Adverse Health Effects of Marijuana Use, New England Journal of Medicine, (2014).

A review of the current state of the science related to the adverse health effects of the recreational use of marijuana, focusing on those areas for which the evidence is strongest.

A New England Journal of Medicine Article about Marijuana, Psychology Today, (2014) summarizes the adverse health effects as published in the New England Journal of Medicine.

UN: cannabis law changes pose ‘very grave danger to public health’, The Guardian, (2014).

United Nations International Narcotics Control Board warns of “very grave danger” from legalizing marijuana.

Damaging Effects of Cannabis Use on the Lungs, Advances in Experimental Medicine and Biology, (2016).

“Cannabis smoke affects the lungs similarly to tobacco smoke, causing symptoms such as increased cough, sputum, and hyperinflation. It can also cause serious lung diseases with increasing years of use. Cannabis can weaken the immune system, leading to pneumonia. Smoking cannabis has been further linked with symptoms of chronic bronchitis. Heavy use of cannabis on its own can cause airway obstruction. Based on immuno-histopathological and epidemiological evidence, smoking cannabis poses a potential risk for developing lung cancer.”

Marijuana use in adolescence may increase risk for psychotic symptoms, American Journal of Psychiatry, (2016).

Regular marijuana use significantly increased risk for subclinical psychotic symptoms, particularly paranoia and hallucinations, among adolescent males.

Heavy, persistent pot use linked to economic, social problems at midlife: Study finds marijuana not ‘safer’ than alcohol, Clinical Psychological Science, (2016).

Science Daily’s review of a research study that followed children from birth up to age 38 has found that people who smoked cannabis four or more days of the week over many years ended up in a lower social class than their parents, with lower-paying, less skilled and less prestigious jobs than those who were not regular cannabis smokers. These regular and persistent users also experienced more financial, work-related and relationship difficulties, which worsened as the number of years of regular cannabis use progressed.

The impact of adolescent exposure to medical marijuana laws on high school completion, college enrolment and college degree completion, Drug & Alcohol Dependence, (2016).

States that have legalized marijuana find an association with higher 12th grade drop out rates, lessened college attainment, and increases in daily smoking. Further, there is a dose/response relationship between adverse impact and years of increased exposure under legalization.

Early marijuana use associated with abnormal brain function, lower IQ, Lawson Health Research Institute, (2016).

“Previous studies have suggested that frequent marijuana users, especially those who begin at a young age, are at a higher risk for cognitive dysfunction and psychiatric illness, including depression, bipolar disorder and schizophrenia.”

Marijuana Users Have Abnormal Brain Structure and Poor Memory, Northwestern Medicine, (2013).

“Teens who were heavy marijuana users — smoking it daily for about three years — had abnormal changes in their brain structures related to working memory and performed poorly on memory tasks, reports a new Northwestern Medicine® study. A poor working memory predicts poor academic performance and everyday functioning. The brain abnormalities and memory problems were observed during the individuals’ early twenties, two years after they stopped smoking marijuana, which could indicate the long-term effects of chronic use. Memory-related structures in their brains appeared to shrink and collapse inward, possibly reflecting a decrease in neurons.”

Young adult sequelae of adolescent cannabis use: an integrative analysis, Lancet Psychiatry, (2014).

Adolescent cannabis use has adverse consequences in young adulthood:

“We recorded clear and consistent associations and dose-response relations between the frequency of adolescent cannabis use and all adverse young adult outcomes. After covariate adjustment, compared with individuals who had never used cannabis, those who were daily users before age 17 years had clear reductions in the odds of high-school completion…and degree attainment…, and substantially increased odds of later cannabis dependence…, use of other illicit drugs…, and suicide attempt.”

Traditional marijuana, high-potency cannabis and synthetic cannabinoids: increasing risk for psychosis, World Psychiatry, (2016).

“Evidence that [THC] is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high-potency cannabis and synthetic cannabinoids.”

Monitoring Marijuana Use in the United States; Challenges in an Evolving Environment, (2016).

“Use of marijuana or any of its components, especially in younger populations, is associated with an increased risk of certain adverse health effects, such as problems with memory, attention, and learning, that can lead to poor school performance and reduced educational and career attainment, early-onset psychotic symptoms in those at elevated risk, addiction in some users, and altered brain development.”

Marijuana use and use disorders in adults in the , 2002–14: analysis of annual cross-sectional surveys, Lancet Psychiatry, (2016).

Commenting on this study to the Associated Press, Dr. Wilson Compton, Deputy Director of said, “if anything, science has shown an increasing risk that we weren’t as aware of years ago.” He added that other research has increasingly linked marijuana use to mental impairment, and early, heavy use by people with certain genes to increased risk of developing

psychosis.

Prenatal marijuana exposure, age of marijuana initiation, and the development of psychotic symptoms in young adults, Psychological Medicine, (2015).

Prenatal marijuana exposure linked to bad childhood outcomes; if effect is further “mediated” through early onset marijuana use, strong association with negative adult outcomes, such as arrest, low educational performance, unemployment.

One in six children hospitalized for lung inflammation positive for marijuana exposure, American Academy of Pediatrics, (2016).

Colorado: 16% of exposed children admitted to hospital for lung inflammation tested positive for MJ metabolite.

Cannabis use increases risk of premature death, American Journal of Psychiatry, (2016).

Cannabis use in youth increases the risk of early death.

Scientists Call for Action Amidst Mental Health Concerns, The Guardian, (2016).

“Most research on cannabis, particularly the major studies that have informed policy, are based on older low-potency cannabis resin.” According to Sir Robin Murray, professor of psychiatric research at King’s College London: “It’s not sensible to wait for absolute proof that cannabis is a component cause of psychosis. There’s already ample evidence to warrant public education around the risks of heavy use of cannabis, particularly the high-potency varieties. For many reasons, we should have public warnings.””

Marijuana use in adolescence may increase risk for psychotic symptoms, American Journal of Psychiatry, (2016).

Chronic marijuana use in adolescent boys increases risk of developing persistent subclinical psychotic symptoms (hallucinations, paranoia). “For each year adolescent boys engaged in regular marijuana use … subsequent symptoms increased by 21% and… paranoia or hallucinations increased by 133% and 92%, respectively. This effect persisted even when [study] participants stopped using marijuana for 1 year.”

Heavy, persistent pot use linked to economic, social problems at midlife, Clinical Psychological Science, (2016).

“Regular long-term [marijuana] users also had more antisocial behaviors at work, such as stealing money or lying to get a job, and experienced more relationship problems, such as intimate partner violence and controlling abuse.”

Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review, Psychiatry, (2016).

This longitudinal study documented adolescent-onset (but not adult-onset) persistent cannabis users showed neuropsychological decline ages 13 to 38 years. “Longitudinal investigations show a consistent association between adolescent cannabis use and psychosis. Cannabis use is considered a preventable risk factor for psychosis… strong

physiological and epidemiological evidence supporting a mechanistic link between cannabis use and schizophrenia… raise[s] the possibility that our current, limited knowledge may only apply to the ways in which the drug was used in the past.”

Marijuana use disorder is common and often untreated, National Institute of Health/NESARC, (2016).

“People with marijuana use disorder are vulnerable to other mental health disorders … onset of the disorder was found to peak during late adolescence. …People with marijuana use disorder…experience considerable mental disability. …Previous studies have found that such disabilities persist even after remission of marijuana use disorder.”

The health and social effects of nonmedical cannabis use, World Health Organization, (2016).

“There is a worrying increasing demand for treatment for cannabis use disorders and associated health conditions in high- and middle-income countries, and there has been increased attention to the public health impacts of cannabis use and related disorders in international policy dialogues.”

AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers, Translational Psychiatry, (2016).

“Smoking cannabis daily doubles an individual’s risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier.”

What’s That Word? Marijuana May Affect Verbal Memory, Internal Medicine, (2016).

Researchers found a “dose-dependent independent association between cumulative lifetime exposure to marijuana and worsening verbal memory in middle age.”

Adolescent Cannabinoid Exposure Induces a Persistent Sub-Cortical Hyper-Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex., Cerebral Cortex, (2016).

“We report that adolescent, but not adult, exposure induces long-term neuropsychiatric-like phenotypes similar to those observed in clinical populations…. findings demonstrate a profound dissociation in relative risk profiles for adolescent versus adulthood exposure to in terms of neuronal, behavioral, and molecular markers resembling neuropsychiatric pathology.”

Cannabis increases the noise in your brain, Biological Psychiatry, (2015).

“At doses roughly equivalent to half or a single joint, ∆9- produced psychosis-like effects and increased neural noise in humans. The dose-dependent and strong positive relationship between these two findings suggest that the psychosis-like effects of cannabis may be related to neural noise which disrupts the brain’s normal information processing activity.”

Marijuana Use: Detrimental to Youth, American College of Pediatricians, (2016).

“Marijuana is the leading illicit substance mentioned in adolescent emergency department admissions and autopsy reports, and is considered one of the major contributing factors leading to violent deaths and accidents among adolescents.”

Chronic Adolescent Marijuana Use as a Risk Factor for Physical and Mental Health Problems in Young Adult Men, Psychology of Addictive Behaviors, (2015).

Evidence suggests that youth who use marijuana heavily during adolescence may be particularly prone to health problems in later adulthood (e.g., respiratory illnesses, psychotic symptoms).

Developmental Trajectories of Marijuana Use among Men, Journal of Research in Crime and Delinquency, (2015).

“Young men who engage in chronic marijuana use from adolescence into their 20s are at increased risk for exhibiting psychopathic features, dealing drugs, and enduring drug-related legal problems in their mid-30s.”

Appraising the Risks of Reefer Madness, Cerebrum, (2015).

“Cannabis is generally accepted as a cause of schizophrenia (though less so in North America, where this topic has received little attention),” notes Dr. R. Murray, an Oxford University Professor of Psychiatry.

Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons, Adán de Salas-Quiroga, (2015).

“Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.” “This study demonstrates that remarkable detrimental consequences of embryonic exposure on adult-brain function, which are evident long after withdrawal, are solely due to the impact of on CB1 receptors located on developing cortical neurons.” Embryonic exposure increased seizures in adulthood and the consequences of prenatal were lifelong; even though the cannabinoid receptors after withdrawal appear normal, there is an apparent impact on connectivity.

Association Between Use of Marijuana and Male Reproductive Hormones and Semen Quality: A Study Among 1,215 Healthy Young Men, American Journal of Epidemiology, (2015).

“Regular marijuana smoking more than once per week was associated with a 28% … lower sperm concentration and a 29% … lower total sperm count after adjustment for confounders.”

Is Marijuana Use Associated With Health Promotion Behaviors Among College Students? Health-Promoting and Health-Risk Behaviors Among Students Identified Through Screening in a University Student Health Services Center, Journal of Drug Issues, (2015).

“Results showed marijuana users were more likely to use a variety of substances and engage in hazardous drinking than non-users.”

Psychosocial sequelae of cannabis use and implications for policy: findings from the Christchurch Health and Development Study, Social Psychiatry and Psychiatric Epidemiology, (2015).

“Findings…suggest that individuals who use cannabis regularly, or who begin using cannabis at earlier ages, are at increased risk of a range of adverse outcomes, including: lower levels of educational attainment; welfare dependence and unemployment; using other, more dangerous illicit drugs; and psychotic symptomatology.”

Young brains on cannabis: It’s time to clear the smoke, Clinical Pharmacology and Therapeutics, (2015).

“There is certainly cause for concern about the amount and frequency of cannabis use among youth….Recent evidence shows that early and frequent use of cannabis has been linked with deficits in short-term cognitive functioning, reduced IQ, impaired school performance, and increased risk of leaving school early – all of which can have significant consequences on a young person’s life trajectory….Heavy cannabis use in adolescence is also a risk factor for psychosis….Youth aged 15-24 spent the largest number of days in a hospital for a primary diagnosis of mental and behavioral disorders due to the use of cannabinoids.”

Association Between Lifetime Marijuana Use and Cognitive Function in Middle Age and Long-term Marijuana Use and Cognitive Impairment in Middle Age, Internal Medicine, (2016).

“These studies have generally shown reduced activity in those with long-term marijuana use in brain regions involved in memory and attention, as well as structural changes in the hippocampus, prefrontal cortex, and cerebellum.”

Denial of Petition To Initiate Proceedings To Reschedule Marijuana, Federal Register/DEA Review of “Scientific Evidence of [Marijuana’s] Pharmacological Effects, If Known”, (2016).

“Individuals with a diagnosis of marijuana misuse or dependence who…initiated marijuana use before the age of 15 years, showed deficits in performance on tasks assessing sustained attention, impulse control, and general executive functioning compared to non-using controls. These deficits were not seen in individuals who initiated marijuana use after the age of 15 years…. Additionally, in a prospective longitudinal birth cohort study of 1,037 individuals, marijuana dependence or chronic marijuana use was associated with a decrease in IQ and general neuropsychological performance compared to pre-marijuana exposure levels in adolescent onset users.

The decline in adolescent-onset users’ IQ persisted even after reduction or abstinence of marijuana use for at least 1 year…. The deficits in IQ seen in adolescent-onset users increased with the amount of marijuana used. Moreover, when comparing scores for measures of IQ, immediate memory, delayed memory, and information-processing speeds to pre-drug-use levels, the current, heavy, chronic marijuana users showed deficits in all three measures.”

The health and social effects of nonmedical cannabis use, World Health Organization, (2016).

“Cannabis is globally the most commonly used psychoactive substance under international control. In 2013, an estimated 181.8 million people aged 15−64 years used cannabis for nonmedical purposes globally (uncertainty estimates 128.5–232.1 million) (UNODC, 2015). There is a worrying increasing demand for treatment for cannabis use disorders and associated health conditions in high- and middle-income countries, and there has been increased attention to the public health impacts of cannabis use and related disorders in international policy dialogues.[…] This publication builds on contributions from a broad range of experts and researchers from different parts of the world. It aims to present the current knowledge on the impact of nonmedical cannabis use on health.”

Source:  https://hudson.org/research/12975-marijuana-threat-assessment-part-one-recent-evidence-for-health-risks-of-marijuana-use

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers) :

Abstract

The growing use and legalization of cannabis are leading to increased exposures across all age groups, including in adolescence. The touting of its medicinal values stems from anecdotal reports related to treatment of a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer’s disease, Parkinson’s disease, post-traumatic stress, inflammatory bowel disease, and anxiety. However, it is critical that societal passions not obscure objective assessments of any potential and realized short- and long-term adverse effects of cannabis, particularly with respect to age of onset and chronicity of exposure.

This critical review focuses on evidence-based research designed to assess both therapeutic benefits and harmful effects of cannabis exposure, and is combined with an illustration of the neuropathological findings in a fatal case of cannabis-induced psychosis.

The literature and reported case provide strong evidence that chronic cannabis abuse causes cognitive impairment and damages the brain, particularly white matter, where cannabinoid 1 receptors abound. Contrary to popular perception, there is little objective data supporting preferential use of cannabis over conventional therapy for restoration of central nervous system structure and function in disease states such as multiple sclerosis, epilepsy, or schizophrenia. Additional research is needed to determine if sub-sets of individuals with various neurological and psychiatric diseases derive therapeutic benefits from cannabis. David E. Mandelbaum, MD, PhD Suzanne M. de la Monte, MD MPH

Departments of Neurology, Pediatrics, Neuropathology and Neurosurgery, Hasbro Children’s Hospital and Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI 02903

Source:    http://dx.doi.org/10.1016/j.pediatrneurol.2016.09.004

Filed under: Effects of Drugs (Papers),Medicine and Marijuana :
 September 12, 2016
Gaining scientific proof of adverse effects of cannabis, a world first
Suppression of thalamocortical projection by chronic administration of Δ9-THC (cannabinoid, active ingredient of marijuana). Photomicrograph of cerebral cortex from transgenic mice expressing GFP in thalamocortical axons at postnatal day 7 (P7). (left) : Normal thalamocortical projections. In the middle layer (layer 4), blobs of GFP showing dense termination of thalamocortical axons can be seen (under number 1~5). (right): Thalamocortical projection at P7 from a mouse received chronic administration of Δ9-THC (P2~7). Massive retraction of thalamocortical projections including middle layer (layer 4) can be observed. Credit: Osaka University

Researchers have clarified important mechanisms involved in the formation of neural circuits in the brain. This group also discovered that delta-9-tetrahydrocannabinol (THC), a psychoactive substance also found in cannabis, causes disruption of neural circuits within the cortex. These results explain why cannabis may be harmful and have potential to find application in the functional recovery of brain injury and in cases of dementia.

Neural activity is known to play an important role in the formation of neural circuits. However, we still do not know much about what kind of neural activities are involved in this formation process. This process is especially complex in projections from the thalamus to the cortex, of which so far we only knew that as these projections develop, unnecessary projections are eliminated, thereby leaving only correct projections.

A group of researchers led by Fumitaka Kimura, associate professor at the Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, has now clarified the involvement of several mechanisms in the formation of this neural circuit. The researchers also put forth scientific evidence that cannabis intake causes the unnecessary trimming of neural connections, leading to a breakdown of neural circuits (Figure 1).

In their study, this group of researchers discovered that in a different section of the cortex, the rule (Spike Timing-Dependent Plasticity: STDP) by which synaptic strength (a functional measure of connections) between neurons was determined suddenly changed at a certain point in development. Building on this finding, the group examined whether a similar STDP change occurred in the projection from the thalamus and the cortex as well. They found that initially, the synapses were strengthened due to the synchronized activities of the pre- (thalamic) and post- (cortical) synaptic neurons. But after the projections had spread widely, the synchronized activities weakened all but some synapses, thereby eliminating unnecessary projections to enable more systematic ones. As the synapses are weakened, endogenous cannabinoid is released from neural cells via these synchronized activities, leading to a regression of unnecessary neuron projections (Figure 2). The researchers also confirmed such regression when cannabinoid was taken in externally.

The researchers also confirmed such regression when cannabinoid was taken in externally.

Gaining scientific proof of adverse effects of cannabis, a world first
Endogenous cannabinoid regulates the termination area of thalamocortical axons.(left): Normal thalamocortical projection terminates within a square area in layer 4 (barrel, indicated in red), revealed by visualization of individual thalamocortical axons at P12.(left): Disorganized projections of thalamocortical axons at P12 in animals in which gene of cannabinoid receptor was knocked out. Thalamocortical axons overshoot layer 4 and invade upper layers (layer 2/3); the axons seem to ignore barrels boundaries. Credit: Osaka University

These findings may have an impact on further research focused on advancing our understanding of the mechanisms involved in the formation of neural circuits and have the potential to lead to the development of new therapies to improve recovery from brain damage and dementia. In addition, the findings provide for the adverse effects of cannabis consumption on brain development and therefore may help to decrease abuse of marijuana.

This research was featured in the electronic version of Journal of Neuroscience on June 29, 2016.

More information: C. Itami et al, Developmental Switch in Spike Timing-Dependent Plasticity and Cannabinoid-Dependent Reorganization of the Thalamocortical Projection in the Barrel Cortex,Journal of Neuroscience (2016). DOI: 10.1523/JNEUROS

Source:  http://medicalxpress.com/news/2016-09-adverse-effects-cannabis-scientifically.html 12 Sept 2016

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers) :

At one point a few days ago I feared to turn on the radio or TV because of the ceaseless accounts of blood, death and screams, one outrage after another, which would pour out of screen or loudspeaker if I did so.

And I thought that one of the most important questions we face is this: How can we prevent or at least reduce the horrifying number of rampage murders across the world?

Let me suggest that we might best do so by thinking, and studying. A strange new sort of violence is abroad in the world. From Japan to Florida to Texas to France to Germany, Norway and Finland, we learn almost weekly of wild massacres, in which the weapon is sometimes a gun, sometimes a knife, or even a lorry. In one case the pilot of an airliner deliberately flew his craft into a hillside and slaughtered everyone on board. But the victims are always wholly innocent – and could have been us.

The culprits of the Charlie Hebdo murders, all had drugs records or connections. The same was true of the Bataclan gang, of the Tunis beach killer and of the Thalys train terrorist

I absolutely do not claim to know the answer to this. But I have, with the limited resources at my disposal, been following up as many of these cases as I can, way beyond the original headlines.

* Those easiest to follow are the major tragedies, such as the Oklahoma City bombing, the Nice, Orlando, Munich and Paris killings, the Anders Breivik affair and the awful care-home massacre in Japan last week. These are covered in depth. Facts emerge that do not emerge in more routine crimes, even if they are present.

Let me tell you what I have found. Timothy McVeigh, the 1995 Oklahoma bomber, used cannabis and methamphetamine. Anders Breivik took the steroid Stanozolol and the quasi-amphetamine ephedrine. Omar Mateen, culprit of the more recent Orlando massacre, also took steroids, as did Raoul Moat, who a few years ago terrorised the North East of England. So did the remorseless David Bieber, who killed a policeman and nearly murdered two others on a rampage in Leeds in 2003.

Eric Harris, one of the culprits of the Columbine school shooting, took the SSRI antidepressant Luvox. His accomplice Dylan Klebold’s medical records remain sealed, as do those of several other school killers. But we know for sure that Patrick Purdy, culprit of the 1989 Cleveland school shooting, and Jeff Weise, culprit of the 2005 Red Lake Senior High School shootings, had been taking ‘antidepressants’.

So had Michael McDermott, culprit of the 2000 Wakefield massacre in Massachusetts. So had Kip Kinkel, responsible for a 1998 murder spree in Oregon. So had John Hinckley, who tried to murder US President Ronald Reagan in 1981 and is now being prepared for release. So had Andreas Lubitz, the German wings pilot who murdered all his passengers last year. The San Bernardino killers had been taking the benzodiazepine Xanax and the amphetamine Adderall.

The killers of Lee Rigby were (like McVeigh) cannabis users. So was the killer of Canadian soldier Nathan Cirillo in 2014 in Ottawa (and the separate killer of another Canadian soldier elsewhere in the same year). So was Jared Loughner, culprit of a 2011 mass shooting in Tucson, Arizona. So was the Leytonstone Tube station knife attacker last year. So is Satoshi Uematsu, filmed grinning at Japanese TV cameras after being accused of a horrible knife rampage in a home for the disabled in Sagamihara.

I know that many wish to accept the simple explanation that recent violence is solely explained by Islamic fanaticism. No doubt it’s involved. Please understand that I am not trying to excuse or exonerate terrorism when I say what follows.

But when I checked the culprits of the Charlie Hebdo murders, all had drugs records or connections. The same was true of the Bataclan gang, of the Tunis beach killer and of the Thalys train terrorist.

It is also true of the two young men who murdered a defenceless and aged priest near Rouen last week. One of them had also been hospitalised as a teenager for mental disorders and so almost certainly prescribed powerful psychiatric drugs.

The Nice killer had been smoking marijuana and taking mind-altering prescription drugs, almost certainly ‘antidepressants’.

As an experienced Paris journalist said to me on Friday: ‘After covering all of the recent terrorist attacks here, I’d conclude that the hit-and-die killers involved all spent the vast majority of their miserable lives smoking cannabis while playing hugely violent video games.’

The Munich shopping mall killer had spent months in a mental hospital being treated (almost certainly with drugs) for depression and anxiety

Now look at the German events, eclipsed by Rouen. The Ansbach suicide bomber had a string of drug offences. So did the machete killer who murdered a woman on a train in Stuttgart. The Munich shopping mall killer had spent months in a mental hospital being treated (almost certainly with drugs) for depression and anxiety.

Here is my point. We know far more about these highly publicised cases than we do about most crimes. Given that mind-altering drugs, legal or illegal, are present in so many of them, shouldn’t we be enquiring into the possibility that the link might be significant in a much wider number of violent killings? And, if it turns out that it is, we might be able to save many lives in future.

Isn’t that worth a little thought and effort?

Source:  PETER HITCHENS FOR THE MAIL ON SUNDAY

PUBLISHED: 00:55, 31 July 2016 | UPDATED: 18:36, 31 July 2016

Filed under: Effects of Drugs (Papers),Global Drug Legalisation Efforts,Social Affairs (Papers) :

The proportion of marijuana-positive drivers involved in fatal motor vehicle crashes in Colorado has increased dramatically since the commercialization of medical marijuana in the middle of 2009, according to a study. The study raises important concerns about the increase in the proportion of drivers in a fatal motor vehicle crash who were marijuana-positive since the commercialization of medical marijuana in Colorado, particularly in comparison to the 34 non-medical marijuana states. 

ShapeThe proportion of marijuana-positive drivers involved in fatal motor vehicle crashes in Colorado has increased dramatically since the commercialization of medical marijuana in the middle of 2009, according to a study by University of Colorado School of Medicine researchers.

With data from the National Highway Traffic Safety Administration’s Fatality Analysis Reporting System covering 1994 to 2011, the researchers analyzed fatal motor vehicle crashes in Colorado and in the 34 states that did not have medical marijuana laws, comparing changes over time in the proportion of drivers who were marijuana-positive and alcohol-impaired.

 The researchers found that fatal motor vehicle crashes in Colorado involving at least one driver who tested positive for marijuana accounted for 4.5 percent in the first six months of 1994; this percentage increased to 10 percent in the last six months of 2011. They reported that Colorado underwent a significant increase in the proportion of drivers in a fatal motor vehicle crash who were marijuana-positive after the commercialization of medical marijuana in the middle of 2009. The increase in Colorado was significantly greater compared to the 34 non-medical marijuana states from mid-2009 to 2011. The researchers also reported no significant changes over time in the proportion of drivers in a fatal motor vehicle crash who were alcohol-impaired within Colorado and comparing Colorado to the 34 non-medical marijuana states.

Stacy Salomonsen-Sautel, Ph.D, who was a postdoctoral fellow in the Department of Pharmacology, is the lead author of the study, which is available online in the journal Drug and Alcohol Dependence. Christian Hopfer, MD, associate professor of psychiatry, is the senior author. 

Salomonsen-Sautel said the study raises important concerns about the increase in the proportion of drivers in a fatal motor vehicle crash who were marijuana-positive since the commercialization of medical marijuana in Colorado, particularly in comparison to the 34 non-medical marijuana states. While the study does not determine cause and effect relationships, such as whether marijuana-positive drivers caused or contributed to the fatal crashes, it indicates a need for better education and prevention programs to curb impaired driving.

Source:. Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado. Drug and Alcohol Dependence, 2014; DOI: 10.1016/j.drugalcdep.2014.04.008

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Transport (Papers),USA :

Between January 1, 2015 and April 22, 2015, the American Association of Poison Control Centers reported getting 1900 calls related to synthetic cannabinoid exposure, proving that the popularity of this alternative to natural marijuana has been steadily increasing. Synthetic cannabinoids, when smoked or ingested, act on the endocannabinoid receptors, similar to delta-9 tetrahydrocannabinol, the primary psychoactive ingredient in marijuana.  While dyspnea related to synthetic cannabinoid use is common, other pulmonary adverse effects have rarely been reported, specifically inhalation fever which is discussed in a recent case published in the American Journal of Case Reports.

The patient, a 29-year-old male, presented to the emergency department with severe agitation after smoking the synthetic cannabinoid K2. Medical history included a diagnosis of schizoaffective disorder for which he was not receiving treatment. To sedate him, multiple doses of lorazepam and haloperidol were used. Physical examination of the patient showed the following:

* Temperature: 100.2º F

* Blood pressure: 110/50 mmHg

* Heart rate: 109/min

* Respiratory rate: 18/min

* Oxygen saturation: 95%

* Chest exam: No crackles, wheeze, rhonchi on auscultation; chest radiograph: diffuse reticular-nodular and interstitial infiltrates

* Cardiovascular exam: JVP not elevated, S1 and S2 heard, no additional heart sounds, murmurs, rubs; rate/rhythm regular

* Lab tests: Leukocytosis with predominant neutrophilia (83.4%); blood culture samples showed no growth after 5 days

* Urine toxicology: Negative for cannabinoids, benzodiazepine, phenycyclidine, opiates, cocaine, barbiturates

The patient was given ceftriaxone 1g IV, azithromycin 500mg IV, magnesium sulfate 2g IV (for hypomagnesemia), potassium phosphate 22mEq IV (for hypophosphatemia), famotidine 40mg daily for GI prophylaxis and heparin 500 Units SC twice daily for prophylaxis of venous thromboembolism. His mental status improved and his fever dissipated 24 hours after admission; repeat chest radiograph showed resolution of the pulmonary infiltrates. Clinicians were unable to re-evaluate his blood levels, as the patient refused repeat blood draws.

Once in stable condition, he was discharged with a diagnosis of inhalation fever due to synthetic cannabinoid and was told to abstain from use of this substance. For empirical treatment of pneumonia, he was given levofloxacin 750mg daily for seven days; he was also given a prescription for risperidone 1mg twice daily for two weeks for his schizoaffective disorder. Though an outpatient appointment was scheduled, the patient did not follow-up and so his long-term outcome is uncertain.

In the United States, there are over 50 types of synthetic cannabinoids; the substances are typically available in herbal blends, potpourri, and incense.  In this patient, given the fever and transient pulmonary infiltrates, inhalation fever is believed to have developed as a consequence to K2 inhalation. Symptoms associated with inhalation fever may include cough, dyspnea, headache, malaise, myalgia and nausea, however, this patient did not experience any of these, apart from leukocytosis which is a feature of this condition.

Treatment generally includes supportive care and avoidance of the causative agent. Other diagnoses considered for this patient included acute hypersensitivity pneumonitis (which may present in a similar manner), chemical pneumonitis (an inflammatory reaction to a particulate), or bacterial pneumonia (given the fever, tachycardia, leukocytosis, and pulmonary infiltrates). Infection, however, was not considered likely given a repeat chest radiograph 24 hours later showed resolution of the pulmonary infiltrates and blood culture was negative.

Given this is the first case to report on inhalation fever as a side effect of synthetic cannabinoid inhalation, further research is needed to understand the mechanism by which this reaction occurred. In the meantime, the authors warn that “as the Emergency Department visits by synthetic cannabinoid abusers are increasing, the importance of physicians being aware of these adverse effects cannot be overstated.”

Source:   Thiru Chinnadurai, Srijan Shrestha, Raji Ayinla. A Curious Case of Inhalation Fever Caused by Synthetic Cannabinoid. American Journal of Case Reports. 2016, doi: 10.12659   6th July 2016    http://www.empr.com/

Filed under: Effects of Drugs (Papers),Synthetics :

Using marijuana and alcohol together greatly increases the amount of THC, marijuana’s active ingredient, in the blood, a new study concludes. Using the two substances together raises THC levels much more than using marijuana by itself.

The researchers say using alcohol and marijuana together considerably increases the risk of car crashes, compared with using marijuana alone.

The study included 19 people who drank alcohol or a placebo in low doses 10 minutes before they inhaled vaporized marijuana in either a low or high dose, Time reports. When a person drank alcohol, their blood concentration of THC was much higher.  The findings are published in Clinical Chemistry.

A  study published last year  found teenagers who use marijuana and alcohol together are more likely to engage in unsafe driving, compared with those who use one of those substances alone.

Teens who used alcohol alone were 40 percent more likely to admit they had gotten a traffic ticket and 24 percent more likely to admit involvement in a traffic crash, compared with teens who didn’t smoke marijuana or drink. Teens who smoked marijuana and drank were 90 percent more likely to get a ticket and 50 percent more likely to be in a car crash, compared with their peers who didn’t use either sub

Source:   http://www.drugfree.org/join-together     28th May2015

Filed under: Alcohol,Cannabis/Marijuana,Drugs and Accidents,Effects of Drugs (Papers) :

A stressed rat will seek a dose of cocaine that is too weak to motivate an unstressed rat. The reason, NIDA researchers report, is that the stress hormone corticosterone increases dopamine activity in the brain’s reward center. When an animal is stressed, the cocaine-induced dopamine surge that drives drug seeking rises higher because it occurs on top of the stress-related elevation.

Graduate student Evan N. Graf, Dr. Paul J. Gasser, and colleagues at Marquette University in Milwaukee, Wisconsin, traced the physiological pathway that links stress and corticosterone to increased dopamine activity and heightened responsiveness to cocaine. Their findings provide new insight into cocaine use and relapse, and point to possible new medication strategies for helping people stay drug free.

Stress Increases Sensitivity to Relapse Triggers

Former drug users who relapse often cite stress as a contributing factor. The Marquette researchers observed that when stress figures in relapse, other relapse promoters are almost always present as well. Dr. Gasser explains, “It’s never one single event that triggers relapse. It’s the convergence of many events and conditions, such as the availability of the drug, cues that remind people of their former drug use, and also stress.” On the basis of this observation, the researchers hypothesized that stress promotes relapse by making a person more sensitive to other relapse triggers.

To test their hypothesis, the researchers put stressed and unstressed rats through an experimental protocol that simulates regular drug use in people followed by abstinence and exposure to a relapse trigger. As the stressor, they used a mild electric foot shock; as the relapse trigger, they administered a low dose of cocaine (2.5 milligrams per kilogram).

The results confirmed the hypothesis. The stressed rats, but not the stress-free animals, responded to the small cocaine dose with a behavior that parallels relapse in people: They resumed pressing a lever that they had previously used to self-administer the drug (see Figure 1, top graph).

stress_hormone

 

Text Description of Graphic

A Stress Hormone Underlies the Effect

Mr. Graf and colleagues turned their attention to the question of how stress sensitizes animals to cocaine’s motivational effect. One likely place to start was with the hormone corticosterone. In stressful situations, the adrenal glands release corticosterone into the blood, which carries it throughout the body and to the brain. Among corticosterone’s physiological roles is that it affects glucose metabolism and helps to restore homeostasis after stress. The Marquette researchers demonstrated that increasing cocaine’s potential to induce relapse also belongs on the list of corticosterone’s effects. Reprising their original experimental protocol with a couple of new twists, they showed that:

  • Corticosterone is necessary for stress to promote relapse to cocaine seeking: The researchers removed rats’ adrenal glands, which prevented the animals from producing corticosterone. In this condition, the animals did not exhibit relapse behavior when exposed to the stressor and low-dose cocaine.
  • Corticosterone in the brain reward center is sufficient by itself to increase cocaine’s potency as a relapse trigger:The researchers injected these same rats with corticosterone, bringing the hormone concentration up to stress levels in the brain reward center (nucleus accumbens, NAc). Now the animals exhibited relapse behavior when exposed to cocaine, even without the stressor (see Figure 1, middle graph).

Enhanced Dopamine Activity…

The researchers next took up the question: What does corticosterone do in the NAc to increase cocaine’s potency to induce relapse? A hypothesis that suggested itself immediately was that the hormone enhances dopamine activity. Dopamine is an important neuromodulator in the NAc, and all addictive drugs, including cocaine, produce their motivating effects by increasing dopamine concentrations in the NAc.

The Marquette team showed that, indeed, stress-level concentrations of corticosterone enhance the cocaine-induced rise in extracellular dopamine in the NAc. In this experiment, the researchers exposed two groups of rats to low-dose cocaine, then measured their NAc dopamine levels with in vivo microdialysis. One group, which was pretreated with corticosterone injections, had higher dopamine levels than the other, which was not pretreated.

The Marquette team firmed up their hypothesis with a further experiment. They reasoned that if corticosterone promotes relapse behavior by increasing dopamine activity, then preventing that enhancement should prevent the behavior. This indeed turned out to be the case. When the researchers injected animals with corticosterone but also gave them a compound (fluphenazine) that blocks dopamine activity, exposure to low-dose cocaine did not elicit relapse behavior.

…Due To Reduced Dopamine Clearance

So far the Marquette team had established that the stress hormone corticosterone promotes relapse behavior by increasing dopamine activity in the NAc. Now they moved on to the next question: How does corticosterone enhance dopamine activity?

To address this question, the researchers considered the cycle of dopamine release and reuptake. In the NAc, as elsewhere in the brain, dopamine activity depends on the concentration of the neurotransmitter in the extracellular space (space between neurons): the higher the concentration, the more activity there will be. In turn, the extracellular dopamine concentration depends on the balance between two reciprocal ongoing processes: specialized neurons releasing dopamine molecules into the space, and specialized proteins drawing molecules back inside the neurons.

Mr. Graf and colleagues discovered that corticosterone interferes with the removal of dopamine molecules from the extracellular space back into cells. It shares this effect with cocaine, but achieves it by a different mechanism.

In this experiment, the researchers measured real-time changes in dopamine concentration in the NAc in response to electrical stimulation of dopamine release in the area. This technique allowed the team to measure both A) the rate of increase in dopamine concentration, indicating the amount of dopamine released; and B) the rate of decrease in dopamine concentration, indicating the rate of dopamine clearance. The scientists measured stimulation-induced increases and decreases in extracellular dopamine concentrations under three conditions: at baseline, after giving the animals a compound that blocks the dopamine transporter (DAT), which is the mechanism whereby cocaine inhibits dopamine removal; and, last, after injecting the animals with corticosterone. They found that:

  • As happens with cocaine, the clearance of extracellular dopamine decreased after DAT blockade.
  • Clearance of extracellular dopamine decreased further after corticosterone.

 

A Candidate Mechanism

One question remained outstanding to complete the picture of how stress potentiates the response to cocaine: What is the mechanism whereby corticosterone reduces dopamine clearance?

Mr. Graf and colleagues noted that previous research provides a likely answer: Corticosterone has been shown to inhibit the functioning of the organic cation transporter 3 (OCT3), which is another of the specialized proteins that, like DAT, remove dopamine from the extracellular space. To confirm this hypothesis, the researchers resorted again to their initial experimental protocol. This time, they injected rats with a compound (normetanephrine) that blocks OCT3, followed by low-dose cocaine. The animals responded by resuming their previously abandoned lever pressing  behavior, proving that OCT3 blockade is sufficient to potentiate the response to cocaine (see Figure 1, bottom graph).

The Marquette researchers say that further studies will be required to definitively establish that OCT3 plays the role their evidence points to. Taken together, however, their experiments trace a complete pathway connecting stress to an animal’s enhanced responses to cocaine (see Figure 2):

  • Stress raises corticosterone levels.
  • Corticosterone blocks OCT3, inhibiting dopamine clearance and thereby raising dopamine activity in the NAc.
  • When a stressed animal is exposed to cocaine, the resulting dopamine surge builds on the foundation of this already higher-than-normal level of dopamine activity.
  • The added elevation of the dopamine surge increases the animal’s motivation to seek the drug.

 

streee_relapse

Figure 2. Stress Amplifies Cocaine’s Effect on Dopamine Release in the Nucleus Accumbens (NAc) The schematic illustrates how stress may enhance cocaine’s motivational effect and increase the risk for relapse. A) Cocaine binds to the dopamine transporter (DAT) on dopamine-releasing neurons in the NAc, reducing dopamine (DA) clearance and, in turn, increasing extracellular dopamine. B) Stress causes release of corticosterone, which inhibits the OCT3 transporter, further reducing dopamine clearance and increasing extracellular dopamine. The resulting heightened dopamine stimulation of medium spiny neurons (MSNs) enhances drug seeking.

Text Description of Graphic

Stress–Relapse Connection Unraveled

“Our findings show that stress doesn’t just cause relapse behavior by itself, but interacts with other ongoing behaviors to influence relapse,” Dr. Gasser says. “This insight provides a better picture of how stress can affect addiction. It helps us understand why treating cocaine addiction is so difficult and will help in designing therapies whether they be based on pharmacotherapy or counseling.” The researchers believe—and are testing as a hypothesis—that stress increases the power of environmental drug-associated cues to trigger relapse, just as it does the power of low-dose cocaine.

Although researchers have long known that stress plays an important role in relapse, pinning down its role experimentally has been a challenge, says Dr. Susan Volman, program officer and health science administrator at NIDA’s Behavioral and Cognitive Science Research Branch. “This study provides a perspective of stress as a stage-setter or modulator for relapse, and it gets all the way down to the molecular mechanism. Based on this team’s findings, OCT3 offers a potential new target for developing pharmacological therapies to help with treating addiction,” Dr. Volman says.

This work was supported by NIH grants DA017328, DA15758, and DA025679.

Source:

Graf, E.N.; Wheeler, R.A.; Baker, D.A. et al. Corticosterone acts in the nucleus accumbens to enhance dopamine signalling and potentiate reinstatement of cocaine seeking. Journal of Neuroscience 33(29):11800-11810, 2013. Full text

Filed under: Addiction,Brain and Behaviour,Effects of Drugs (Papers),Treatment :

DENVER (CBS4) – The results of a new study about the impact of Colorado’s marijuana legalization is raising troubling questions for parents. The study cites a significant increase in marijuana-related traffic deaths, hospital visits and school suspensions. The parents CBS4’s Melissa Garcia spoke with say they’re concerned about their children seeing messages promoting pot all over town. Activists say it’s the way pot is marketed and sold that has started to create some serious problems.

“I never dreamed in a million years that this would happen to my son,” said parent Kendal, who didn’t want to use his last name.

Kendal came home one evening to find his 13-year-old son unconscious from what he says was a marijuana overdose.

He was grey. His heart wasn’t beating and he wasn’t breathing,” he said.

Kendal used CPR to resuscitate him and later talked to his son’s high school peer and supplier.

“I had heard from kids that there was 60 percent of this particular high school using drugs, and she shook her head and said, ‘That’s way low,’” Kendal said.

“Kendal’s story breaks my heart, but I’ve got to tell you we have heard that from hundreds and hundreds and hundreds of parents throughout the state,” said Diane Carlson, Smart Colorado co-founder.

Carlson says Colorado’s child and teen use of marijuana has become an epidemic.

“Kids have no idea how dangerous or harmful Colorado’s pot is,” she said.Carlson says Colorado’s child and teen use of marijuana has become an epidemic.

According to a report released this month by the Rocky Mountain High Intensity Drug Trafficking Area, Colorado saw a 29 percent increase in emergency room visits, and a 38 percent increase in hospitalizations during retail marijuana’s first year.

The study states that over 11 percent of Colorado’s 12 to 17 year-olds use pot — 56 percent higher than the national average. It also cites a 40 percent increase in drug-related suspensions and expulsions — the vast majority from marijuana.

Carlson says the culprit is its commercialization. “Marijuana might have been legalized in our state; it did not have to mean massive commercialization and promotion of marijuana use,” she said.

Source: http://denver.cbslocal.com/2015/09/20/smart-colorado

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Global Drug Legalisation Efforts,Parents :

The lobby calling to decriminalise drugs focuses too much on gang violence. This overlooks death and health destruction among drug users. Photograph: Lawrence Lawry/Science Photo Library
The real horror of drugs stems not from gangs selling them, but from their effects on users, writes Chris Luke.

The wonderfully mischievous Mae West memorably skewered the perennial dilemma surrounding illicit intoxication when she quipped, “To err is human, but it feels divine!” And of course, it is a truth – almost universally acknowledged – that humans love to self-medicate, to seek oblivion and respite from the “grim predicament of existence”, with whatever mind-altering substance they can get hold of, be it 21st century psychotropic or ancient herbal concoction.
It seems equally likely that a debate has raged for ever between those who fret about the effects of such intoxicants on humanity, and those who see them as divine anaesthetics, soporifics and tonics.

The problem with contemporary substance misuse is mainly to do with its sheer scale and unnatural geography. These can be attributed to the global trading which took off in the 17th century, and to modern chemistry which led in the mid-19th century to the refining of organic produce into powders and liquids. These could be conveniently consumed by wealthy Europeans and Americans in a variety of oral, smoke-able and injectable formulations.

The acceleration, since Victorian times, of mechanised global trading and the dissemination of simplified chemistry kits now means that all sorts of chemical contraband are routinely transported thousands of miles from their source, and are easily and universally available for a small sum.

The illicit drug trade is arguably the most successfully globalised of all. Unfortunately, this enormous commercial success for “drug barons” (and sometimes the difference between life and death for dirt-poor drug-cultivators) has created a global pandemic of substance misuse with immensely problematic consequences.

For the most part, these tend to be viewed through the prisms of crime control and drug addiction treatment, and a remarkable number of commentators are now arguing – as did Dr Paul O’Mahony recently in these pages – for “decriminalisation” as the solution. Their central thesis is that it is the violent drug gangs which cause the main problems associated with substance misuse, and that legalisation would squeeze these menacing middlemen out of the equation.

Sadly, I think that this is extraordinarily naive and completely misses the point.
As a doctor who has been on the “receiving end” of industrial levels of substance misuse for many years (in inner-city hospital emergency departments in Dublin, Edinburgh, Liverpool, and now Cork), I am convinced that the question of “legality” of drugs is largely irrelevant in terms of the hazards of drugs to society in general and people’s health in particular.

Putting it very simply, the criminality of users is almost never an issue. It is the deaths, destruction of health and communities and the distraction from the primary function of the emergency department, due to substance misuse, that are of interest to me.

And as for Fintan O’Toole’s recent assertion, in The Irish Times, that “there is no great evidence that the demand is actually higher now . . . than it was a century ago”, I would point out that there is no funding for research into the healthcare frontline workload. So he will have to take my word that, while the appetite for them may not vary much over time, the intoxicants du jour in Ireland are much more worrisome than they were, say, in the post-war period, adding incalculably as they do, in terms of complexity and labour-intensity, to the existing tobacco and alcohol burdens.

The notions of “legalising”, “purifying” and “controlling” once-illegal drugs are frankly laughable in today’s risk-averse society. But drug users (including those who consume alcohol and tobacco) are prone to utter hypocrisy and self-delusion when it comes to their own prescriptions.

The fact is that people are no longer prepared to accept even minimal levels of risk when it comes to existing, legal and fastidiously purified pharmaceuticals (thalidomide is notorious but all medicines carry a risk of occasionally tragic adverse effects) and patients eagerly litigate, even after rare and unpredictable complications from the medications they have been prescribed.

The same would immediately apply to consumers of (hypothetically) legalised “hard drugs” like cocaine and heroin – and even cannabis – whose natural (ie “pure”) effects will always be unpredictably catastrophic for some individuals and inevitably disastrous for society, as dysphoric or delirious people interact with their hazard-ridden environment, as well as with other individuals who may often be less than sympathetic to their drug-addled fellow citizens. In addition, just because a commodity is legal doesn’t mean that it won’t be of interest to criminal gangs: think petrol, tobacco and alcohol and simply look North, after all.

Setting aside such specious reasons for “decriminalising” drugs, it is vital that people grasp the pivotal reality about drug misuse: the hideous and worsening global epidemic of violence – be it in British and Irish cities or Caribbean hotel rooms – is primarily fuelled by the effects of alcohol, cannabis and cocaine on the human psyche, and not by the illegality of the drugs. Drugs (including drink) derange. That is the whole point of taking them, and those who are easily or already deranged will do terrible things to the people around them as a direct result.

Sadly, “anti-prohibitionists” continue wilfully to forget that before drugs (like cocaine, cannabis or opium) were illegal, they were legal – with violent, woeful consequences. My greatest fear is that the ignorance of this seems invincible.

Chris Luke is consultant in emergency medicine in Cork University Hospital and Mercy University Hospital, Cork.

Source 2008 The Irish Times Monday, August 4, 2008

Filed under: Effects of Drugs (Papers),Social Affairs (Papers) :

Abstract

Smoking cannabis daily doubles an individual’s risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual’s acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis—which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content—and also ±7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.

Discussion

To our knowledge, this study provides the first evidence that the acute psychotic effects of cannabis are predicted by variation at the rs2494732 locus of the AKT1 genotype. No evidence was found for an interaction of the COMT Val158Met genotypes with cannabis use, in producing psychotomimetic symptoms in this group of healthy cannabis users. Cannabis dependence predicted non-intoxicated schizotypal symptoms, but neither genotype had any impact on these. COMT Val158Met genotype had a marginal impact on performance on a working memory task when non-intoxicated and when memory load was low; however, at higher load, schizotypy was the only emerging predictor of performance. When intoxicated with cannabis, gender was the only predictor of working memory performance, with poorer performance in females at a high working memory load.

In the current study, which is the largest ever to be conducted on the acute response to cannabis, psychotomimetic symptoms while intoxicated were found to be predicted by variation at the rs2494732 locus of the AKT1 genotype in healthy young cannabis smokers, increasing with C allele dosage. These data are very important as acute psychotic response to cannabis is thought to be a marker of the risk of developing psychosis from smoking the drug.1 Two previous studies have implicated this polymorphism in the interaction with cannabis and psychosis,9, 18 but this work concentrated on individuals who were at familial risk of schizophrenia. This study is the first to demonstrate that the acute response to cannabis is modulated by AKT1 in otherwise healthy cannabis smokers. The mechanism for this modulation of acute effects may be through the interaction of AKT1 with dopamine.2, 9Our sensitivity analyses suggested that these effects may be confined to dependent cannabis smokers but further investigation of these data with larger samples is required.

AKT1 codes for a protein that is a serine/threonine kinase, which has a variety of functions, one of which is as a signalling molecule downstream of the dopamine D2 (DRD2) receptor. Decreased AKT1 functionality may result in enhanced responses to DRD2 receptor stimulation.19 THC has been found to acutely induce dopamine release in

rats20, 21 and in humans,22, 23 although not in all studies.24 Dopamine release is thought to occur via the blockade of cannabinoid 1 (CB1) receptors on GABAergic neurons that target pyramidal cells. These neurons normally exert an inhibitory effect on the firing of dopamine neurons that project back to the nucleus accumbens, so agonism of CB1 receptors by THC may produce increased dopamine release. This THC-mediated increase in dopamine release may be further exacerbated by decreased AKT1 functionality. Elevated levels of mesolimbic dopamine are known to have a role in the development of psychotic symptoms, potentially through disrupted salience attribution.25

In contrast to the role of variation at the rs2494732 locus of AKT1, this study found no support for the direct involvement of the functional polymorphism of the COMT gene in mediating acute psychotic response to cannabis. This is in contrast to one previous small-scale acute laboratory study giving acute THC to patients with schizophrenia,26 and other work that suggested that COMT may mediate the psychotomimetic risk of cannabis3 but in agreement with subsequent larger studies that failed to replicate these findings.4, 27 There was a marginal effect of COMT on working memory performance at a low load when not intoxicated. This polymorphism of COMT initially caused some excitement as several studies emerged demonstrating its association with working memory,28, 29 but this finding was not confirmed by meta-analyses,30 which suggested that this may be a case of publication bias.

Greater schizotypal symptoms predicted in poorer working memory performance on the more difficult section of the task among drug-free cannabis users. This echoes recent findings of poorer working memory in individuals high in schizotypy31 and indeed of the relationship between working memory performance and transition to psychosis.32 Working memory impairment is considered a central cognitive impairment in schizophrenia, and there is some evidence that such impairments are related to symptoms, particularly to negative symptoms.33, 34

Only gender predicted acute working memory impairment from cannabis, with greater impairment in females. Very few studies have examined gender differences in neurocognitive acute response to THC, with those that have using very small samples and in finding little evidence of gender differences.35 However, this study examined the acute effects of cannabis in over 400 cannabis smokers. There is an emerging preclinical literature that might explain this effect. CB1 density has been found to vary by gender, with animal studies reporting greater CB1 receptor density among males across several brain regions.36, 37 However, across their lifetime, adult female brains show increases in CB1 receptor density, with levels eventually surpassing those observed in males.38 Furthermore, greater CB1 de-sensitization after exposure to THC in the prefrontal cortex, hippocampus, striatum, amygdala and midbrain is seen in female adolescent rats.36, 37 Preclinical studies have also demonstrated that female rats preferentially metabolize THC to its most highly active metabolite, while male rats metabolize THC to multiple compounds.39 In combination, these findings may in part explain the finding of greater acute working memory impairment from cannabis in females. This also may partly be driven by gender differences in frequency of cannabis use. Users who smoked cannabis less frequently experienced stronger effects, and as there was a higher proportion of low frequency female cannabis users compared to males this may have contributed to the observed gender differences in working memory following the drug.

Strengths of this study include the large sample size for assessing acute cannabis effects. We also used independent verification of the cannabinoid content of the cannabis consumed and drug history. Further, the hypothesis-driven approach we took to genetic analysis was a strength, examining only loci implicated in previous studies and, therefore, circumventing some of the problems of type I error that have dogged earlier research. However, inevitably there are several limitations of the study. For the cannabis use data, while verifying past 3 months use with hair analysis, we inevitably relied on retrospective self-reports of drug use, which are particularly complicated as cannabis is known to acutely impair episodic memory. However, we opted to use years of cannabis use in this model as this was considered the most reliable to estimate. As we purposely recruited a young group of cannabis users, there was restricted variation in years used and future studies may investigate this further. We used a predominantly white Caucasian sample. However, it is unlikely that ethnic differences in allele frequency at rs2494732 biased the outcome of the study, as there was no difference between the frequency of rs2494732 alleles across the dichotomized ethnic groups. In addition, analyses with only Caucasian participants gave the same results to the analysis containing all ethnicities.

In summary, we found that the AKT1 rs2494732 C allele was associated with increased psychotomimetic symptoms after smoking cannabis. The other factor impacting on acute psychotomimetic response to cannabis was baseline schizotypy. Gender was the only factor to predict acute working memory impairment, with poorer performance in females. When drug free, cannabis dependence weakly predicted schizotypal symptoms and COMT genotype had a marginal impact on working memory, along with ethnicity. The findings of this study contribute to a recent and growing body of evidence suggesting that variation at the AKT1 locus confers details of the risk of cannabis smoking for schizophrenia. This is likely to be in the context of numerous other genetic variants, so the clinical utility at the moment is unclear. It is nonetheless encouraging that there is concordance between genetic influences on acute effects of cannabis and those mediating risk of psychosis. However, the fact that AKT1 is relevant to the biology of psychotic symptoms suggests that this might be a promising direction for novel therapeutics for cannabis-induced psychosis.

Source:  Citation: Translational Psychiatry (2016) 6, e738; doi:10.1038/tp.2015.219 Published online 16 February 2016 

For complete paper log on to: http://www.nature.com/tp/journal/v6/n2/full/tp2015219a.html

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers) :

CNN– Last week, the government released its National Survey on Drug Use and Health. It didn’t make much of a news splash, but it should have — and in years past, it would have.

When a serious war is taking place, officials throughout the administration hold press conferences and issue statements while print and televised media across the country report on it. Almost none of this happened, although the reasons for talking and reporting are greater than they have been in a very long time.

Here’s the takeaway: Illicit drug abuse is seriously affecting our children, our schools, our workplaces and our society. And it is on the rise. In 2009, nearly 22 million Americans were regularly abusing illicit drugs: a rise of 1.5 million abusers of marijuana from 2008 and a rise of 2.3 million users from 2007, a rise of 205,000 abusers of Ecstasy from 2008, a rise of 188,000 abusers of methamphetamine from 2008 and a rise of 800,000 abusers of prescription drugs from 2008.

Then there’s the death toll. Nearly 40,000 Americans are killed each year by drug overdoses — not drug-related car accidents, not drug-related gang violence or homicide; those are an entirely different and eye-popping set of numbers. By overdose alone, we lose the equivalent of more than one 9/11 a month and almost eight times as many Americans as have been killed in Iraq and Afghanistan since 2001 (deaths the national media reports on weekly, if not daily).

There are more people dying from drug overdose in America than people dying from gun violence. In several states, drug overdose deaths outnumber deaths caused by car crashes. But these drug-death statistics receive almost no media attention.

Who, outside those that toil in the fields of addiction and recovery, knows these numbers? And how many people caught this in another recent report: Almost 30 percent of public school students ages 12-17 attend schools that are both “gang and drug-infected.” This accounts for almost 6 million children attending schools where drugs and violence dominate their campuses. Places of learning, places once known as safe.

Keeping drugs from children should be our main focus and concern. As Joseph Califano, the founder of the Center on Addiction and Substance Abuse, points out, a child who gets to age 21 without using illegal drugs “is virtually certain never to do so.” But fewer and fewer children are getting the message they need about the dangers and toxicity of illegal drugs, both from our national leaders and our culture. The message the dominant culture in America does send on drug use and abuse is the wrong one.

President Obama may be struggling to find an issue on which leaders from both sides of the aisle can come together. We suggest the growing drug abuse epidemic as ideal. But our president, a man popular with the youth of America, a man children look up to and listen to, has been silent on the issue, the very one with which he could make a dramatic difference in the lives of young people.

As for the popular culture, the message has been even more damaging. Where once television shows actively promoted the dangers of drug use, several of our more popular shows, from “Weeds” to “Entourage” to “Mad Men,” make drug use a laugh line.

Back when our country was making a serious assault on drug abuse, a show like “Weeds” would never be aired. Today it is promoted in full page ads in our nation’s most popular magazines. This, for a comedy about the life and times of a marijuana-growing and -dealing family.  As the head of the network that produces and airs “Weeds” put it, “Our ratings were va-va-va-voom! Who said hedonism is passé?” This, for a show where one is lured to root for a family responsible for the death of a DEA agent, children dropping out of school, gang violence and rape.

In the meantime, the state of California has certified a proposition for November’s ballot that would legalize the individual possession of dozens of joints of marijuana, even as more and more studies come out revealing the connection between marijuana use, psychosis and psychotic symptoms, among other ill-health effects; even as a recent Rand Corp. study found that such a legalization scheme in California could increase use by as much as 50 to 100 percent. Just what California needs. The most recent polling shows this proposition has an even chance of passing.

With all this, it should be no real surprise the drug numbers are on the increase. Our national leaders are silent, our culture makes laugh lines of drug use and serious numbers of serious people are advocating further legalization.

Legalization, however, is a siren song that truly will shipwreck more of our youth. Even with marijuana as prevalent and accessible as it is to young people, there is a reason the numbers for alcohol and tobacco use are higher than illicit drug abuse. When one talks to children, they give the answer: It is found in the word “illegal.” Legalization removes stigma, is the handmaiden of availability and, as Joe Califano has pointed out, “availability is the mother of use.”

The verbal and cultural detoxification of the dangers of drugs has shown its cost in the cultural message that has been sent out. The only question that remains is how much higher a price do we want our children to pay with the further verbal, cultural and legal detoxification of the toxic?

Once upon a time, our national and popular cultural leaders took a strong stand against drug use, and a unified, concerted message was disseminated to help reduce drug use in America. It worked. In the late 1980s and early 1990s, use was reduced by more than 50 percent. But it took effort from our political leaders, our cultural leaders, television, movies and schools — everyone got involved to help create a “sobriety chic” where drug use was not glamorized, and the media gave intense coverage to the devastation wrought by drugs.

That is exactly what is needed again, and now. We know how to do this. There is a rare group of actors and entertainers who have been lucky, fortunate, rare enough to overcome their addictions. Society has cheered for them and repaid them for their recovery at the box office. We should find a way for them to convey to the public their cautionary stories as to what it was like thinking they were going to die, or waking up in a cold jail cell, about their ruined relationships and the time they wish they had back.

At the same time, let’s start a national campaign with those who have not had drugs ruin their lives. Let them be the new national role models for young people. We should see public service announcements and ads from the likes of Beyonce, Reese Witherspoon, Jennifer Lopez, Taylor Swift, Tim McGraw, the Jonas Brothers; from the likes of the Williams Sisters and the Manning brothers; from Jimmy Johnson and Danika Patrick.

This issue needs such a campaign. In drug recovery circles, there is a popular saying: If you do the same thing over and over again, you will get the same result. This message has a very helpful converse however, if we repeat the strategies we used that worked once before, i.e., in the late 1980s and early 1990s, we can also get the same result.

This is our plea to the country’s national and cultural leaders: Address it, talk to our youth about it, make a campaign of it and, as for Hollywood and the rest of California: Stop with the drug use and legalization “chic.” Such a national campaign worked before, it can work again.

Source:  By William J. Bennett, Alexandra Datig and Seth Leibsohn, Special to CNN September 24, 2010   http://edition.cnn.com/2010/OPINION/09/24/bennett.drug.abuse/

Filed under: Effects of Drugs (Papers) :

One evening in April, Ethan Darbee, a 24-year-old paramedic in Syracuse, responded to a call on the city’s south side: unknown man down. Rolling up to the scene, he saw a figure lying motionless on the sidewalk. Darbee raked his knuckles across the man’s sternum to assess his level of consciousness. His eyelids fluttered. Inside the ambulance, Darbee hooked him up to a heart monitor, and he jerked involuntarily. The odd reaction puzzled Darbee. Why would the guy recoil from an electrode sticker but not a sternal rub? The driver started for the hospital. Darbee sat in the captain’s chair in the back of the rig, typing on a laptop. Then he heard a sound no paramedic ever wants to hear: the click of a patient’s shoulder harness unlatching. Swivelling around, he found himself eyeball to eyeball with his patient, who was now crouched on all fours on top of the stretcher, growling.

That same evening, Heather Drake, a 29-year-old paramedic, responded to a call at an apartment complex on the west side. When she arrived, four firefighters were grappling with a 120-pound woman who was flailing and flinging vomit at anyone who came near her. A bystander shouted that the woman was high on ‘‘spike’’ — the prevailing local term for synthetic marijuana, which is more commonly known around the country as spice. But Drake didn’t believe it. Spike didn’t turn people into violent lunatics. Phencyclidine (PCP) or synthetic cathinones (‘‘bath salts’’) could do that, maybe even a joint soaked in formaldehyde — but not spike. Drake sprayed a sedative up the woman’s nose and loaded her into the ambulance. A mayday call from another crew came over the radio. In the background static of the transmission, Drake could hear Ethan Darbee yelling.

Darbee’s patient had sprung off the stretcher and knocked him to the floor of the ambulance, punching him repeatedly in the face. Darbee grasped the side-door handle and tumbled into the street. Within moments, the police arrived and quickly subdued the man. Two days later, 19 more spike overdoses would swamp local emergency rooms, more in one day in Syracuse than the number of overdoses reported statewide in most states for all of April.

Syracuse, where I’ve lived almost my entire life, has struggled with synthetic drugs before. William Harper, a local businessman and two-time Republican candidate for City Council, moonlighted as the kingpin of bath salts in New York for two years before the Drug Enforcement Administration took him down in 2011. Was there a spike kingpin out there now, flooding the street with a bad batch? Perhaps, but similar outbreaks occurred in several states along the Gulf of Mexico in April, and the American Association of Poison Control Centers reports that between January and June, the nationwide number of synthetic marijuana ‘‘exposures’’ — that is, reported contact with the substance, which usually means an adverse reaction —

had already surpassed totals for 2013 and 2014, and that 15 people died from such exposure. Maybe there was a larger cause.

Every state has banned synthetic cannabinoids, the chemicals in spike that impart the high. Although the active ingredients primarily come from China, where commercial labs manufacture them to order like any other chemical, spike itself is produced domestically. Traffickers spray the chemicals on dried plant material and seal the results in foil pouches; these are then sold on the Internet or distributed to stores across the country, which sell them sometimes under the counter, as in Syracuse, or sometimes right by the cash register, depending on local laws. Unlike marijuana, cocaine and other naturally occurring drugs, synthetic cannabinoids can be tweaked on a molecular level to create novel, and arguably legal, drugs.

Since 2008, when authorities first noted the presence of synthetic cannabinoids in ‘‘legal marijuana’’ products, periodic surges in overdoses have often coincided with new releases, and emergency doctors have had to learn on the fly how to treat them. This latest surge is notable for the severity of symptoms: seizures, extreme swings in heart rate and blood pressure, kidney and respiratory failure, hallucinations. Many patients require such enormous doses of sedatives that they stop breathing and require intubation, and yet they still continue to struggle violently. Eric Kehoe, a shift commander at the Rural Metro ambulance company that employs Darbee and Drake, said bath-salts overdoses are easier to deal with. ‘‘You might find them running naked down the middle of the street,’’ he said, but ‘‘you could talk them down. These people here — there’s no point. You can’t even reason with them. They’re just mute. They have this look about them that’s just like a zombie.’’

Syracuse is one of the poorest cities in America — more than a third of the people here live below the poverty line. After I made a few visits to Upstate University Hospital’s emergency department, where most spike cases in the area end up, it became clear to me that the vast majority of serious users here don’t resemble the victims typically featured in reefer-madness-type stories about the dangers of ‘‘designer drugs.’’ They aren’t curious teenagers dabbling in what they thought was a legal high dispensed from a head shop. They’re broke, often homeless. Many have psychiatric problems. They’ve smoked spike for months, if not years. They buy it from rundown convenience stores and corner dealers in the city’s worst neighborhoods, fully aware that it’s an illegal drug with potentially severe side effects. Doctors could tell me what happened when people overdosed on spike, but they couldn’t tell me why anyone would smoke it in the first place, given the possible consequences.

‘‘It’s crazy,’’ was all that one overdose patient could tell me. ‘‘Syracuse is Spike Nation, man. I don’t know who called it that, but that’s what they’re saying.’’

Slide Show | Syracuse’s Spike Epidemic One of the poorest cities in America has become a hotbed for synthetic marijuana.

The visible center of Syracuse’s spike epidemic is the Mission District, a three-block wedge bounded by treeless boulevards and a red railroad trestle with the pronouncement LIVES CHANGE

HERE painted on it in huge white letters. Before urban renewal gutted the neighborhood in the 1960s, it was home to a typewriter factory and a rail yard surrounded by blue-collar homes and fringed by mansions that have long since been bulldozed or carved up into boarding houses. The sprawling Rescue Mission campus, which includes a men’s shelter and a soup kitchen, lends the district its name. The shelter explicitly forbids spike, along with alcohol and other drugs. But at any time during the day, a knot of people can be found under the trestle, dealing and smoking spike, and sometimes passing out from it. One unseasonably hot May afternoon, while I was combing a creek bank for discarded spike packets, a man shouted at me from a bridge: ‘‘That’s a lot of spike down there!’’

He introduced himself as Kenneth, a 44-year-old barber and spike addict with fingertips stained highlighter-yellow by spike resin. He had thin, expressive lips, and when he spoke, his words flowed in multiple stanzas. We sat in the shade under the trestle to talk. Kenneth was in prison when he first smoked spike, which he praised as a ‘‘miracle drug’’ because it didn’t show up on a drug test. ‘‘An addict is always trying to get slick, always trying to get over, always trying to beat a urine, always trying to beat a parole officer, always trying to get high without getting in trouble,’’ he said. ‘‘So I’m loving this drug! I come home, and it’s all over the place.’’

That was a year ago, after Kenneth got out of prison. For a time, he said, he considered dealing spike but decided that smoking it was all the trouble he could afford. Now he hated the stuff. Nobody he knew would choose it over real weed — if real weed were legal. In this way, spike was less a drug of choice than one of necessity. Now he was hooked, he said, and trying to quit. ‘‘It’s an annoying drug,’’ he said, comparing it to crack. ‘‘It’s great in the first two minutes. But then you got to keep lighting up, and lighting up, and lighting up. It’s not like marijuana, smoking a blunt and you’re high for two or three hours.’’

I asked him if he was afraid of landing in the hospital with a tube in his throat, or even dying. The risk of death isn’t a deterrent to an addict, he said — it’s a selling point. Take Mr. Big Shot, for example, a brand of spike that had a reputation on the street for knocking people unconscious. That’s the one everybody wanted, including Kenneth: ‘‘One joint lasted me six hours! I would light it up, take about three lungs, and turn it off. It was that strong. Even the guy in the store where I bought it from said, ‘Listen, smoke this in your house, don’t go into the street with this.’ ’’ If there was a spike dealer in the city selling bad stuff, Kenneth wasn’t aware of it, or he wouldn’t say. In his opinion, people were losing control on spike because they were smoking way too much of it. It was that simple.

‘‘That’s what all these guys do all day long,’’ he said, pointing to a group of loud-talking men hanging out at the other end of the trestle. ‘‘That’s what they’re doing right now.’’ (Kenneth, now 45, recently told me he had kicked his spike habit.)

Other spike users I spoke to in the Mission District made the same argument. One of them was Tyson, a 27-year-old drifter with shaggy brown hair who affected an air of party-dude bonhomie. He’d shot up, smoked, swallowed or snorted just about every drug there is, he said. Last fall, he started using spike for the same reason Kenneth did — to foil mandatory drug tests. Now he was living on the street, waiting for a bed to open up in a rehab facility. I bought him an iced coffee and a wedge of poundcake at the Starbucks in Armory Square, an upscale neighborhood of shops and restaurants three blocks from the Mission District. We sat on a sun-dappled bench, watching lawyers and insurance executives come and go. When I

asked him why so many people were overdosing on spike in Syracuse, Tyson blamed novice smokers.

‘‘The first week or so of smoking spike, there’s no control over it,’’ he said. ‘‘I’d smoke it and black out and come to three hours later, hugging a pole.’’

They can’t all be novices, I pointed out. Many of the spike users I talked to at Upstate University Hospital were plenty experienced, and they had ended up in the emergency room regardless. Tyson slurped a blob of whipped cream from his cup and reconsidered the question. His answer was rambling and profane, but it gave me deeper insight into how the spike economy works in Syracuse.

Spike, Tyson said, is a ‘‘poverty drug.’’ A five-gram bag goes for $10 in the store, but it is often subdivided and resold on the street as $1 ‘‘sticks,’’ or joints, and $2 ‘‘freestyle’’ portions — spike poured directly from the bag into the hand of the buyer. Many of the users I spoke to claimed that, in addition to being dirt-cheap, spike was addictive. There are no studies to back up this claim. Toxicologists know only that synthetic cannabinoids bind to certain receptors in the brain, and they understand nothing about the drug’s long-term health effects. Scientific proof aside, Tyson said he knew spike users who performed sex acts for a few dollars. ‘‘That’s how you know that spike is definitely addictive,’’ he said. ‘‘People are out tricking for it.’’

Tyson also explained how easy spike is to get in Syracuse. He ticked off the names of corner stores that sold it from behind the counter. Some required users to know code words — ‘‘Skittles,’’ for example — while others sold spike to anybody who asked for it, including children. Along with the stores, and the entrepreneurs peddling sticks to subsidize their own habits, street dealers offered bags of spike purchased in bulk from distributors in New York City.

‘‘That dude over there, with the headphones on?’’ Tyson said. ‘‘He does it.’’ He pointed his chin toward a young man in a leather coat crossing the street. ‘‘He’s got bags on him right now, but he does that pop-top.’’

‘‘Pop-top’’ is slang for the local spike sold in resealable pouches, the cheapest of the cheap. ‘‘You don’t know where it’s been, who did what with it,’’ Tyson said. No brand of spike is tested for its pharmacological effects, but pop-top spike doesn’t even have the benefit of a street rep. It’s the ditch weed of Spike Nation: rank, wet and worst of all, weak — unless you get a ‘‘hotspot,’’ an unpredictably powerful batch. ‘‘Seventeen joints, you might be fine. Eighteenth joint might put you down for six hours,’’ Tyson said. ‘‘That’s probably going to be what’s going to give somebody a heart attack.’’

Tyson said he’d seen a pop-top operation once, in a dingy basement on Syracuse’s north side. Potpourri was spread atop silk screens on Ping-Pong tables, then doused with unknown chemicals from a spray bottle. What pop-top manufacturers lacked in quality control, they made up for in marketing talent. Their spike was even cheaper than the store-bought variety, and new brands hit the street every month. They also produced clever knockoffs, stuffing their inferior spike into pouches identical to popular store brands. ‘‘That’s the name of the game right now, dude,’’ Tyson said. ‘‘Who can have the best-looking bag.’’

Since the attack on Ethan Darbee, the number of spike overdoses in Syracuse has fallen by half, just as mysteriously as it rose. Maybe spike smokers are being more careful, or doctors are reporting overdoses less frequently. Maybe a bad batch of spike finally ran its course. The answer doesn’t really matter. In a year, or a month, or perhaps tomorrow, the chemicals will be completely different, and we’ll be talking about another surge in emergencies.

The problem is resistant to criminal prosecution, or even basic police work. The Syracuse Police Department has a cellphone video of a spike overdose that they use for training purposes. It was taken in the first week of the outbreak, when the police were responding to as many as 20 overdoses a day. A lieutenant played the video for me one afternoon on a computer at the police station. It starts with a man writhing on the floor in a corridor of an apartment building. The man isn’t under arrest, but his hands are cuffed behind his back, for his own safety, until an ambulance can get there. The man screams the same unintelligible words over and over in a hysterical falsetto. He bangs the back of his head against the wall and hammers his bare heels against the floor. Ragged flaps of pink skin hang off his kneecaps. His bottom lip is literally chewed away. The video ends abruptly with the man in mid-scream. The lieutenant jerked his thumb toward the computer screen. ‘‘Now,’’ he said to me, ‘‘try to get his name and phone number.’’

When the bath-salts outbreak peaked in 2012, the city passed an ordinance equating possession of synthetic drugs with minor infractions like loitering. It also gives the police the authority to confiscate spike from users and, with probable cause, from stores as well. But the ordinance, which pushed spike sales onto the street, did little to prevent the surge of overdoses that hit the city in April. Bill Fitzpatrick, the Onondaga County district attorney, responded to the recent ‘‘crisis,’’ as he put it, by notifying store owners in May that he would charge them with reckless endangerment if they were caught selling spike, a misdemeanor punishable by up to a year in prison. That was the extent of his authority. ‘‘What I would ask from the federal government is some sort of sanction against China,’’ a frustrated Fitzpatrick told me. ‘‘Forget about the doctrines of Mao Zedong or Karl Marx — what

better way to subvert American society than by shipping this garbage over here and making it attractive to our future generations?’’

In March, the D.E.A. did arrest one Chinese national, a suspected manufacturer who made the mistake of traveling to the United States on business. For the most part, though, federal prosecutors have focused on arresting United States distributors under the controlled-substance-analogue statute, which was designed specifically to target synthetics. According to the statute, prosecutors must prove that the cannabinoids are ‘‘substantially similar’’ to previously banned cannabinoids both chemically and pharmacologically, and that they’re meant for human consumption. That’s why every bag of spike carries the disclaimer ‘‘Not for Human Consumption’’ as a legal fig leaf.

Carla Freedman, assistant United States attorney for the Northern District of New York, has successfully prosecuted many synthetic-drug cases under the statute. She won convictions against not just Syracuse’s bath-salts kingpin but also the owner of a chain of upstate head shops and the members of a Syracuse family who cranked out 200 pounds of spike a month in a rented house with the aid of a cement mixer. ‘‘If you keep taking out smoke shop after smoke shop, you’re putting your finger in the dike,’’ Freedman said. ‘‘If you take out the manufacturer and shut his business down, you stop production for a while.’’

Her current case concerns three associates of a Los Angeles-based organization called Real Feel Products Inc., who are charged with conspiring ‘‘to distribute one or more controlled-substance analogues.’’ Real Feel has done its business in the open, and indeed claims on its website to rank as ‘‘the Top 5 counter culture distribution company in North America.’’ Since Freedman charged the defendants under the analogue statute, their most likely defense will be to argue that they have changed their products frequently enough to keep them within the realm of legality. It’s Freedman’s job to prove that they didn’t. If they had sold heroin instead of spike, they’d already be in jail, and none of this would be an issue. As if more evidence were necessary to prove that synthetic drugs are the new frontier, Real Feel was also at one point developing a reality television show about growing its business.

Neither Fitzpatrick nor Freedman nor Syracuse’s mayor, Stephanie Miner, had any idea who, or what, was causing the overdoses. In Miner’s view, spike was just the drug of the moment, as heroin was last year and bath salts the year before that. She said she believes the real problem is centered on ‘‘undiagnosed trauma’’ that drives people to use drugs — any drugs — in the first place.

‘‘You can’t arrest your way out of these problems,’’ Miner said. ‘‘If somebody thinks that you can use the law to correct behavior that results from mental health issues? Not gonna happen.’’

The next day I went for a ride along with Police Officer Jacob Breen. Just four years out of the academy, Breen still enjoyed patrolling a beat and showed a keen interest in the social fabric of the city’s tough south- and west-side neighborhoods. After decades of economic decline, Syracuse has become one of the most segregated cities in the country, with a predominantly black underclass trapped in the urban core and middle-class whites living in the suburbs. Onondaga County, where Syracuse is the largest city, also has the third-highest rate of ‘‘zombie homes’’ — abandoned by their owners but not yet reclaimed by the banks — in the state. Cruising from block to block, Breen glanced back and forth between the road and a laptop wedged between our seats that displayed mug shots of felons on open warrants, the majority of them young black men. We passed a dilapidated two-story house, its boarded-up windows tagged with graffiti. The front door was ajar. ‘‘Open for business,’’ Breen said, craning his head around to get a glimpse through the door.

What bothered Breen most about the spike problem was how little he could do about it. Dealers, he knew, didn’t care about being hit with an appearance ticket for violating the city ordinance. He had to spend much of his time running around the city to protect ambulance crews from being attacked by freaked-out spike heads — ‘‘a waste of police resources,’’ he said. Sure enough, around 5 p.m., dispatch put out a call regarding a spike overdose. Four officers were already on the scene when we arrived. They stood in the yard of a tidy white house, trying to coax a man down from a set of stairs. The man was in his 40s, with a shaved head and a scraggly beard. Oblivious to the officers, who seemed to know him, he stared at the sky, rolling his eyes.

‘‘Hey, Will, c’mon,’’ one officer said. ‘‘You want to crawl down?’’ Paramedics wheeled a gurney to the stairs, and the situation escalated quickly. When the police laid hands on him, Will began jerking spastically and didn’t stop, even after he was strapped to the gurney and loaded into the ambulance.

Nurses at the hospital discovered three bags of spike on Will. But there was also a sandwich bag filled with what appeared to be small stones. Breen took the spike and the ‘‘moon rocks,’’ as he called them, to the Public Safety Building downtown. While he went to fetch a drug-test field kit, the supervising officer, Sergeant Novitsky, examined the haul. The moon rocks baffled him. ‘‘I just don’t want to touch it,’’ he said.

Whatever it was, it certainly wasn’t spike. The kit returned negative results for amphetamines, cocaine, LSD, marijuana, MDMA, methadone, methamphetamine and PCP as well. Breen and Novitsky weren’t sure what to do next. Toss the rocks into an evidence locker? Send them to the crime lab? Neither possibility appealed to Breen. ‘‘The lab’s not testing anything we’re sending,’’ he complained. ‘‘They won’t unless it’s a criminal case.’’ Novitsky shrugged. Overdoses weren’t criminal cases. At my suggestion, Breen decided to take it to Ross Sullivan, an emergency-room doctor at Upstate who has been investigating the toxicology of synthetic drugs.

We parked outside the entrance of Upstate’s emergency department and waited in the dark for the handoff. This was how knowledge of synthetic drugs was being advanced — an ersatz drug deal between a rookie cop and a toxicologist, with a reporter acting as middleman. It was absurd, but it was also somehow fitting. The synthetic-drug industry, and the response to it, are based on improvisation. A molecule is tweaked in a Chinese lab, triggering a chain reaction that goes all the way down the line from dealers to users to paramedics and the police to doctors and lawyers. Just when everybody seems to have a handle on it, the molecule gets tweaked again, and the cycle begins anew. Whatever these rocks were, Upstate’s doctors might very well see a flood of overdoses on it next year.

For what it’s worth, the “moon rocks” described at the end of this article are likely methylone, an analog of MDMA that acts as a CNS stimulant and empathogen. User’s have described methylone’s effects as variously being similar to MDMA or LSD. A 2012 paper from The Annals of Toxicology describes 3 fatal intoxications:  Pearson JM, et al. Three fatal intoxications due to methylone. J Anal Toxicol. 2012 Jul;36(6):444-51.

Source:Search   http://mobile.nytimes.com/2015/07/12/magazine/spike-nation.html?referrer=

Filed under: Effects of Drugs (Papers),Social Affairs :

When you smoke marijuana, there’s an almost immediate effect on your brain, sense of perception, and heart rate. There may be long-term effects as well.

 

The Effects of Marijuana on the Body

Marijuana comes from the Cannabis plant. The flowers, seeds, leaves, and stems of the plant must be shredded and dried before they can be used. Most people who use marijuana smoke it, but it can be mixed into food, brewed into tea, or even used in a vaporizer. One of the ingredients in marijuana is a mind-altering chemical called delta-9-tetrahydrocannabinol (THC).

When you inhale marijuana smoke into your lungs, it is quickly released into your bloodstream on its way to your brain and other organs. It takes a little longer to be absorbed when you eat or drink it.

The effects of marijuana on the body are immediate. Longer-term effects may depend on how you take it, how much you take, and how often you use it. Since its use has long been illegal in the United States, large-scale studies have been difficult to manage.

In recent years, the medicinal properties of marijuana are gaining acceptance in mainstream America. Medical marijuana is now legal in 23 states and the District of Columbia. THC and another ingredient called cannabidol (CBD) are the main substances of therapeutic interest. National Institutes of Health-funded research into the possible medicinal uses of THC and CBD is ongoing.

In addition to medicinal use, recent legislation has made marijuana a legal recreational drug in Colorado and Washington State. With the potential for increased recreational use, knowing the effects that marijuana can have on your body is as important as ever.

Respiratory System

 

Much like tobacco smoke, marijuana smoke is made up of a variety of toxic chemicals that can irritate your bronchial passages and lungs. If you’re a regular smoker, you’re more likely to wheeze, cough, and produce phlegm. You’re also at increased risk of bronchitis and lung infections. Marijuana may aggravate existing respiratory illnesses like asthma and cystic fibrosis.

Marijuana smoke contains carcinogens. It has the potential to elevate your risk of developing lung cancer. However, studies on the subject have had mixed results. According to the National Institute of Drug Abuse(NIDA), there is no conclusive evidence that marijuana smoke causes lung cancer. More research is needed.

Circulatory System

THC moves from your lungs into your bloodstream and throughout your body. Within minutes, your heart rate may increase by 20 to 50 beats per minute, according to the NIDA. That rapid heartbeat can continue for up to three hours. For people with heart disease, this faster heartbeat could raise the risk of heart attack.

One of the telltale signs of recent marijuana use is bloodshot eyes. They look red because marijuana causes blood vessels in the eyes to expand or dilate. Marijuana may help stop the growth of blood vessels that feed cancerous tumors.

 Central Nervous System

 

When you inhale marijuana smoke into your lungs, it doesn’t take long for THC to enter your bloodstream. From there, it is quickly transported to your brain and the rest of your organs. When you get marijuana from food or drink, it is absorbed a little more slowly.

THC triggers your brain to release large amounts of dopamine, a naturally occurring “feel good” chemical. That’s what gives you a pleasant “high.” It may heighten your sensory perception, as well as your perception of time. In the hippocampus, THC changes the way you process information, so your judgment may be impaired. It may also be difficult to form new memories when you’re high.

Changes also take place in the cerebellum and basal ganglia, upsetting your balance, coordination, and reflex response. All those changes mean that it’s not safe to drive.

Very large doses of marijuana or high concentrations of THC can cause hallucinations or delusions. According to the NIDA, there may be an association between marijuana use and some mental health problems like depression and anxiety, but more research is needed to understand the connection. In people who have schizophrenia, marijuana use can make symptoms worse.

When you come down from the high, you may be tired or feel a bit depressed. In some people, marijuana can cause anxiety. About nine percent of marijuana users develop an addiction, according to the NIDA. Symptoms of withdrawal may include irritability, insomnia, and loss of appetite.

In young people whose brains are not yet fully developed, marijuana can have a lasting impact on thinking and memory skills. If you use marijuana when pregnant, it can affect the brain of your unborn baby. Your child may be more prone to trouble with memory, concentration, and problem-solving skills.

THC can lower pressure in the eyes, which can ease symptoms of glaucoma for a few hours. According to theAmerican Academy of Ophthalmology, more research is needed to understand the active ingredients in marijuana and whether or not it’s a good treatment for glaucoma.

The pharmacologic effect of marijuana extends throughout the central nervous system. It is thought to ease pain and inflammation. It may also be of use in controlling spasms and seizures.

Digestive System

 

Smoking marijuana can cause stinging or burning in your mouth and throat. When you take oral THC, it is processed in your liver. Marijuana can ease nausea and vomiting. It can also increase appetite, which can be useful to people living with cancer or AIDS.

Immune System

Some research indicates that THC affects the immune system. Studies involving animals showed that THC might damage the immune system, making you more vulnerable to illness. Further research is needed.

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers),Health,USA :

Source: https://learnaboutsam.org/

Filed under: Cannabis/Marijuana,Effects of Drugs,Effects of Drugs (Papers),Environment,Social Affairs,Social Affairs (Papers),USA :

Young men who use cannabis may be putting their fertility at risk by inadvertently affecting the size and shape of their sperm, according to new research. In the world’s largest study to investigate how common lifestyle factors influence the size and shape of sperm, a research team found that sperm size and shape was worse in samples ejaculated in the summer months, but was better in men who had abstained from sexual activity for more than six days.

(Stock image) Credit: © milkovasa / Fotolia

In the world’s largest study to investigate how common lifestyle factors influence the size and shape of sperm (referred to as sperm morphology), a research team from the Universities of Sheffield and Manchester also found that sperm size and shape was worse in samples ejaculated in the summer months but was better in men who had abstained from sexual activity for more than six days.

However, other common lifestyle factors reported by men, including smoking cigarettes or drinking alcohol, appeared to have little effect.

The study, published in the medical journal Human Reproduction, recruited 2,249 men from 14 fertility clinics around the UK and asked them to fill out detailed questionnaires about their medical history and their lifestyle. Reliable data about sperm morphology was only available for 1,970 men and so the researchers compared the information collected for 318 men who produced sperm of which less than four per cent was the correct size and shape and a control group of 1,652 men where this was above four per cent and therefore considered ‘normal’ by current medical definitions.

Men who produced ejaculates with less than four percent normal sperm were nearly twice as likely to have produced a sample in the summer months (June to August), or if they were younger than 30 years old, to have used cannabis in the three month period prior to ejaculation.

Lead author Dr Allan Pacey, Senior Lecturer in Andrology at the University of Sheffield, said: “Our knowledge of factors that influence sperm size and shape is very limited, yet faced with a diagnosis of poor sperm morphology, many men are concerned to try and identify any factors in their lifestyle that could be causing this. It is therefore reassuring to find that there are very few identifiable risks, although our data suggests that cannabis users might be advised to stop using the drug if they are planning to try and start a family.”

Previous research has suggested that only sperm with good sperm morphology are able to pass into the woman’s body following sex and make their way to the egg and fertilize it. Studies in the laboratory also suggest that sperm with poor morphology also swim less well because their abnormal shape makes them less efficient. Dr Andrew Povey, from the University of Manchester’s Institute of Population Health, said: “This research builds on our study of two years ago which looked at the risk factors associated with the number of swimming sperm (motile concentration) in men’s ejaculates.

“This previous study also found that there were relatively few risk factors that men could change in order to improve their fertility. We therefore have to conclude again that there is little evidence that delaying fertility treatment to make adjustments to a man’s lifestyle will improve their chances of a conception.”

Although the study failed to find any association between sperm morphology and other common lifestyle factors, such as cigarette smoking or alcohol consumption, it remains possible that they could correlate with other aspects of sperm that were not measured, such as the quality of the DNA contained in the sperm head.

Professor Nicola Cherry, originally from the University of Manchester but now at the University of Alberta, commented on a recent companion paper published by the group in the Journal of Occupational and Environmental Medicine: “In addition to cannabis exposure shown in this paper, we also know that men exposed to paint strippers and lead are also at risk of having sperm with poor morphology.”

Source:

University of Sheffield. “Sperm size, shape in young men affected by cannabis use.” ScienceDaily. ScienceDaily, 4 June 2014. <www.sciencedaily.com/releases/2014/06/140604202946.htm>.

Filed under: Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Europe,Health :

February 24, 2015

Work loads in high school can be extreme, causing some kids to think about cheating or taking study drugs. GSE senior lecturer Denise Pope comments on the problem and possible solutions, such as cutting homework load and ensuring kids get enough “play time, down time and family time.”

In a shifting economy without any assurances of success, there’s a lot of pressure on students to succeed in school. More and more kids are going to college and the application process is competitive. To help stand out, students are taking on tougher course loads, along with extracurricular activities and leadership roles. In order to pack everything in, some kids turn to prescription drugs like Adderall and Ritalin to stay awake and focus on school work and test prep. They can obtain the medication from doctors, peers and sources they find online. However, many of these students, both in high school and in college, don’t know the physical or neurological ramifications of taking drugs that haven’t been prescribed to them by a doctor.

“We live in this culture of excellence,” said Michael McCutcheon, a counseling psychology phD candidate at New York University, on KQED’s Forum, “and if you are at a competitive high school and you know the culture really only celebrates success or money, then everything is riding on this test.” That overwhelming pressure – the feeling that every test and grade matters for ones future – combined with ease of access to these drugs makes their use seductive. Stanford Graduate School of Education senior lecturer Denise Pope found similar experiences among thousands of high school students she has interviewed or observed in her work.

“These kids are completely overloaded,” Pope said. “They come from high achieving schools, but these kids feel like there’s more homework than there is time in a day.” She cited increased pressure to take Advanced Placement or honors classes that require lots of homework, along with the explosion of extracurricular activities and the time students devote to them as some of the reasons for increased stress.

“The kids who cheat in high school, absolutely cheat in college,” Pope said. “My guess would be that if this is negative coping strategy that you are employing, it’s your go-to strategy when you have the stress and overload in college.”

Indeed, study drugs are most often used by high achieving high school students and among college student-athletes and those who participate in the Greek system. A 2009 review of the literature on study drugs found that anywhere between five and nine percent of middle and high school students, and five to 35 percent of college students use prescription drugs to stay awake and focus longer than they would normally.

What Study Drugs Do to the Brain

Drugs like Adderall and Ritalin are prescribed to kids with Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD). These kids are easily distracted by visual or auditory background noises, which can overwhelm them and

make it hard to focus. People with ADD or ADHD don’t produce enough dopamine in the brain, which the drugs help correct.

“They are meant to increase dopamine in the brain, which regulates two things: executive functioning and the rewards system in the brain,” said Michelle Goldsmith, assistant clinical professor at Stanford. “Both of those things come into play when we talk about attention.”

For kids who actually need Adderall or Ritalin, the brain’s dopamine pathways aren’t strong enough to circulate the neural signals that make certain mental processes go. For those kids the added dopamine can have a huge influence on ability to focus, but also comes with some less desirable side effects when the drug wears off like fatigue, depression and mood-swings. There’s a lot less known about how the drug affects brains that start out with normal dopamine levels because clinicians consider it too risky to conduct a study that would subject “normal” students to the drug.

“The question is do they really help normal people with learning,” Goldsmith said, “There hasn’t been any reason to study them because the risks are so significant.” Those risks include depression, psychosis, mood swings, suicidal thoughts, seizures, decreased appetite and insomnia.

Read the full story at KQED. Denise Pope is a senior lecturer at the Stanford Graduate School of Education and co-founder of Challenge Success(link is external).

Source:   https://ed.stanford.edu/     http://blogs.kqed.org/mindshift/2015/02/teaching-kids-to-learn-without-study-dru. 24th February 2015

Filed under: Education Sector (Papers),Effects of Drugs (Papers) :

Cocaine addicted individuals may continue their habit despite unfavorable consequences like imprisonment or loss of relationships because their brain circuits responsible for predicting emotional loss are impaired, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published today in The Journal of Neuroscience.

The study focuses on the difference between a likely reward (or loss) related to a given behavior and a person’s ability to predict that outcome, a measurement known as Reward Prediction Error, or RPE. Such RPE signaling is believed to drive learning in humans, which guides future behavior. After learning from an experience, we can, in the best case, change our behavior without having to go through it again, and thus maximize rewards and avert expected losses. Past research has determined that prediction of actual reward or loss is managed by shifting levels of the nerve signaling chemical dopamine produced by nerve cells in the midbrain, where changes in dopamine levels accompany unexpected gains and losses.

The Mount Sinai study recorded the brain activity of 75 subjects (50 cocaine users and 25 healthy controls) using EEG, a test that detects electrical activity in the brain, while subjects played a gambling game. Each person had to predict whether or not they would win or lose money on each trial.

Results showed that the group of the 50 cocaine users had impaired loss prediction signaling, meaning they failed to trigger RPE signals in response to worse-than-expected outcomes compared to the 25 healthy people comprising the control group. The results offer insights into the compromised ability of addicted individuals to learn from unfavorable outcomes, potentially resulting in continued drug use and relapse, even after encountering numerous losses.

“We found that people who were addicted to cocaine have impaired loss prediction signaling in the brain,” said Muhammad Parvaz, PhD, Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai and the lead author of the study. “This study shows that individuals with substance use disorder have difficulty computing the difference between expected versus unexpected outcomes, which is critical for learning and future decision making. This impairment might underlie disadvantageous decision making in these individuals.”

Next, the study looked at individual differences among the 50 cocaine users. Half of the subjects had used cocaine within 72 hours of the study and the other half had abstained for at least 72 hours. The cocaine addicted individuals with the more recent use had higher electrical activity associated with the brain’s reward circuit when they had an unpredicted compared to a predicted win, a pattern that was similar to the 25 healthy controls. The cocaine users who had abstained for at least 72 hours did not show this higher activity in response to an unpredicted win. These findings are consistent with the hypothesis that in addiction the drug is taken to normalize a certain brain function, which in this case is RPE signaling of better-than-expected outcomes.

“This is the first time a study has targeted the prediction of both gains and losses in drug addiction, showing that deficits in prediction error signaling in cocaine addicted individuals are modulated by recent cocaine use,” said principal investigator Rita Goldstein, PhD, Chief of Neuropsychoimaging of Addiction and Related Conditions, Chief of the Brain Imaging Center, and Professor of Psychiatry and Neuroscience at the Icahn School of Medicine. “Direction of results supports the self-medication hypothesis in drug addiction whereby drug self-administration improves response to reward in drug addicted individuals. The reductions in prediction of loss across all cocaine addicted individuals included in this study are also of great interest; they could become important markers that can be used to predict susceptibility for addiction or relapse or to develop targeted interventions to improve outcome in this devastating, chronically relapsing disorder.”

Source:  The Journal of Neuroscience.   3rd Feb 2015

Filed under: Brain and Behaviour,Cocaine,Drug use-various effects,Effects of Drugs (Papers) :

The American Academy of Paediatrics published a policy statement in January about the impact of marijuana use on youth. The AAP is strongly opposed to legalizing marijuana due to the potential impact on child and adolescent health.

Marijuana use is common in the U.S. The Substance Abuse and Mental Health Services Administration estimates that more than 12 percent of those over age 12 years have used marijuana in the last year; the rate of use has been increasing since the 1990s. Statistics show that if this trend continues, marijuana use will overtake cigarette smoking for high school seniors.

The active ingredient in marijuana is a chemical called tetrahydrocannabinol. This chemical stimulates brain receptors and produces hallucinations, illusions, dizziness, altered perception, impaired thinking and sedation.    Currently, 23 states and the District of Columbia permit marijuana to be prescribed by a doctor for medical purposes. Two states, Colorado and Washington, allow its sale for recreational purposes and Alaska, Oregon and the District of Columbia voted in November to legalize marijuana.

There are many actual and potential risks from legalized marijuana. Legalizing marijuana portrays marijuana use as harmless and results in the commercialization and marketing of a proven harmful substance. Even with strictly enforced age restrictions, increased adolescent use would occur.

Commercialization will lead to the production of stronger marijuana products. The concentration of the active ingredient in marijuana has increased four times since the 1980s. The ingestion risk of edible marijuana products such as cookies and chocolates is 10 times higher when compared to smoking marijuana. Smoking effects are seen within seconds, but oral ingestion effects are much slower. This increases the risk of ingesting more of the chemical before feeling satisfied.

Accidental ingestion of marijuana-laced food products has led to young children being admitted to intensive care units for sedation and respiratory failure in the states that have legalized marijuana. Common negative effects in teens include decreased scholastic and sports participation and performance, a loss of interest in outside activities, a withdrawal from peer interactions, increased risk-taking behaviors, decreased driving skills, damaged lung function and increased interpersonal problems with family and friends

Marijuana is an addictive substance. It is estimated that 9 percent of all those who experiment with marijuana will become addicted to it. When this estimate is limited to teens, the addiction risk increases to 17 percent. The 2012 National Survey on Drug Use and Health reported that 2.7 million people in the U.S. over age 12 met the Diagnostic and Statistical Manual criteria for addiction to marijuana.

Addiction symptoms are often overlooked because withdrawal symptoms may be minor or absent. Studies have repeatedly shown that teens who use marijuana several times per week have difficulty quitting, and the younger a child is when marijuana use starts, the greater the deleterious effects and the higher the chance for addiction.

Marijuana legalization poses a monumental risk to children and teens. The history of alcohol misuse by teens proves the limited potential of regulations and penalties to limit access by teens. The answer is clear. Legalizing marijuana is a risk we should not take.

JOE BARBER, M.D., is a pediatrician and child neurologist at Children’s Community Care Pediatrics-Erie Pediatrics. He is division chief of the Department of Pediatrics at Saint Vincent Hospital and is active on social media (www.drjoebarber.com).

 Source: www.goerie.com   6th Feb 2014

Filed under: Effects of Drugs (Papers),Law (Papers) :

This article originally appeared on VICE Romania

Ana Iorga is a Romanian neuromarketing pioneer, who specialises in market research using EEG sensors, biometric measures and implicit-association tests. Attending an advertising conference in Amsterdam last month, Ana staged an impromptu experiment to measure the effect that weed has on the brain using the EEG helmet she tends to carry around in her bag.

“I noticed how quite a few of the attendees grabbed a joint between breaks, and I kept wondering what goes on in their brains during those moments. Because I don’t possess any mind-reading techniques, I thought about comparing their brain activity before and after smoking,” she told me when she got back.

Two of her colleagues were kind enough to sacrifice themselves to the shrine of science; One evening, after dinner, one of them lit a spliff and the other got to munching on a space cookie.

 


The first participant – EEG trajectory before smoking

“Before consuming the products, we went to the hotel bar and I recorded their brain activity. After 15 minutes, I repeated the measures. I was convinced that I’d see a decrease in brain activity, because they said they felt slower, more absent and more relaxed. I was very surprised by the result.”

 


The first participant – EEG trajectory after smoking

Your brain contains billions of cells called neurons, which communicate with each other through electricity. The simultaneous communication between billions of neurons produces a large quantity of electric brain activity, which can be detected and measured through EEG technology. Because these electric impulses are triggered periodically as waves, they’re called “brain waves”.

EEG sensors measure the activity of neurons located on the surface of the cerebral cortex, and in the case of the two subjects, they showed a very high frequency and amplitude after smoking – the cerebral rhythm being visibly changed compared to the initial situation. This translates into a brain activity contrasting heavily with the participants’ mood (in stand-by mode and relaxed mode).

 


The second participant – EEG trajectory before eating the space cookie

Often, studies claim that THC has the effect of slowing down the cerebral rhythm when it is associated with a state of relaxation, and of speeding up when it is associated with visual hallucinations or tripping. With Ana’s two subjects, “it was clear that the cerebral rhythm was faster after smoking and that wave amplitude was larger – which doesn’t mean that things function chaotically, but that the brain is in a higher alert state. Maybe the guy was tripping or had some sort of bizarre feelings,” explains Laura Crăciun – a neurologist.

Crăciun emphasises that in the case of the first subject there is an imbalance standing out between the left hemisphere’s cerebral electricity [which deals with logic, language and math processes] and the right [where creativity, intuition, art and music processes take place] and along the sequence from the wave recording taken before smoking. That means that the imbalance is not exclusively determined by cannabis smoking.

Both subjects had consumed moderate quantities of alcohol at dinner, which didn’t interfere with the process very much. During the experiment, the two weren’t asked to perform any tasks, as their brain activity was measured in stand-by and relaxation mode.

 


The second participant – EEG trajectory after eating the space cookie.

“With the subject who ate a space cookie, the effect was both a slowing down [the basic wave frequency rhythm of both hemispheres went down] and speeding up of the amplitude, which is associated with a state of sleep-like, profound relaxation.”

“On the first recording, the cerebral rhythm is visibly faster – in the right hemisphere, because I can’t see a big difference in the left one – as well as less symmetrical and steady, but I wouldn’t say the effect is a “disturbance” over the brain waves, but more likely a state of awareness,” Crăciun added.

Source: http://www.vice.com/en_uk/ 15th Feb 2015

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Europe :

Teens can’t control impulses and make rapid, smart decisions like adults can — but why?

Research into how the human brain develops helps explain. In a teenager, the frontal lobe of the brain, which controls decision-making, is built but not fully insulated — so signals move slowly.  “Teenagers are not as readily able to access their frontal lobe to say, ‘Oh, I better not do this,’ ” Dr. Frances Jensen tells Fresh Air’s Terry Gross.

Jensen, who’s a neuroscientist and was a single mother of two boys who are now in their 20s, wrote The Teenage Brain to explore the science of how the brain grows — and why teenagers can be especially impulsive, moody and not very good at responsible decision-making. “We have a natural insulation … called myelin,” she says. “It’s a fat, and it takes time. Cells have to build myelin, and they grow it around the outside of these tracks, and that takes years.”  This insulation process starts in the back of the brain and heads toward the front. Brains aren’t fully mature until people are in their early 20s, possibly late 20s and maybe even beyond, Jensen says.

“The last place to be connected — to be fully myelinated — is the front of your brain,” Jensen says. “And what’s in the front? Your prefrontal cortex and your frontal cortex. These are areas where we have insight, empathy, these executive functions such as impulse control, risk-taking behavior.”   This research also explains why teenagers can be especially susceptible to addictions — including drugs, alcohol, smoking and digital devices.

Interview Highlights

On why teenagers are more prone to addiction

Addiction is actually a form of learning. … What happens in addiction is there’s also repeated exposure, except it’s to a substance and it’s not in the part of the brain we use for learning — it’s in the reward-seeking area of your brain. … It’s happening in the same way that learning stimulates and enhances a synapse. Substances do the same thing. They build a reward circuit around that substance to a much stronger, harder, longer addiction.

Just like learning a fact is more efficient, sadly, addiction is more efficient in the adolescent brain. That is an important fact for an adolescent to know about themselves — that they can get addicted faster.

It also is a way to debunk the myth, by the way, that, “Oh, teens are resilient, they’ll be fine. He can just go off and drink or do this or that. They’ll bounce back.” Actually, it’s quite the contrary. The effects of substances are more permanent on the teen brain. They have more deleterious effects and can be more toxic to the teen than the adult.

On the effects of binge drinking and marijuana on the teenage brain

Binge drinking can actually kill brain cells in the adolescent brain where it does not to the same extent in the adult brain. So for the same amount of alcohol, you can actually have brain damage — permanent brain damage — in an adolescent for the same blood alcohol level that may cause bad sedation in the adult, but not actual brain damage. …

Because they have more plasticity, more substrate, a lot of these drugs of abuse are going to lock onto more targets in [adolescents’] brains than in an adult, for instance.

We have natural cannabinoids, they’re called, in the brain. We have kind of a natural substance that actually locks onto receptors on brain cells. It has, for the most part, a more dampening sedative effect. So when you actually ingest or smoke or get cannabis into your bloodstream, it does get into the brain and it goes to these same targets.

It turns out that these targets actually block the process of learning and memory so that you have an impairment of being able to lay down new memories. What’s interesting is not only does the teen brain have more space for the cannabis to actually land, if you will, it actually stays there longer. It locks on longer than in the adult brain. … For instance, if they were to get high over a weekend, the effects may be still there on Thursday and Friday later that week. An adult wouldn’t have that same long-term effect.

On marijuana’s effect on IQ

People who are chronic marijuana users between 13 and 17, people who [use daily or frequently] for a period of time, like a year plus, have shown to have decreased verbal IQ, and their functional MRIs look different when they’re imaged during a task. There’s been a permanent change in their brains as a result of this that they may not ever be able to recover.

It is a fascinating fact that I uncovered going through the literature around adolescence is our IQs are still malleable into the teen years. I know that I remember thinking and being brought up with, “Well, you have that IQ test that was done in grade school with some standardized process, and that’s your number, you’ve got it for life — whatever that number is, that’s who you are.”

It turns out that’s not true at all. During the teen years, approximately a third of the people stayed the same, a third actually increased their IQ, and a third decreased their IQ. We don’t know a lot about exactly what makes your IQ go up and down — the study is still ongoing — but we do know some things that make your IQ go down, and that is chronic pot-smoking.

On teenagers’ access to constant stimuli

We, as humans, are very novelty-seeking. We are built to seek novelty and want to acquire new stimuli. So, when you think about it, our social media is just a wealth of new stimuli that you can access at all times. The problem with the adolescent is that they may not have the insider judgment, because their frontal lobes aren’t completely online yet, to know when to stop. To know when to say, “This is not a safe piece of information for me to look at. If I go and look at this atrocious violent video, it may stick with me for the rest of my life — this image — and this may not be a good thing to be carrying with me.” They are unaware of when to gate themselves.

On not allowing teenagers to have their cellphones at night

It may or may not be enforceable. I think the point is that when they’re trying to go to sleep — to have this incredibly alluring opportunity to network socially or be stimulated by a computer or a cellphone really disrupts sleep patterns. Again, it’s also not great to have multiple channels of stimulation while you’re trying to memorize for a test the next day, for instance.

So I think I would restate that and say, especially when they’re trying to go to sleep, to really try to suggest that they don’t go under the sheets and have their cellphone on and be tweeting people.  First of all, the artificial light can affect your brain; it decreases some chemicals in your brain that help promote sleep, such as melatonin, so we know that artificial light is not good for the brain. That’s why I think there have been studies that show that reading books with a regular warm light doesn’t disrupt sleep to the extent that using a Kindle does.

Source:   http://www.mprnews.org/story/2015/01/28/npr-teen-brains

Filed under: Addiction (Papers),Effects of Drugs (Papers),Prevention (Papers),Social Affairs (Papers) :

A case report of the synthetic amphetamine 2,5-dimethoxy-4-chloroamphetamine. Burish MJ1, Thoren KL2, Madou M1, Toossi S1, Shah M1.

Abstract

Although traditional hallucinogenic drugs such as marijuana and lysergic acid diethylamide (LSD) are not typically associated with seizures, newer synthetic hallucinogenic drugs can provoke seizures. Here, we report the unexpected consequences of taking a street-bought hallucinogenic drug thought to be LSD. Our patient presented with hallucinations and agitation progressing to status epilepticus with a urine toxicology screen positive only for cannabinoids and opioids. Using liquid chromatography high-resolution mass spectrometry, an additional drug was found: an amphetamine-derived phenylethylamine called 2,5-dimethoxy-4-chloroamphetamine. We bring this to the attention of the neurologic community as there are a growing number of hallucinogenic street drugs that are negative on standard urine toxicology and cause effects that are unexpected for both the patient and the neurologist, including seizures.

Source:  Neurohospitalist. 2015 Jan;5(1):32-4. doi: 10.1177/1941874414528939.

Filed under: Effects of Drugs (Papers) :

van Amsterdam J1, Brunt T2, van den Brink W3. Author information

* 1Amsterdam Institute for Addiction Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands jan.van.amsterdam@amc.uva.nl.

* 2Trimbos Institute (Netherlands Institute of Mental Health and Addiction), Utrecht, The Netherlands.

* 3Amsterdam Institute for Addiction Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk.

The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed.

Source:  J Psychopharmacol. 2015 Jan 13. pii: 0269881114565142. [Epub ahead of print]

Filed under: Effects of Drugs (Papers) :

In the 1980s and 90s two successive waves of heroin use swept Britain resulting in massively escalating levels of addiction, deaths, crime, and HIV. At the same time the use of other drugs, cannabis, cocaine, etc was also increasing. There was a widespread sense of crisis with the fear that control of our cities would be lost to drug gangs, drug related crime would continue to grow exponentially, and injecting drug use would become a major route for the transmission of HIV across the population. The drug treatment system was under resourced with lengthy waiting times and high levels of drop out. In 1992 the Major government launched the first national drug strategy “Tackling Drugs Together” to grip these problems.

Fast forward to 2014. Drug use is falling, down from 12% in 2004 to 9% now. The use of heroin peaked at the end of the 1990s at 450,000, it is now 260,000. Young people are shunning heroin with typical users now in their 40s rather than the vulnerable teenagers of popular imagination. Drug related crime has fallen dramatically with investment in treatment initiated during the Blair government enabling offenders and other users to access treatment in days rather than months. The quality of treatment has improved with lower drop out and improved outcomes. The Home Office estimate 30% of the reduction in crime since 2000 is attributable to ready access to treatment which currently prevents 4.9m crimes a year. Levels of HIV among drug injectors is among the lowest in the world, 2% compared to 20% in the USA and 70% in parts of Russia, a legacy of the harm reduction policies pioneered by Norman Fowler as health secretary in the Thatcher government.

None of this featured in last weeks critique in the Huffington Post of the failures of current policy from Caroline Lucas and Julian Huppert, or in their speeches in last Thursdays parliamentary debate. Instead we had a tired unevidenced assertion that policy is a failure, in Nick Clegg’s dramatic language, “on an industrial scale”. Why are outcomes that would have been a cause of celebration in 1992 consistently derided as failure?

The major difference between 1992 and today is that the crisis has abated. There is no longer a plausible argument that drug misuse is spiralling out of control with potentially disastrous consequences for social stability. The absence of crisis frees up ideologues of right and left to posture either about the “failed war on drugs” on the left or the “calamitous consequences of 1960s hedonism” on the right.

The value of the drug debate as a badge of moral and political affiliation is too potent to allow inconvenient truths to intrude. The reality of less use and less harm has to be airbrushed out of the debate if the power of the opposing polemics is to be sustained.

The commentariat’s  self indulgence is buttressed by a political/media culture in which no government policy is allowed to succeed. Ministers are wary of claiming success, fearing charges of complacency today, and ridicule tomorrow if events turn for the worse. Perhaps surprisingly, success is more likely to be buried in Whitehall than failure. Civil servants, policy advocates, and service providers have learned to sidestep inconvenient good news to sustain an ever evolving narrative of failure which is the best route to maintain the high media and political salience on which future funding, policy influence and employment depend.

To highlight the hidden successes of current drug policy is not to deny the continuing challenges and deficits. In England drug related deaths rose alarmingly last year after falling significantly since 2008. The immediate and long term health risks of “legal highs” present an unknown threat. The lack of integration between drug and mental health services is a continuing scandal. Locking people up to protect them from themselves is difficult to justify. But the reality of our drug problem today is that fewer people are using drugs, fewer are becoming addicted, and the social and economic costs of drug use are shrinking.

Any evidence based change to policy needs to acknowledge its successes as well as its deficits. It isn’t enough to dust off arguments from the sixth form debating society as MPs did in the commons this week. The calls for a radical change in policy do not sit well with a significantly shrinking problem. Proponents of change need to explain, not only how reform will prevent imprisonment of users, a laudable aim, but also how they would prevent increases in use and harm arising as a consequence. To steer a sensible pragmatic evidence based route through these policy challenges requires all the evidence to be on the table, including the surprisingly good news that some people would prefer to see ignored.

Source:   http://www.huffingtonpost.co.uk/paul-hayes/drug-policy-uk-untold-success-story  4th Nov 2014

Filed under: Effects of Drugs (Papers),Law (Papers),Social Affairs (Papers) :

Albert Stuart Reece

Medical School, University of Queensland, Highgate Hill, Brisbane, QLD, Australia

 Introduction 

Cannabis is the most widely used illicit drug worldwide. As societies reconsider the legal status of cannabis, policy makers and clinicians require sound knowledge of the acute and chronic effects of cannabis. This review focuses on the latter.

Methods

Asystematic review of Medline, PubMed, PsychInfo, and Google Scholar using the search terms “cannabis,” “marijuana,” “marihuana,” “toxicity,” “complications,” and “mechanisms” identified 5,198 papers. This list was screened by hand, and papers describing mechanisms and those published in more recent years were chosen preferentially for inclusion in this review. Findings. There is evidence of psychiatric, respiratory, cardiovascular, and bone toxicity associated with chronic cannabis use. Cannabis has now been implicated in the etiology of many major long-term psychiatric conditions including depression, anxiety, psychosis, bipolar disorder, and an amotivational state.

Respiratory conditions linked with cannabis include reduced lung density, lung cysts, and chronic bronchitis.

Cannabis has been linked in a dose-dependent manner with elevated rates of myocardial infarction and cardiac arrythmias. It is known to affect bone metabolism and also has teratogenic effects on the developing brain following perinatal exposure. Cannabis has been linked to cancers at eight sites, including children after in utero maternal exposure, and multiple molecular pathways to oncogenesis exist. Conclusion. Chronic cannabis use is associated with psychiatric, respiratory, cardiovascular, and bone effects. It also has oncogenic, teratogenic, and mutagenic effects all of which depend upon dose and duration of use.

Introduction

According to the United Nations Office of Drugs and Crime, there are some 165 million users of cannabis worldwide, making it the most widely used illicit drug.1 This review examines the psychiatric, respiratory, cardiovascular, and bone effects associated with chronic cannabis use and the neurodevelopmental, genotoxic, mutagenic, and oncogenic effects of cannabis.

Methodology

A systematic review of Medline, PubMed, PsychInfo, Google, Scholar, Scopus, Proquest, Web of Knowledge, and Ebsco- Host using the search terms “cannabis,” “marijuana,” or “marihuana” identified 14,065 papers, excluding duplicates. When the search terms “toxicity,” “complications,” and “mechanisms” were added, the list narrowed to 5,198 papers.

This list was screened by hand, and original papers describing mechanisms and those published in more recent years were chosen preferentially. Review papers are cited where appropriate to introduce a large or detailed field for the interested reader. Few case reports are included and they are specifically flagged where they occur; those that are cited have been included largely because they suggest important pathophysiological mechanisms.

Psychiatric and social disorders

An authoritative meta-analysis of cannabis-related psychopathology has been published,2 with an accompanying editorial.3  Another review found an elevated risk of psychosis in many studies, with an odds ratio (OR) of about 2.3.4 A similar meta-analysis from the Netherlands found a pooled OR for psychosis of 2.1.5 Several studies from diverse cultures have confirmed the elevated risk of psychosis and schizophreniform spectrum disorders5–17 following high levels of cannabis use, particularly when cannabis consumption has commenced at a young age.14,18 Cannabis use has been found to exacerbate pre-existing psychotic disorders.5,15 There is a similar and increasing literature around both bipolar disorder19–21 and depression.22–25 Although the psychoneurological  effects of cannabis are usually stereotypically characterized as a depressant, both its use and the withdrawal state are accompanied frequently by psychomotor agitation, which has been implicated causally with interpersonal violence.26 Interestingly, in a series of forensic examinations of suicide, cannabis use was associated with the most  violent means of death, particularly severe motor vehicle accidents.27

In 1972 Nahas28 drew attention to the devastating effects of cannabis in Egypt as quantified by carefully prepared and formally psychologically documented surveys from that country. Higher levels of anxiety, impaired memory, poor concentration, impaired learning ability, and psychomotor impairment including reduced quality and quantity of work were seen in these users. In addition, a common dependency syndrome was observed, which made exit from the dependent state both difficult and rare.28 Geographical microclustering of cannabis use has been demonstrated, which has the effect of establishing local socially normative use patterns.29 Both  in northern Africa and in New Zealand communities exist where cannabis use is common, and intellectual impairment, psychomotor slowing, poor work capacity, and severe social deprivation are entrenched.30–32 Lee and colleagues33,34 have published several descriptions of heavy, problematic, and refractory cannabis use in remote indigenous communities of the Northern Territory and across northern Australia more generally. A substantial proportion (31–62%) of users’ median weekly income and up to 10% of the total community income were spent on cannabis. Ninety percent smoked cannabis heavily (more than six cones daily) and were not able to cease use. Severe mental illness was commonplace, as were depression, suicidal ideation, auditory hallucinations, and imprisonment. There was less participationin employment, education, or training. Community violence escalated when cannabis supplies from distant centers were interrupted. Most users had not “matured out” of dependent cannabis use even 5 years later. It is particularly noteworthy that these same communities had largely successfully defeated alcohol abuse, primarily by tight restrictive policies aimed at severely curtailing alcohol supply. The authors concluded that cannabis was both an important cause and a consequence of ongoing severe social disadvantage and deprivation.

Respiratory effects

Both the Thoracic Society of Australia and New Zealand35 and the British Lung Foundation4 have issued major statements in recent years acknowledging the known deleterious effects of cannabis on the lungs. Cannabis is smoked differently from tobacco. Users commonly inhale deeply to a  maximal breath and then retain the smoke in the lungs, which generates higher pressures during breath holding and on expiration.35–37 Cannabis smoke stimulates inflammation in the airways so that its long-term use is associated with the development of chronic bronchitis. A New Zealand study38 demonstrated large airway inflammation and obstruction and hyperinflation but was seldom associated with macroscopic emphysema, with a dose equivalence of one cannabis joint to 2.5–5 cigarettes. These findings were supported by an accompanying editorial39 and press release.40 Decreased lung density has also been noted with increased lung volumes, signs of destruction of lung tissue, cyst formation, and emphysematous change with secondary pneumothorax because of bullous rupture.41–43 Cannabis smoke is known to contain several potent carcinogens including anthrocyclines, nitrosamines, polycyclic aromatic hydrocarbons, terpenes, and vinyl chloride.4,35,44–47 As a consequence, cannabis use is associated with cancer of the lung.30–32

Cardiovascular effects

Cannabis exposure is known to cause phasic systemic vasodilation, mild hypertension, and tachycardia often associated with postural hypotension, and a reduced duration and increased heart rate response to exercise.48–51 Some but notall these effects are mediated by the autonomic nervous system. Tolerance to many of these acute effects with time appears. In most young healthy patients such changes are clearly generally well tolerated,48,50 but this is not universally true and several exceptions cited below are of considerable pathophysiological interest. Such generic reassurances cannot be provided to patients with pre-existing coronary or atherosclerotic disease.50,52 Several case reports associate cannabis use with infarctions of kidney,53 brain,54–60 heart61–65, and digits,66,67 and of priapism in humans with sickle cell disease.68 An association between cannabis use and pedal gangrene has also been described in a 27-year old.67 Some 50 cases of cannabis arteritis have been reported in the literature.67 Cannabis use can acutely trigger myocardial infarction,69 which has also been documented in a 25-year-old man with no other cardiac risk factors and normal coronary arteries at angiography.62 Coronary no-flow phenomenon has been observed after acute cannabis use.57 Cardiomyopathy has also been reported in a young man.70 One large study of 1,913 adults conducted in the United States found both a significant association between myocardial infarction and cannabis use, and a dose– response effect, with adjusted hazard ratios of 2.5 and 4.2 for less than weekly and weekly use, respectively.52 Reversible cerebral vasospasm71 as well as slowing and flow reversal in the middle cerebral artery72 has also been documented and attributed to cannabis use. On the contrary, the same authors also reported an increase of blood flow in the cerebral frontal lobes.73 Several case reports have described a cannabis-associated inflammatory angiitis,61,74,75 which can be so severe as to mimic Buerger’s disease (thromboangiitis obliterans or “disappearing artery syndrome”). In a study in 19 patients, alterations of the cardiac pressure cycle were found with a highly significant prolongation of both electromechanical systole (by 17 ms) and left ventricular ejection time, in the context of a reduced pre-ejection period (systolic pressure upstroke), a tachycardia of 132 bpm, and unchanged brachial systemic pressures.76 These more abrupt cardiac pressure changes imply increased cardiac work in the context of a prolonged QTc interval and reduced opportunity for myocardial perfusion (the “Buckberg index”), which is limited to the diastolic phase of the cardiac cycle.77,78 Hence, this scenario combines both an adverse mechanical and electrical profile in the context of reduced coronary perfusion and an altered endothelial, coagulation, angiogenic,79 and inflammatory milieu.

Cannabis has also been linked with elevated rates of cardiac arrhythmias in several case reports.80  Generally, these are supraventricular and trivial,81–83 but well-documented cases of lethal ventricular arrythmias do exist57 and one such was recently reported from a man who survived and whose episode was recorded on his implantable defibrillator.84 Elevated plasma concentrations of the endocannabinoid 2-arachidonylglycerol status have been associated in an Italian study of 62 patients with an exacerbation of the cardiovascularrisk profile with worse concentrations of total  cholesterol, high-density lipoprotein cholesterol, body mass index, intra-abdominal obesity, and adiponectin.85

Bones

Cannabinoid receptors are present on bones. Physiological studies have shown that cannabinoids have an important role in the regulation of bone density86; blockade or modulation of CB1 cannabinoid activity protects from bone loss.87 Heavy cannabis use in humans is associated with substantial bone loss.54 Interestingly, CB2 stimulation appears to be causally associated with stimulation of both endosteal and periostealbone growth by mechanisms involving inhibition of osteoclastogenesis, osteoblast stimulation, and favorable modulation of the RANKL (receptor activated NF-kB ligand) – osteoprotegerin system, matrix metalloproteinase inhibition, inhibition of adrenergic sympathetic signaling to bone, and inhibition of  bone marrow monocyte-directed hemopoiesis88–99 (the bone marrow-derived monocyte is believed to be the immediate precursor of the multinucleate osteoclast). Cannabis use is also known to be associated with profound loss of alveolar bone from the jaws,100–103 often in the context of severe erosive periodontitis.104,105

Maternal cannabis use and fetal development Not all the studies in this field have returned results confirming a link between maternal cannabis use and later deleterious changes in the offspring.106 However, maternal cannabis use has been shown to reduce body weight at birth.107 Many birth abnormalities were identified in a large Hawaiian sample over 6 years. Of 54 birth defects studies, 39% were noted in cannabis-exposed babies.108 Many of these defects were major and involved the brain (encephalocoele, hydrocephaly, microcephaly, anophthalmia/microphthalmia), cardiovasculature (tetralogy of Fallot, ventricular septal defect, atrial septal defect, and right and left heart atretic syndromes), gastrointestinal system (pyloric stenosis, intestinal atresias and stenoses, and gastroschisis), and limbs (polydatyly, syndactyly, and reduction deformities of the upper and lower limbs); oro-facial clefts were also reported. One large American study found a somewhat elevated risk of anencephaly (OR =1.7, CI = 0.9–3.4).109 The association with gastroschisis has been confirmed by other investigators.110

The dominant theme to emerge from studies of perinatal exposure is that of impaired executive cortical functioning reflected in reduced attention and analytical behavior and visuospatial analysis and hypothesis testing;111 parent-rated behavioral problems, language comprehension, and distractibility112; and inattention, hyperactivity, impulsivity, and substance use disorders.113 Indeed, close agreement between human and animal studies of perinatal exposure has been shown.113 Such changes emerge from as early as the first weeks of life and persist in children in longitudinal studies into the school ages. Importantly, cannabis seemed to potentiate other causes of disadvantage such as smoking, low protein nutrition, and early age of first maternal pregnancy,and child sexual abuse implying that cannabis use by disadvantaged groups compounds other functional deficits.112,114 Lower school age child IQ was also noted in another large longitudinal follow-up study.115 It is important to note, however,  that such reductions in intellectual performance, executive function, memory, sustained attention, and verbal ability are also seen in samples of low-risk upper middle class children of school age.116 Equally, it is important to note that careful studies controlling for such pertinent confounding psychosocial variables find strong persistent effects of cannabis exposure.117 Maternal prenatal cannabis use has been found to predict later cannabis use during adolescence both as age of onset and frequency of use, a relationship that persisted after adjustment for many other risk factors.118

Genotoxicity, mutagenicity, and oncogenesis

Cannabis use is associated with cancer of the lung30–32 (OR = 2.3, 4.1, and 5.7), head and neck44,119 (OR = 4.1, 2.6, and 3.1), larynx (OR = 1.7 and 2.3), prostate (OR = 3.1)120, cervix (OR = 1.4),120 testes (OR = 1.7),121 and brain (OR = 2.8).122 Cannabis has also been linked with tumors of the urothelial tracts.123–125 Several authors have also found evidence of a dose–response relationship, either with dose, duration, or the combined lifetime total duration of cannabis consumption. 31,32,44,121 A report from Tunisia showed an eightfold rise in lung cancer risk, but initially did not demonstrate a dose– response relationship; tobacco is frequently mixed with cannabis in that country.30 A later expanded revision of these data from the same area in northern Africa was able to demonstrate a relationship with the total dose duration of cannabis exposure.121 Of great concern is the evidence of inheritable tumors such as childhood neuroblastoma (OR = 1.8, 4.7),126 rhabdomyosarcoma,45 and leukemia (OR = 11), particularly non-lymphoblastic leukemia,127 in cannabis-exposed pregnant mothers. It should be noted that not all epidemiological studies have been positive,128 with some studies failing to demonstrate such a link, possibly because cannabis exposure in the study population was limited.45 For example, a study conducted in Los Angeles did not observe an association with lung cancer, which the authors attributed to the relatively few cases exposed to significant amounts of cannabis.129 Similarly, a New Zealand study of head and neck cancer was recently found to be negative, a finding attributed by the authors to uncontrolled confounding and inadequate sampling of the New Zealand population.128 Cannabinoids liberate radical species both by receptor binding (nitrogen-centered species130–132 ) and by uncoupling mitochondrial oxidative phosphorylation via stimulation of the matrix protein uncoupling protein 2.133,134 Nitric oxide generation at the cell membrane occurs via both CB1130 and non-CB1/2 receptor-mediated131 mechanisms. Indeed, it has been shown that oxidation135 of the DNA base guanosine to oxo-guanosine is a normal part of endocannabinoid signaling. This potentially very serious and inherently mutagenic defect is overcome during normal signaling by activation of the base excision DNA repair pathway within cells. The capacity of such DNA repair pathways is well known to be limited, so the possibility exists that with pathological overstimulation, as might occur during substantial cannabis use, the resulting major genetic defects would become fixed and eventually translated into altered mRNAs, micro-RNAs,genetic expression, and protein sequences. Cannabis is known to stimulate the oncogenic MAP kinase pathway,136 which is potently oncogenic, and to be involved particularly in the genesis of non-lymphocytic leukemias.137 A strongly positive association between cannabis consumption and this tumor has been found.127 Cannabinoids block topoisomerase II, an enzyme that untwists and makes accessible the dominant coding DNA strand and plays a vital role in DNA repair, meiotic chromosomal replication, mRNA transcription, and DNA hypermutation in prelymphocytes.138,139

Cannabinoids also impair RAD-51, another enzyme involved in the accurate repair of DNA breaks. Mice chromosomal studies imply that cannabinoids also interfere with the normal maintenance of the ends of chromosomes.140 Chromosomal ends or telomeres are made up of many copies of a 6-nt repeat structure (T–T–A–G–G–G) and are protected by a complex of proteins collectively called “shelterin.”141,142 Telomeres are maintained by an enzyme called telomerase, which is absent from most cells but is present in stem cells, gonads (testes and ovaries), and cancers. 143,144 The length of the telomeres has been shown recently to be proportional to the age, the health, and the reproductive fitness of stem cells in a variety of in vivo tissue niches.145 It is of concern that the chromosomal damage was shown in mice not only for tetrahydrocannabinol but also for cannabidiol (and cannabinol),140 a non-psychoactive cannabinoid that has been added to commercial cannabis sprays supposedly to confer safety!146

The involvement of cannabinoids with at least three enzymes involved in DNA repair raises questions about their potential genetic toxicity, a subject that remains largely uninvestigated. Gonadal stem cell and genetic toxicity have implications for cell growth inhibition, fetal malformations, and inheritable defects including cancers. Indeed, evidence of cannabis-induced altered DNA expression,147 a higher incidence of 21 birth defects,107 and an 11-fold rise in inherited leukemias in the offspring of cannabis users127 have been documented. Other studies have produced similar findings,148 including tissues of the germ line.149 The presence of such major chromosomal abnormalities in sperm cells but not in circulating white blood cells149 is consistent with the inhibition by cannabinoids of telomerase, which is well known to be present in stem cells, germ cells, and cancer cells but not in the nuclei of normal tissue.150–152

Conclusions

In summary, now there is evidence for the implication of cannabis in various psychiatric, respiratory, cardiovascular, and bone pathologies.153,154 The reports of social disruption, disorganization, and deprivation consequent on widespread heavy cannabis use from a number of communities around the world are of substantial concern. The features associated with chronic cannabis use imply that a clear public health cautionary message is warranted along the lines employed for other environmental intoxicants such as tobacco, which should be targeted strategically to young and otherwise vulnerable populations.

Declaration of interest: There is no conflict of interest to declare.

This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden.

Source:  Reece, Albert Stuart(2009)’Chronic toxicology of cannabis’,Clinical Toxicology,47:6,517 — 524

To link to this Article: DOI: 10.1080/15563650903074507

URL: http://dx.doi.org/10.1080/15563650903074507

Filed under: Cannabis/Marijuana,Effects of Drugs (Papers),Health :

Background 

Debate continues about the consequences of adolescent cannabis use. Existing data are limited in statistical power to examine rarer outcomes and less common, heavier patterns of cannabis use than those already investigated; furthermore, evidence has a piecemeal approach to reporting of young adult sequelae. We aimed to provide a broad picture of the psychosocial sequelae of adolescent cannabis use.

Methods

We integrated participant-level data from three large, long-running longitudinal studies from Australia and New Zealand: the Australian Temperament Project, the Christchurch Health and Development Study, and the Victorian Adolescent Health Cohort Study. We investigated the association between the maximum frequency of cannabis use before age 17 years (never, less than monthly, monthly or more, weekly or more, or daily) and seven developmental outcomes assessed up to age 30 years (high-school completion, attainment of university degree, cannabis dependence, use of other illicit drugs, suicide attempt, depression, and welfare dependence). The number of participants varied by outcome (N=2537 to N=3765).

Findings

We recorded clear and consistent associations and dose-response relations between the frequency of adolescent cannabis use and all adverse young adult outcomes. After covariate adjustment, compared with individuals who had never used cannabis, those who were daily users before age 17 years had clear reductions in the odds of high school completion (adjusted odds ratio 0·37, 95% CI 0·20–0·66) and degree attainment (0·38, 0·22–0·66), and substantially increased odds of later cannabis dependence (17·95, 9·44–34·12), use of other illicit drugs (7·80, 4·46–13·63), and suicide attempt (6·83, 2·04–22·90).

Interpretation 

Adverse sequelae of adolescent cannabis use are wide ranging and extend into young adulthood. Prevention or delay of cannabis use in adolescence is likely to have broad health and social benefits. Efforts to reform cannabis legislation should be carefully assessed to ensure they reduce adolescent cannabis use and prevent potentially adverse developmental effects.

Funding Australian Government National Health and Medical Research Council.

Source:  Lancet Psychiatry 2014; 1: 286–93

Filed under: Effects of Drugs (Papers) :

Abstract

To review and summarise the literature reporting on cannabis use within western communities with specific reference to patterns of use, the pharmacology of its major psychoactive compounds, including placental and fetal transfer, and the impact of maternal cannabis use on pregnancy, the newborn infant and the developing child. Review of published articles, governmental guidelines and data and book chapters. Although cannabis is one of the most widely used illegal drugs, there is limited data about the prevalence of cannabis use in pregnant women, and it is likely that reported rates of exposure are significantly underestimated. With much of the available literature focusing on the impact of other illicit drugs such as opioids and stimulants, the effects of cannabis use in pregnancy on the developing fetus remain uncertain. Current evidence indicates that cannabis use both during pregnancy and lactation, may adversely affect neurodevelopment, especially during periods of critical brain growth both in the developing fetal brain and during adolescent maturation, with impacts on neuropsychiatric, behavioural and executive functioning. These reported effects may influence future adult productivity and lifetime outcomes. Despite the widespread use of cannabis by young women, there is limited information available about the impact perinatal cannabis use on the developing fetus and child, particularly the effects of cannabis use while breast feeding. Women who are using cannabis while pregnant and breast feeding should be advised of what is known about the potential adverse effects on fetal growth and development and encouraged to either stop using or decrease their use. Long-term follow-up of exposed children is crucial as neurocognitive and behavioural problems may benefit from early intervention aimed to reduce future problems such as delinquency, depression and substance use.

Introduction

About 3.9% (or 180.6 million) of the world’s population between 15 and 64 years of age use cannabis, making it one of the most widely used illegal psychoactive drugs in the world.[1] In some countries, cannabis has been used by up to 40% of adults at some point during their lives.[2] Cannabis is accepted as a relatively harmless recreational agent in many parts of the world[3] despite gathering evidence of its detrimental impact on both the adult[4] and the developing[5] central nervous system. Severe cannabis use, for example, decreases the metabolism of the prefrontal and temporal cortex,[63] and chronic exposure doubles the risk of psychosis and memory and cognitive dysfunction, most likely from neurotransmitter dysregulation.[7] This risk of neurological impairment is especially pronounced if cannabis is consumed during periods of critical brain development, such as adolescence.[8]

Cannabis, however, is one of the most commonly used illicit drugs in pregnancy and lactation.[1,2] Approximately 2.5% of women admit to continued cannabis use even during pregnancy.[9] This is of great concern because its lipophilic nature[10]allows it to readily cross many types of cell barriers, including the blood/brain and transplacental membranes. Cannabis metabolites are consequently easily detectable in many types of human tissues,[11] including the placenta, amniotic fluid and the fetus.[12] The effects of cannabis on the developing fetus may, however, be subtle and not be detectable for many months to years after birth, as the aetiology of some of the ‘softer’ neurological signs such as aggressive behaviours[5] or other neuropsychological problems[13] are difficult to be attributed unequivocally to cannabis exposure due to frequently concurrent negative environmental influences such as parental drug use, poverty[14] and psychiatric co-morbidity.[15]

Evidence regarding the effects of perinatal cannabis exposure, that is, during pregnancy and lactation, is plentiful but, unfortunately, ambiguous. In this review, we offer an overview of this problem, including discussion about the potential effects of this practice on the unborn, newborn and older child and adolescent. We also discuss some of the pertinent issues associated with perinatal management, including the utility of drug screening and the practical aspects of breast-feeding in the known cannabis user. Our overall aim is to provide the health practitioner with some guidance for advising women who use cannabis in pregnancy, including best available information on the potential effects of cannabis use on their unborn baby and future childhood development.

What Is Cannabis?

Cannabis is a genus of flowering plant with three main varieties: sativa, indica and ruderalis. It has been used for thousands of years for its fibre (hemp) and for its medicinal and psychoactive effects that are mediated through a unique family of at least 85 different compounds called cannabinoids, the most abundant of which are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC is the only cannabinoid with psychoactive properties, and plants are categorised according to the amount of THC or ratio of THC/CBD they contain. Hemp-producing cannabis strains are specifically bred, as per the United Nations Convention, to produce low THC levels.[16]

Cannabinoids are most abundant in the floral calyxes of the plant. The forms and strengths of THC obtained are dependent on the part of the plant that is used as well as the process used to extract and manufacture the plant product. Hash oil is the strongest, followed by hashish (resin) and marijuana (dried leaves/flowers). Cannabis may be inhaled by smoking with tobacco or through a water pipe or ingested in foods and drinks.[17] Most countries in the world have criminalised the growing and recreational use of cannabis, but controlled programmes in some countries such as the United States, Holland and Canada allow regulated use of medicinal cannabis, including the synthetic compounds dronabinol and nabiolone, for the management of conditions, such as cancer-related nausea[18] and neuropathic pain.[19]

Pharmacodynamics of Cannabis

Endocannabinoids are naturally occurring arachidonic acid metabolites[20] that are essential for the regulation of movement, memory, appetite, regulation of body temperature, pain and immunity.[21] Endogenous endocannabinoids and plant-derived phytocannabinoids exert their effects by activating the cannabinoid receptors of the endocannabinoid system. To date, five cannabinoid receptors have been identified, including the cloned CB1 and CB2 receptors.[22] The CB1 receptor is predominantly located in the central nervous system while the CB2 receptor is largely confined to immune cells and the retina.[23,24]

Psychoactive drugs, such as cannabis, are generally lipophilic and of small molecular size, enabling them to readily cross the blood–brain or other cellular (for example, placental) barriers. In animal studies, fetal blood and tissue THC concentrations are around 10% lower than maternal blood levels,[25] but in the rat model repeated dosing of the dam, particularly at higher doses, resulted in significantly higher plasma concentrations in the fetus as compared with single acute dosing. This suggests that heavy and chronic cannabis use may result in concentration of active cannabinoids in the developing fetus.[26] No similar human studies exist, but when plasma concentrations were measured in human cord blood samples, THC levels were found to be 3 to 6 times lower than in simultaneously collected maternal blood, with a similar concentration gradient being noted for the metabolite 9-carboxy-THC.[27]

Endogenous cannabinoids and cannabinoid receptors are expressed early in the developing fetal brain. CB1 receptors are identifiable in white matter and cell proliferative regions and are involved in critical neurodevelopmental events, such as neuronal proliferation, migration and synaptogenesis. Endocannabinoids are also pivotal in regulating neural progenitor cell commitment and survival.[28] Cannabis exposure during pregnancy therefore has the potential to induce supra-physiological stimulation of the endogenous cannabinoid system, which may then disrupt the ontogeny of endogenous endocannabinoid signalling and interfere with synaptogenesis and the development of neuronal interconnections. In addition to the possible effects of cannabis use on endocannabinoid-mediated neuronal maturation, it appears that cannabis exposure in pregnancy may also disrupt developing neurotransmitter systems. Dopaminergic neurones are expressed very early in the developing brain and exert trophic effects on neuronal cells.[29] Cannabis exposure during pregnancy disrupts tyrosine hydroxylase activity, the rate-limiting enzyme in dopamine synthesis, which has the potential to impact on the maturation of dopaminergic target cells.[28] Disturbances in dopamine function have consequently been associated with an increased risk of neuropsychiatric disorders, such as drug addiction,[30] schizophrenia[31] and depression.[32] Prenatal THC has also been noted to alter endogenous enkephalin precursor and the expression of opioid and serotonin receptors in animal models.[28]Whether these changes are implicated in the future risk of addictive behaviours and depression in the human is as yet uncertain.

Is There a Genetic Susceptibility to the Effects of Cannabis?

The effect of phytocannabinoids on mature neuronal cells is complex. Both neurotoxic and neuroprotective effects have been described depending on the cannabinoid, the cell type and the stage of cell differentiation.[22] There is evidence that individual susceptibility to cannabis, at least in the adolescent onset user, may be substantially influenced by heredity. Adolescent catechol-O-methyltransferase (COMT) knock-out mice, as compared with wild type, are more vulnerable to cannabinoid-induced modification of expression of schizophrenia-related behaviours.[33] In humans, neuroimaging studies demonstrate that chronic consumption of cannabis beginning before the age of 16 years is associated with alterations in the volume of the caudate nucleus and amygdala in users with specific COMT gene polymorphisms that produce increased copies of the val allele.[34] The presence of the COMT gene polymorphism val158met and the SLC6A4 gene 5-HTTLPR polymorphism in young adult cannabis users, on the other hand, has a moderating effect of decreased performance on executive functioning.[35]Whether genetic susceptibility influences the long-term neuropsychiatric and cognitive outcomes of gestational cannabis-exposed children has not been explored but could lead to individual direction of early intervention and supportive services to ameliorate possible undesirable outcomes.

The Prevalence of Cannabis Use in Pregnant Women

Cannabis is the most frequently used substance in any drug-taking population. In the gravid population, it accounts for >75%,[35] and generally self-reporting from developed Western countries such as Australia[36] and the United Kingdom[37] place the prevalence of cannabis use at up to 5% of all pregnant women. However, the certainty of these estimates is limited due to the variability of self-reporting rates.[37] Although many illicit drug users stop or decrease drug use during pregnancy, cannabis users often continue to use throughout pregnancy and while breast feeding.[38] Persisting cannabis use throughout pregnancy may, in part, be due to widespread societal acceptance of cannabis as a relatively harmless recreational agent compared with other ‘hard’ drugs of dependency such as heroin,[3, 36] and certainly more study into why this occurs is warranted. It must be noted that cannabis use in pregnancy is frequently accompanied by other forms of drug use or abuse. Many women continue to smoke tobacco and/or consume alcohol. Using record linkage data collected over a 5-year period, Burns et al. [39]demonstrated that 12% of cannabis users were concurrently identified as using opioids, 10% as using stimulants and 4% were identified as having an alcohol-related diagnosis during pregnancy. Almost 50% reported that they smoked >10 cigarettes per day. Identifying cannabis use in a pregnant woman therefore should prompt investigation into exposure to other substances.

Detecting Cannabis Use in Pregnancy

Optimal identification of drug exposure has a crucial impact on pregnancy and long-term health outcomes for both the mother and her child.[40] Early detection of drug use allows for timely implementation of harm-reduction strategies designed to moderate drug use as well as to minimise the impact of drug-using lifestyles (for example, unstable home situations, poor nutrition, poverty) on the family. Supportive care may favour changes that alter drug-using behaviours,[41] although it must also be acknowledged that complete cessation or abstinence of drug use is not possible for many women. Nevertheless, early detection facilitates ongoing support and may produce potentially valuable lifestyle changes that go beyond the perinatal period.

Other health issues may be addressed with timely detection of drug use. Ongoing drug use and abuse is frequently associated with psychiatric co-morbidities, and the impact of this on the mother and her family can be further complicated by socioeconomic problems, such as domestic violence and ongoing drug use by co-addicted partners.[42] Reducing drug use may also not be possible without appropriate identification and management of underlying psychiatric co-morbidities, such as anxiety disorders or depression. Evidence suggests that these psychiatric co-morbidities themselves may be a significant trigger for drug use[33] and that the co-existence of mental health problems may independently impact on pregnancy outcomes. Maternal depressive illness, for example, is strongly correlated with an increased risk of preterm delivery,[43–46]and of course, the earlier in pregnancy drug-dependent women have access to psychosocial supports, the higher the likelihood is of them to establish appropriate living conditions for their family and of addressing financial and any associated legal problems.

In addition to specific supports targeting drug use, detection of drug use in pregnancy also permits implementation of strategies that provide drug-using mothers with specific mothercraft and intensive postnatal support, such as intensive home-visiting programmes. Such programmes have been demonstrated to decrease the risk of childhood morbidity and mortality in high-risk disadvantaged adolescent parents.[47] Similarly, targeted education in other aspects of routine parenting, such as safe sleeping practices, may be beneficial as the incidence of night-time Sudden Infant Death Syndrome is significantly higher (for as yet uncertain reasons), in cannabis-exposed infants.[48]

Screening for drug and alcohol use should be considered a normal part of the standard antenatal interview process. Screening tools used in this setting are generally questionnaires that are designed to be administered face-to-face by the provider to the patient. They are not intended to specifically diagnose a substance abuse problem but rather to determine if a patient may be at risk for alcohol or drug problems and would therefore benefit from a more comprehensive evaluation. Ideally, a screening tool should be administered multiple times during each pregnancy, because patients may be more willing to disclose substance abuse problems once they develop rapport with a provider. Screening tests can also provide an opportunity to educate the patient about alcohol and drug abuse and the benefits of addressing these problems while pregnant. Asking every patient relevant but sensitive questions in a health context lessens the stigma associated with the topic. However, administering these screens in the antenatal period can be problematic. Seib et al. [49] demonstrated that while only 15% of the patients being screened were uncomfortable with the process, staff compliance was an issue, with 25% of women not being screened adequately or not being screened at all. All maternity hospitals should therefore encourage staff training to ensure that health providers are comfortable and familiar with screening processes used for their particular local area.

In contrast to the proven effectiveness of specific screening tests for identifying alcohol consumption in pregnancy,[50] the evidence for the efficacy of formal screening tests for drug use in the antenatal period is not as clear. Few screening tools have been directly evaluated for their efficacy in detecting drug, or more specifically cannabis, use in pregnancy. Phillips et al. [102]found that direct questioning by midwives using a structured screening tool facilitated drug use disclosure during early antenatal consults but that the use of some forms of questionnaires, for example, the Drug Abuse Screening Test (DAST-10), had only a sensitivity of 0.47 when self-reporting was validated against positive toxicology screens.[51] Again, we suggest that all staff involved in maternity care be trained to administer (and act on) drug screening tools confidently and without prejudice.

Toxicology screening for drug metabolites is generally carried out with the expectation of increasing the likelihood of detecting undisclosed drug use in pregnancy. Either maternal urine and hair samples or newborn urine, hair and meconium samples can be collected and analysed for the presence of drug metabolites, but only maternal toxicology screening has any value if the intention is to implement harm-minimisation strategies early in pregnancy. Newborn toxicology screening primarily focuses on identifying families at risk of ongoing drug use, to address child protection concerns that may be associated with parental drug use and to provide appropriate treatment for suspected cases of withdrawal or intoxication.[41]

Depending on the locale, toxicology screens may increase the chance of drug detection by up to fivefold,[52] but the general applicability of such screening programmes has often been limited by their selective application to perceived high-risk groups, such as infants of certain racial groups.[51,53] The value of screening maternal urine for drug metabolites is limited by the narrow time frame in which many drugs are excreted after use. Drug testing for cannabis is particularly problematic as there is generally a wide variability in individual excretion profiles.[53] Cannabis metabolites may also be undetectable in the naive user after 48 h. However, they can be potentially detectable in the urine for several weeks in chronic users, making it difficult to determine whether or not a positive urine sample represents past or recent ongoing use.

Maternal hair samples can also be used to detect substance use in pregnancy. However, hair toxicology has not been proven to be of great value in the detection of undisclosed cannabis use in pregnancy. Ostrea et al. [54] compared the sensitivity and specificity of maternal interview, maternal hair analysis and newborn meconium analysis in detecting perinatal exposure to opioids, cocaine and cannabis. Although hair and meconium analysis showed a high sensitivity in detecting opioid and cocaine exposure as compared with interview, hair and meconium analysis demonstrated a sensitivity of only 21% and 23%, respectively, as compared with a sensitivity of 58% for detection by maternal interview. The use of maternal hair samples is further complicated, because results may be affected by passive exposure to environmental cannabis smoke.[55] It is possible to distinguish between environmental contamination and true exposure by assaying for the derivative, Δ9-tetrahydrocannabinolic acid-A (THCA-A), as low concentrations of THCA-A compared with other metabolites suggests environmental contamination,[56] but this increases the complexity and expense of maternal hair analysis and will therefore not be considered suitable in most facilities for routine screening purposes.

Neonatal urine testing by immunoassay provides rapid results but is limited by the short time frame in which an infant will excrete recently used drug metabolites post delivery, resulting in a high rate of false negatives. In contrast, meconium that is collected within the first 2 days of life can be used to detect maternal cannabis use from the second trimester onwards. Neonatal hair samples can also be examined for evidence of exposure during the last trimester of pregnancy, as this is when fetal hair grows. Both meconium and neonatal hair sampling have been shown to be helpful in confirming suspicion of maternal cannabis use, at least in the second and third trimesters of pregnancy. A direct comparison between sensitivity of meconium and neonatal hair testing has found meconium to be more sensitive but is limited by the need to collect a sample within a few days of birth. Hair samples may be useful in confirming prenatal exposure to cannabis for up to 3 months after delivery but facilities for hair analysis remain limited for many care practitioners.

Although both maternal and newborn toxicology screening can increase the likelihood of detecting drug use in pregnancy, most authors do not recommend their routine use because of the expense and the burden on laboratory time constraints. Rather, they suggest toxicology testing be selectively used where there is a suspicion of maternal drug use that can not be confirmed by maternal interview.[41,57]

The Impact on the Fetus and Newborn Infant

It is difficult to determine the direct effects of maternal cannabis use on the developing fetus because of the often high prevalence of other concurrent drug use, including tobacco,[48, 58] and other adverse parenting and lifestyle issues, including poor nutrition, poverty and stress. The endogenous cannabinoid system has a crucial role in maintaining and regulating early pregnancy. Human placental studies have determined that the CB1 receptor is present in all the placental membrane layers[59] and that stimulation of these receptors will impair fetal growth by inhibiting cytotrophoblastic proliferation.[60] In a large population-based prospective cohort study, maternal cannabis use during pregnancy was found to be associated with growth restriction in mid-pregnancy and late pregnancy, with effects on low birth weight being most pronounced if maternal cannabis use continued throughout pregnancy.[61] These growth effects remained significant even after adjustment for potential confounding variables, such as exposure to tobacco and self-reporting of cannabis use (raising the possibility of selection bias). To date, there is no known association between cannabis exposure and spontaneous abortions of either chromosomally normal or abnormal fetuses,[62] and any such links are probably more likely to be related to concomitant stressful life events than to cannabis use per se.[63]

Although some animal studies indicate that cannabis may be teratogenic in very high doses, there is no firm link between gestational cannabis use and congenital malformations in humans.[64] Reports of associations between cannabis use in pregnancy and gastroschisis remain unsubstantiated.[65] A study of almost 420 000 Australian live births over a 5-year period by Burns et al. [39] found that in utero cannabis exposure increased the risk of neonatal intensive care unit admissions, predominantly for prematurity, but there was no relation to any increased risks of perinatal death.

Significant newborn withdrawal or intoxication syndromes requiring pharmacological treatment have not been described with exclusive gestational cannabis exposure, but subtle neurobehavioural disturbances such as exaggerated and prolonged startle reflexes and increased hand–mouth behaviour have been described.[66] High-pitched cries[67] and sleep cycle disturbances with EEG (electroencephalography) changes have been noted,[68] suggesting that prenatal cannabis affects newborn neurophysiological function. Pharmacological treatment for neonatal cannabis withdrawal has not been described, although this may be secondary to a lack of definitive evaluation techniques. Indeed, cannabis withdrawal has been described as a’mild narcotic withdrawal’,[69] and further study into additional treatments, evaluation and long-term outcomes is required.

Long-term Growth and Neurodevelopment

Of greater concern, however, is the increasing evidence that in utero cannabis exposure may impair long-term growth and neurodevelopment, particularly in terms of cognition and behaviour. Evidence from population-based human studies and in vitroanimal data indicates that interference with the endocannabinoid system disrupts normal neurobiological development,[70]particularly of neurotransmitter maturation[5] and neuronal survival.[22]

A longitudinal cohort study of growth parameters in children exposed to cannabis and cigarettes during pregnancy found that cannabis-exposed children have smaller head circumferences at birth, which increase in disparity in adolescence.[71] It must be noted that head growth, especially during the first month of life, is significantly associated with future intelligence quotient.[72]

Most studies, nevertheless, do not support measureable differences in neurodevelopmental outcomes in infants aged <2 years after cannabis exposure, but by early childhood and school age, cannabis-exposed children acquire visual–perceptual tasks and language skills more slowly and show increased levels of aggression and poor attention skills, particularly in girls.[73] The levels of cognitive and intellectual deficits are also related to the timing and degree of in utero exposure. Heavy use (defined as >1 joint per day) during the first trimester was associated with lower verbal reasoning scores in 648 children at 6 years of age when compared with their non-exposed peers, while second trimester use was associated with deficits of composite, short-term memory and quantitative scores.[74]

Problems with tasks requiring visual memory, analysis and integration appear to persist beyond late childhood[75] into adolescence.[76] The long-term effects of in utero cannabis exposure on visuospatial working memory were explored by Smithet al. [78] using functional magnetic resonance imaging. They demonstrated that in 19 to 21-year olds, high levels of maternal prenatal cannabis use was associated with significantly more neural activity in the left inferior and middle frontal gyri, parahippocampal gyrus, middle occipital gyrus and cerebellum and right inferior and middle frontal gyri.[77] The specific learning problems identified in these children appear to significantly interfere with school achievement scores[78] from as early as 6 years of age.

The aetiology of these problems is uncertain. In utero cannabis exposure alters neurotransmitter homeostasis, including ventral striatal dopamine D2 gene regulation[79] and expression,[80] and these changes have been linked to a risk of future neuropsychiatric problems, including disorders of impulse control associated with addiction behaviours.[79] Further, a significantly increased risk of childhood depressive symptoms and attention problems was identified at age 10 years in a large prospective cohort study documenting the use of cannabis in low-income pregnant women.[81] The same group of investigators also demonstrated that the risk of delinquency at 14 years was significantly increased in a prospective longitudinal study of cannabis-exposed children.[82] Other factors, however, are undeniably important in the expression of adverse behaviours during the teenage years. For example, the risk of adverse behaviours, including early initiation of drug abuse, is more likely in an intrauterine drug-exposed child if they are male or simultaneously exposed to other problems such as violence.[83] There is no firm association with prenatal cannabis and future psychiatric problems such as psychosis,[84] but depressive symptoms are increased.[82] Assisting the family unit with moderating adverse environmental influences from as early as possible after birth may have the potential to decrease future problems in young people affected by prenatal cannabis exposure.

The effects of cannabis on future physical growth are still to be determined. CB1 receptors mediate energy incorporation into adipose tissue and reduce energy expenditure. The Ponderal Indices of adolescents exposed to prenatal cannabis are higher than non-exposed children,[85] but further work needs to be done to determine their risk of developing clinically important sequelae such as appetite problems, dyslipidemia and diabetes, which are all common manifestations in chronic adult cannabis users.[86]

Medical Cannabis

In recent years, there has been a re-emergence in the use of medicinal cannabis to treat a variety of conditions, including amelioration of neurogenic pain and management of chemotherapy- and pregnancy-associated hyperemesis.[87] Increasing numbers of states in the United States, for example, have legalised medical marijuana for certain specific indications.[88]However, it is not known whether the long-term effects of prenatal exposure to medicinal cannabis used in a controlled manner differ from the effects of cannabis used as a recreational drug during pregnancy, and urgent study is required. At this point in time, any advice about medicinal cannabis use during pregnancy must take into consideration both the potential benefits of the substance with regards to maternal well being and potential impact of this type of cannabis exposure on the developing fetus.

Lactation

Cannabis and its metabolites readily pass in to breast milk in variable concentrations that depend considerably on the amount of drug ingested by the mother. When cannabis is regularly consumed by breast-feeding mothers, human milk THC concentrations may be up to eightfold higher than simultaneously measured maternal plasma concentrations.[89] Certainly, even bovine consumption of cannabis results in detectable metabolites in at least 30% of children even up to the age of 3 years.[90] There are substantial concerns that continued maternal cannabis use during the first month of life may impede neurodevelopment at 1 year of age,[91] but the effects of postnatal exposure is difficult to delineate from prenatal use as most mothers will not begin using cannabis as a de novo habit after birth.

Delta 9-THC inhibits gonadotropin, prolactin, growth hormone and thyroid-stimulating hormone release and stimulates the release of corticotropin, thereby inhibiting the quantity and reducing the quality of breast milk.[92] The Academy of Breastfeeding Medicine, in line with most professional bodies, recommends against breastfeeding whenever illicit drug use has occurred in the 30-day period before birth. This is especially pertinent if substance abuse is ongoing post delivery or if the mother is not engaged in substance abuse treatment programmes.[93–95] Unfortunately, specific recommendations with respect to breast feeding while using cannabis are hampered by the lack of substantial and definitive studies. In particular, occasional users should be counselled on a case-by-case basis and made aware of the risks of maternal intoxication while caring for an infant and the potential neurodevelopmental sequelae on their child, should cannabis usage become a regular activity.

Recommendations for the Management of Women Using Cannabis in Pregnancy

There are no known ‘safe’ threshold limits for cannabis use in pregnancy, and currently, there are also no specific pharmacological treatments for cannabis dependency. Evidence overwhelmingly indicates that cannabis use during pregnancy and possibly in the postnatal period remains a significantly under-recognised problem that has the potential to cause long-term harm. However, there are a variety of approaches that can facilitate identification of cannabis use in women presenting for pregnancy care that may allow implementation of harm-minimisation procedures to reduce long-term risks for both the mother and her child.

Carefully directed and sensitive histories should be routinely taken to elucidate cannabis and other substance use in pregnancy. In some high-risk cases, toxicological screening may be appropriate where heightened suspicions are not in keeping with maternal history offered. Due to increasing concerns about long-term neurodevelopmental, behavioural and possibly even metabolic consequences of perinatal cannabis exposure, women should be objectively informed of the possible impact of cannabis use during pregnancy and lactation and be strongly advised to stop using cannabis wherever possible. If complete abstinence is not possible, women should be advised to reduce regular cannabis use during pregnancy, as current evidence indicates that daily use of cannabis is most strongly associated with future adverse neurobehavioural outcomes. A harm-reduction approach focusing on minimising risks to the woman and her baby rather than complete cessation may be most effective in this scenario. Engaging women into an antenatal service that provides drug relapse prevention support or referring women to drug and alcohol services should be considered, particularly where an antenatal service cannot offer specific drug and alcohol counselling services itself. Cognitive behavioural therapy centred around drug relapse and prevention support and tobacco cessation education is recommended. Midwives and doctors should ask women about their level of cannabis use and their willingness to change their drug-use behaviours at each antenatal contact. General health education, including the adverse effects from continued cannabis and tobacco exposure and safe sleeping guidelines should be reinforced. Depending on family circumstances, the benefits of breast feeding, even with continued cannabis use, may outweigh the negative side-effects, especially in infrequent cannabis users. Each institution should work towards a policy of ensuring best practices for their particular population of cannabis users.

During the postnatal period, mothers should be advised not to smoke either tobacco or cannabis around their infants and children. They should be educated about the risks of passive smoke exposure as well as the potential effect of cannabis use on a mother’s decision-making ability. Mother-crafting support may be required to ensure best infant care, including safe sleeping practices. Of particular note, counselling cannabis-using fathers is also crucial as continued paternal cannabis triples the risk of Sudden Infant Death Syndrome[96] ( ).

Summary of recommendations

Issue

Detection of maternal use

Recommendations                         

Antenatal drug and alcohol questions best to screen large populations

Maternal and infant toxicology most likely unhelpful unless maternal history is ambiguous56

Early detection may help implement harm-minimisation strategies

Issue

Fetal effects

Recommendations

No definitive link to increased spontaneous abortions97 or congenital abnormalities64, 65  Intrauterine growth restriction, including head size of fetus, common61

Issue

Neonatal effects

Recommendations

Severe withdrawal uncommon but mild symptoms similar to an opioid-type withdrawal is recognised69

Need for pharmacological treatment from cannabis only exposure uncommon

Transient high pitched cry67 and sleep disturbances68 noted

Increased risk of sudden infant death syndrome96

Issue

Effects on childhood and later life

Recommendations

Small head circumference may persist into teenage life

Risk of long-term problems correlated with severity of prenatal exposure,74 particularly on visual memory and executive function74, 75 that may persist to late childhood75 and adolescence76

Aggression and attention problems noted in toddlers (especially girls)73

Issue

Lactation

Recommendations

Cannabis and metabolites cross the milk barrier, and levels in milk may be higher than maternal plasma89

Effects of continued use during lactation may impair early (<1 year) neurodevelopment90

Issue

General

Recommendations

Screen all pregnant women for drug use with a well-validated questionnaire

Cease or decrease use as early as possible—chronic/heavy use (>1 joint per day) increases risk of long-term adverse outcomes for the child

Lactation recommendations must be taken on a case by case basis. Mother must be aware of dangers of breast feeding while intoxicated, of passage of cannabis and metabolites into milk and of possible adverse influence of continued cannabis exposure via breast milk on childhood neurodevelopmental outcomes There is insufficient current evidence to provide definitive recommendations for the use of medicinal cannabis

Conclusion

It is not uncommon for the health-care professional caring for pregnant women to encounter the problem of maternal cannabis use during the antenatal period. Although cannabis is viewed by many as a harmless recreational drug when compared with other illicit drugs, there is mounting evidence to suggest that prenatal cannabis exposure can have a negative effect on fetal growth and that exposure to cannabis during periods of critical brain development, particularly during the fetal and adolescent periods, has the propensity to significantly adversely impact on neurodevelopmental and behavioural outcomes. Ultimately, long-term changes in neurobehaviour, particularly those involving executive functioning, may adversely affect adult educational and vocational outcomes. As health-care professionals, we have a responsibility to seek to actively identify women who use cannabis in the antenatal period and inform them of the possible risks of their cannabis use in a non-threatening and non-judgmental manner. Currently, pregnant and breast-feeding cannabis users should be advised to cease use where possible or substantially decrease their drug use. At this point in time, there remains ongoing uncertainty about both short- and long-term implications of cannabis use during pregnancy and lactation, especially if use is intermittent. Further adequately powered studies are required to resolve this pressing dilemma.

Key Notes

1. Regular cannabis use in pregnancy is a widespread but an under-recognised problem.

2. Fetal growth is possibly affected by gestational cannabis exposure, but the dose-response relationship has not been well defined.

3. There is evidence that regular cannabis use in pregnancy significantly increases the risk of future neurodevelopmental and behavioural problems, with particular effect on executive functioning.

4. Pregnant and breast feeding cannabis users should be identified early and advised to either decrease or where possible cease cannabis use entirely.

Source:  J Perinatol. 2014;34(6):417-424. 

Filed under: Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),Health :

Bertha K. Madras1

Division on Alcohol and Drug Abuse, Harvard University Medical School, McLean Hospital,

Belmont, MA 02478

The current watershed in legal status and rising use of marijuana can be traced to a Cal-ifornia ballot initiative (Prop. 215, its legal successor SB420), that enabled widespread access to smokeable or edible forms of marijuana for self-reported medical conditions. Circumventing the Food and Drug Adminis-tration (FDA) drug approval process, the movement in California was replicated by ballot or legislative initiatives in 23 states and the District of Columbia, and culminated in the legalization of marijuana in 2012 by Washington state and Colorado. The shifting status of marijuana reflects a change in public perception and belief that marijuana is harm-less. Marijuana use in the population over age 12 is escalating; 60% of 12th graders do not perceive marijuana as harmful, and daily or nearly daily use has risen dramatically in this cohort (1, 2). Paradoxically, public perception of marijuana as a safe drug is rising simulta-neously with accumulating evidence that frequent marijuana use is associated with adverse consequences, especially among youth (3). In PNAS, Volkow et al. register compelling new observations that marijuana abusers manifest adaptive behavioral, physiological, and biological responses, which conceivably contribute to marijuana addiction and com-promised function (4). In response to a dopamine challenge (methylphenidate) and compared with non-using controls, marijuana abusers self-reported blunted reward (less “high”) and heightened negative responses (anxiety and restlessness), which were associated with attenuated dopamine responses in brain and cardiovascular responses.

Dopamine, Reward, the Adapted Brain

The role of the neurotransmitter dopamine in drug reward and addiction is the key to understanding the rationale for interrogating dopamine function in long-term marijuana abusers.Thedopaminehypothesisofaddiction was formulated by preclinical observations showing that opiates, cocaine, amphetamine, nicotine, alcohol, and (delta-9)-tetrahydro-cannabinol(THC,thepsychoactiveconstituent of marijuana), raise extracellular dopamine levels in the dopamine-rich nucleus accum-bens, a brain region associated with reward (5, 6). Repeated drug-induced dopamine surges were subsequently shown to engender neuroadaptive changes in brain regions implicated in drug salience, drug reward, motivation, memory, and executive function (7–9). In humans dependent on alcohol, cocaine,  methamphetamine, nicotine, or heroin, adaptation of dopamine signalling is manifest by reduced D2 dopamine receptor availability and blunted dopamine release in cocaine, heroin, and alcohol abusers challenged with a psychostimulant (10–14). In-terrogation of whether marijuana abusers manifest parallel adaptive changes in dopamine signaling has yielded inconsistent results (15).

By integrating behavioral and brain-imaging measures following a dopamine challenge (methylphenidate) in marijuana abusers, Volkow et al. (4) add a new di-mension to clarifying the impact of long-term marijuana use on brain dopamine response. Methylphenidate, a surrogate for dopamine, elevates extracellular levels of dopamine (and norepinephrine) by blocking the dopamine transporter (DAT) in dopa-mine-expressing neurons. As the DAT sequesters dopamine in dopamine-releasing neurons, the blockade raises extracellular dopamine levels in dopamine-rich brain regions. The rapid rise in dopamine triggers self-reports of a “high.” Marijuana abusers self-reported blunted measures of “high,” drug effects, increased anxiety, and rest-lessness. The magnitude and peak behavioral effects of methylphenidate were more robust in controls than marijuana abusers. Cardiovascular responses (diastolic blood pressure, pulse rate) were also attenuated in the abusers. Significantly, the younger marijuana use was initiated, the higher the scores for negative emotionality. These findings reinforce the accumulating evidence that earlier age of initiation of mar-ijuana abuse is associated with worse out-comes (3, 16). Collectively this phase of the study suggests that brain dopaminergic, pos-sibly noradrenergic systems, are significan-tly modified in long-term, heavy marijuana abusers. These changes conceivably contribute to reduced rewarding effects, emotion-ality and motivation, increased propensity for addiction, with early initiators being more vulnerable.

D2/D3 dopamine receptors are critical mediators of the initial responses to drugs of abuse. PET imaging of brain revealed a more complex pattern of change in dopamine signaling than previously reported for other specific drugs of abuse. D2/D3 dopamine receptor availability, measured with the D2/D3 receptor antagonist [11C]raclopride, was not reduced in marijuana abusers, in contrast to reduced dopamine receptor availability observed in subjects with other specific substance use disorders (11–14).

This conclusion remains tentative, as the age of the marijuana-abusing cohort was considerably younger than drug-abusing subjects previously interrogated for D2 dopamine receptor availability.

[11C]Raclopride can also serve as an in-direct measure of dopamine production, release, and extracellular levels (17). Reduced [11C]raclopride binding-site availability is detectable following administration of a psy-chostimulant (e.g., methylphenidate or amphetamine), which elevates the extracellular dopamine by blocking transport or promoting its release from neurons. The dopamine surge competes with [11C]raclopride for binding to the D2/D3 receptor, with [11C]raclopride displacement proportional to extracellular dopamine. In marijuana abusers, diminished dopamine responses were observed in the ventral striatum compared with controls, and were inversely correlated with addiction severity and craving. The attenuated responses to methylphe-nidate are consistent with decreased brain reactivity to dopamine stimulation in marijuana abusers, which conceivably contributes to the increase in stress responses, irritability, and addictive behaviors. Thus, marijuana joins the roster of other abusable drugs in promoting blunted dopaminergic responses in a brain region implicated in drug reward, but deviates from other drugs in that it apparently does not promote a decline in D2/D3 receptor availability.

The study yielded several unanticipated discoveries. Marijuana abusers displayed enhanced dopamine release in the substantia nigra/subthalamic nucleus, which correlated with marijuana and tobacco craving, as well as addiction severity. Because this brain re-gion has relatively high densities of the D3 receptor, this preliminary finding reinforces the need to expand PET imaging to multiple, discrete brain regions, with higher-resolution cameras, and to enlist other probes capable of selective monitoring of each of five dopamine receptor subtypes. Another surprising obser-vationwasthedecreaseindistributionvolume in the cerebellum by methylphenidate in con-trols, but not in marijuana abusers, another manifestationofabluntedresponse.Thisbrain region characteristically is used as a reference region to normalize for nonspecific binding (“baseline”) of PET imaging probes if comparing group differences, possibly resulting in overestimates of the methylphenidate re-sponse in other brain regions of marijuana abusers. This finding, which may reflect vas-cular changes engendered by marijuana, highlights the necessity of heightened scrutiny ofthe cerebellum asa“neutral”baseline region for dopamine receptor monitoring in group comparisons.

Collectively, abnormal behavioral responses to a methylphenidate challenge implicate dopamine signaling adaptation in mari-juana abusers. Even though a decrease in striatal D2 receptor density does not ac-count for the responses, other components of the synapse (e.g., DAT, dopamine syn-thetic capacity, the dopamine signaling cascade, events downstream of dopamine receptors) conceivably contribute to mani-festations of blunted subjective responses.

Future Multidisciplinary Research

The current research (4), providing strong evidence that marijuana abuse is associated with blunted dopamine responses and re-ward, is a major contribution to a growing body of evidence that heavy marijuana use is associated with brain changes that could be detrimental to normal brain function. Numerous other brain-imaging studies have been conducted in heavy adult marijuana users (e.g., ref. 18), with reported changes in brain morphology and density, defor-mation of specific structures, altered con-nectome (e.g., hippocampus), and function.

The current research, which integrates be-havioral and physiological changes within the context of a specific neurochemical substrate, dopamine, provides important leads for in-tegrating with other changes gleaned from MRI technologies. Intriguingly, evidence that dopamine receptor signaling can affect ex-pression of genes encoding axonal guidance molecules that are critical for brain devel-opment and neuroadaptation (19) may pro-vide a link between drug-induced receptor activity and gross and discrete altered mor-phology and circuitry characteristic of the drug-adapted brain.

There remains a compelling need for prospective, integrated longitudinal research in this field, especially in adolescent mari-juana users, as the impact of marijuana on the developing brain is more robust with early age of initiation (3, 16). Imaging studies are predominantly snapshots in time, relying on self-reports of marijuana use, dose, and frequency, with subjects of varying ages, group sizes, differing imaging tech-niques, and other variables that confound meta-analyses or integration of data from different sites to expand study power. A critical longitudinal study showing a signifi-cant IQ decline in early marijuana users is a prime example of the direction in which the field should be going, but with co-ordinated brain-imaging approaches (20).

Preclinical studies can circumvent the limitations of some clinical metrics, and es-tablish causality for specific changes that are not feasible to measure in humans. Yet the divergence of the human brain anatomically and functionally limits unfettered extrapola-tion from animals to humans. Large-scale, multicenter prospective longitudinal human research starting before initiation of drug use and extending for three decades of life is needed to further pursue causal relation-ships of marijuana and adverse consequences reported in numerous shorter-term studies. Research design could include: (i) brain im-aging to document occurrence of, resolution, or persistence of structural, circuitry, vascu-lar, and associated and neuropsychological decrements; (ii) neurocognitive function; (iii) behavioral, emotional assessment; (iv) neural, cognitive, epigenetic, proteomic, and affec-tive markers; and (v) preclinical, relevant parallel studies.

In view of the growing public health con-cerns of escalating high-dose, high-frequency marijuana use, early age of initiation and daily use, high prevalence of marijuana addiction, rising treatment needs, the void of effective treatment, high rates of relapse, association with psychosis and IQ reduc-tion, a rising tide of emergency room epi-sodes, and vehicular deaths, constitute compelling reasons to expand marijuana research and to clarify its underlying biology and treatment targets/strategies. Longitudinal studies that begin before initiation of use, and that integrate brain imaging with behavioral, cognitive, and other parameters, will facilitate shaping of public perception and public policy with more informed scientific evidence.

1 Center for Behavioral Health Statistics and Quality (2013) National

Survey on Drug Use and Health (Substance Abuse & Mental Health Services Administration, Rockville, MD).

2 Johnston LD, et al. (2013) Monitoring the Future: National Survey Results on Drug Use, 1975–2013 — Overview, Key Findings on Adolescent Drug Use. (Institute for Social Research, University of Michigan, Ann Arbor) Avaliable at http://monitoringthefuture.org// pubs/monographs/mtf-vol1_2013.pdf. Accessed July 13, 2014.

3 Volkow ND, Baler RD, Compton WM, Weiss SR (2014) Adverse health effects of marijuana use. N Engl J Med 370(23):2219–2227.

4 Volkow ND, et al. (2014) Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci USA, 10.1073/ pnas.1411228111.

5 Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85(14):5274–5278.

6 Chen JP, et al. (1990) Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berl) 102(2):156–162. 7 Hyman SE, Malenka RC, Nestler E (2006) Neural mechanisms of addiction: The role of reward-related learning and memory. Annu Rev Neurosci 29:565–598.

8 Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuro-psychopharmacology 35(1):217–238.

9 Volkow ND, Wang GJ, Fowler JS, Tomasi D (2012) Addiction circuitry in the human brain. Annu Rev Pharmacol Toxicol 52:321–336. 10 Volkow ND, et al. (1997) Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386(6627):830–833.

11 Martinez D, et al. (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58(10):779–786.

12 Martinez D, et al. (2012) Deficits in dopamine D(2) receptors and presynaptic dopamine in heroin dependence: Commonalities and differences with other types of addiction. Biol Psychiatry 71(3): 192–198.

13 Wang GJ, et al. (2012) Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry 17(9):918–925.

14 Fehr C, et al. (2008) Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse. Am J Psychiatry 165(4):507–514.

15 Ghazzaoui R, Abi-Dargham A (2014) Imaging dopamine transmission parameters in cannabis dependence. Prog Neuropsychopharmacol Biol Psychiatry 52:28–32. 16 Lynskey MT, et al. (2003) Escalation of drug use in early-onset cannabis users vs co-twin controls. JAMA 289(4): 427–433.

17 Seeman P, Guan HC, Niznik HB (1989) Endogenous dopamine lowers the dopamine D2 receptor density as measured by [3H]raclopride: Implications for positron emission tomography of the human brain. Synapse 3(1):96–97.

18 Batalla A, et al. (2013) Structural and functional imaging studies in chronic cannabis users: A systematic review of adolescent and adult findings. PLoS ONE 8(2):e55821.

19 Jassen AK, Yang H, Miller GM, Calder E, Madras BK (2006) Receptor regulation of gene expression of axon guidance molecules: Implications for adaptation. Mol Pharmacol 70(1):71–77.

20 Meier MH, et al. (2012) Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci USA 109(40):E2657–E2664.

Source: www.pnas.org/cgi/doi/10.1073/pnas.1412314111 PNAS Early Edition

Filed under: Brain and Behaviour,Cannabis/Marijuana,Effects of Drugs (Papers) :

Loyola adolescent medicine expert talks about the potential dangers of marijuana for teens 

Whether states should legalize marijuana for recreational and medical use is a hot topic across the country. As the debates continue a potentially dangerous environment is being created where more preteens, teens and young adult are beginning to use the substance with the feeling that it is safe. In fact, 36 percent of all seniors in high school and 7 percent of eighth-graders report using the drug in the past month, according to a recent study. Though public perception is that marijuana is a harmless drug, research is showing it can have a damaging impact on developing brains and may lead to life-long addiction.

“Teens are seeing marijuana as a safe substance, but its effects on the adolescent brain can be dangerous, especially if there is heavy use. As the stigma of marijuana use becomes less the number of teens using the drug has increased. More high-schoolers in the U.S. now smoke marijuana than they do cigarettes,” said Garry Sigman, MD, director of the adolescent medicine division at Loyola University Health System and professor in the Department of Pediatrics at Loyola University Chicago Stritch School of Medicine.

Marijuana is an addictive substance and, according to Sigman, adolescents are 2-4 times more likely to become dependent on the drug within two years after first use compared with adult users. “Marijuana is the most common substance addiction being treated in adolescents in rehabilitation centers across the country. Like all addictive substances, marijuana is used to lessen uncomfortable feelings like anxiety and depression. Because the type of addiction is seen as less ‘intense’ in comparison to other substances such as cocaine or heroin, many people don’t realize that marijuana can cause dependence and has a withdrawal syndrome,” Sigman said.

Some adolescents use marijuana only occasionally because of peer pressure at a party or in a social setting, but others self-medicate with marijuana to cope with emotions and stress. One of the signs of a substance-use disorder is when drugs are used often to cope with uncomfortable feelings.

Addiction isn’t the only hazard for adolescents when it comes to smoking marijuana. Research shows that heavy use can lead to neurotoxicity and alternations in brain development leading to:
• Impairment in thinking
• Poor educational outcomes and perhaps a lower IQ
• Increased likelihood of dropping out of school
• Symptoms of chronic bronchitis
• Increased risk of psychosis disorders in those who are predisposed.

“Parents should inform themselves about the scientific facts relating to marijuana and the developing brain and be able to discuss the topic calmly and rationally. They need to explain that the dose of the drug in a ‘joint’ is three to four times higher than in years past, and that if the parents occasionally used during their lives, they now know that the risk is present if used before adulthood,” Sigman said.

Source:  http://www.newswise.com/articles/view/623773/?sc=dwtn    Sept. 2014

Filed under: Drug use-various effects,Effects of Drugs (Papers),Marijuana and Medicine :

The fall of the Roman Empire is the subject of much debate, and includes attention to the possible role of their aqueducts, lined with lead. More likely, the decline was the result of lead poisoning caused by the consumption of grape juice boiled in lead cooking pots. The aristocracy of Rome consumed as much as two liters of wine a day — almost three bottles — adding alcoholism to the risk of lead poisoning. 

Lead poisoning has an impact on intelligence, even at concentrations as low as 10 micrograms per deciliter. In the New England Journal of Medicine on April 17, 2003, Richard L. Canfield writes that children between the ages of 3 and 5 suffer a decline of 7.4 IQ points from environmental lead exposure. That figure represents a substantial loss of intellectual capacity. There is no effective treatment for children so exposed. One can be grateful for a dedicated public health campaign to mitigate this powerful yet avoidable toxin in the lives of children.

That said, no one is advocating that pregnant woman splash lead-based paint in their nursery. Unlike another substance that also holds high risk during the prenatal period. Incredibly, it is a substance that for pregnant women is more than permitted, it is encouraged by some advocates. That substance is marijuana. In the life of the developing adolescent, heavy marijuana exposure is associated with brain abnormalities, emotional disruption, memory decline, and yes, loss of IQ; a decline of an estimated 8 points into adulthood, according to research by M. Meier in the Proceedings of the National Academy of Sciences in October, 2012. But what of prenatal exposure, from maternal marijuana use?

The website Cannabis Culture provides an answer in a 1998 article. The opening graphic is of a dreamy, topless woman who is in the late-term of her pregnancy. She is curled around a hookah. Under advice from a “Dr. Kate,” she is told that smoking marijuana while pregnant is not only safe, but that “cannabis can be a special friend to pregnant women in times of need.” It is said to mellow out those periods of morning sickness and to reduce anxiety.

The potential impact of such misinformation is widespread. According to the 2012 National Survey of Drug Use and Health, the rate of illicit drug use in 2012 was 18.3 percent among pregnant women aged 15 to 17. The drug being used is overwhelmingly marijuana.

An article by L. Goldschmidt in Neurotoxical Teratology in April/May 2000 concluded “Prenatal marijuana use was significantly related to increased hyperactivity, impulsivity and inattention syndrome (as well as) increased delinquency.” The marijuana used by pregnant women in this study would almost certainly be seen today as low-potency.

Recent research is even more specific concerning the damage. For instance, Xinyu Wang published on Dec. 15, 2004 in Biological Psychiatry results from examination of foetal brains. It noted, “Marijuana is the illicit drug most used by pregnant women, and behavioral and cognitive impairments have been documented in cannabis-exposed offspring.”

Their results showed “specific alterations of gene expression in distinct neuronal populations of the fetal brain as a consequence of maternal cannabis use.” The reduction was correlated with the amount of maternal marijuana intake during pregnancy, and particularly affected male fetuses. The THC “readily crosses the placenta and can thus affect the fetus,” while “longitudinal human studies have shown motor, social, and cognitive disturbances in offspring who were exposed to cannabis prenatally.” Finally, “school children exposed in utero to marijuana were also weak in planning, integration and judgment skills.”

The authors also note “Depending on the community, 3 percent to 41 percent of neonates born in North America are exposed in utero to marijuana.” Marijuana, the president has assured us in an interview with  David Remnick  (The New Yorker, Jan. 27, 2014), is “no more dangerous than alcohol.” To which he could now add, “and for the newly born, only marginally more dangerous than lead.” With this president, you take your assurances where you may.

In Colorado today, marijuana is treated as a legal recreational indulgence and is hawked as a medicine. Moreover, adolescent use of this substance, in the form of the new, highly potent industrial dope now being produced, is soaring. Included in that population of adolescent users are young females, some of whom are, or shortly will be, pregnant.

Murray is a former White House chief scientist and currently a senior fellow at the Center for Substance Abuse Policy at Hudson Institute in Washington, D.C.

Source:http://www.utsandiego.com/news/2014/sep/25/pregnancy-marijuana/    Sept   2014

Filed under: Drug use-various effects,Effects of Drugs,Effects of Drugs (Papers),Marijuana and Medicine,Medicine and Marijuana,Parents,Social Affairs :

Patients taking opioid painkillers for chronic pain not associated with cancer — conditions such as headaches, fibromyalgia and low-back pain — are more likely to risk overdose, addiction and a range of debilitating side effects than they are to improve their ability to function, a leading physicians group declared Wednesday.

A leading physicians group has laid out the conditions that should govern the long-term use of opioid painkillers such as OxyContin. (Toby Talbot / Associated Press)

http://www.latimes.com/local/lanow/la-sci-sn-painkiller-deaths-20140916-story.html

The long-term use of opioids may not, in the end, be beneficial even in patients with more severe pain conditions, including sickle-cell disease, destructive rheumatoid arthritis and severe neuropathic pain, the American Academy of Neurologists opined in a new position statement released Wednesday.

But even for patients who do appear to benefit from opioid narcotics, the neurology group warned, physicians who prescribe these drugs should be diligent in tracking a patient’s dose increases, screening for a history of depression or substance abuse, looking for signs of misuse and insisting as a condition of continued use that opioids are improving a patient’s function.

In disseminating a new position paper on opioid painkillers for chronic non-cancer pain, the American Academy of Neurology is hardly the first physicians group to sound the alarm on these medications and call for greater restraint in prescribing them. But it appears to be the first to lay out a comprehensive set of research-based guidelines that outline which patients are most (and least) likely to benefit from the ongoing use of opioids — and what practices a physician should follow in prescribing the medications for pain conditions.

The statement would govern the prescribing of morphine, codeine, oxycodone, methadone, fentanyl, hydrocodone or a combination of those drugs with acetaminophen. It was published Wednesday in the journal Neurology.

The American Academy of Neurology’s position statement also urges physicians to work with officials to reverse state laws and policies enacted in the late 1990s that made the prescribing of opioid pain medication vastly more commonplace.

The position paper notes that despite a national epidemic of painkiller addiction that has claimed more than 100,000 lives in just over a decade, many of the laws and practices adopted in the late 1990s remain unchanged. It adds that prescription drug monitoring programs — online databases that would allow physicians to quickly check on all controlled substances dispensed to a patient — “are currently underfunded, underutilized and not interoperable across state lines or healthcare systems.” The result is that patients’ tendency to develop a tolerance for opioid drugs — and to require ever-higher doses to achieve pain relief — often go unnoticed. The result is not only addiction and misuse, but an escalating risk of accidental overdose, since opioid narcotics depress breathing and, especially when mixed with alcohol or other sedative drugs, can prove deadly.

In the age group at highest risk for overdose — those between 35 and 54 — opioid use has vaulted ahead of firearms and motor vehicle crashes as a cause of death.

The American Academy of Neurology statement cites studies showing that roughly half of patients taking opioids for at least three months are still on opioids five years later. Research shows that in many cases, those patients’ doses have increased and their level of function has not improved.

In addition to screening patients for depression or past or present drug abuse, physicians prescribing a long-term course of opioids to patients with pain should draw up an “opioid treatment agreement” which sets out the responsibilities of patients and physicians. Physicians should track dose increases and assess changes in a patient’s level of function, and if a specific daily dose is reached (a “morphine equivalent dose” of 80-120 mg) and a patient’s pain is not under control, doctors should seek the help of a pain specialist.

The statement also recommends against prescribing any benzodiazepines or other sedating drugs to patients who take opioid painkillers. And it recommends the “prudent use” by physicians of random urine testing for patients taking opioids to detect misuse of the drugs or abuse of other, non-prescribed drugs. When a physician takes on the care of a patient who has taken opioid painkillers for more than three months and has aberrant behaviour or a history of overdose, he or she should consider a trial aimed at weaning the patient off such medication.

Source:   www.laties.com  1st October 2014

Filed under: Addiction (Papers),Drug use-various effects,Effects of Drugs (Papers),Social Affairs (Papers),Treatment :

The only thing green about that bud is its chlorophyll.

You thought your pot came from environmentally conscious hippies? Think again. The way marijuana is grown in America, it turns out, is anything but sustainable and organic. Check out these mind-blowing stats, and while you’re at it, read Josh Harkinson’s feature story, “The Landscape-Scarring, Energy-Sucking, Wildlife-Killing Reality of Pot Farming.”

 

 

 

 

 

 

 

 

 

 

 

 

Sources: Jon Gettman (2006), US Forest Service (California outdoor grow stats include small portions of Oregon and Nevada), Office of National Drug Control Policy, SF Public Utilities Commission, Evan Mills (2012).

 

Filed under: Effects of Drugs (Papers),Environment,USA :

100 Americans die of drug overdoses each day. How do we stop that? By now, virtually everyone has heard that actor Philip Seymour Hoffman died last Sunday of an apparent heroin overdose. What fewer people know is that, on the same day, roughly 100 other Americans also likely died from drug overdoses — statistically speaking.

The rise of fatal overdoses over the last 15 years is startling. In 2010, according to the Centers for Disease Control and Prevention, there were 38,329 fatal drug overdoses in the United States, more than double the 16,849 fatal overdoses observed in 1999. Overdosing  is now the leading cause of accidental death in the United States, accounting for more deaths than traffic fatalities or gun homicides and suicides. Fatal overdoses from opiate medications such as oxycodone, hydrocodone, and methadone have quadrupled since 1999, accounting for an estimated 16,651 deaths in 2010. Earlier this week, I discussed the overdose issue with my colleague Keith Humphreys. Humphreys is one of the nation’s leading addiction researchers. He teaches psychiatry at Stanford and is a scientist in the VA Palo Alto Health Care System. Below is an edited transcript of our conversation.

Harold Pollack: Let’s start by noting who you are, and why anybody would want to ask your views regarding drug abuse and overdose.

Keith Humphreys: I’m a professor of psychiatry at Stanford University and lead the mental health policy section in my department. I’m also a scientist in the VA Palo Alto Health Care System–though I should make clear that I’m a VA scientist, not a spokesperson for the VA’s official views. I’ve researched drugs and addiction for about 25 years. I’m also a trained clinician, and I’ve treated people for addiction. Last but not least, I work extensively with public policy makers. I was a senior policy adviser at the White House Office of National Control Policy (the “drug czar’s” office) for the first year of the Obama administration. I also served an advisory role within the Bush administration. I work with many states, legislatures, and governors, on how to design policies that reduce the destructive effects of addiction.

HP: Among other things, you are a prolific movie reviewer. Of course, our phone call today is occasioned by Philip Seymour Hoffman’s death. Before we discuss the policy issues, how were you touched by Hoffman’s work as an actor?

KH: He was one of the very best actors this country has produced within the last 20 years. I’m struck by the range of things he could do and by his ability to make audiences care about characters who were difficult, strange or unhappy.

People will always remember him for his Oscar-winning performance in Capote. That’s appropriate because he was brilliant.. But he was also outstanding in some smaller films that not many people saw.  I’ve been encouraging people interested in addiction to seeOwning Mahoney. It’s about a gambling addict, and it’s based on a true story. The film captures how someone who seems to be doing well in many dimensions can still experience an addiction, and experience the emotional emptiness that often goes with that addiction. I don’t know how much of Hoffman’s own life went into that performance, but it’s pitch perfect. It only becomes more powerful when you realize that he himself was suffering from an addiction, albeit of a different sort.

HP: I believe his death is a reminder of two things. First, addiction can exist in people’s lives alongside wonderful connections with other people, wonderful accomplishments, and wonderful abilities. Second, this problem touches so many people in so many different ways. We hold many stereotypes about what opiate addiction is like, what heroin users are like. These stereotypes just don’t match the human experience of many people with opiate use disorders or the experiences of their friends and family members.

KH: That is true; the stereotypes don’t match reality. Most people who have drug problems also have jobs. A huge proportion of people having difficulties with prescription drugs are women; a huge proportion are “nice, middle class people.” While I’m gratified that Hoffman’s death has galvanized discussion, some of this discussion has perpetuated harmful stereotypes. Some are saying: “Philip Seymour Hoffman, that’s the Hollywood lifestyle for you, they’re all into drugs, and all that…” This characterization ignores the fact that, statistically speaking, more than 100 Americans whose names we’ll never know died of drug overdose on the same day that Mr. Hoffman did. Overdose is not a Hollywood story. It’s an American story about an epidemic that’s affecting all layers of American society.

HP: Many people don’t realize that overdose is the leading cause of accidental death in the U.S. I gave a talk about five years ago in Chicago, and I mentioned that we had more overdose deaths than traffic fatalities. My audience literally did not believe me. People were absolutely convinced that I had mis-transcribed the numbers. Every year, America loses a little over 32,000 people in auto crashes, and something like 38,000 from overdose deaths annually.

KH: Yeah, it’s remarkable if you compare overdoses to AIDS, which at its peak was taking about the same number of lives. The difference in reaction is really startling. We appropriately became galvanized about HIV/AIDS, and implemented much better public policy to prevent HIV-related deaths. It’s much harder to get traction on the overdose issue, or even to get people to believe how prevalent the problem actually is.

HP: Why do you think it’s hard to get people galvanized around overdose?

KH: AIDS inspired incredible activism in part because it was localized in particular communities that already had a shared identity. That probably helped groups like Gay Men’s Health Crisis organize politically. People knew each other. They loved the people who were dying. There isn’t a comparable pre-existing  community of people affected by overdose. It’s spread all over. The people who are dying and their loved ones don’t necessarily know each other.. Also, there are also many people — as was true of AIDS — who feel that overdose is just punishment for immoral behavior and therefore isn’t a problem at all.

I should add one other thing which you know well. In drug policy, we have so much culture war screaming that it’s very hard to address issues like overdose that take some planning, thought, and reflective approaches to public policy…. The polarized and uncivil atmosphere in drug policy  generates much heat but very little light regarding what we should do to address this problem. Evidence is often left aside as people start screaming at each other. Overdose is a public health problem and everyone should be working together to save lives.

HP: Within the world of injection drug use, the HIV epidemic sometimes overshadowed the continual reality that overdose was always a prevalent cause of mortality. If you read the classic cohort studies of street injection drug users, you’ll find that there tended to be a one or two percent annual overdose fatality rate in many of those studies. That’s incredibly high in groups of fairly young people who are not dying of other things.

The overdose threat was always there, perhaps in a fashion that led people to think of it as a condition rather than a problem. It became easy to see overdose as just another unavoidable background fact, which we couldn’t really influence. It became easy to see overdose as yet another cost of doing business if you’re engaged in this behavior.

You recently mentioned that most “overdoses” are really not overdoses in the sense that one might think, where people are getting a much  more powerful dose than they were expecting. Can you explain that?

KH: News reports about batches of “killer heroin” are typically overblown. But unusually strong doses of a drug are in fact rarely the cause of overdose. Toxicology results after a fatal overdose usually indicate that the victim has consumed either their normal dosage level or a dose slightly lower than their normal level. It’s too late to fix the language, but “poisoning” might be a better term than overdose.

You might ask: Why would an experienced user die from taking their normal dose? Typically overdose occurs because they’ve had a loss of tolerance. This loss of tolerance often arises because they haven’t used for a while. Maybe they had a voluntary period of abstinence. Maybe they were in jail, and their body can no longer handle the same dose.

The other leading cause of loss of tolerance is consumption of other substances. This is particularly true of alcohol, which seems to lower the body’s ability to tolerate opiates (so do benzodiazepines). Most of what we call “opiate overdoses” are really polydrug overdoses: alcohol and heroin, alcohol and oxycontin, benzodiazepine, alcohol and Vicodin, combinations like that.

HP: This is an important point easily lost. Many, maybe most people who have a serious drug problem are using more than one substance. Alcohol and other substances are usually in the mix. That poly-substance use complicates efforts to treat people medically. It also complicates the behavioral dimensions of substance use disorders.

KH: That is true, and that is even more true today than it was 20 years ago. If you go back to people who are now in their 60s, there were a lot of people who just were alcoholics. They did not touch other drugs. You see more mixing as you move through the baby boomer generation. And now with adolescents and young adults there’s really a poly-pharmacy of everything: legal pharmaceuticals, illegal street drugs, alcohol. You meet a drug user, and virtually always you’re meeting a poly-drug user.

HP: Philip Seymour Hoffman was a little older, age 46. That’s a pretty typical age for many overdose fatalities. He was having this interrupted period of use in some form. It is ironic that people’s efforts to quit or to reduce their drug use can create such vulnerability for overdose.

KH: That vulnerability helps to explain why it is such a hard decision for people who are on various kind of orally-administered opiate substitute medications, like buprenorphine or methadone, to decide whether they want to stay on them. A former heroin user who is taking these medications is still taking an opiate. You have much lower risk of overdose or HIV infection while you’re on them. At the same time, many people want to be weaned off these medications. Maybe they don’t like the potential health consequences of being on an opiate forever. Maybe they just don’t like the inconvenience or cost. People must decide: “Do I really need this, or can I go without it?”

It’s a really tough decision, because if you are able to successfully transition from them, you may like your life better. On the other hand, your tolerance will decline. So if you do relapse – particularly if you return to injection use — it could be a higher-risk event than it would if you had never gone off the opiates. Many people have strong ideologically tinged feelings about this issue and say it’s always a good idea or always a bad idea to go off of opiate substitution medication. In real life situations with real individuals, it’s a hard decision.

HP: Given these realities, I am very concerned about various detox programs that advertise heavily, but that have uncertain results. If you open some airline flight magazines you’ll sometimes see an ad that says, “Come to the desert for two weeks. You can tell your friends and family that you’re on vacation. We’ll detox you of everything, and you’ll come back a new man.”

KH: What a recipe for overdose!  It’s such a horrible promise to hold out to desperate people and their families. By the way, those programs are usually cash-pay only. They promise to take away your addiction in two weeks but what they really take is your money.

HP: We know that relapse rates for straight detox are almost 100 percent, if detox is not followed up with careful interventions and monitoring. I sometimes wonder whether some very-wealthy people such as Philip Seymour Hoffman are actually getting evidence-based treatment when they seek help.

KH: I don’ think they do. Some are checking into rehabs that don’t seem much different than luxury hotels. I suspect, actually, that you might get better care being a working class veteran, or someone who happens to live near a primary care doctor who has trained him or herself using buprenorphine than you would being a rich and famous person in that luxury tier of care.

The other thing is—and I don’t want single out Hollywood as the only example–there is a lot of enabling of high-status addicts. Rich people, high-status people such as physicians and politicians are sometimes immune from life pressures that provide other people with valuable warning flags. Powerful people can often evade many common legal, financial and social consequences of addiction . They can get into way deeper trouble before someone finally says, “Hey, I think you need to take a look at this problem.”

HP: Michael J. Fox notes an episode in his memoir, when he’s caught driving recklessly and is basically let off the hook by a local police officer. In hindsight Fox realizes how problematic such episodes were for him. Similar challenges arise with college drinking. Students aren’t driving anywhere if they live on campus. They don’t have to wake up early because they don’t have class until eleven o-clock. So they can get blasted and avoid some of the usual social constraints on alcohol consumption they would face in another environment. Most people regulate their own substance use because they start to get negative cues from their life experience. If you attenuate these cues, you may be making someone more vulnerable to longer-term problems.

KH: For related reasons, you can see why substance use disorders might become widespread in a community where there’s very little employment, where people have a huge amount of time with nothing to do, not much fun to do, and not many demands on them…

HP: I want to get back to prescription drug abuse. We’re facing serious problems with medications like Oxycodone. Yet many of the problems that we associate with illegal markets are much less present in the prescription opiate scene. There’s little violence on the supply side of this market. People are buying a medically produced product. They know the potency and the dosage. They’re not getting street drugs that have (say) fentanyl mixed in. One might have thought that this would be a safer environment for people. It doesn’t seem to have turned out that way.

KH: No, it didn’t. Many people were surprised by that, and I’m one of them. I had assumed, as many people did, that heroin overdoses come from the fact that it’s a black market product. This illegality implies that sometimes there’s going to be impurities and the potency is going to dangerously vary from time to time. There’s a very nice paper just out by Professors Shane Darke and Michael Farrell, who are two of the world’s leading experts on the topic. As these authors relate, toxicology studies of overdosed people very rarely find that impurities played an important role. As I said before, victims didn’t particularly receive high doses, either. Such findings surprised me. The fact that we’ve got 16,000 people a year dying from pure or legally-manufactured opiate analgesics shows you that it’s really not about the unpredictability of illegal markets, it’s about the drugs per se.

HP: Just to note the numbers, in 1999 there were about 4,000 prescription opiate overdoses. In 2010, there were about 16,000. By comparison, there are about 10,000 gun homicides in the United States.

KH: It is pretty amazing. Many people are focusing on the return of heroin and saying, “It’s all the fault of criminals.” You’ve got to remember, 4 in 5 of people today who start using heroin began their opioid addiction on  prescription opioids. The responsibility doesn’t start today with the stereotypical criminal street dealer. We basically created this problem with legally manufactured drugs that were legally prescribed. This really flies in the face of the argument that  if we just had a flow of legal drugs, the harms would be minimal.

HP: What did the industry do wrong and what did policymakers do wrong with these prescription opiates. You and I wrote a piece where we noted that a third of the Wounded Warrior group had a substance use disorder. Something is amiss here. What went wrong?

KH: In the late 1990s, many medical societies became appropriately concerned about poor pain management in the United States. Many patients were not receiving needed pain relief, which was and remains a very serious problem. That worthy concern for improved pain management became fused with  the pharmaceutical industry’s profit-seeking goals, which they pursued through aggressively pushing opioids in primary care settings and doing a lot of deceptive marketing. Purdue Pharma was fined $600 million  for deceiving regulators, doctors and patients about the addiction and overdose risks of OxyContin. They told prescribers not to worry, saying that the drug wouldn’t be abused and there was little risk in even very high doses.  These claims turned out to be untrue.

Many good-hearted, well-intended prescribers were so swept up in the need to relieve pain that they were not sufficiently critical of the potential downsides of flooding the country with these medications. Here’s one stunning statistic. The U.S. accounts for  99% of the world’s hydrocodone consumptions is a spectacular level of prescribing.

U.S. prescribers also write more prescriptions for opiate painkillers each year than there are adults in the United States.  When an addictive substance is prescribed on that scale, there will inevitably be substantial leakage out of the medical system. This would be true even if every single doctor proved to be honest and well-trained. And every single doctor isn’t.

A small number of criminal doctors realized that this was a cash cow and started setting up pain pill mills in places like Florida that had weak regulations.  The clinics advertised nakedly with promises such as, “No pill, no pain. Cash only, no I.D. required,” and thereby fueled an opioid epidemic all across the Southeastern states. At one point, 49 of the top 50 prescribers of opiates in the United States were located in Broward County, Florida. That small group of doctors who were intentionally criminal were part of the problem. The rest of it was the far larger number of doctors who were well intended but just didn’t know any better. I was on a public radio call-in program yesterday and heard multiple stories  of people with mild pain being written refillable prescriptions for large numbers of opioid painkillers.. There’s a lot of that andit’s irresponsible and dangerous. What happens is either the person takes all the medicine, which they shouldn’t, and maybe they start then developing a problem. Alternatively, they take two pills and then there’s a bunch of Vicodin or OxyContin sitting in the medicine cabinet for someone else to find: a local teenager, a friend of a friend, a guest at a party. Overprescribing and then loose storage fueled the epidemic. It’s still true today. When you ask people who abuse prescription opioids, “Where do you get them?” Their usual source is friends and family, not street purchases. It’s frightening, we’ve flooded the whole country with these things and they’re everywhere.

HP: It shows harm reduction is a difficult challenge, because this market doesn’t have many of the harms that we usually think of when we talk about harm reduction, and yet it produces a lot of fatalities.

KH: Right, as you know there’s different types of harm. There’s market harms and then there’s harms down at the end of a user. For sure, there is some violence around the black market in hydrocodone and oxycodone, but since these drugs are mostly coming from people who wear stethoscopes and white coats, that’s not clearly not a primary locus of violence.

The more than 16,000 overdose deaths from prescription opioids each year disproves the idea that it’s easy to regulate addictive drugs if they are produced and provided legally. We can reduce the violence in markets, but we’ve paid a real cost in public health harms and in safety failures from reckless corporate behavior.

HP: Can I ask you an embarrassingly basic question? If someone like Philip Seymour Hoffman presumably had access to all sorts of prescription opioids, why does he end up injecting heroin?

KH: That’s actually a good question. Cost drives many people to heroin. It’s more expensive to buy oxycodone than it is to buy heroin. Presumably that was a less pressing concern for Mr. Hoffman. Perhaps the intensity of the rush of injected heroin was more reinforcing to him than opioid medications were. The prescription medications have a longer, slower cycle of action in the body. His heroin use could also be the result of habit. He had experienced a heroin problem before, many years ago. It could be that that was the drug that he knew best or was available in the networks of dealers he used. I’m speculating about somebody I don’t know, but those are some possible reasons.

For most people it’s cost. Add one other thing; when people lose their health insurance, they may need the opioids to manage their pain. People sometimes end up buying street drugs including heroin to manage their pain because they have lost the insurance that used to cover their pain medication.

HP: The first heroin user that I knowingly had ever met had actually hurt his back at work. He had been on pain medication. And that basically led him down the road to his use of injected heroin. Many people suffer some sort of muscular skeletal injury. Powerful prescription pain medications can set in motion a cycle which can lead to addiction or that can reinforce someone’s disabilities.

KH: This happens all the time.

HP: Downstream, there will be more people having overdoses. What can we do as a public health policy to be more effective to prevent people from dying?

KH: One thing is to equip more people with Naloxone. Naloxone is an opiate antagonist that rapidly knocks opioids out of the brain receptor to which they bind. For someone who has stopped breathing due to heroin, for example, or oxycodone, it immediately starts them breathing again. It wakes them up, and creates an opportunity for more extensive medical care. It doesn’t remove the addiction, but in an overdose emergency it gives another 30-90 minutes to get someone to the hospital.

Some cities have distributed Naloxone (also known as Narcan) to police and firefighters. There are also programs that train family members. Let’s say you’re a mom or a dad and your teenager is addicted to heroin and might overdose at some point, you can learn how to administer Naloxone, and how to do CPR and put somebody in a rescue position.

That requires new laws, typically. If you’re not a licensed medical professional  you can’t legally administer prescribed medication to someone whom you find overdosed.  So when cities or states start expanding access to naloxone  they typically create regulations exempting people from that medical requirement and also from any liability, if, in good faith, they used Naloxone to try to save somebody’s life.

There is also an important role here for what are called Good Samaritan laws. Suppose a group of teenagers are at a party. They’re drinking and maybe popping some Vicodin or the like and then somebody falls to the floor and stops breathing. You don’t want everyone to be afraid to call 911 out of worry that they’ll get arrested. A Good Samaritan law would say that there would be a different kind of legal arrangement for people who overdosed or who are contacting authorities to say somebody had overdosed, so that the fear of punishment doesn’t prevent the saving of a life.

HP: Would you give Naloxone to street users so that they could help each other in situations where they are the people present?

KH: That is certainly being done. If you had an infinite budget, maybe everybody should carry Naloxone, every single person. If you think about it from the point of view that we only have so much money, which is always the case, ninety percent of what is distributed directly to users is ultimately not accounted for, it’s not used or it’s lost. Whereas if you distribute to police, firefighters, ambulance, and other first responders, virtually none of it goes to waste. All of it gets used to save people. From that point of view, my policy preference is the one with the first responders because I know funds are always limited, and I think you’re going to save more lives that way than by distributing it among users.

HP: Well the first responders should obviously have it. You could waste 90 percent of this stuff, and you still wouldn’t need to save very many lives to justify the return on investment for a small Naloxone kit. I guess the training would be expensive.

KH: If budget were no concern, you’d want to have everybody in the country to carry it.  But if you’re a city and you’ve got a $50,000 grant to do a Naloxone access expansion program, and your police and firefighters don’t have it, that’s where you will probably save the most lives.

HP: So there’s Naloxone and Good Samaritan Laws, what else should we be thinking about in policy?

KH: Expanding access to a range of addiction treatments. Such treatments could include psychotherapies, 12-step based treatment, and medications like buprenorphine, methadone and naltrexone. Residential options, such as Oxford House, are also important. Treatments that engage addicted people for long periods are especially valuable. As we discussed, short-term detoxes may be actually worse than nothing.  There’s been more beneficial movement in this regard in the last couple years than there has in the last 50. As you know, the Affordable Care Act specifies that substance use disorder treatment must be covered as a mandatory healthcare benefit. Every single plan on the health exchanges now covers drug and alcohol treatments at the same level as other disorders.

The new expanded Medicaid provided under ACA also covers addiction treatment.  Concurrent with that, the Obama Administration has just released the regulations implementing the 2008 Mental Health Parity and Addiction Equity Act which affects employer-provided insurance.. For the more than 100 million people who receive insurance through large employers, any benefits offered for addiction treatment have to be comparable to those for other medical conditions. Because of these two laws as well some recent improvements in what Medicare covers, more people have good insurance in the public and private sector to cover addiction treatments than in any time in U.S. That’s an extraordinary change in the public policy environment. It will take some time for the capacity of the health care system to catch up to it, but the coverage is now there in a way it never has been before.

HP: How about the striking number of overdose deaths among people released from correctional settings.

KH: We don’t want to incarcerate anybody that we don’t have to. But many people with opiate problems are in the criminal justice system. A huge proportion of property crime is driven by people with problems with opiates. Similar statistics exist for petty theft and muggings. The challenge is to find alternatives to incarceration that manages people in the community while addressing their drug use and protecting public safety. These alternatives could be drug courts, or it could also be things like Hope Probation where people are regularly tested for drug use, and if they use they endure swift, certain but not severe consequences..

For example, maybe they have to spend just one night in jail if they go back to use, and then they’re out the next day. Those kinds of programs should be used much more instead of putting drug-addicted criminal offenders in prison. If someone does endure a prison sentence of any length, then it’s really critical to do the transition planning, because the death rate of people just leaving prison who are addicted to opioids is appalling. In Scotland, 1 in 200 male heroin addicts dies within 14 days of prison release.

Scotland has a worse heroin problem than we do. Nonetheless, the basic principle would apply here. The stereotype is it’s easy to get drugs in prison. But it’s actually much, much harder  than it is on the street. Most people who go into prison dependent on opioids are not able to get a regular supply of opioids in prison. So they’re tolerance drops dramatically. They go out of prison, maybe they’re celebrating their release, they have a few drinks, they take their normal dose of opioids, and they die because they don’t have the tolerance anymore to be able to have that dose in their body without shutting off their breathing.

HP: Two challenges make this issue especially difficult. One is that the systems that we have are pretty passive. When you leave jail or prison you really have to present for intervention. Of course it’s just not going to happen until somebody has a crisis. We could also do a better job of preparing people for predictable risks and specifically warning them about this. Because we don’t want to talk to drug users about some realities of relapse, we may not be giving them sufficient resources to protect them against overdose. KH: There’s a closely watched clinical trial under way in England, run by my friend John Strang. Heroin-addicted people leaving prison are going to be given training in overdose reversal, and a supply of Naloxone. That will be very interesting to see whether that works. I suspect that it will be helpful even if no Naloxone is ever used because it will reorient prison staff as to what their responsibilities are when somebody leaves prison. It’s more than just shoving them out the door and saying, “Good luck to you….”

HP: I like that there is an actual field trial. So we have an opportunity for evidence-based policy. If you take an issue like Naloxone distribution, most people have very strong policy preferences. If you talk to people about these issues, you can go an awfully long way before anyone gets to any sentence that is in any way influenced by data. It would be nice to see what we can accomplish. I suspect the impact will be more modest than what many of the supporters are hoping, but it will be real. Most substance abuse policies are helpful but not decisive when they’re effective.

KH: It’s hard to change human behavior. That’s not just true in addiction. It’s also true of weight loss programs, getting people to use seat belts, and more. Fortunately, even if you can change half the behavior of half of the people, you can produce absolutely massive benefits in the public health and public safety sphere.

HP: Weight loss is a great example because we know randomized trials of diets show real benefits for some of them, but very small effects. There is also almost universal non-adherence to the strictures of any of the diets. In a way, needle exchange makes us ripe for disappointment, because it requires such minor behavior change and because people generally like new, sharp needles. If you look at almost anything else, for example trying to get people to use condoms for HIV prevention, it’s a much tougher behavioral challenge.

KH: That’s right. That’s been the challenge for the oral version of the medication naltrexone. If you are addicted to opioids and you get buprenorphine or methadone, it’s still reinforcing. You’re activating opiate receptors, and that feels good. Naltrexone blocks the effect of opiates, and it’s been very hard to get drug users to take that up.  It’s kind of like walking into a bar and saying, “Hey, everybody, I have a pill that would make the alcohol you’re now consuming not feel very good. Line up everybody, no crowding please.” Nobody would give you the time of day. That medication has had a hard time getting traction just because it doesn’t sound very appealing to the average opiate addict.

HP: It’s very appealing if you have many other cues in your life that are raising your urgency, if you’re already very highly motivated. Some of these methods are especially effective for doctors are trying to get off of opiates because they have many powerful external motivations that are further reinforcing their efforts to address the behavior.

KH: We’ve learned a lot from the way doctors are managed when they have an addiction. They face regular testing with swift and certain responses. A lot of people say, “Well, that’s doctors, but they are different from most addicts.” But it turns out that those same principles of regular testing with consequences has worked really well in tougher populations. That’s the findings of Hope Probation, and for Alcohol 24/7 Sobriety too.

Diffusing those principles would be really productive, because most of these people wind up in the criminal justice system. They engage in other crimes, and the criminal justice system normally does nothing, nothing, nothing, and then suddenly brings down the hammer. We have to do a better job of responding mildly but consistently and swiftly to the drug use of people who are on probation and parole. It’s a much better way to change people’s behavior.

HP: Let’s talk a little bit about some upstream issues. Given that these opiate medications are out there and they’re being widely misused, how can we change the way we do business so that there are fewer people emerging with these addiction disorders on these medications?

KH: We need to have way-better prescribing practice. Most of that involves provider education for well-intended medical professionals. A small amount involves criminal justice actions against few really bad people who run pill mills that should be shut down. A model of what is needed most is what happened in the Puget Sound Health System. They internally decided among their own staff to take a look at how they were prescribing opioids. They met in groups, they developed consensus procedures, they took a look at providers who were prescribing at high levels, patients who were being prescribed high levels. They learned about alternative methods of pain management.  It’s a great example of responsible group practice medicine, and they were able to keep the people they were taking care of healthy while prescribing a lot less opioids. We need more examples of that around the country so that people don’t think pain management always means more opioids.

We also need better ways for the public to dispose of excess of opioids. Many people don’t realize that you can’t legally just walk back to your doctor or your pharmacist and say, “I didn’t take these 15 fentanyl tablets, can you take them?” They’re not allowed to accept them. There’s been some movement on fixing that in Washington, but far too slow. The DEA runs “take back prescription” days. That’s fantastic, but that’s one or two days a year. Disposal needs to become normative, so that when you went into Wal-Mart, for example, there would be a bin where you could just toss your extra prescriptions in, the things you didn’t use.

It’s kind of like where we are now is like the beginning of recycling. Recycling glass and plastic was once this weird practice that a few people did. Then maybe there were special events and special centers that did recycling. Now millions of people do it without thinking,it’s automatic. We need to make it simple so that it just becomes automatic. You’d never leave leftover medication in your cabinet. You bring it back to the pharmacist on your regular trip to the grocery store.

We could also implement better procedures around surgeries. We have 40 million surgeries a year. Something like 5 to 10 percent of those result in persistent pain, persistent opioid use, or both. That means we are potentially generating a large number of people at risk for  prescription opioid dependence.  And some of those people may end up ultimately  going to the street heroin market, as did  the person you knew with the back injury.

There’s some exciting work underway that could teach us how to reduce this risk of iatrogenic addiction after surgery. The amount of pain and fear patients have right at the time of operation predicts how much pain and opiate use they’ll have later.  Relaxation exercises or anti-anxiety medications administered moments before surgery could therefore produce long term benefits in terms of reduced pain and opiod use down the road.   My colleague Dr. Ian Carroll is leading a clinical trial on this question now, and along with some related studies being done around the country it could teach surgical teams  how to reduce post-operative pain and the risk of opioid addiction at the same time.   That would be a huge benefit to public health.

Source:  www.WashingtonPost.com 7th Feb 2014

Filed under: Effects of Drugs (Papers) :

Since the drive to legalise medical marijuana began in the US in the 1990s, marijuana use doubled and the perception of its harm halved. As Colorado and Washington formally legitimise and sanction its recreational use, these dangerous inverse trends can only continue, Kathy Gyngell warns.

On 1 January, to much media fanfare, Colorado became the first state in the US to legalise smoking dope. Since then, our TV screens and newspapers have brought us the less-than-salutary sight of long lines of customers queuing for their ‘soma’, in freezing temperatures to boot, begging the question of whether the denizens of Colorado have nothing better to do with their lives. Out of sight are the financial vultures wheeling to cash in on this hot new market.  Price  – Colorado ran out of pot in the first week – is not putting off its addicted customers.

The ‘medical’ marijuana business was already worth about  $1.4billion dollars last year.  Once pot can be pushed legitimately, once banks decide that investing is this boom is not a moral bridge too far, the sky will be the ceiling on the value of this business.

This is why the recent research finding about teen marijuana use and their perceptions of risk are so worrying. The 2013 Monitoring the Future Survey (an annual survey of 8th, 10th and 12th-graders by the National Institute on Drug Abuse and the University of Michigan) reports that far fewer teenagers in the US today view regular marijuana use as harmful as their counterparts did before the campaign to legalise medical marijuana began in the 1990s. Rising use has been accompanied by diminishing perceptions of harm. Evidence points to this being a direct outcome of legalising marijuana for purported medical use – the political sleight of hand used by 21 states to decriminalise it since 1996.

It is no coincidence that marijuana is the only drug in the US whose use is on the rise. This is in contrast to use of all other illicit drugs which are all in persistent decline, particularly cocaine, the use of which has dropped by 75% in 25 years, as the recent United Nation’s World Drug Reports confirm.

Marijuana alone is on a persistent incline upward – and not just for adults. Its use by high-school seniors has doubled since 1991. Last year, teen use rose again, from 11.4% to 12.7% (8th graders) and from 28% to just under 30% (10th graders). A worrying 36% of high-school seniors used pot in the last year.  One in every 15 of them (6.5%) used it daily.

What this latest survey exposes is the Pandora’s box of medical marijuana. Of the 12th graders sampled by the survey who had used marijuana in the 12 months prior to being questioned and who lived in states that passed such laws, one third of them (34%) said that one of their sources of marijuana was another person’s medical marijuana prescription. 6% reported getting it from their own prescription.

The States with medical marijuana laws have failed to prevent its diversion to young people. They have given adolescents another way of obtaining the drug, exposing them to more risk.

The knowledge of this, sadly, did not stop the selfish and dope-loving adult population in Colorado from voting for the drug’s full legalisation. Yet the impact on their teens was clear within two years of medical marijuana being legalised there in 2009. For in just those two years, regular (last month) high school drug use leapt from 19% to 30% and school expulsions rose by a third, marijuana being the first reason for them. Since full legalisation “pot problems” in Colorado’s state schools have reportedly got even worse.

“Kids are smoking before school and during lunch breaks. They come into school reeking of pot,” one school resource officer said. “Students don’t seem to realise that there is anything wrong with having the pot – they act like having marijuana was an ordinary thing and no big deal.” Marijuana is freely available in Colorado. Any resident can legally get two ounces of marijuana a day (at an average of $150 an ounce) and “self-medicate” for almost any reason though even a heavy marijuana user only would get through a quarter of an ounce a day.  Observers say that state “regulation” of the medical marihuana industry was a tragic joke. One group, Smart Colorado, reports that 700 medical marijuana licenses have already been issued in Denver; that legalisation means each of these license holders is now eligible to apply for a recreational license as well. To put this number into context, it compares with the approximately 201 liquor establishments and 123 pharmacies in the city of Denver. No wonder law enforcement officials report that more marijuana is flowing into the black market and out of Colorado in greater quantities than ever before.

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Tina Trent, a local blogger on crime and justice issues, hopes that “the reality of legalisation” will be a wake-up call to people in Colorado and other places as they see “people smoking pot in public and every third storefront in the tourist district turning into a head shop”. How, she asks, do you address bus drivers legally smoking pot before their shifts start, and all sorts of people smoking ‘medicinal’ pot all day long, and then getting behind the wheel? Trent, who has written a major report on the drug legalisation movement in California, is urging the public to counter the propaganda from the “professional pro-drug groups funded by George Soros”. She adds that “Legislators need to seriously consider the facts about marijuana abuse by young people”.

Her plea has fallen on deaf ears. Despite significant increases in health detection rates of risky marijuana use in Colorado since 2009, despite sharp increases in school age marijuana use, despite evidence of significant diversion from adults to youth, despite the ever expanding body of scientific evidence charting the multiple and significant health and mental health harms… there has been no government response to this violation of federal drug laws.  It seems President Obama’s Department of Justice has decided to put up the white flag to drug use. Such liberality may appeal to the human rights lobby but it is priming a public-health time bomb.

How can he not be aware of the risks associated with early initiation and regular use of marijuana by young people? Given the now hard scientific evidence concerning marijuana’s impact on young people’s cognitive ability, executive functioning and long term IQ, as well as its risk of inducing psychosis and violence in anyone who takes enough, to say nothing of its enhanced cancer risks – surely this recent ‘normalisation’ of cannabis use would be of considerable concern to the Obama administration? It seems not.

obama

But how long can the president, with teenage children of his own, remain so casual about rising teen pot use under his watch? That is my question for 2014.

Source: www.addictiontoday.org   January 2014

Filed under: Education Sector,Effects of Drugs (Papers),USA :

Global FX Smoking Tobacco Quitting Taxing Tobacco – Click here for full pdf file which contains graphics.

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On the basis of current smoking patterns, with a global average of about 50% of young men and 10% of young women becoming smokers and relatively few stopping, annual tobacco-attributable deaths will rise from about 5 million in 2010 to more than 10 million a few decades hence,1-3 as the young smokers of today reach middle and old age. This increase is due partly to population growth and partly to the fact that, in some large populations, generations in which few people smoked substantial numbers of cigarettes throughout adult life are being succeeded by generations in which many people did so. There were about 100 million deaths from tobacco in the 20th century, most in developed countries.2,3 If current smoking patterns persist, tobacco will kill about 1 billion people this century, mostly in low- and middle-income countries. About half of these deaths will occur before 70 years of age.1-4

The 2013 World Health Assembly called on governments to reduce the prevalence of smoking by about a third by 2025,5 which would avoid more than 200 million deaths from tobacco during the remainder of the century.2,3 Price is the key determinant of smoking uptake and cessation.6-9 Worldwide, a reduction of about a third could be achieved by doubling the inflation-adjusted price of cigarettes, which in many low- and middle-income countries could be achieved by tripling the specific excise tax on tobacco. Other interventions recommended by the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) and the WHO six-point MPOWER initiative4 could also help reduce consumption7,8 and could help make substantial increases in specific excise taxes on tobacco politically acceptable. Without large price increases, a reduction in smoking by a third would be difficult to achieve.

The WHO has also called for countries to achieve a 25% reduction between 2008 and 2025 in the probability of dying from noncommunicable disease between 30 and 70 years of age.10 Widespread cessation of smoking is the most important way to help achieve this goal, because smoking throughout adulthood substantially increases mortality from several major noncommunicable diseases (and from tuberculosis).1-3,11-19

To help achieve a large reduction in smoking in the 2010s or 2020s, governments, health professionals, journalists, and other opinion leaders should appreciate the full eventual hazards of smoking cigarettes from early adulthood, the substantial benefits of stopping at various ages, the eventual magnitude of the epidemic of tobacco-attributable deaths if current smoking patterns persist, and the effectiveness of tax increases and other interventions to reduce cigarette consumption.

Three Key Messages for Smokers in the 21st Century

First, the risk is big. Large studies in the United Kingdom, the United States, Japan, and India have examined the eventual effects on mortality in populations of men and of women in which many began to smoke in early adult life and did not quit.11-16 All these studies showed that in middle age (about 30 to 69 years of age), mortality among cigarette smokers was two to three times the mortality among otherwise similar persons who had never smoked, leading to a reduction in life span by an average of about 10 years. This average reduction combines zero loss for those not killed by tobacco with an average loss of well over a decade for those who are killed by it.

Second, many of those killed are still in middle age, losing many years of life. Some of those killed in middle age might have died soon anyway, but others might have lived on for decades. On average, those killed in middle age by smoking lose about 20 years of life expectancy as compared with persons who have never smoked.1

Third, stopping smoking works. Those who have smoked cigarettes since early adulthood but stop at 30, 40, or 50 years of age gain about 10, 9, and 6 years of life expectancy, respectively, as compared with those who continue smoking.

 Eventual Hazards of Smoking

Tobacco is the biggest external cause of noncommunicable disease and is responsible for even more deaths than adiposity both in high-income countries such as the United States20 and globally.21 The risks in middle age are much greater for smokers who started in early adulthood than for those who started later. This means that the ratio of mortality among smokers to that among persons who have never smoked is much more extreme now (Figure 1, and the 50-year trends shown in the Supplementary Appendix, available with the full text of this article at NEJM.org) than it was half a century earlier, when the epidemic of smoking-attributable deaths was at an earlier stage.11-15

Cigarette smoking was uncommon throughout the world in 1900, but smoking rates increased substantially in many high-income countries during the first half of the 20th century, first among men and then, in some countries, among women.22 By 1950 in the United States and the United Kingdom, substantial numbers not only of men but also of women smoked, and rates of lung cancer were increasing steeply, particularly among men.1 In 1950, major studies in both countries23,24 showed that smoking was a cause of most deaths from lung cancer, and subsequent reports showed that smoking caused even more deaths from other diseases than from lung cancer.25,26

After 1950, cigarette consumption continued to rise for some decades in high-income countries, and it has risen among men (though generally not among women) in many low- and middle-income countries. Although there has been widespread cessation in many high-income countries (in some, consumption per adult has been halved since the 1970s),22 about 1.3 billion people worldwide now smoke, most in low- and middle-income countries where cessation is uncommon.4 Two thirds of all smokers live (in descending order of numbers of smokers) in China, India, the European Union (in which central tobacco legislation can influence 28 countries), Indonesia, the United States, Russia, Japan, Brazil, Bangladesh, and Pakistan. 27,28 In India, manufactured cigarettes are now displacing bidis (locally manufactured small cigarettes).29 Cigarette consumption in China continues to rise steeply and now accounts for more than 2 trillion of a worldwide total of about 6 trillion cigarettes smoked per year.30 A useful approximation suggested by studies in high-income countries is that 1 ton of tobacco yields about 1 million cigarettes and causes about 1 death, so just 1 trillion cigarettes consumed a year will eventually cause about 1 million deaths a year.

One reason why the mid-century evidence of hazard was not at first taken seriously, even in countries where it was generated, is the delay of about half a century between widespread adoption of smoking by young adults and the main effect on mortality in later life.1-3 Among all U.S. adults, for example, cigarette consumption averaged 1, 4, and 10 per day in 1910, 1930, and 1950, respectively, after which it stabilized. The long-delayed result of this increase in consumption during the first half of the century was seen only in the second half of the century; tobacco caused about 12% of all U.S. deaths in middle age in 1950 but about 33% of such deaths in 1990.1 A similar pattern was seen about 40 years later among Chinese men, who consumed about 1, 4, and 10 cigarettes per day in 1952, 1972, and 1992, respectively. In 1990, tobacco caused about 12% of all deaths among middle-aged Chinese men, and it could well cause about 33% in 2030.31,32 (Tobacco causes few deaths in Chinese women, because less than 1% of Chinese women born in each decade since 1950 smoke.27,31)

Because men started smoking before women, the effects in middle-aged men are now apparent in most high-income countries. The full eventual effects of persistent smoking in women, however, can be assessed directly in only a few countries (e.g., the United States and the United Kingdom) and only in the present (21st) century. The ratio of mortality from lung cancer among U.S. women who currently smoke to the (constant) mortality among women who have never smoked has increased greatly during the past half-century: it was only 3 in the 1960s, but it was 13 in the 1980s and 26 (similar to that among men) in the 2000s.14 The reason for the jump from a ratio of 3 to a ratio of 26 is that in the 2000s many U.S. women in their 60s who were smokers had smoked ever since early adulthood, whereas in the 1960s few women in their 60s who were smokers had done so.

Even though mortality from lung cancer among U.S. women was still low in the 1960s, women who were then in their 20s and who continued to smoke without quitting faced substantial hazards 40 years later.13,14 Similarly, among men in low- and middle-income countries where many smoke but the death rates in middle age from smoking are not yet substantial, a full decade of life expectancy will eventually be lost by young adults who continue to smoke. Tobacco already accounts for about 12 to 25% of deaths among men in low- and middle-income countries such as China,31,32 India,16-18 Bangladesh,33 and South Africa34; given current smoking patterns, these proportions are likely to increase. Worldwide, about half a billion of the children and adults younger than 35 years of age already smoke or will do so if current uptake rates persist, and given current cessation patterns, relatively few will quit.27 In all countries, young adults who smoke face about a decade of life lost if they continue and hence have much to gain by stopping.

 Rapid Benefits of Stopping

Whereas tobacco-attributable mortality increases slowly after the uptake of smoking, the effects of cessation emerge more rapidly.11-15 Persons who began smoking in early adulthood but stopped before 40 years of age avoid more than 90% of the excess risk during their next few decades of life, as compared with those who continue to smoke, and even those who stop at 50 years of age avoid more than half the excess risk, although substantial hazards persist 11-15

The ratio of former smokers to current smokers in middle age is a useful measure of the success of tobacco control. Among persons 45 to 64 years of age in the European Union and the United States, there are now about as many former smokers as current smokers28,35; by contrast, in most low- and middle-income countries (with the notable exception of Brazil), there are far fewer former smokers than current smokers. Cessation is the only practicable way to avoid a substantial proportion of tobacco-attributable deaths before 2050, because a substantial reduction by 2025 in uptake by adolescents will have its main effect on mortality only after 2050.2,3

 Effects of Increasing Cigarette Prices

Comprehensive tobacco-control programs using several price and nonprice interventions can substantially raise smoking-cessation rates and decrease initiation of smoking.4 Uruguay implemented most of the FCTC provisions and reduced consumption more rapidly than otherwise similar Argentina, which implemented only a few of the provisions.36 Large increases in specific excise taxes on tobacco are particularly important, because they can have a substantial and rapid effect on consumption.6-9 Reviews of comprehensive control programs in various U.S. states37,38 and other high-income areas39 concur that higher prices account for much, but not all, of the decline in smoking.

Similarly, an International Agency for Research on Cancer review of more than 100 econometric studies confirmed that tobacco taxes and consumption are strongly inversely related.9 It concluded that a 50% increase in inflation-adjusted tobacco prices reduces consumption by about 20% in both high-income countries and low- and middle-income countries,6-9 corresponding to a price elasticity (percent consumption change per 1% price change) of about −0.4. Hence, doubling inflation-adjusted prices should reduce consumption by about one third (in which case revenues would increase, because the effect of reduced demand would be outweighed by the extra revenue per pack). Some of the effect among adults is due to quitting (or not starting), and some is due to reduced consumption per smoker.9 Higher taxes are particularly effective in poorer or less educated groups6-9,39 and help prevent young people who are experimenting with smoking from becoming regular smokers.40

The two major types of tobacco tax are specific excise taxes (which, being based on quantity or weight, are difficult for the industry to manipulate) and ad valorem taxes (which are based on manufacturer-defined price and can be manipulated more easily). In many high-income countries, about 50 to 60% of the retail price of the most-sold brand is a specific excise tax on tobacco or some variation of it (as in the European Union), but in low- and middle-income countries, this proportion is typically only about 35 to 40% .4,6 A low specific excise tax on tobacco is the main reason that cigarettes are about 70% cheaper (even after adjustment for purchasing power) in many low-income countries than in high-income countries. Moreover, rapid income growth in many low- and middle-income countries is making the lower-priced tobacco products more affordable41 and helping cigarettes to displace bidis in India.29

A low reliance on specific excise taxes on tobacco by China,42 India,29 Indonesia,43 and most low- and middle-income countries4,6 means that the prices of commonly sold cigarette brands vary greatly within each country (by a factor of more than 10 in China, as compared with a factor of only about 2 in the United Kingdom and the United States), and this continued availability of low-cost brands discourages smoking cessation. In contrast, high specific excise taxes on tobacco of all brands encourage cessation rather than switching (by narrowing the price gap between the most and least expensive cigarettes), are easier to administer than ad valorem taxes, and produce a steadier revenue stream.9 In many low- and middle-income countries, although specific excise taxes on tobacco account for less than half the total retail price of cigarettes, tripling them approximately doubles the retail price, partly by triggering smaller increases in other taxes (e.g., sales tax) and markup. In most high-income countries, specific excise taxes on tobacco already account for more than half the retail price, so even just doubling them would approximately double prices.

The United States and the United Kingdom took more than 30 years to halve cigarette consumption per adult.22 With the use of large tax increases, however, France and South Africa halved consumption in less than 15 years.3,44,45 From 1990 to 2005, France tripled inflation-adjusted cigarette prices by raising taxes 5% or more every year in excess of inflation, halved cigarette consumption, and doubled inflation-adjusted tobacco revenues. Today, the ratio of former smokers to current smokers in France comfortably exceeds the European average.28,35 Over a similar period, South Africa also tripled the inflation-adjusted price of cigarettes, halved cigarette consumption, and doubled tobacco revenues.45 Additional revenue can be used to fund tobacco-control programs or broader health efforts; much of the revenue from the 2009 U.S. taxation increase of 53 cents per pack of 20 cigarettes is allocated to expand children’s health insurance.46

 Other Effective Interventions

Though tobacco advertising is banned throughout the European Union, China, and some other countries, cigarettes are still among the most heavily advertised and promoted products in the world, with spending on tobacco marketing reaching $8.6 billion annually in the United States alone.47 In 2011 Australia, which had already banned advertising, introduced plain packaging for tobacco products, removing all brand imagery. The brand is printed only in small standard lettering below a pictorial warning. Recent evidence suggests that plain packaging increases cessation attempts.48,49 New Zealand will introduce plain packaging in 2014, and the United Kingdom is considering it. Plain packaging goes beyond the prominent, rotating pictorial warning labels on tobacco products that have helped increase cessation attempts in Canada, Thailand, and elsewhere.50 Pictorial warnings can reach even illiterate persons, and half the deaths from tobacco in India occur among the illiterate.29

In the United States and the United Kingdom, bans on tobacco advertising on television coincided with the start of the long-term downturn in sales,51 although these partial bans on advertising allowed the industry to shift to other forms of advertising or promotion. More comprehensive bans on all direct and indirect advertising or promotion of any tobacco goods or trademarks further help to reduce consumption52,53 and have the advantage of severing any dependence of the media on the tobacco industry. Bans on smoking in public places reduce nonsmokers’ exposure to tobacco smoke and can also help decrease overall consumption,54,55 as can mass-media campaigns.51,56 In populations with many long-term smokers, low-cost epidemiologic studies of various types that monitor the changing extent to which tobacco is causing premature death help to raise political awareness of tobacco hazards and to provide information for the individual smoker.1,16,33,34

Throughout the world, most former smokers managed to quit unaided, but physician support or telephone-based or Internet-based counseling and support can increase the likelihood of success.57 In motivated persons, pharmacologic treatments or electronic cigarettes, or e-cigarettes, can also increase quit rates.57,58 The eventual role of e-cigarettes remains uncertain, however, particularly if the tobacco industry controls the marketing of both traditional and e-cigarettes.

 Death and Taxes

The WHO reports4 that although many countries now use nonprice interventions, only a few (including Mauritius, Mexico, the Philippines, Poland, and Turkey) have been using large increases in specific excise taxes on tobacco to reduce smoking.6 A large increase in inflation-adjusted price is, however, a key component of any realistic strategy to reduce smoking substantially during the 2010s or 2020s. The Bill and Melinda Gates Foundation, Bloomberg Philanthropies, the World Bank, and the Asian Development Bank are therefore providing technical advice for some ministries of finance to counter misleading tax advice from the tobacco industry.29,42,43,59 Manufacturers’ worldwide profits of about $50 billion in 201260 (approximately $10,000 per tobacco-attributable death) yield enormous political influence that is used, among other things, to try to prevent large tax increases.

Smuggling is a concern when tobacco taxes rise; about 10% of all cigarettes manufactured worldwide are already untaxed.61 Use of specific excise taxes on tobacco (rather than ad valorem taxes), stronger tax administration, and practicable controls on organized smuggling can, however, limit the problem.62 Even with some smuggling, large tax increases can substantially reduce consumption and increase revenue (Figure 4), especially if supported by better tax enforcement.61

Tripling inflation-adjusted specific excise taxes on tobacco would, in many low- and middle-income countries, approximately double the average price of cigarettes (and more than double prices of cheaper brands), which would reduce consumption by about a third and actually increase tobacco revenues by about a third. In countries in which the government owns most of the industry, as in China, the distinction between taxes and profit is fairly arbitrary, but doubling the average prices would still substantially reduce consumption and increase revenue. Worldwide, raising specific excise taxes on tobacco to double prices would raise about another $100 billion (in U.S. dollars) per year in tobacco revenues, in addition to the approximately $300 billion that the WHO estimates governments already collect on tobacco.4 Conversely, if a decrease in smoking by about a third were somehow achieved without increasing the inflation-adjusted price, tobacco tax revenues would decrease by about $100 billion.6

The main argument for reducing smoking is, however, the hundreds of millions of tobacco-related deaths if current smoking patterns persist. Indeed, in reviewing options to achieve a grand convergence by 2035 among the risks of premature death in low-, middle-, and high-income countries, the Lancet Commission on Investing in Health63 recently identified a substantial increase in specific excise taxes on tobacco as the single most important intervention against noncommunicable diseases, as did the 2013 World Health Assembly.5 Losses or gains in tobacco revenue are of secondary importance; indeed, tobacco taxes are a small percentage of overall revenue in most countries (except China), and money not spent on tobacco is spent on other taxable goods or services.7 Attainment of the WHO target of a decrease of about a third in the prevalence of smoking by 2025, involving major decreases not only in high-income countries but also in populous low- and middle-income countries, would prevent several tens of millions of tobacco-attributable deaths during the next few decades2,3,63 and about 200 million tobacco-attributable deaths during the century as a whole, mostly among people who are already alive, both by helping smokers to quit and by helping adolescents not to start.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

We thank Jillian Boreham and Hong-Chao Pan for the Supplementary Appendix on 50-year smoking-attributed mortality trends in the United Kingdom, United States, and Poland; Judith MacKay for comments and Cathy Harwood, Leslie Newcombe, and Joy Pader for editorial assistance on an earlier draft of the manuscript; Catherine Hill and Corne van Walbeek for French and South African data; and Ayda Yurekli for WHO tax-revenue estimates.

Source Information

From the Center for Global Health Research, St. Michael’s Hospital and Dalla Lana School of Public Health, University of Toronto, Toronto (P.J.); and the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Richard Doll Building, University of Oxford, Oxford, United Kingdom (R.P.).

Address reprint requests to Dr. Jha at prabhat.jha@utoronto.ca.

Filed under: Effects of Drugs (Papers) :

Teens who regularly use marijuana may be at risk for developing serious psychiatric disorders such as schizophrenia, a new study suggests.

This is because regular marijuana use in adolescence, but not adulthood, may permanently damage brain function and cognition, according to new research.

Scientists from the University of Maryland School of Medicine hope that the latest findings will help warn policy makers contemplating legalizing marijuana about the potential long-term dangers of the drug.

“Over the past 20 years, there has been a major controversy about the long-term effects of marijuana, with some evidence that use in adolescence could be damaging,” senior author Asaf Keller, Ph.D., Professor of Anatomy and Neurobiology at the University of Maryland School of Medicine said in a news release.

Previous studies have suggested that children who start using marijuana before the age of 16 are significantly more likely to develop permanent cognitive deficits and psychiatric disorders like schizophrenia.

“There likely is a genetic susceptibility, and then you add marijuana during adolescence and it becomes the trigger,” Keller explained.

The current study wanted to identify the biological evidence and determine whether marijuana use during adolescence really comes with permanent health risks.

In the study, researchers examined the cortical oscillations in mice. Cortical oscillations, or patterns of neuronal activity, are believed to underlie the brain’s various functions.  Researchers say that these oscillations are very abnormal in people with schizophrenia and in other psychiatric disorders.

The study revealed that mice exposed to very low doses of the active ingredient in marijuana for 20 days had “grossly altered” cortical oscillations in adulthood.  Researchers said these mice also exhibited impaired cognitive abilities.

“We also found impaired cognitive behavioral performance in those mice. The striking finding is that, even though the mice were exposed to very low drug doses, and only for a brief period during adolescence, their brain abnormalities persisted into adulthood,” lead researcher Sylvina Mullins Raver, a Ph.D. candidate in the Program in Neuroscience

in the Department of Anatomy and Neurobiology at the University of Maryland School of Medicine, said in a statement.

After repeating the experiment in adult mice, researchers found that the cortical oscillations and ability to perform cognitive behavioral tasks remained normal in mice exposed to the drug only after they’ve fully matured. Researchers said this suggests that it was only marijuana exposure during the critical period of adolescence that impaired cognition through this mechanism.

Further analysis revealed that that the frontal cortex, the brain area that controls executive functions such as planning and impulse control, is significantly more affected by the drugs during adolescence. Researchers noted that the frontal cortex is also the area most affected in schizophrenia.

While the latest study was on mice, researchers believe that the findings have implications for humans as well. They say the next step is to continue researching the underlying mechanisms that cause these changes in cortical oscillations.

“The purpose of studying these mechanisms is to see whether we can reverse these effects,” explained Keller. “We are hoping we will learn more about schizophrenia and other psychiatric disorders, which are complicated conditions. These cognitive symptoms are not affected by medication, but they might be affected by controlling these cortical oscillations.” The latest findings are published in the journal Neuropsychopharmacology.

Source:  http://www.counselheal.com/articles/6163/20130724/marijuana-use-adolescence-adulthood-linked-permanent-brain-damage.htm   24.07.13

Filed under: Effects of Drugs (Papers) :

The threat to public safety on the roadways posed by marijuana-impaired driving has been pushed to the top of nation’s agenda by the legalization of marijuana in Colorado and Washington as well as by the legalization of “medical” marijuana in 18 states and the District of Columbia. Marijuana has significant impairing psychological and physiological effects on driving. Marijuana use by drivers puts everyone at risk on our nation’s roadways; research shows that marijuana is a major cause of impaired driving and serious and fatal injury crashes.

To address marijuana-impaired driving, there has been an interest in identifying an impairment standard for marijuana that is the equivalent to the 0.08 g/dl Blood Alcohol Concentration (BAC) now used to prosecute alcohol-impaired drivers. Proposals have been put forward ranging from 2 ng/ml to 5 ng/ml tetrahydrocannabinol (THC) in whole blood. The science on this issue is clear: it is not possible to identify a valid impairment standard for marijuana or any other drug equivalent to the 0.08 g/dl limit for alcohol.

Alcohol is a poor model for studying the impairing effects of drugs because it is metabolized in simpler ways. Unlike alcohol, there is no close relationship between blood levels of drugs (or drug metabolites) and impairment. The vast number of impairing drugs and drug combinations often used with marijuana prevent any single measure from effectively covering all drivers. For example, a combination of low levels of alcohol and low levels of marijuana is severely impairing. Tolerance is another important factor preventing setting blood limits for marijuana and other drugs.  The Obama administration has strongly endorsed the implementation of drug    laws which specify that the presence of THC or marijuana metabolites (as well as other drugs) in a driver’s system is itself (i.e.“ per se”)   a criminal violation.   Zero tolerance laws use the limits of detection, the lowest concentration needed to reliably detect a drug.

Drastically different from zero tolerance, the marijuana legalization measure passed in 2012 in Washington State included a 5 ng/ml THC    limit for drivers age 21 and older. The 5 ng/ml  limit provides the appearance of protecting the public, but in reality it only protects marijuana users driving under the influence of marijuana from prosecution. Nearly all marijuana users test below 5 ng/ml of active THC in blood only a few hours after their last use.  A study of impaired drivers in Sweden with measurable THC in blood (>0.3 ng/ml) showed that 43% had THC concentrations less than 1 ng/ml; 61% had THC concentrations below 2 ng/ml 2  and over 90% of had THC levels under 5 ng/ml even though all of these drivers were judged to be impaired.

Because of the unavoidably long delay between arrest and blood collection, it is certain that THC concentrations were higher when these drivers were stopped for suspicion of drugged driving because of rapidly declining THC levels after marijuana use stops. THC concentrations were higher when drivers did not have other detected drugs in their blood “suggesting either more recent use or more frequent use of cannabis in these individuals.” Researchers concluded that the majority of drivers impaired by recent marijuana use would not be identified at cutoffs between 3 ng/ml and 5 ng/ml because THC is rapidly cleared from the blood after smoking marijuana. Therefore, under a 5 ng/ml THC  limit, only 10% of the drivers identified as impaired in this study would have been prosecuted.

Although Washington’s 5 ng/ml THC  limit is a poor policy for public safety, the law remains stronger than the 5 ng/ml THC permissible inference limit signed into law in Colorado after several previous failed attempts to pass      marijuana bills. While under the Washington law, a driver arrested for suspicion of drugged driving who tests at or above 5 ng/ml THC is in violation of the  law, in Colorado there is merely an inference that the same driver was under the influence when arrested and the driver can fight the charge in court. Given that over 70% of drivers in Colorado arrested for suspicion of driving under the influence of marijuana test below 5 ng/ml THC, these drivers are unlikely to be prosecuted at all.13 Moreover, the “permissible inference” will give almost all of the remaining 30% of arrested drivers a free pass to drive stoned. Underage drivers in Washington are subject to a zero tolerance      limit while in Colorado minors are subject to the same 5 ng/ml permissible inference limit as drivers age 21 and older.

Michigan uses the zero tolerance   standard for all Schedule I controlled substances, including marijuana; however, in May 2013, the Michigan Supreme Court ruled that “medical” marijuana users were not subject to the zero tolerance  standard for marijuana. In cases of drugged driving by an approved “medical” marijuana user, the state must prove the driver was impaired by marijuana at the time of arrest. This is similar to the way drivers impaired by

legally prescribed controlled drugs are treated in many states. In these states, drivers with valid prescriptions for controlled drugs can be prosecuted for drugged driving using the impairment standard. The prosecution of these drivers under the impairment standard is more challenging and less likely to be successful. The proliferation of drivers using “medical” marijuana has reignited calls for the development of a marijuana impairment standard.

The U.S. Department of Transportation (DOT) provides an important precedent for the use of the zero tolerance      standard.   DOT has successfully used this standard for nearly three decades for all safety-sensitive personnel including commercial drivers, airline pilots and train engineers. Any detected evidence of recent marijuana use is a violation because it is incompatible with the safe operation of vehicles. Either this standard is unwarranted for the people engaged in these safety-sensitive actions or it is the standard that should be applied to all motor vehicle drivers. The Institute for Behavior and Health, Inc. (IBH) strongly supports that the zero tolerance standard be applied to all drivers to protect the public safety on the nation’s roads and highways.

Advocates for permissive marijuana laws fear that the implementation of zero tolerance – or even in Colorado fear that 5 ng/ml – THC  drugged driving laws will translate to law enforcement officers targeting innocent marijuana users who will be wrongly prosecuted for impaired driving. Their concerns in part stem from a misunderstanding of the enforcement and drug and alcohol testing procedures related to driving under the influence (DUI). Individuals arrested for DUI have demonstrated behavioral impairment warranting their arrest before they are tested for alcohol or drugs. After arrest, these drivers now are tested for the presence of alcohol at the police station. If drivers produce a BAC of 0.08 g/dl (or higher), the testing procedure almost always stops. Typically only drivers arrested for impairment with low or zero BACs are tested for the presence of drugs. This means that only drivers who have already been arrested for being impaired will be drug tested.

Marijuana advocates also fear  drugged driving laws because of a misperception that most drivers testing positive for marijuana will not be impaired and will only test positive for marijuana (or its metabolites) because of use that occurred long before the arrest. As noted, drivers are tested for drugs only after they are arrested for DUI, or alternatively, if they are involved in serious or fatal crashes depending on the state procedures. No matter the circumstances under which drug testing of drivers takes place, the testing is unfortunately almost always long-delayed. Drug testing of DUI suspects typically is administered between 90 and 120 minutes after arrest while drug testing of injured drivers is done a few hours or longer after crashes.

Crucially important new research has shown that daily chronic marijuana users show observable deficits in driving skills as long as three weeks of abstinence compared to controls. It is possible that impairment was even longer lasting given that subjects were not tested after three weeks following their last use of marijuana. This is part of a large body of research that supports the use of the zero tolerance limit for marijuana.

Meta-analyses of epidemiological studies have concluded that smoking marijuana doubles risk of motor vehicle crash.   Studies of drivers involved in motor vehicle crashes support this conclusion. A study of seriously injured drivers admitted to a Maryland Level-1 shock trauma center showed that 26.9% of all seriously injured drivers tested positive for marijuana; half of drivers age 16 to 20 were positive for marijuana. A study of fatally injured drivers in Washington State showed 12.7% tested positive for marijuana and that among alcohol-positive drivers, 17.3% also tested positive for marijuana. The combination of marijuana use and alcohol is of great concern as evidence shows that low doses of marijuana combined with low doses of alcohol causes severe impairment. These data also show that combining alcohol and marijuana is common among seriously injured and fatally injured drivers.

Despite the evidence that marijuana use by drivers is a serious threat to public safety, there has been limited implementation and enforcement of drugged driving laws nationally, in part due to the widespread misperceptions actively spread by marijuana advocates who seek to limit any restrictions on drivers who use marijuana. Letting drivers arrested for DUI who test positive for marijuana walk away with no charge is a serious highway safety risk. New research conclusively demonstrates the folly of this approach.

Source:   www.ibhinc.org.   June 10th 2013

 

Filed under: Effects of Drugs (Papers),Transport (Papers) :

—Substances previously unknown to most psychiatrists, synthetic cathinones (SCs)—commonly referred to as bath salts—have catapulted to the front line of substance abuse in the past 2 years. In 2010, there were 302 Poison Control calls related to the SC 3,4-methylenedioxypyrovalerone (MDPV). For the first 11 months of 2011, this number increased to 5625.1

SCs are sold online, in “head shops,” and in convenience stores. These substances have been marketed as bath salts, plant food, and other seemingly benign compounds in order to be sold over the counter and avoid FDA regulations. Most packages include the warning, “not for human consumption.”

Naturally occurring cathinones are derived from the khat plant (Catha edulis). Active ingredients in SCs include MDPV; 4-methylmethcathinone (mephedrone); and 3,4-methylenedioxy-N-methylcathinone (methylone). The structure is similar to that of amphetamines. The Table lists some aliases of bath salts.

Sometimes viewed as “legal cocaine,” the over-the-counter status of SCs gives the illusion that they are safe. These substances produce sought-after effects (eg, euphoria, elevated mood, increased alertness, aphrodisiac). The most common method of ingestion is injection, followed by snorting and oral ingestion, but they are also taken rectally. Typical dosages range from 3 to 20 mg, with peak absorption within 1.5 hours.2 Effects can last for 3 to 4 hours, followed by a crash period of 2 to 4 hours. With mephedrone, effects may last more than 24 hours.3

Common physical signs of use and intoxication include the following:
• Tachycardia
• Hypertension
• Hyperthermia
• Diaphoresis • Seizures
• Tremors • Motor automatisms
• Mydriasis • Paranoia • Irritability
• Anxiety
• Psychosis

Bath salt use can mimic other medical problems when it results in seizures, hyperthermia, or cardiovascular issues. Concurrent use of serotonergic drugs and SCs may increase the risk of serotonergic syndrome. Kidney damage from rhabdomyolysis, ischemia, and hypoperfusion has also been reported.4

An investigation of 35 emergency department patients who used bath salts in Michigan from November 2010 to March 2011 noted diffuse organ system involvement.5 This report found that 91% of patients had neurological involvement, 77% had cardiovascular involvement, and 49% had psychological involvement. Liver failure developed in one patient 12 days after initial presentation. In addition to reports of hyperthermia and multiorgan failure, deaths have occurred. One death was a result of acute intoxication. Another reported death by suicide was thought to be from the direct psychological effect of MDPV.6

Legal regulation of SCs is difficult because each compound, as opposed to the class, must be individually banned. The Drug Enforcement Administration (DEA), and not the FDA, regulates the products because they are “not intended for consumption.” On October 21, 2011, the DEA exercised its emergency scheduling authority to ban the 3 most common SCs: mephedrone, MDPV, and methylone. In July 2012, President Barack Obama signed into law a federal ban of 31 synthetic substances, 10 of which were bath salts.7 This law also inhibited the sale of synthetic drugs and placed mephedrone and MDPV on the FDA list of substances that cannot be sold for any reason. As a result of this action, these 3 compounds became Schedule I substances, making possession illegal.

The challenge continues as new synthetic compounds emerge, including a-pyrrolidinovalerophenone (a-PVP) and pentedrone, among others. Many of these substances are first seen in Europe before they appear in the US.

Although not revealed via routine drug screens, SCs are detectable by mass spectroscopy. This laboratory test should be obtained on patients with symptoms of ingestion, as well as chemistry panels to test for renal function and liver function. Because of the cardiac effects and the propensity to cause a myocardial infarction, an ECG should also be obtained.5

Treatment of cathinone use is symptomatic. The mainstay of acute intoxication treatment is benzodiazepines. The administration of lorazepam(Drug information on lorazepam) allows for a more careful titration of dose based on symptoms compared with a longer-acting benzodiazepine. Psychotic symptoms can persist after autonomic symptoms have abated and may necessitate antipsychotic medication and psychiatric hospitalization. Antipsychotics may lower the seizure threshold. Psychosis usually resolves within 4 days, but there are reports of psychosis lasting for weeks.8 There have been several reports of violence and suicide after SC ingestion.6,9 All individuals with known or suspected SC use should have thorough violence and suicide risk assessments. When evaluating for violence risk, physicians should look for the presence of delusions, specifically persecutory delusions. A history of violence and of mental illness increases the risk of violence in an intoxicated individual.

The suicide risk assessment should focus not only on thoughts of the patient but also on intent. Attention should be placed on actions taken during the time of intoxication. One should not assume that suicide risk is completely tied to SC intoxication; risk should also be assessed outside of intoxication. Once brought to the attention of the health care provider, the intoxicated individual should be monitored until no longer symptomatic, even if this requires hospitalization.

Conclusion SCs are marketed under several different names and product classes. Symptoms of intoxication mimic those of cocaine and amphetamines. Intoxication can involve most organ systems. Some symptoms of use are serious, and death has been reported. Treatment is symptomatic and should include suicide and violence risk assessments. The 3 most common compounds have been made illegal—but new synthetic compounds are already appearing and are likely to come to light for the psychiatric practitioner.

Source: www.psychiatrictimes.com 30th April 2013 Jason Beaman, DO and Erin E. Hayes, Dr Beaman is a Fellow in Forensic Psychiatry at Case Western Reserve University in Cleveland

Filed under: Effects of Drugs (Papers) :

In the past decade or so, research with MRI and functional MRI has revolutionised what we know about how the human brain develops. We now understand that the brain undergoes protracted development, continuing throughout adolescence and beyond.

1.Adolescence is defined as the period starting with the physical and hormonal changes associated with puberty and ending when an individual attains a stable, independent role in society.2 Although the point marking the end of adolescence varies with culture, the end of the teenage years represents a working consensus in developed countries. One brain region that develops substantially during the teenage years is the prefrontal cortex, which is involved in executive functions, such as decision making, inhibitory control, and planning,3,4 and in social understanding and self-awareness.5 A key finding from structural MRI studies is that the volume of grey matter, which contains brain cell bodies and synapses, changes between childhood and adulthood. In the prefrontal cortex, grey matter increases in volume during childhood, peaks in early adolescence, and then declines in adolescence and throughout the 20s.1 The loss of grey matter during adolescence is thought to be due, at least partly, to synaptic pruning—the process by which excess synapses are eliminated. Supporting this notion, findings from studies of post-mortem human brain tissue have shown a decline in the number of synapses in the prefrontal cortex during adolescence.6 Synaptic pruning is partly dependent on environmental input: synapses that are used are strengthened; synapses that are not used are pruned away.7 In this way, synaptic pruning sculpts neuronal circuitry according to the environment during sensitive periods of brain development. Although a great deal of evidence supports early periods of sensitivity to sensory information,7 less is known about the existence of later sensitive periods. Meier and colleagues’ study8 provides some evidence that adolescence might represent a period of brain development that is particularly sensitive to environmental input. The researchers investigated the association between self-reported persistent cannabis use and changes in cognitive ability in 1037 participants of the Dunedin longitudinal study, which has followed this cohort in Dunedin, New Zealand, from birth to their current age of 38 years. Cognitive ability was assessed from IQ and various neuropsychological measures, including working memory, processing speed, perceptual reasoning, and verbal comprehension.

Cannabis use over the past year was reported at five time points between 18 and 38 years. A major strength of this study was that cognitive ability had already been tested at the age of 13 years, before first cannabis use, so the researchers had a baseline measure with which to compare the results of a second test in the same individuals 25 years later. The findings showed that persistent cannabis use is associated with a statistically significant decline in cognitive ability. That is, the more persistent the cannabis use, the greater the cognitive decline. Second, the association between persistent cannabis use and cognitive decline was significantly greater for people who began using cannabis before, compared with after, 18 years. Third, if cannabis use started in adolescence (before 18 years), the cognitive deficit remained significant when people had stopped using for at least 1 year before testing.

These findings provide prospective evidence from a large cohort that adolescent cannabis use is more damaging to cognitive abilities during adulthood than is adult use. The results remained significant after adjustment for other possible confounding factors, including alcohol and so-called hard-drug dependence (eg, heroin, cocaine, or amphetamines), years of education, and diagnosis of schizophrenia. But we still have to be cautious about interpreting the correlation between cannabis use and reduced cognitive ability as a direct causal relation. Perhaps a third factor— for example, decreased motivation or a psychiatric disorder developed in adolescence, such as anxiety or depression—leads people to smoke cannabis and perform poorly on IQ and neuropsychological tests.

Nevertheless, this study is important because it suggests that adolescence is a period of brain development that is sensitive to environmental factors. Cannabis seems to have long lasting negative consequences on a broad spectrum of cognitive abilities, perhaps because persistent cannabis use during adolescence affects how brain circuitry develops.9 Could training and rehabilitation programmes reverse the decline in cognitive ability associated with cannabis use in people younger than 18 years? This is a question for future research. People can relearn sensory information that has been lost because of lack of sensory input in early sensitive periods of brain development, but only via fairly intensive training and under certain conditions.10 The implications of this study are far reaching. Other environmental influences—for example, alcohol, tobacco, and drug treatments—might also negatively affect the developing brain in the long term. Conversely, if the adolescent brain is particularly malleable, this might be a key time for positive effects of the environment, such as teaching, rehabilitation, and training. As highlighted in a recent Series in The Lancet,11 global health and education policy should include a greater focus on adolescence, when the brain is still highly adaptable and can be shaped by the environment


Source: www.thelancet.com Published online October 30, 2012

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers) :

The major media do not want to cover the issue of marijuana causing mental illness. But because a prominent Democrat, Patrick Kennedy, has raised it, the media have nowhere left to hide. The news that he says marijuana “Destroys the brain and expedites psychosis” was big news and a big headline in The Washington Post.

Kennedy fought alcoholism and an addiction to prescription drugs and is now taking on the marijuana lobby, while getting verbal abuse from the potheads in return. The Marijuana Policy Project calls his new group, SAM (Smart Approaches to Marijuana), the “new threat” and “a dangerous, new national anti-marijuana organization.”

The group’s website features such stories as:

* Marijuana use linked with significant IQ loss

* Medical marijuana laws hurt kids, doctor says

* Legalize pot? No, reform laws

Kennedy, the younger son of Edward M. Kennedy and a former member of Congress from Rhode Island, was strong and direct, telling the Post, “Marijuana destroys the brain and expedites psychosis. It’s just overall a very dangerous drug.” The paper said Kennedy wants “to shift the debate from legalization to prevention and treatment—despite what appears to be a growing social acceptance of the drug.”

That “growing social acceptance” is being driven by the drug-friendly media, the pro-drug entertainment industry, and a dope lobby led by the Drug Policy Alliance that is mostly funded by billionaires such as George Soros.

Kennedy’s involvement follows other experts who have been discussing marijuana’s threat. Mental health expert Clayton Cramer tells Accuracy in Media, “The studies that have been done on the subject clearly demonstrate not just a correlation between mental illness and marijuana use, but a causal connection.”

However, the pro-marijuana movement is on the move, with the state of Oregon sinking so low as to authorize the use of “medical marijuana” for a 7-year-old child with leukemia. The child’s father, who is divorced from the girl’s mother, reported the marijuana use to child welfare officials and said that he found the little girl “stoned out of her mind.”

The prospect of Patrick Kennedy’s involvement gives hope to those who believe the U.S. has been surrendering the war on drugs. Reuters broke the story, “Patrick Kennedy On Marijuana: Former Rep. Leads Campaign Against Legal Pot,” which was picked up by the Huffington Post and other liberal outlets. Kennedy “is taking aim at what he sees as knee-jerk support for marijuana legalization among his fellow liberals,” it said. The dope lobby never expected a certified liberal—and the son of a liberal icon—to lead a new charge against them.

SAM is a bipartisan group, chaired by Kennedy, which includes George W. Bush’s former speechwriter and Daily Beast columnist David Frum, Harvard Professor Sharon Levy, Kevin Sabet, and other public health professionals and lawmakers.

Levy authored a resolution for the American Academy of Pediatrics opposing the use of “medical marijuana” in children, while Sabet served in the Obama Administration as Senior Advisor at the White House Office of National Drug Control Policy (ONDCP). Sabet has debated Ethan Nadelmann of the Soros-funded Drug Policy Alliance.

On its website, Frum argues against marijuana legalization. Equally significant, SAM talks about where marijuana legalization is heading—a takeover by the tobacco industry, which has openly speculated about marijuana becoming an “alternative product line.”

SAM declares, “We know if it’s legalized, marijuana will be commercialized, too. A commercial marijuana industry will act just as the tobacco industry acts. Big Tobacco may even take over a marijuana industry once it’s up and running.” Since tobacco companies lied to America for more than a century about the dangers of smoking, SAM suggests the truth about marijuana will also be concealed by the commercial and other special interests eager to make money from the product.

In fact, left-wing British journalist Patrick Cockburn has already written about a “tobacco moment” for marijuana consisting of the connection between marijuana use and psychotic episodes that is comparable to the scientific recognition that tobacco smoking causes lung cancer and other illnesses. Cockburn wrote a series of blockbuster articles in the British media on how his own son went insane smoking marijuana.

Clayton Cramer, author of My Brother Ron: A Personal and Social History of the Deinstitutionalization of the Mentally Ill, says that the damage is being done through

“the active promotion of marijuana use, especially among young people, who are the greatest risk of marijuana inducing schizophrenia.” In addition to mental illness, a recent international study found a link between “persistent cannabis use and neuropsychological decline.” In other words, marijuana causes damage to intelligence, memory and attention.

Source: http://www.aim.org/aim-column/a-kennedy-shocks-the-pro-dope-liberal-media/

Filed under: Effects of Drugs (Papers),USA :

Please read this article in light of the claim by pro-pot lobbyists that drug cartels will magically disappear when marijuana is legalized.

California has had some form of legalization since 1996, yet their public lands are overrun with illegal grow operations. See below. Monte

http://framework.latimes.com/2012/12/22/environmental-impact-of-marijuana-growing-california/#/0

Posted By: Jerome Adamstein

Posted On: 6:32 p.m. | December 22, 2012

State scientists, grappling with an explosion of marijuana-growing in the North Coast, recently studied aerial imagery of a small tributary of the Eel River, spawning grounds for endangered Coho salmon and other threatened fish.

In the remote, 37-square-mile patch of forest, they counted 281 outdoor pot farms and 286 greenhouses, containing an estimated 20,000 plants — mostly fed by water diverted from creeks or a fork of the Eel. The scientists determined the farms were siphoning roughly 18 million gallons from the watershed every year, largely at the time when the salmon most need it.

“That is just one small watershed,” said Scott Bauer, the state scientist in charge of the Coho recovery on the North Coast for the Department. of Fish and Game. “You extrapolate that for all the other tributaries, just of the Eel, and you get a lot of marijuana sucking up a lot of water.… This threatens species we are spending millions of dollars to recover.”

The marijuana boom that came with the sudden rise of medical cannabis in California has wreaked havoc on the fragile habitats of the North Coast and other parts of the state. With little or no oversight, farmers have illegally mowed down timber, graded mountaintops flat for sprawling greenhouses, dispersed poisons and pesticides, drained streams and polluted watersheds.

Because marijuana is unregulated in California and illegal under federal law, most growers still operate in the shadows, and scientists have little hard data on their collective impact. But they are getting ever more ugly snapshots.

Source: e-mail from monte@montestiles.com 24.12.2012

Filed under: Effects of Drugs (Papers) :

Many people experiment with cannabis during their adolescence and early adulthood, and new research shows this is a particularly dangerous age because the brain is still developing. A recent study reported in the Oxford University Press found compelling evidence that brain reacts differently to cannabis exposure that commences during adolescence compared with adulthood.

The aim of the study was to examine the “white matter” pathways within the brain to see if they are changed through long-term heavy cannabis use. It was also hypothesized that the earlier someone started heavy and regular cannabis use the more severe the affect would be on these pathways in the brain.

White matter is the tissue through which messages pass between different areas of gray matter within the brain. Using a computer network as an analogy, the gray matter can be thought of as the actual computers themselves, whereas the white matter represents the network cables connecting the computers together. There are three different kinds of tracts, or bundles of axons which connect one part of the brain to another and to the spinal cord, within the white matter: projection tracts that extend vertically between higher and lower brain and spinal cord centers; commissural tracts cross from one cerebral hemisphere to the other through bridges called commissures; and association tracts that connect different regions within the same hemisphere of the brain.

To measure the effect of cannabis on the “white matter” pathways, the study looked at long term habitual users of cannabis with a minimum usage of twice a month for the past 3 years (although most recruited in the study had substantially greater use than this) and compared them with healthy non-users. In-depth brain imaging and brain connectivity mapping techniques were performed in each of the 59 cannabis users with longstanding histories of heavy use and the 33 healthy non-users who served as controls.

After examining the habitual heavy cannabis users, researchers found the axonal pathways were impaired in the right fimbria of the hippocampus, splenium of the corpus callosum and commissural fibers. It is also important to note that all of these areas that were impaired have an abundance of cannabinoid receptors.

The amount of damage to these pathways was also directly associated with the age at which regular cannabis use commenced. This resulted in long term users having greater instance of anxiety and depressive symptoms and lower Global Assessment of Functioning scores (a measurement of social, occupational and psychological functioning).

This association presents compelling evidence for white matter reacting differently to cannabis exposure commencing during adolescence compared with adulthood, most likely due to the high concentration of cannabinoid receptors contained within structures, such as the corpus callosum and fornix during adolescence.

These results suggest that long-term cannabis use is hazardous particularly to white matter in the developing brain of adolescents and young adults. Damage to these vital pathways during brain development may later lead to cognitive impairment and vulnerability to psychosis, depression and anxiety disorders, all of which are significant

public health concerns. White matter alterations have been associated with various functional and clinical outcomes in schizophrenia, including illness, symptomatic and cognitive measures.

Source: http://www.medscape.com/viewarticle/766633?src=journalnl 16th Oct 2012

Filed under: Effects of Drugs (Papers) :

This paper comprises three decades of scientific study on the negative and potential positive effects of marijuana and human health.

JUST THE FACTS: Marijuana and Health

Marijuana is the subject of heated debate in our country. Despite one’s view on marijuana policy, it is critical to be well-versed in the science.

Marijuana is one of the most misunderstood drugs of our time. Sifting through the rhetoric about the drug can be difficult, but now we have a plethora of scientific studies from which to draw firm conclusions about the use of the drug and its public health implications.

Marijuana and The Brain

Marijuana use directly affects the brain, specifically the parts of the brain responsible for memory, learning, attention, and reaction time. These effects can last up to 28 days after abstinence from the drug.1

1 Hall W & Degenhard L (2009). Adverse health effects of non-medical cannabis use. Lancet, 374:1383-1391.

2 Giedd. J. N. (2004). Structural magnetic resonance imaging of the adolescent brain. Annals of

the New York Academy of Sciences, 1021, 77-85. And see 3 See, for example http://news.olemiss.edu/index.php?option=com_content&view=article&id=4545%3Acannabispotency051409&Itemid=10

Science confirms that the adolescent brain, particularly the part of the brain that regulates the planning complex cognitive behaviour, personality expression, decision making and social behaviour, is not fully developed until the early to mid-20s. Developing brains are especially susceptible to all of the negative effects of marijuana and other drug use.2

What makes marijuana harmful? Three simple letters: T-H-C

Marijuana contains about 500 components, most of which we know little about. The most prominent component is called THC. Scientists have found that THC is what produces the “high” users experience. In today’s street marijuana, which is usually smoked, producers have increased THC levels by more than four-fold3, and reduced the natural levels of other components that have actually been shown to reduce the high. Higher THC content can increase all of the usual negative effects of the

drug. 4, 5 In the U.S., for example, since 1990, more people have gone to the emergency room after using marijuana even though the overall numbers of marijuana users has remained relatively stable.6,7

4 Hall W & Degenhard L (2009). Adverse health effects of non-medical cannabis use. Lancet, 374:1383-1391.

5 NIDA, Research Report Series: Cannabis Abuse, 2010

6 Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (2011). Drug Abuse Warning Network, 2008: National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. SMA 11-4618. Rockville, MD.

7 See for example Compton, W., Grant, B., Colliver, J., Glantz; M., Stinson, F. (2004). Prevalence of Cannabis Use Disorders in the United States: 1991-1992 and 2001-2002Journal of the American Medical Association.. 291:2114-2121. And Sabet, K. (2006). The (often unheard) case against cannabis leniency. In Pot Politics (Ed. M. Earleywine).Oxford University Press, pp. 325-355.

8 Hall W & Degenhard L (2009). Adverse health effects of non-medical cannabis use. Lancet, 374:1383-1391.

9 Tetrault, J.M., et al. Effects of cannabis smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 167, 221-228 (2007).

10 Hoffman, D.; Brunnemann, K.D.; Gori, G.B.; and Wynder, E.E.L. On the carcinogenicity of marijuana smoke. In: V.C. Runeckles, ed., Recent Advances in Phytochemistry. New York: Plenum, 1975.

11 See, for example: Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review. Lancet 370(9584):319–328, 2007. Also Large, M., Sharma S, Compton M., Slade, T. & O., N. (2011). Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Archives of General Psychiatry. 68. Also see Arseneault L, et al. (2002). Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. British Medical Journal. 325, 1212-1213.

12 Hall W & Degenhard L (2009). Adverse health effects of non-medical cannabis use. Lancet, 374:1383-1391.

The main health harms of marijuana can be summarized as follows:

Heart: Marijuana use can cause an increase in the risk of a heart attack more than four-fold in the hour after use, and provokes chest pain in patients with heart disease. 8

Lungs: Research has shown marijuana smoke to contain carcinogens and to be an irritant to the lungs, resulting in greater prevalence of bronchitis, cough, and phlegm production.9 Marijuana smoke contains 50-70 percent more carcinogenic hydrocarbons than does tobacco smoke, as reported by the American Lung Association.10 Scientists have not found a definitive marijuana-lung cancer link.

Mental Health: Marijuana use has been shown to be significantly linked with mental illness, especially schizophrenia and psychosis, but also depression and anxiety.11

Pregnancy: Marijuana smoking during pregnancy has been shown to decrease birth weight, most likely due to the effects of carbon monoxide on the developing fetus.12

Marijuana and Addiction

An often heard phrase is that “marijuana is not addictive.” In fact, scientific research has found that 1 in 10 marijuana users will become addicted to the drug. And if one begins in adolescence, that

number rises to 1 in 6.13 Users who try to quit experience withdrawal symptoms that include irritability, anxiety, insomnia, appetite disturbance, and depression. 4, 5 Additionally, data from the National Institute on Drug Abuse found that in 1993 marijuana comprised approximately 8% of all treatment admissions, but by 2009 that number had increased to 18%.14 For those under 18, marijuana related treatment admissions increased by 188 percent from 1992 to 2006 while other drugs remained steady.15

13 Wagner, F.A. & Anthony, J.C. From first drug use to drug dependence; developmental periods of risk for dependence upon cannabis, cocaine, and alcohol. Neuropsychopharmacology 26, 479-488 (2002).

14 Substance Abuse and Mental Health Services Administration. (2009). Office of Applied Studies. Treatment Episode Data Set (TEDS): 2009 Discharges from Substance Abuse Treatment Services, DASIS.

15 Substance Abuse and Mental Health Services Administration. (2009). Office of Applied Studies. Treatment Episode Data Set (TEDS): 2009 Discharges from Substance Abuse Treatment Services, DASIS.

Also see Non-medical cannabis: Rite of passage or Russian roulette? (2011).Center on Addiction and Substance Abuse, Columbia University.

16 Room, R., Fischer, B., Hall, W., Lenton, S. and Reuter, P. (2010). Cannabis Policy: Moving Beyond Stalemate, Oxford, UK: Oxford University Press.

17 MacCoun, R. J. (2011), What can we learn from the Dutch cannabis coffee shop system?. Addiction, 106: 1899–1910.

18 Drummer, O.H., Gerostamoulos, J., Batziris, H., Chu, M., Caplehorn, J.R., Robertson, M.D., Swann, P. (2003). The incidence of drugs in drivers killed in Australian road traffic crashes. Forensic Science International, 134(2-3), 154-162.

19 European Monitoring Centre for Drugs and Drug Addiction. (2003) Drugs and driving: ELDD comparative study. Lisbon, Portugal: Author. Retrieved March 29, 2011 from http://www.emcdda.europa.eu/attachements.cfm/att_5738_EN_Quantities.pdf

20 Mørland J. (2000) Driving under the influence of non-alcoholic drugs, Forensic Science Review, 12, 80-105.

21 ROSITA Roadside Testing Assessment: www.rosita.org

22 DRUID: www.druid-project.eu

23 Verstraete, A.G. & Raes, E. (Eds.). (2006). Rosita-2 Project Final Report. Ghent Belgium: Ghent University.

24 M. Asbridge, J. A. Hayden, J. L. Cartwright. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ, 2012; 344 (feb09 2): e536 DOI:10.1136/bmj.e536

Data in the United States is corroborated with data from other countries. In the European Union, the percentage of marijuana as the primary reason for entering treatment increased by 200 percent from 1999 to 2006, and currently stands at around 30 percent of all admissions.16 The Netherlands has the highest rate of marijuana addiction in Europe.17

Marijuana and Driving

In the past decade, researchers from all corners of the world have documented the problem of marijuana use and driving.18,19,20,21,22,23 Linked to deficits in the parts of the brain that are important for driving, including the impairment of motor coordination and reaction time, a widely-cited article in the British Medical Journal from 2012 concluded that marijuana use doubles the risk of car crashes.24

Another recent meta-analysis of nine studies found that marijuana “…use by drivers is associated with a significantly increased risk of being involved in motor vehicle crashes.”25

25 Li, M., Brady, J., DiMaggio, C., Lusardi, R., Tzong, K. and Li, G. (in press). Cannabis use and motor vehicle crashes. Epidemiologic Reviews.

26 Meier et al. (2012). Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of Sciences.

27 Fergusson, D. M. and Boden, J. M. (2008), Cannabis use and later life outcomes. Addiction, 103: 969–976.

28 Macleod, J.; Oakes, R.; Copello, A.; Crome, I.; Egger, M.; Hickman, M.; Oppenkowski, T.; Stokes-Lampard, H.; and Davey Smith, G. Psychological and social sequelae of cannabis and other illicit drug use by young people: A systematic review of longitudinal, general population studies. Lancet 363(9421):1579-1588, 2004.

29 Ellickson, P.L.; Martino, S.C.; and Collins, R.L. Cannabis use from adolescence to young adulthood: Multiple developmental trajectories and their associated outcomes. Health Psychology 23(3):299-307, 2004.
30 National Institute on Drug Abuse (NIDA). (2011). Research Report Series: Cannabis Abuse. Accessed November 2011 at http://www.drugabuse.gov/ResearchReports/Cannabis/cannabis4.html

Marijuana use and Performance at School and on the Job

One of the most well designed studies on marijuana and intelligence, released in 2012, found that marijuana use reduces IQ by as much as eight points by age 38 among people who started using marijuana regularly before age 18 but then stopped.26 Other studies have found that marijuana use is linked with dropping out of school, and subsequent unemployment, social welfare dependence, and a lower self-reported quality of life than non-marijuana abusing people.27

According to the U.S. National Survey on Drug Use and Health, youth with poor academic results were more than four times as likely to have used marijuana in the past year than youth with an average of higher grades. This is consistent with an exhaustive meta-analysis examining four dozen different studies by Macleod and colleagues, published by Lancet, who found that marijuana use is consistently associated with reduced grades and a reduced chance of graduating from school.28 Ellickson and colleagues at the RAND Corporation surveyed almost 6,000 students aged 13 to 23 and found that the teens who smoked cannabis from once a week to monthly at age 13, decreased their abuse by age 18, and as young adults smoked 3 to 10 times a year, lagged behind all other groups in earnings and education when resurveyed at age 29.29

In addition, studies have linked employee marijuana use with “increased absences, tardiness, accidents, workers’ compensation claims, and job turnover.”30

Health Recap

To recap, the science is emerging on the effects of marijuana, but we can say with some certainty that marijuana use is significantly linked with:

· Addiction

· Heart and Lung Complications (the jury is out on a connection to lung cancer, though)

· Mental Illness

· Car Crashes

· IQ loss and poor school outcomes

· Poor quality of life outcomes

· Poor job performance

Science has learned more about marijuana in the past twenty years than in the preceding two hundred. Ironically, however, there has been a major incongruence between the scientific knowledge gained and the public’s understanding of the drug. People often refer to their own experiences with marijuana rather than what scientific data has taught us. It is important to be aware of the growing scientific literature about a drug that is widely misunderstood.

Source: www.drugree.org. Article by Dr. Kevin Sabet, Assoc. Professor University of Florida

Filed under: Effects of Drugs (Papers) :

Abstract

Background: Opioid analgesics and benzodiazepines are often misused in clinical practice. We determined whether implementation of a centralized prescription network offering real-time access to patient-level data on filled prescriptions (PharmaNet) reduced the number of potentially inappropriate prescriptions for opioids and benzodiazepines.

Methods: We conducted a time series analysis using prescription records between Jan. 1, 1993, and Dec. 31, 1997, for residents of the province of British Columbia who were receiving social assistance or were 65 years or older. We calculated monthly percentages of filled prescriptions for an opioid or a benzodiazepine that were deemed inappropriate (those issued by a different physician and dispensed at a different pharmacy within 7 days after a filled prescription of at least 30 tablets of the same drug).

Results: Within 6 months after implementation of PharmaNet in July 1995, we observed a relative reduction in inappropriate filled prescriptions for opioids of 32.8% (95% confidence interval [CI] 31.0%–34.7%) among patients receiving social assistance; inappropriate filled prescriptions for benzodiazepines decreased by 48.6% (95% CI 43.2%–53.1%). Similar and statistically significant reductions were observed among residents 65 years or older.

Interpretation: The implementation of a centralized prescription network was associated with a dramatic reduction in inappropriate filled prescriptions for opioids and benzodiazepines.

Source: Canadian Medical Association Journal September 4, 2012

Filed under: Canada,Effects of Drugs (Papers) :

A NIDA-supported clinical trial, the Maternal Opioid Treatment: Human
Experimental Research (MOTHER) study, has found buprenorphine to be a safe and effective alternative to methadone for treating opioid dependence during pregnancy. Women who received either medication experienced similar rates of pregnancy complications and gave birth to infants who were comparable on key indicators of neonatal health and development. Moreover, the infants born to women who received buprenorphine had milder symptoms of neonatal opioid withdrawal than those born to women who received methadone.

Methadone and buprenorphine maintenance therapy are both widely used to help individuals with opioid dependence achieve and sustain abstinence. Methadone has been the standard of care for the past 40 years for opioid-dependent pregnant women.

However, interest is growing in the possible use of buprenorphine, a more recently approved medication, as another option for the treatment of opioid addiction during pregnancy.

“Our findings suggest that buprenorphine treatment during pregnancy has some advantages for infants compared with methadone and is equally safe,” says Dr. Hendrée JonesExternal link, please review our disclaimer., who led the multicenter study while at the Johns Hopkins University School of Medicine and is now at RTI International.

A Rigorous Trial Design
Methadone maintenance therapy (MMT) enhances an opioid-dependent woman’s chances for a trouble-free pregnancy and a healthy baby. Compared with continued opioid abuse, MMT lowers her risk of developing infectious diseases, including hepatitis and HIV; of experiencing pregnancy complications, including spontaneous abortion and miscarriages; and of having a child with challenges including low birth weight and neurobehavioral problems.

Along with these benefits, MMT may also produce a serious adverse effect. Like most drugs, methadone enters fetal circulation via the placenta. The fetus becomes dependent on the medication during gestation and typically experiences withdrawal when it separates from the placental circulation at birth. The symptoms of withdrawal, known as neonatal abstinence syndrome (NAS) include hypersensitivity and hyperirritability, tremors, vomiting, respiratory difficulties, poor sleep, and low-grade fevers. Newborns with NAS often require hospitalization and treatment, during which they receive medication (often morphine) in tapering doses to relieve their symptoms while their bodies adapt to becoming opioid-free.

The MOTHER researchers hypothesized that buprenorphine maintenance could yield methadone’s advantages for pregnant women with less neonatal distress. Buprenorphine, like methadone, reduces opioid craving and alleviates withdrawal symptoms without the safety and health risks related to acquiring and abusing drugs. Therapeutic dosing with buprenorphine, as with methadone, avoids the extreme fluctuations in opioid blood concentrations that occur in opioid abuse and place physiological stress on both the mother and the fetus. However, unlike methadone, buprenorphine is a partial rather than full opioid and so might cause less severe fetal opioid dependence than methadone therapy.

The MOTHER study recruited women as they sought treatment for opioid dependence at six treatment centers in the United States
and one in Austria. All the women were 6 to 30 weeks pregnant. The research team initiated treatment with morphine for each woman, stabilized her dose, and then followed with the daily administration of buprenorphine therapy or MMT for the remainder
of her pregnancy. Throughout the trial, the team increased each woman’s medication dosage as needed to ease withdrawal symptoms.

The study incorporated design features to ensure that its findings would be valid. Among the most notable were measures taken to prevent biases that might arise if staff and participants knew which medication a woman was getting.

To treat the participants without knowing which medication each woman was receiving, the study physicians wrote all prescriptions in pairs, one for each medication, in equivalent strengths. Study pharmacists matched the patient’s name and ID number to her medication group and filled only the prescription for the medication she was taking.

Each day, participants dissolved seven tablets under their tongues and then swallowed a syrup. If a woman was in the buprenorphine group, one or more of her tablets contained that medication, depending on her prescribed dosage, while the rest of the tablets and the syrup were placebos. If a woman was in the methadone group, the syrup contained that medication in her prescribed strength and the tablets all were placebos. In this way, each woman’s complement of medications appeared identical to that of every other participant. The placebo tablets and syrup were crafted to look, taste, and smell like the active medications.

As Good For Mothers, Better for Infants
Of 175 women who started a study medication, 131 continued until they gave birth. Those who received MMT and those given buprenorphine experienced similar pregnancy courses and outcomes. The two groups of women did not differ significantly in maternal weight gain, positive drug screens at birth, percentage of abnormal fetal presentations or need for Cesarean section, need for analgesia during delivery, or serious medical complications at delivery.

As the MOTHER researchers had hypothesized, the infants whose mothers were treated with buprenorphine experienced milder NAS than those infants exposed to methadone (see graph). Whereas most infants in both groups required morphine to control NAS, the buprenorphine group, on average, needed only 11 percent as much, finished its taper in less than half the time, and remained in the hospital roughly half as long as the infants exposed to methadone.

At Dr. Gabriele Fischer’s Medical University of Vienna site in Austria, three women became pregnant for a second time during the time MOTHER was enrolling participants. This development allowed researchers to compare the two medications’ relative safety and efficacy in individual women as well as across groups. During her second pregnancy, each of the three women took the alternative medication to the one she took in her first pregnancy. In each instance, the child born following buprenorphine treatment exhibited milder NAS symptoms than the one born following methadone treatment. This result suggests that differences in the effects of the two medications, rather than women’s individual differences in physiology, underlie the group findings.

“Buprenorphine may be a good option for pregnant women, particularly those who are new to treatment or who become pregnant
while on this medication,” says Dr. Jones. “If a patient is on methadone maintenance and stable, however, she should remain on methadone.”

MOTHER researchers observed that although the women in their buprenorphine and methadone groups benefited equally from treatment, the drop-out rate was higher in the buprenorphine group (33 vs. 18 percent). This difference was not statistically
significant. The researchers speculate that if it is meaningful, it may be owing to factors other than different responses to the two medications. They surmise that the experimental treatment protocols may have moved patients from morphine to buprenorphine too rapidly, causing discomfort, or that buprenorphine may have been easier than methadone to discontinue when women decided to become abstinent.

The MOTHER study did not include women with some substance use disorders that are commonly comorbid with opioid abuse.

“Future studies should compare neonatal abstinence syndrome, birth outcomes, and maternal outcomes of these two medications for pregnant women who also abuse alcohol and benzodiazepines,” Dr. Jones says.

“The field also needs data on neonatal outcomes when pregnant women are treated with buprenorphine combined with naloxone, the current first-line form of buprenorphine therapy for opioid dependence,” Dr. Jones notes. The MOTHER study administered buprenorphine without naloxone to avoid exposing the fetus to a second medication with potential adverse effects.

“Research challenges remaining after this brilliant study are to determine the factors that resulted in the differential drop-out rates between the two medications,” says Dr. Loretta P. Finnegan, who did pioneering work in the assessment and treatment of NAS. “Additionally, researchers need to conduct followup research on these children to determine the longer term significance of the differences in newborn withdrawal symptoms.” Dr. Finnegan, now president of Finnegan Consulting, was formerly the medical advisor to the director of the Office of Research on Women’s Health at the National Institutes of Health.

“Neonatal abstinence syndrome is a terrible experience for infants, and there is a great need to improve care for this condition,” says Dr. Jamie Biswas of NIDA’s Division of Pharmacotherapies and Medical Consequences of Drug Abuse. “Dr. Jones’ study is a superb contribution to this area of clinical research, and the robust results should provide more treatment options for a syndrome that affects thousands of infants each year.”

Sources:
Unger, A., et al. Randomized controlled trials in pregnancy: Scientific and ethical aspects. Exposure to different opioid
medications during pregnancy in an intra-individual comparison. Addiction 106(7):1355–1362, 2011. Abstract Available


Filed under: Addiction (Papers),Effects of Drugs (Papers),Intervention (including testing) (Papers),Social Affairs (Papers) :
1. INCREASED USE AMONG ADULTS AND YOUTH
The number of teenage and adult users will double or triple if marijuana is legalized. This will mean an additional 17 to 34 million adult and young users in the United States. [FN1]
Marijuana businesses will promote their products and package them in attractive ways to increase their market share (see attached pictures of marijuana “candy”).
ASK YOURSELF: Do you think increased marijuana use among teenagers and adults is good for our country and its future?
2. NEGATIVE IMPACT ON YOUTH
Marijuana can cause disinterest in activities, lower grades and isolation from the family. It can permanently impair brain development. Problem solving, concentration, motivation and memory are negatively affected. Teens who use marijuana are more likely to engage in delinquent and dangerous behavior and experience increased risk of schizophrenia and depression including being three times more likely to have suicidal thoughts. [FN2]
Marijuana-using teens are more likely to have multiple sexual partners and engage in unsafe sex. [FN3]
Our drug treatment facilities are full of young people dealing with marijuana related problems. One study of children in treatment showed that, 48% were admitted for abuse or addiction to marijuana, while only 19.3 % for alcohol and 2.9 % for cocaine, 2.4 % for methamphetamine and 2.3 % for heroin. [FN4]
Marijuana use accounts for tens of thousands of marijuana related complaints at emergency rooms throughout the United States each year. Over 99,000 are young people. [FN5]
Despite arguments by the drug culture to the contrary, marijuana is addictive. [FN6] The levels of THC (marijuana’s psychoactive ingredient) have never been higher. Higher potency marijuana is a major factor why marijuana is the number one drug causing young people to enter treatment and why there has been a substantial increase in the number of Americans in treatment for marijuana dependence. [FN7]
ASK YOURSELF: Would you want your son or daughter to become involved in using marijuana?
3. IMPAIRED AND DANGEROUS DRIVING
Marijuana significantly impairs the ability to safely operate a motor vehicle. Driving problems include: decreased handling performance, inability to maintain headway, impaired time and distance estimation, increased reaction times, sleepiness, impaired sustained vigilance and lack of motor coordination. [FN8]
Marijuana is the most prevalent drug found in fatally injured drivers testing positive for drugs. [FN9]
More than 12 % of high school seniors admitted to driving under the influence of marijuana in the two weeks prior being surveyed. [FN10]
13 % of high school seniors said they drove after using marijuana while only 10 % drove after having five or more drinks. Vehicle accidents are the leading cause of death among those aged 15 to 20. [FN11]
A study of high school students showed that about 28,000 seniors each year admitted that they were in at least one accident after using marijuana. [FN12]
ASK YOURSELF: Do you want more impaired drivers on our interstates and roadways?
4. INCREASED-RISK EMPLOYEES
Employees who tested positive for marijuana had 55% more industrial accidents and 85% more injuries compared to those that tested negative on a pre-employment exam and they had absenteeism rates 75% higher than those that tested negative. [FN13]
Marijuana use can cause impairment of short-term memory, attention, motor skills, reaction time, and the organization and integration of complex information. Marijuana use can cause decreased motivation and can cause mental health problems. Employees who use marijuana off-duty are still effected by it at work for the next few days. Impaired cognition can remain for a long period. Memory defects can last as long as six weeks. [FN14]
Employers may be liable for the actions of employees who use marijuana especially those employees in safety sensitive positions.
ASK YOURSELF: If you were an employer, would you want to hire an employee who uses marijuana?
5. MARIJUANA USE AND TRAUMA
A study of all patients admitted to a shock-trauma unit showed 34.7% had used marijuana very recently. [FN15]
In a study of seriously injured drivers admitted to a shock-trauma center, 26.9 % of the drivers tested positive for marijuana. [FN16]
ASK YOURSELF: Is using marijuana a safe thing to do?
If you answered ‘no’ to any one of the above questions, then you should also say ‘no’ to legalizing marijuana for recreational use.
FOR MORE INFORMATION VISIT: www.dfaf.org
References
[FN1] Based on experience in the US and Europe when marijuana laws have been relaxed, the number of users will double or triple. See, Speaking Out Against Drug Legalization, U.S. Department of Justice, Drug Enforcement Administration (DEA), Washington, DC U.S.A. 2010, www.DEA.gov, pages 46 and 57; Currently, there are 16.7 million regular marijuana users in the US (12 years old or older.) SAMHSA, 2009 Annual Survey on Drug Use and Health, September 2010; The benchmark surveys of drug use show that that perception of harm with respect to marijuana has dropped off since the drive to legalize marijuana began. The benchmark surveys are the Monitoring the Future Survey, which has tracked drug use among American high school students annually since 1975 and the National Household Survey on Drug Abuse, which has tracked drug use among Americans ages 12 and older since 1972. Monitoring the Future, National Institutes of Health, National Institute on Drug Abuse, available on the Internet at www.monitoringthefuture.org; Overview of Findings from the 2002 National Survey on Drug Use and Health (Office of Applied Studies, NHSDA Series H-21, DHHS Publication No. SMA 03- 3774). Rockville, MD; Conducted for SAMHSA (the Substance Abuse and Mental Health Services Administration, Department of Health and Human Services) by North Carolina’s Research Triangle Institute.
[FN2] DEA Position on Marijuana, U.S. Department of Justice, Drug Enforcement Administration (DEA), Washington, DC U.S.A. July 2010, www.DEA.gov, pages 23-26 and 33-34; Speaking Out Against Drug Legalization, DEA, pages 51-53
[FN3] Bovassco, G., American Journal of Psychiatry, 2001
[FN4] “Non-medical Marijuana: Rite of Passage or Russian Roulette?” July 1999 obtained at website www.casacolumbia.org; Kaplan, H.B., Martin, S.S., Johnson, R.J., and Robbins, C.A., Escalation of marijuana use: Application of a general theory of deviant behavior. Journal of Health and Social Behavior.1986:27:44-61; Clayton, R.R., and Leukefeld, C.G., The prevention of drug use among youth; implications of “legalization” Journal of Primary Prevention. 1992:12:289-302
[FN5] Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration http://DAWNinfo.samhsa.gov/
9[FN6] The Occurrence of Cannabis Use Disorders and Other Cannabis Related Problems Among First Year College Students, Addictive Behaviors 33(3):397-411, March 2008; Compton, Dewey & Martin, Cannabis dependence and tolerance production, Advances in Alcohol and Substance Abuse 1990:9:129-147; Miller & Gold, The diagnosis of marijuana cannabis dependence, Journal of Substance Abuse Treatment 1989:6:183-192; Clayton & Leukefeld, The prevention of drug use among youth: implications’ of legalization, Journal of Prevention 1992:12:289-302; Kaplan, Martin, Johnson & Robbins, Escalation of marijuana use: Application of a general theory of deviant behavior, Journal of Health and Social Behavior 1986:27:44-61; “Regular or Heavy Use of Cannabis Was Associated with Increased Risk of Using Other Illicit Drugs” Addiction, 2006; 101:556-569; “As Marijuana Use Rises, More People Are Seeking Treatment for Addiction” -Wall Street Journal, 2 May 2006; “Twenty-Five Year Longitudinal Study Affirms Link Between Marijuana Use and Other Illicit Drug Use” – Congress of the United States,14 March 2006; “New Study Reveals Marijuana is Addictive and Users Who Quit Experience Withdrawal”- All Headline News, 6 February 2007; “Escalation of Drug Use in Early Onset Cannabis Users Vs. Co-twin Controls” – Journal of the American Medical Association, 2003; 289:4
[FN7]  New Report Finds Highest-Ever Levels of THC in US Marijuana, June 12, 2008, http://www.whitehousedrugpolicy.gov/news/press08/061208.html
[FN8] National Highway Traffic Safety Administration, Use of Controlled Substances and Highway Safety; A Report to Congress (U.S. Dept. of Transportation, Washington, D.C., 1988); “White House Drug Czar Launches Campaign to Stop Drugged Driving.” Office of National Drug Control Policy Press Release. 19 November 2002
[FN9] “One-third of Fatally Injured Drivers with Known Test Results Tested Positive for at Least one Drug in 2009.CESARFAX. Vol. 19, Issue 49. December 20, 2010. www.cesar.umd.edu.
[FN10] Ibid.
[FN11] Drug-Impaired Driving by Youth Remains Serious Problem. NIDA News Release, October 29, 2007. http://www.drugabuse.gov/newsroom/07/NR10-29.html.
[FN12] O’Malley, Patrick and Johnston, Lloyd. “Unsafe Driving by High School Seniors: National Trends from 1976 to 2001 in Tickets and Accidents After Use of Alcohol, Marijuana and Other Illegal Drugs.” Journal of Studies on Alcohol. May 2003; The DEA Position On Marijuana, DEA.gov
[FN13] Abbie Crites-Leoni, Medicinal Use of Marijuana: Is the Debate a Smoke Screen for Movement Toward Legalization? 19 J. Legal Med. 273, 280 (1998) (citing Schwartz, et al., Short- Term Memory Impairment in Cannabis-Dependent Adolescents, 143 Am. J. Dis. Child. 1214 (1989))
[FN14] ONDCP, “Marijuana: Know the Facts”, October 2010
[FN15] Soderstrum, C., Trifillis, A., Shankar, B., Clark, W., and Cowley, R. Marijuana and Alcohol Use among 1023 Patients. Archives of Surgery, 123 (June 1988): 733–37; Skolnick, Illicit Drugs take still another toll; death or injury from vehicle-associated trauma, JAMA 1990:263:3122-3125; Soderstrom, Drug involvement among drivers admitted to a regional trauma center, Presented at the Transportation Research Board 70th Annual Meeting (Washington, D.C., Jan. 15, 1991).
[FN16] DuPont, Robert. “National Survey Confirms that Drugged Driving is Significantly More Widespread than Drunk Driving.” Commentary, Institute for Behavior and Health, July 17, 2009. page 1. http://www..ibhinc.org.
Some of this information was borrowed with permission from: Healthy and Free Colorado, affiliated with the Colorado Drug Investigators Association, POB 372394, Denver, CO 80237
WHO’S REALLY IN PRISON FOR MARIJUANA?
Drug legalization advocates claim that prisons are overflowing with people convicted for only simple possession of marijuana. This claim is aggressively pushed by groups seeking to relax or abolish marijuana laws. A more accurate view is that the vast majority of inmates in prison for marijuana have been found guilty of more than simple possession. They were convicted for drug trafficking, or for marijuana possession along with other offences. Many of those in prison for marijuana entered a guilty plea to a marijuana charge to avoid a more serious charge. In the US, just 1.6 percent of the state inmate population were held for offences involving only marijuana, and less than one percent of all state prisoners (0.7 percent) were incarcerated with marijuana possession as the only charge. An even smaller fraction of state prisoners were first time offenders (0.3 percent). The numbers on the US federal prisons are similar. In 2001, the overwhelming majority of offenders sentenced for marijuana crimes were convicted for trafficking and only 63 served time for simple possession. [FN1]
Plea Bargains Distort the Picture
The standard practice in drug cases is for the offender to be given the opportunity to plead guilty in exchange for lighter punishment thus sparing the taxpayers the expense and risk of a trial. If the offender is only charged with one crime, the prosecutor will typically offer a shorter sentence to a lesser charge. If the offender has multiple charges, the common practice is to dismiss one charge in exchange for a guilty plea to another lesser charge, especially if the government feels the offender can provide valuable assistance to law enforcement by providing information on drug trafficking.
Drug legalization advocates claim that nearly one-third of all federal drug defendants are charged with marijuana offences. [FN2] However, only a tiny percentage of that number are actually convicted for marijuana possession. [FN3]
There are a number of circumstances under which a simple-possession marijuana offender might receive a sentence to prison. For example, this may happen if:
1. the marijuana offence was committed while the offender was on probation or parole;
2. an offender charged with a more serious crime pleads guilty to the lesser offence of marijuana possession but as part of a plea bargain is required to serve a prison sentence;
3. the offender has a criminal history, particularly one involving drugs or violent crime;
4. the violation took place in a designated drug-free zone (such as on school property); or
5. the marijuana sentence runs concurrent with the sentence for one or more other offences;
How Much Marijuana Did the Average Offender Possess to Get a Prison Sentence?
According to US Bureau of Justice Statistics estimates based on a survey of federal prisoners, the median amount of marijuana involved in the conviction of marijuana-only possession offenders was 115 pounds. [FN4] This is far more than is needed for personal use.
References
[FN1]  Who’s Really in Prison for Marijuana?, Office of National Drug Control Policy,
www.whitehousedrugpolicy.gov; Substance Abuse and Treatment, State and Federal Prisoners, 1997,” BJS Special Report, January 1999, NCJ 172871; Unpublished BJS estimates based on the 1997 Survey of Inmates in State and Federal Correctional Facilities, National Archive of Criminal Justice Data; Prison and Jail Inmates at Midyear 2002, Bureau of Justice Statistics Bulletin, April 2003, NCJ 198877; Prisoners in 2002, Bureau of Justice Statistics, July 2003, NCJ 200248; Who’s Really in Prison for Marijuana?, Office of National Drug Control Policy, www.whitehousedrugpolicy.gov
[FN2] Pot Violators Comprise Largest Percentage of Federal Drug Offenders, Department of Justice Study Shows, NORML News, August 30, 2001; Who’s Really in Prison for Marijuana?, Office of National Drug Control Policy, www.whitehousedrugpolicy.gov
[FN3] US Sentencing Commission’s 2001 Sourcebook of Federal Sentencing Statistics; Who’s Really in Prison for Marijuana?, Office of National Drug Control Policy, www.whitehousedrugpolicy.gov
[FN4] Who’s Really in Prison for Marijuana?, Office of National Drug Control Policy, www.whitehousedrugpolicy.gov
WE CANNOT LEGALIZE MARIJUANA BECAUSE ITS USE HAS DESTRUCTIVE HEALTH AND SOCIAL CONSEQUENCES.
Most of the arguments in favor of drug legalization focus on marijuana. However, marijuana is far more powerful today than it was years ago and it serves as an entry point for the use of other illegal drugs. This is known as the “gateway effect.” Despite arguments from the drug culture to the contrary, marijuana is addictive. This addiction has been well described in the scientific literature and it consists of both a physical dependence (tolerance and subsequent withdrawal) and a psychological habituation. [FN1]
According to a US report released in June of 2008, the levels of THC – the psychoactive ingredient in marijuana – have reached the highest ever amounts since scientific analysis of the drug began in the late 1970s. The average amount of THC has now reached average levels of 9.6 percent (the highest level in one of the samples was 37.2 percent). This compares to the average of just under 4 percent reported in 1983. Additionally, higher potency marijuana may be contributing to a substantial increase in the number of American teenagers in treatment for marijuana dependence. According to the U.S. 2006 National Survey on Drug Use and Health (NSDUH), among Americans age 12 and older there are 14.8 million current (past-month; 6.0 percent) users of marijuana and 4.2 million Americans (1.7 percent) classified with dependency or abuse of marijuana. Additionally, the latest information from the U.S. Treatment Episode Data Set (TEDS, 2006), reports that 16.1% of drug treatment admissions were for marijuana as the primary drug of abuse. This compares to 6% in 1992. A similar trend is taking place in the Netherlands, where new data indicate that the number of people seeking assistance for cannabis there has risen, from 1,951 in 1994 to 6,544 in 2006 – a 235 percent increase.  [FN2] In 2006, the average THC concentration in Dutch marihuana was 16% which is even higher than that in the US. [FN3]
Marijuana is an addictive drug. It poses significant health consequences to its users, including those who may be using it for “medical” purposes. In the U.S., marijuana is the number one drug that young people are in treatment for. [FN4]
The use of marijuana in early adolescence is particularly dangerous. Adults who used marijuana early were five times more likely to become dependent on any drug and eight times more likely to use cocaine and fifteen times more likely to use heroin later in life.” [FN5]
The damage to health caused by marijuana
Drug legalization advocates claim that marijuana is less dangerous than drugs like cocaine, heroin, and methamphetamine. Some European countries have lowered the classification of marijuana based on the false perception that it is less harmful. However, studies over the last few years give us a lot of new information about marijuana. They show that marijuana is not harmless but that it is toxic and addictive. Recent studies show the following destructive effects of marijuana use: [FN6]
birth defects
      the worsening of pain
      respiratory system damage
      links to cancer
      AIDS – marijuana opens the door to Kaposi’s sarcoma
      brain damage
      strokes
      immune system damage
      mental illness
      violence
      infertility
hepatitis
References
[FN1] http://www.unodc.org/unodc/en/frontpage/why-should-we-care-about-cannabis.html; The Occurrence of Cannabis Use Disorders and Other Cannabis Related Problems Among First Year College Students, Addictive Behaviors 33(3):397-411, March 2008;Compton, Dewey & Martin, Cannabis dependence and tolerance production, Advances in Alcohol and Substance Abuse 1990:9:129-147; Miller & Gold, The diagnosis of marijuana cannabis dependence, Journal of Substance Abuse Treatment 1989:6:183-192; Clayton & Leukefeld, The prevention of drug use among youth: implications’ of legalization, Journal of Prevention 1992:12:289-302; Kaplan, Martin, Johnson & Robbins, Escalation of marijuana use: Application of a general theory of deviant behavior, Journal of Health and Social Behavior 1986:27:44-61; Bailey, Flewelling & Rachal, Predicting continued use of marijuana among adolescents: the relative influence of drug-specific and social context factors, Journal of Health and Social Behavior 1992:33:51-66; “Regular or Heavy Use of Cannabis Was Associated with Increased Risk of Using Other Illicit Drugs” Addiction, 2006; 101:556-569; “As Marijuana Use Rises, More People Are Seeking Treatment for Addiction” -Wall Street Journal, 2 May 2006; “Twenty-Five Year Longitudinal Study Affirms Link Between Marijuana Use and Other Illicit Drug Use” – Congress of the United States,14 March 2006; “New Study Reveals Marijuana is Addictive and Users Who Quit Experience Withdrawal”- All Headline News, 6 February 2007; “Cannabis Withdrawal Among Non-Treatment-Seeking Adult Cannabis Users” -The American Journal on Addiction, 2006; 15:8-14; “Escalation of Drug Use in Early Onset Cannabis Users Vs. Co-twin Controls” – Journal of the American Medical Association, 2003; 289:4
[FN2]  New Report Finds Highest-Ever Levels of THC in US Marijuana, June 12, 2008, http://www.whitehousedrugpolicy.gov/news/press08/061208.html
[FN3] The Netherlands Drug Situation 2007 – National Drug Monitor, European Monitoring Centre for Drugs and Drug Addiction 2008, pgs. 107 and 108
[FN4] Non-medical Marijuana: Rite of Passage or Russian Roulette?” July 1999 obtained at website www.casacolumbia.org; The Occurrence of Cannabis Use Disorders and Other Cannabis Related Problems Among First Year College Students, Addictive Behaviors 33(3):397-411, March 2008.
[FN5] What Americans Need to Know about Marijuana.” Office of National Drug Control Policy. October 2003. Page 9.; The DEA Position On Marijuana, DEA.gov
[FN6]  Birth Defects – Risk of Selected Birth Defects with Prenatal Illicit Drug Use, Hawaii, 1986-2002, Journal of Toxicology and Environmental Health, Part A, 70: 7-18, 2007
Pain – “Too Much Cannabis Worsens Pain” – BBC News, 24 October 2007; “Study Finds that Marijuana Won’t Stop Multiple Sclerosis Pain”- Neurology, 2002; 58:1404-1407
Respiratory System Damage – “Marijuana Associated with Same Respiratory Symptoms as Tobacco,” YALE News Release. 13 January 2005. www.yale.edu/opa/newsr/05-01-13-01.all.htm (14 January 2005); Marijuana Smoke Contains Higher Levels of Certain Toxins Than Tobacco Smoke, Science Daily, December 18, 2007; Marijuana Smokers Face Rapid Lung Destruction – As Much as 20 Years Ahead of Tobacco Smokers, Science Daily, January 27, 2008; “Respiratory and Immunologic Consequences of Marijuana Smoking”- Journal of Clinical Pharmacology, 2002; 42:71S-81S
Cancer – “Association Between Marijuana Use and Transitional Cell Carcinoma”- Adult Urology, 2006; 100-104
AIDS/HIV – “Marijuana Component Opens The Door For Virus That Causes Kaposi’s Sarcoma” -Science Daily, 2 August 2007
Brain Damage – “Neurotoxicology; Neurocognitive Effects of Chronic Marijuana Use Characterized.” Health & Medicine Week. 16 May 2005; “Marijuana May Affect Blood Flow in Brain” – Reuters, 7 February 2005;
Strokes – “More Evidence Ties Marijuana to Stroke Risk” – Reuters Health, 22 February 2005
Immune System Damage – “Immunological Changes Associated with Prolonged Marijuana Smoking” -American College of Allergy, Asthma and Immunology, 17 November 2004
Mental Illness, Schizophrenia, Depression – Kearney, Simon. “Cannabis is Worst Drug for Psychosis.” The Australian. 21 November 2005; Curtis, John. “Study Suggests Marijuana Induces Temporary Schizophrenia-Like Effects.” Yale Medicine. Fall/Winter 2004; “Cannabis-Related Schizophrenia Set to Rise, Say Researchers” – Science Daily, 26 March 2007; “Report: Using Pot May Heighten Risk of Becoming Psychotic” – Associated Press, 26 July 2007; “Marijuana Linked to Schizophrenia, Depression” – British Medical Journal, 21 November 2007; “Anterior Cingulate Grey-Matter Deficits and Cannabis Use in First-Episode Schizophrenia” The British Journal of Psychiatry, 2007; 190: 230-236; Marijuana Increases the Risk of Both Psychosis In Non-Psychotic People As Well As Poor Prognosis For Those With Risk of Vulnerability to Pyschoses” American Journal of Epidemiology, 2002; 156:319-327; Psychophysiological Evidence of Altered Neural Synchronization in Cannabis Use: Relationship to Schizotypy” Am J Psychiatry, 2006; 163:1798-1805
Violence – “Cannabis ‘Linked to Aggression'” – Scotsman.com News, Press Association 2006; “Marijuana Had a Greater Effect on Increasing the Degree of Violent Behavior in Non-Delinquent Individuals Than in Delinquent Individuals” – J Addict. Dis. 2003; 22:63-78
Infertility – “Marijuana Firmly Linked to Infertility” – Scientific American, 22 December 2000
Hepatitis –  Clinical Gastroenterology and  Hepatology 2008, Vol. 6, No.1, pages 69-75, captioned “Influence of Cannabis use on Severity of Hepatitis C Disease”
Filed under: Addiction (Papers),Effects of Drugs (Papers),Medicine and Marijuana :

When we say that someone is “addicted” to a behavior like gambling or eating or playing video games, what does that mean? Are such compulsions really akin to dependencies like drug and alcohol addiction — or is that just loose talk?

This question arose recently after the committee writing the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (D.S.M.), the standard reference work for psychiatric illnesses, announced updated definitions of substance abuse and addiction, including a new category of “behavioral addictions.” At the moment, the only disorder featured in this new category is pathological gambling, but the suggestion is that other behavioral disorders will be added in due course. Internet addiction, for instance, was initially considered for inclusion but was relegated to an appendix (as was sex addiction) pending further research.

Skeptics worry that such broad criteria for addiction will pathologize normal (if bad) behavior and lead to overdiagnosis and overtreatment. Allen J. Frances, a professor of psychiatry and behavioral sciences at Duke University who has worked on the D.S.M., has said that the new definitions amount to “the medicalization of everyday behavior” and will create “false epidemics.” Health insurance companies are fretting that the new diagnostic criteria may cost the health care system hundreds of millions of dollars annually, as addiction diagnoses multiply.

There is always potential for misuse when diagnostic criteria are expanded. But on the key scientific point, the D.S.M.’s critics are wrong. As anyone familiar with the history of the diagnosis of addiction can tell you, the D.S.M.’s changes accurately reflect our evolving understanding of what it means to be an addict.

The concept of addiction has been changing and expanding for centuries. Initially, it wasn’t even a medical notion. In ancient Rome, “addiction” referred to a legal dependency: the bond of slavery that lenders imposed upon delinquent debtors. From the second century A.D. well into the 1800s, “addiction” described a disposition toward any number of obsessive behaviors, like excessive reading and writing or slavish devotion to a hobby. The term often implied a weakness of character or a moral failing.

“Addiction” entered the medical lexicon only in the late 19th century, as a result of the over-prescription of opium and morphine by physicians. Here, the concept of addiction came to include the notion of an exogenous substance taken into the body. Starting in the early 20th century, another key factor in diagnosing addiction was the occurrence of physical withdrawal symptoms upon quitting the substance in question.

This definition of addiction was not always carefully applied (it took years for alcohol and nicotine to be classified as addictive, despite their fitting the bill), nor did it turn out to be accurate. Consider marijuana: in the 1980s, when I was training to become a doctor, marijuana was considered not to be addictive because the smoker rarely developed physical symptoms upon stopping. We now know that for some users marijuana can be terribly addictive, but because clearance of the drug from the body’s fat cells takes weeks (instead of hours or days), physical withdrawal rarely occurs, though psychological withdrawal certainly can.

Accordingly, most doctors have accepted changes to the definition of addiction, but many still maintain that only those people who compulsively consume an exogenous substance can be called addicts. Over the past several decades, however, a burgeoning body of scientific evidence has indicated that an exogenous substance is less important to addiction than is the disease process that the substance triggers in the brain — a process that disrupts the brain’s anatomical structure, chemical messaging system and other mechanisms responsible for governing thoughts and actions.

For example, since the early 1990s, the neuropsychologists Kent C. Berridge and Terry E. Robinson at the University of Michigan have studied the neurotransmitter dopamine, which gives rise to feelings of craving. They have found that when you repeatedly take a substance like cocaine, your dopamine system becomes hyper-responsive, making the drug extremely difficult for the addicted brain to ignore. Though the drug itself plays a crucial role in starting this process, the changes in the brain persist long after an addict goes through withdrawal: drug-using cues and memories continue to elicit cravings even in addicts who have abstained for years.

Furthermore, a team of scientists led by Nora Volkow at the National Institute on Drug Abuse have used positron emission tomography (PET) scans to show that even when cocaine addicts merely watch videos of people using cocaine, dopamine levels increase in the part of their brains associated with habit and learning. Dr. Volkow’s group and other scientists have used PET scans and functional magnetic resonance imaging to demonstrate similar dopamine receptor derangements in the brains of drug addicts, compulsive gamblers and overeaters who are markedly obese.

The conclusion to draw here is that though substances like cocaine are very effective at triggering changes in the brain that lead to addictive behavior and urges, they are not the only possible triggers: just about any deeply pleasurable activity — sex, eating, Internet use — has the potential to become addictive and destructive.

Disease definitions change over time because of new scientific evidence. This is what has happened with addiction. We should embrace the new D.S.M. criteria and attack all the substances and behaviors that inspire addiction with effective therapies and support.

Howard Markel, a physician and a professor of the history of medicine at the University of Michigan, is the author of “An Anatomy of Addiction: Sigmund Freud, William Halsted, and the Miracle Drug Cocaine.”

Source: www.nytimes.com 5th June 2012


Filed under: Addiction,Addiction (Papers),Effects of Drugs (Papers) :

Kouimtsidis C., Reynolds M., Coulton S. et al.
Drugs: Education, Prevention and Policy: 2011, early online publication.
Request reprint using your default e-mail program or write to Dr Kouimtsidis at drckouimtsidis@hotmail.com

Compromised by an inability to interest enough patients, the only randomised UK trial of cognitive-behavioural therapy for methadone patients was unable to be definitive but did find some signs of benefit and that the therapy had pulled some of the intended psychological levers.

Summary Cognitive approaches to treating substance misuse problems are still relatively new and it is important to understand how they work. Relevant treatment models emphasise the role of: self-efficacy to cope with situations associated with drug use without using; developing skills to cope with these situations as well as skills to generate broader lifestyle changes; and changing patients’ expectations of the positives and negatives of using the substance. Successful treatment is theorised to result from a reduction in the extent to which patients expect positive outcomes from substance use, an increase in their negative expectations, and enhanced self-efficacy and coping skills.

The featured study was the first study to directly test this model in the context of substitution treatment for opiate dependence. The findings derive from the UKCBTMM United Kingdom Cognitive Behaviour Therapy Study In Methadone Maintenance Treatment. study, which investigated the effectiveness and cost-effectiveness of cognitive-behavioural therapy for patients in opiate substitute prescribing programmes, itself the first randomised controlled trial of a psychosocial intervention in this setting in the UK.

At several UK treatment centres, the study randomly allocated substitute prescribing patients to keyworking only or keyworking plus cognitive-behavioural therapy, and assessed whether the additional therapy improved outcomes six and 12 months later. Additional therapy was offered weekly for 24 weeks but typically patients attended only four sessions. Therapists and keyworkers were recruited from existing staff and the therapists were trained and supervised in the therapy.

Perhaps because so few patients were eligible for and prepared to join the trial (just 60 did so of 369 who were eligible), though there were outcome gains from the extra therapy, none were statistically significant. Nevertheless, as measured by their effect sizes, A standard way of expressing the magnitude of a difference (eg, between outcomes in control and intervention groups) applicable to most quantitative data. Enables different measures taken in different studies to be compared or (in meta-analyses) combined. Based on expressing the difference in the average outcomes between control and experimental groups as a proportion of how much the outcome varies across both groups. The most common statistic used to quantify this difference is called Cohen’s d. Conventionally this is considered to indicate a small effect when no greater than 0.2, a medium effect when around 0.5, and a large effect when at least 0.8. In the featured study effect sizes were expected to be about 0.3. the gains were as large as expected in terms of reductions in the severity of addiction and heroin use, and improved compliance with prescribed methadone use. The cost of the extra therapy was more than outweighed by savings in health, social, economic, work, and criminal justice costs. Perhaps because patients had already been in methadone treatment for on average five months, these savings were less than in some other studies, and the difference in cost savings between therapy and non-therapy groups was not statistically significant.

Main findings

However, the featured report was less concerned with whether extra cognitive-behavioural therapy improved the end result of methadone treatment, than with how it might have done so. One way was expected to be by improving how well patients coped with life’s problems, a concept measured by a standard questionnaire which assessed different aspects of this ability. Relative to keyworking only, as expected, at six months the therapy was followed by a significant improvement in the degree to which patients positively reappraised problems, and a non-significant improvement in problem solving. Other domains where additional improvements were expected (logical analysis, seeking guidance and seeking alternatives) improved to roughly the same degree regardless of the extra therapy. Six months later (and 12 months after therapy had started) a similar analysis revealed that nearly all the expected mechanisms had improved after cognitive-behavioural therapy but deteriorated without it. The exception was logical analysis, where the reverse pattern was seen. Despite these trends, none of differences between patients who had or had not been offered cognitive-behavioural therapy were statistically significant, so chance variation could not be ruled out.

As expected, the degree to which patients felt confident that they could resist the urge to use drugs (‘self-efficacy’) increased after cognitive-behavioural therapy but decreased (at six months) or increased less (at 12 months) without this therapy. Patients were also asked about the good and bad consequences they expected from cutting down their heroin use. These measures changed in the opposite to what was expected; patients offered the therapy became relatively less positive and more negative about cutting down. Again, none of these differences between the two groups of patients were statistically significant.

Further analyses not reported here assessed changes among only patients who attended at least one session of their intended psychosocial intervention and related changes to the number of therapy sessions attended.

The authors’ conclusions

Though no definite conclusions can be taken from this study, there are indications that the therapy may be effective through at least some of the intended mechanisms, but also that methadone-maintained patients at services as configured in England in the 2000s generally reject the chance for this form of extra therapy.

The fact that few patients were prepared to join the study and that those who did attended few therapy sessions suggest there could be major barriers to implementing cognitive-behavioural therapy in routine practice in the British drug treatment system, perhaps associated with a culture of limited psychological therapy and relatively low expectations of clients’ engagement and compliance with treatment.

With such a small sample there is a heightened possibility that real differences made by the therapy will fail to meet conventional criteria for statistical significance and be mistakenly dismissed as chance variation. That this might have happened is suggested by the fact that the relative increase in days free of heroin use after six months was as great as expected. With a larger sample, it might well have also proved statistically significant. Economic analyses also found non-significant but appreciable net social cost-savings. The featured analysis supplements these outcome findings with indications that cognitive-behavioural therapy may have fostered some but not all of the crucial problem-solving skills.

The main seemingly counter-productive finding related to expectations about the pros and cons of reducing heroin use as measured by a scale yet to be validated. Also, more sessions of therapy did not further enhance the presumed psychological mechanisms through which the therapy worked. Nor were these mechanisms significantly related to substance use and other outcomes – again, perhaps due to the small sample size.

While appreciating the limits set by sample size, the non-significant trends suggesting that the therapy worked though the intended mechanisms were generally small in size. Of 22 comparisons between the two sets of patients, in only one had a mechanism (positively reappraising life’s problems) changed to a statistically significant degree in the expected direction – a result to be expected purely by chance. Together with a few counterproductive trends, these minor changes in the mechanisms thought to be specific to cognitive-behavioural therapy do not suggest it has a special role (that is, over and above other forms of psychological therapy) as a supplement to routine keyworking in the circumstances of the trial. At the same time the findings suggest that extra therapeutic contact did help stabilise patients who were prepared to accept it. Whether this needed to be cognitive-behavioural or a recognised therapy of any kind is impossible to tell from the study. Broader research offers little support for a distinctive role in addiction treatment for cognitive-behavioural approaches, results from which are generally equivalent to other approaches. It also seems that, at least in the mid 2000s, a steep hill remained to be climbed before formal psychological interventions of any kind were routinely and expertly implemented inBritain’s methadone clinics. How far that has changed is unclear. Details below.

CBT in methadone treatment

Guidelines from Britain’s National Institute for Health and Clinical Excellence (NICE) recommend cognitive-behavioural therapy not as a routine means of further stabilising patients, but to help with lingering anxiety and/or depression among those already stabilised in maintenance treatment. However, the analyses which led NICE to counsel against routine use did not show that cognitive-behavioural therapy was ineffective, just that it was not convincingly more effective than other well structured therapies.

Published in 2007, these guidelines did not have available to them the latest update of an authoritative meta-analytic A study which uses recognised procedures to combine quantitative results from several studies of the same or similar interventions to arrive at composite outcome scores. Usually undertaken to allow the intervention’s effectiveness to be assessed with greater confidence than on the basis of the studies taken individually. review conducted for the Cochrane collaboration which combined results from studies comparing structured psychosocial interventions against normal counselling among methadone and other opiate substitution patients. Taking in new studies available up to 2011, it found that overall such interventions had improved neither retention nor outcomes (including opiate use) to a statistically significant degree. In particular, the same was true of the family of behavioural interventions including cognitive-behavioural therapy. Contrary to expectations, this update found contingency management conferred no significant benefits, contradicting both its earlier findings and the NICE guidelines referred to above.

In the Cochrane review, verdicts in respect of cognitive-behavioural therapy rested on three studies, one of which does not appear to have reported substance use outcomes but did find greater improvements in psychological health. Relative to drug counselling alone, so too did a study of male US ex-military personnel starting methadone treatment. A year later, in this study cognitive-behavioural patients had improved more on a much wider range of psychological, social and crime measures, but not in respect of substance use. From methadone plus routine drug counselling only, so complete were the reductions in opiate use that little space was left for additional therapy to further improve outcomes. These two US studies are supplemented by a German study which found that group cognitive-behavioural therapy led to significantly greater post-therapy reductions (at the six-month follow-up) in drug use than routine methadone maintenance alone. The effect was largely due to changes in cocaine use, but there were also minor extra improvements in abstinence from opiate-type drugs and benzodiazepines. What these three studies suggest is that offering extra psychotherapy (not necessarily cognitive-behavioural therapy in particular) improves psychological and social adjustment and perhaps too helps reduce non-opiate substance use, but that methadone maintenance itself as implemented in these studies was such a powerful anti-opiate use intervention that further gains on this front were harder to engineer.

CBT in substance use treatment generally

If in terms of core substance use outcomes, cognitive-behavioural therapy in methadone maintenance does little to improve on routine counselling, this will simply be in line with findings in respect of the therapy’s role in treating drug and alcohol problems in general. A review combining results from relevant studies suggested that it remains to be shown that cognitive-behavioural therapies are more effective than other similarly extensive and coherent approaches. Studies which directly tested this proposition often found little or no difference, even when the competing therapy amounted simply to well structured medical care.

The implication is that choice of therapy can be made on the basis of what makes most sense to patient and therapist, availability, cost, and the therapist’s training. In respect of cost and availability, cognitive-behavioural therapy may (more evidence is needed) prove to have two important advantages. The first is that effects may persist and even amplify without having to continue in therapy. The second is that it lends itself to manualisation to the point where it can be packaged as an interactive computer program and made available in services lacking trained therapists – potentially a crucial advantage for widespread implementation.

Will CBT help methadone patients leave treatment?

Beyond core substance use outcomes is what in Britain is now a priority issue – whether more intensive therapy, even if it seems to add little to the powerful opiate use reduction effect of methadone treatment, might help people gain sufficient psychological and social stability to leave this treatment, and leave it sooner. In respect of psychotherapy in general and cognitive-behavioural therapy in particular, this remains a live possibility with some support from studies of during and post-treatment changes, though none have directly tested whether these enable patients to more safely leave the shelter of substitute prescribing programmes.

However, from the starting point revealed by the featured study, there seems a long way to go before structured psychosocial interventions of any kind are routine in Britain’s methadone services. An earlier report from the study commented that services were overstretched and understaffed and suffered from high staff turnover. Very few staff had been trained in psychological interventions and sometimes even basic individual client keyworking was extremely limited. Difficulties in engaging clients in the study were attributed partly to a low level of psychological interventions in services, which in turn led to low expectations of clients engaging with these interventions. Perhaps too, the authors speculated, some clients were reluctant to become involved in more intensive treatment or to address psychological issues not previously identified in usual clinical care. Most tellingly, the researchers observed “a nihilistic view of psychological intervention and clients’ capacity for change among some staff”.

In this climate, and with the added burden of research procedures, the small proportion of patients prepared to accept therapy and attend more than a few sessions is likely to be an underestimate of the possible caseload if cognitive-behavioural therapy were well promoted as a part of usual care, especially if elements of the approach were incorporated in keyworking rather than offered as an optional add-on.

In a different set of services probably sampled in the mid-2000s, perfunctory brief encounters focused on dose, prescribing and dispensing arrangements, attendance records, and regulatory and disciplinary issues characterised the keyworking service offered by some British criminal justice teams to offenders on opiate substitute prescribing programmes. However, ‘relapse prevention’ was the most common therapeutic activity in the sessions, featuring in 44% of the last sessions recalled by the staff, a term often taken to imply cognitive-behavioural approaches. What staff included under this heading was unclear, and the time given to it averaged just seven minutes, but is does suggest that there is a platform which could be built on. Unfortunately the need to do this building to foster recovery and treatment exit has coincided with resource constraints which make widespread training in and implementation of fully fledged therapy programmes seem unlikely.

Thanks for their comments on this entry in draft to Christos Kouimtsidis of the Herts Partnership NHS Foundation Trust in England. Commentators bear no responsibility for the text including the interpretations and any remaining errors.

Last revised 16 December 2011

Source: www.findings.org.uk

Filed under: Addiction,Addiction (Papers),Education Sector (Papers),Effects of Drugs (Papers),Health,Heroin/Methadone,Treatment,Treatment and Addiction :

 

Research suggests marijuana may be a ‘component cause’ of psychosis

Joseph M. Pierre, MD
Co-Chief, Schizophrenia Treatment Unit, VA West Los Angeles Healthcare Center, Health Sciences Associate Clinical Professor, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA

Over the past 50 years, anecdotal reports linking cannabis sativa (marijuana) and psychosis have been steadily accumulating, giving rise to the notion of “cannabis psychosis.” Despite this historic connection, marijuana often is regarded as a “soft drug” with few harmful effects. However, this benign view is now being revised, along with mounting research demonstrating a clear association between cannabis and psychosis.
In this article, I review evidence on marijuana’s impact on the risk of developing psychotic disorders, as well as the potential contributions of “medical” marijuana and other legally available products containing synthetic cannabinoids to psychosis risk.

CANNABIS USE AND PSYCHOSIS

Cannabis use has a largely deleterious effect on patients with psychotic disorders, and typically is associated with relapse, poor treatment adherence, and worsening psychotic symptoms.1,2 There is, however, evidence that some patients with schizophrenia might benefit from treatment with cannabidiol,3-5 another constituent of marijuana, as well as delta-9-tetrahydrocannabinol (?-9-THC), the principle psychoactive constituent of cannabis.6,7
Three meta-analyses have concluded cannabis use is associated with an increased risk of psychosis

The acute psychotic potential of cannabis has been demonstrated by studies that documented psychotic symptoms (eg, hallucinations, paranoid delusions, derealization) in a dose-dependent manner among healthy volunteers administered ?-9-THC under experimental conditions.8-10 Various cross-sectional epidemiologic studies also have revealed an association between cannabis use and acute or chronic psychosis.11,12
In the absence of definitive evidence from randomized, long-term, placebo-controlled trials, the strongest evidence of a connection between cannabis use and development of a psychotic disorder comes from prospective, longitudinal cohort studies. In the past 15 years, new evidence has emerged from 7 such studies that cumulatively provide strong support for an association between cannabis use as an adolescent or young adult and a greater risk for developing a psychotic disorder such as schizophrenia.13-19 These longitudinal studies surveyed for self-reported cannabis use before psychosis onset and controlled for a variety of potential confounding factors (eg, other drug use and demographic, social, and psychological variables). Three meta-analyses of these and other studies concluded an increased risk of psychosis is associated with cannabis use, with an odds ratio of 1.4 to 2.9 (meaning the risk of developing psychosis with any history of cannabis use is up to 3-fold higher compared with those who did not use cannabis).11,20,21 In addition, this association appears to be dose-related, with increasing amounts of cannabis use linked to greater risk—1 study found an odds ratio of 7 for psychosis among daily cannabis users.16
There are several ways to explain the link between cannabis use and psychosis, and a causal relationship has not yet been firmly established (Table 1).1-7,11-19,21-25 Current evidence supports that cannabis is a “component cause” of chronic psychosis, meaning although neither necessary nor sufficient, cannabis use at a young age increases the likelihood of developing schizophrenia or other psychotic disorders.26 This risk may be greatest for young persons with some psychosis vulnerability (eg, those with attenuated psychotic symptoms).16,18
The overall magnitude of risk appears to be modest, and cannabis use is only 1 of myriad factors that increase the risk of psychosis.27 Furthermore, most cannabis users do not develop psychosis. However, the risk associated with cannabis occurs during a vulnerable time of development and is modifiable. Based on conservative estimates, 8% of emergent schizophrenia cases and 14% of more broadly defined emergent psychosis cases could be prevented if it were possible to eliminate cannabis use among young people.11,26 Therefore, reducing cannabis use among young people vulnerable to psychosis should be a clinical and public health priority

Source: www.currentpsychiatry.com Vol.10 Sept 2011

Filed under: Effects of Drugs (Papers),USA :

 

Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Addiction affects neurotransmission and interactions within reward structures of the brain, including the nucleus accumbens, anterior cingulate cortex, basal forebrain and amygdala, such that motivational hierarchies are altered and addictive behaviors, which may or may not include alcohol and other drug use, supplant healthy, self-care related behaviors. Addiction also affects neurotransmission and interactions between cortical and hippocampal circuits and brain reward structures, such that the memory of previous exposures to rewards (such as food, sex, alcohol and other drugs) leads to a biological and behavioral response to external cues, in turn triggering craving and/or engagement in addictive behaviors.
The neurobiology of addiction encompasses more than the neurochemistry of reward.1 The frontal cortex of the brain and underlying white matter connections between the frontal cortex and circuits of reward, motivation and memory are fundamental in the manifestations of altered impulse control, altered judgment, and the dysfunctional pursuit of rewards (which is often experienced by the affected person as a desire to “be normal”) seen in addiction–despite cumulative adverse consequences experienced from engagement in substance use and other addictive behaviors. The frontal lobes are important in inhibiting impulsivity and in assisting individuals to appropriately delay gratification. When persons with addiction manifest problems in deferring gratification, there is a neurological locus of these problems in the frontal cortex. Frontal lobe morphology, connectivity and functioning are still in the process of maturation during adolescence and young adulthood, and early exposure to substance use is another significant factor in the development of addiction. Many neuroscientists believe that developmental morphology is the basis that makes early-life exposure to substances such an important factor.
Genetic factors account for about half of the likelihood that an individual will develop addiction. Environmental factors interact with the person’s biology and affect the extent to which genetic factors exert their influence. Resiliencies the individual acquires (through parenting or later life experiences) can affect the extent to which genetic predispositions lead to the behavioral and other manifestations of addiction. Culture also plays a role in how addiction becomes actualized in persons with biological vulnerabilities to the development of addiction.
Other factors that can contribute to the appearance of addiction, leading to its characteristic bio-psycho-socio-spiritual manifestations, include:
a. The presence of an underlying biological deficit in the function of reward circuits, such that drugs and behaviors which enhance reward function are preferred and sought as reinforcers;
b. The repeated engagement in drug use or other addictive behaviors, causing neuroadaptation in motivational circuitry leading to impaired control over further drug use or engagement in addictive behaviors;
c. Cognitive and affective distortions, which impair perceptions and compromise the ability to deal with feelings, resulting in significant self-deception;
d. Disruption of healthy social supports and problems in interpersonal relationships which impact the development or impact of resiliencies;
e. Exposure to trauma or stressors that overwhelm an individual’s coping abilities;
f. Distortion in meaning, purpose and values that guide attitudes, thinking and behavior;
g. Distortions in a person’s connection with self, with others and with the transcendent (referred to as God by many, the Higher Power by 12-steps groups, or higher consciousness by others); and
h. The presence of co-occurring psychiatric disorders in persons who engage in substance use or other addictive behaviors.
Addiction is characterized by2:
a. Inability to consistently Abstain;
b. Impairment in Behavioral control;
c. Craving; or increased “hunger” for drugs or rewarding experiences;
d. Diminished recognition of significant problems with one’s behaviors and interpersonal relationships; and
e. A dysfunctional Emotional response.
The power of external cues to trigger craving and drug use, as well as to increase the frequency of engagement in other potentially addictive behaviors, is also a characteristic of addiction, with the hippocampus being important in memory of previous euphoric or dysphoric experiences, and with the amygdala being important in having motivation concentrate on selecting behaviors associated with these past experiences.
Although some believe that the difference between those who have addiction, and those who do not, is the quantity or frequency of alcohol/drug use, engagement in addictive behaviors (such as gambling or spending)3, or exposure to other external rewards (such as food or sex), a characteristic aspect of addiction is the qualitative way in which the individual responds to such exposures, stressors and environmental cues. A particularly pathological aspect of the way that persons with addiction pursue substance use or external rewards is that preoccupation with, obsession with and/or pursuit of rewards (e.g., alcohol and other drug use) persist despite the accumulation of adverse consequences. These manifestations can occur compulsively or impulsively, as a reflection of impaired control.
Persistent risk and/or recurrence of relapse, after periods of abstinence, is another fundamental feature of addiction. This can be triggered by exposure to rewarding substances and behaviors, by exposure to environmental cues to use, and by exposure to emotional stressors that trigger heightened activity in brain stress circuits.4
In addiction there is a significant impairment in executive functioning, which manifests in problems with perception, learning, impulse control, compulsivity, and judgment. People with addiction often manifest a lower readiness to change their dysfunctional behaviors despite mounting concerns expressed by significant others in their lives; and display an apparent lack of appreciation of the magnitude of cumulative problems and complications. The still developing frontal lobes of adolescents may both compound these deficits in executive functioning and predispose youngsters to engage in “high risk” behaviors, including engaging in alcohol or other drug use. The profound drive or craving to use substances or engage in apparently rewarding behaviors, which is seen in many patients with addiction, underscores the compulsive or avolitional aspect of this disease. This is the connection with “powerlessness” over addiction and “unmanageability” of life, as is described in Step 1 of 12 Steps programs.
Addiction is more than a behavioral disorder. Features of addiction include aspects of a person’s behaviors, cognitions, emotions, and interactions with others, including a person’s ability to relate to members of their family, to members of their community, to their own psychological state, and to things that transcend their daily experience.   Behavioral manifestations and complications of addiction, primarily due to impaired control, can include:
a. Excessive use and/or engagement in addictive behaviors, at higher frequencies and/or quantities than the person intended, often associated with a persistent desire for and unsuccessful attempts at behavioral control;
b. Excessive time lost in substance use or recovering from the effects of substance use and/or engagement in addictive behaviors, with significant adverse impact on social and occupational functioning (e.g. the development of interpersonal relationship problems or the neglect of responsibilities at home, school or work);
c. Continued use and/or engagement in addictive behaviors, despite the presence of persistent or recurrent physical or psychological problems which may have been caused or exacerbated by substance use and/or related addictive behaviors;
d. A narrowing of the behavioral repertoire focusing on rewards that are part of addiction; and
e. An apparent lack of ability and/or readiness to take consistent, ameliorative action despite recognition of problems.
Cognitive changes in addiction can include:
a. Preoccupation with substance use;
b. Altered evaluations of the relative benefits and detriments associated with drugs or rewarding behaviors; and
c. The inaccurate belief that problems experienced in one’s life are attributable to other causes rather than being a predictable consequence of addiction.
Emotional changes in addiction can include:
a. Increased anxiety, dysphoria and emotional pain;
b. Increased sensitivity to stressors associated with the recruitment of brain stress systems, such that “things seem more stressful” as a result; and
c. Difficulty in identifying feelings, distinguishing between feelings and the bodily sensations of emotional arousal, and describing feelings to other people (sometimes referred to as alexithymia).
The emotional aspects of addiction are quite complex. Some persons use alcohol or other drugs or pathologically pursue other rewards because they are seeking “positive reinforcement” or the creation of a positive emotional state (“euphoria”). Others pursue substance use or other rewards because they have experienced relief from negative emotional states (“dysphoria”), which constitutes “negative reinforcement.“ Beyond the initial experiences of reward and relief, there is a dysfunctional emotional state present in most cases of addiction that is associated with the persistence of engagement with addictive behaviors. The state of addiction is not the same as the state of intoxication. When anyone experiences mild intoxication through the use of alcohol or other drugs, or when one engages non-pathologically in potentially addictive behaviors such as gambling or eating, one may experience a “high”, felt as a “positive” emotional state associated with increased dopamine and opioid peptide activity in reward circuits. After such an experience, there is a neurochemical rebound, in which the reward function does not simply revert to baseline, but often drops below the original levels. This is usually not consciously perceptible by the individual and is not necessarily associated with functional impairments.
Over time, repeated experiences with substance use or addictive behaviors are not associated with ever increasing reward circuit activity and are not as subjectively rewarding. Once a person experiences withdrawal from drug use or comparable behaviors, there is an anxious, agitated, dysphoric and labile emotional experience, related to suboptimal reward and the recruitment of brain and hormonal stress systems, which is associated with withdrawal from virtually all pharmacological classes of addictive drugs. While tolerance develops to the “high,” tolerance does not develop to the emotional “low” associated with the cycle of intoxication and withdrawal. Thus, in addiction, persons repeatedly attempt to create a “high”–but what they mostly experience is a deeper and deeper “low.” While anyone may “want” to get “high”, those with addiction feel a “need” to use the addictive substance or engage in the addictive behavior in order to try to resolve their dysphoric emotional state or their physiological symptoms of withdrawal. Persons with addiction compulsively use even though it may not make them feel good, in some cases long after the pursuit of “rewards” is not actually pleasurable.5 Although people from any culture may choose to “get high” from one or another activity, it is important to appreciate that addiction is not solely a function of choice. Simply put, addiction is not a desired condition.
As addiction is a chronic disease, periods of relapse, which may interrupt spans of remission, are a common feature of addiction. It is also important to recognize that return to drug use or pathological pursuit of rewards is not inevitable.
Clinical interventions can be quite effective in altering the course of addiction. Close monitoring of the behaviors of the individual and contingency management, sometimes including behavioral consequences for relapse behaviors, can contribute to positive clinical outcomes. Engagement in health promotion activities which promote personal responsibility and accountability, connection with others, and personal growth also contribute to recovery. It is important to recognize that addiction can cause disability or premature death, especially when left untreated or treated inadequately.
The qualitative ways in which the brain and behavior respond to drug exposure and engagement in addictive behaviors are different at later stages of addiction than in earlier stages, indicating progression, which may not be overtly apparent. As is the case with other chronic diseases, the condition must be monitored and managed over time to:
a. Decrease the frequency and intensity of relapses;
b. Sustain periods of remission; and
c. Optimize the person’s level of functioning during periods of remission.
In some cases of addiction, medication management can improve treatment outcomes. In most cases of addiction, the integration of psychosocial rehabilitation and ongoing care with evidence-based pharmacological therapy provides the best results. Chronic disease management is important for minimization of episodes of relapse and their impact. Treatment of addiction saves lives †
Addiction professionals and persons in recovery know the hope that is found in recovery. Recovery is available even to persons who may not at first be able to perceive this hope, especially when the focus is on linking the health consequences to the disease of addiction. As in other health conditions, self-management, with mutual support, is very important in recovery from addiction. Peer support such as that found in various “self-help” activities is beneficial in optimizing health status and functional outcomes in recovery. ‡
Recovery from addiction is best achieved through a combination of self-management, mutual support, and professional care provided by trained and certified professionals.

Source: www.asam.org April 2011

Explanatory footnotes:
1. The neurobiology of reward has been well understood for decades, whereas the neurobiology of addiction is still being explored. Most clinicians have learned of reward pathways including projections from the ventral tegmental area (VTA) of the brain, through the median forebrain bundle (MFB), and terminating in the nucleus accumbens (Nuc Acc), in which dopamine neurons are prominent. Current neuroscience recognizes that the neurocircuitry of reward also involves a rich bi-directional circuitry connecting the nucleus accumbens and the basal forebrain. It is the reward circuitry where reward is registered, and where the most fundamental rewards such as food, hydration, sex, and nurturing exert a strong and life-sustaining influence. Alcohol, nicotine, other drugs and pathological gambling behaviors exert their initial effects by acting on the same reward circuitry that appears in the brain to make food and sex, for example, profoundly reinforcing. Other effects, such as intoxication and emotional euphoria from rewards, derive from activation of the reward circuitry.

While intoxication and withdrawal are well understood through the study of reward circuitry, understanding of addiction requires understanding of a broader network of neural connections involving forebrain as well as midbrain structures. Selection of certain rewards, preoccupation with certain rewards, response to triggers to pursue certain rewards, and motivational drives to use alcohol and other drugs and/or pathologically seek other rewards, involve multiple brain regions outside of reward neurocircuitry itself.
2. These five features are not intended to be used as “diagnostic criteria” for determining if addiction is present or not. Although these characteristic features are widely present in most cases of addiction, regardless of the pharmacology of the substance use seen in addiction or the reward that is pathologically pursued, each feature may not be equally prominent in every case. The diagnosis of addiction requires a comprehensive biological, psychological, social and spiritual assessment by a trained and certified professional.
3. In this document, the term “addictive behaviors” refers to behaviors that are commonly rewarding and are a feature in many cases of addiction. Exposure to these behaviors, just as occurs with exposure to rewarding drugs, is facilitative of the addiction process rather than causative of addiction. The state of brain anatomy and physiology is the underlying variable that is more directly causative of addiction. Thus, in this document, the term “addictive behaviors” does not refer to dysfunctional or socially disapproved behaviors, which can appear in many cases of addiction. Behaviors, such as dishonesty, violation of one’s values or the values of others, criminal acts etc., can be a component of addiction; these are best viewed as complications that result from rather than contribute to addiction.
4. The anatomy (the brain circuitry involved) and the physiology (the neuro-transmitters involved) in these three modes of relapse (drug- or reward-triggered relapse vs. cue-triggered relapse vs. stress-triggered relapse) have been delineated through neuroscience research.  Relapse triggered by exposure to addictive/rewarding drugs, including alcohol, involves the nucleus accumbens and the VTA-MFB-Nuc Acc neural axis (the brain’s mesolimbic dopaminergic “incentive salience circuitry”–see footnote 2 above). Reward-triggered relapse also is mediated by glutamatergic circuits projecting to the nucleus accumbens from the frontal cortex.
Relapse triggered by exposure to conditioned cues from the environment involves glutamate circuits, originating in frontal cortex, insula, hippocampus and amygdala projecting to mesolimbic incentive salience circuitry.
Relapse triggered by exposure to stressful experiences involves brain stress circuits beyond the hypothalamic-pituitary-adrenal axis that is well known as the core of the endocrine stress system. There are two of these relapse-triggering brain stress circuits – one originates in noradrenergic nucleus A2 in the lateral tegmental area of the brain stem and projects to the hypothalamus, nucleus accumbens, frontal cortex, and bed nucleus of the stria terminalis, and uses norepinephrine as its neurotransmitter; the other originates in the central nucleus of the amygdala, projects to the bed nucleus of the stria terminalis and uses corticotrophin-releasing factor (CRF) as its neurotransmitter.
5. Pathologically pursuing reward (mentioned in the Short Version of this definition) thus has multiple components. It is not necessarily the amount of exposure to the reward (e.g., the dosage of a drug) or the frequency or duration of the exposure that is pathological. In addiction, pursuit of rewards persists, despite life problems that accumulate due to addictive behaviors, even when engagement in the behaviors ceases to be pleasurable. Similarly, in earlier stages of addiction, or even before the outward manifestations of addiction have become apparent, substance use or engagement in addictive behaviors can be an attempt to pursue relief from dysphoria; while in later stages of the disease, engagement in addictive behaviors can persist even though the behavior no longer provides relief.

 

Filed under: Addiction (Papers),Effects of Drugs (Papers) :

 Several jurisdictions in the U.S. have taken steps toward decriminalizing marijuana possession for personal use or when prescribed by a physician for medicinal purposes. Other jurisdictions have pending ballot initiatives or legislative bills proposing such changes in the law.
The Board of Directors of the National Association of Drug Court Professionals (NADCP) has determined that it is essential for drug court practitioners to be fully and objectively informed about the effects of marijuana on their participants and the public at-large. This document briefly reviews the scientific evidence concerning the effects of marijuana.

Incarceration for Marijuana Possession

It is exceedingly rare to be incarcerated in the U.S. for the use or possession of marijuana. According to the National Center on Addiction & Substance Abuse at Columbia University (CASA, 2010), less than 1 percent (0.9%) of jail and prison inmates in the U.S. were incarcerated for marijuana possession as their sole offense.
Excluding jail detainees who may be held pending booking or release on bond, the rates are even lower. Prison inmates sentenced for marijuana possession account for 0.7 percent of state prisoners and 0.8 percent of federal prisoners (see Table). And, considering that many of those prisoners pled down from more serious charges, the true incarceration rate for marijuana possession can only be described as negligible.
State Prisoners Federal Prisoners
Marijuana offense only 1.6% N.R.
Marijuana possession only 0.7% 0.8%
First-time marijuana possession 0.3% N.R.

Source: Office of National Drug Control Policy, Who’s Really in Prison for Marijuana? [NCJ #204299] (citing BJS, 1999, Substance abuse and treatment, state and federal prisoners, 1997 [NCJ #172871]; U.S. Sentencing Commission, 2001 Sourcebook of Federal Sentencing Statistics). N.R. = not reported. 2

Addiction Potential

By the early 1990’s, the scientific community had concluded from rigorous laboratory and epidemiological studies that marijuana is physiologically and psychologically addictive. Every drug of abuse has what is called a dependence liability, which refers to the statistical probability that a person who uses that drug for nonmedical purposes will develop a compulsive addiction. Based upon several nationwide epidemiological studies, marijuana’s dependence liability has been reliably determined to be 8 to 10 percent (Anthony et al., 1994; Brook et al., 2008; Budney & Moore, 2002; Kandel et al., 1997; Munsey, 2010; Wagner & Anthony, 2002). This means that one out of every 10 to 12 people who use marijuana will become addicted to the drug.
Importantly, the dependence liability of any drug increases with more frequent usage. Individuals who have used marijuana at least five times have a 20 to 30 percent likelihood of becoming addicted to the drug, and those who use it regularly have a 40 percent likelihood of becoming addicted (Budney & Moore, 2002).
The hallmark feature of physical addiction is the experience of uncomfortable or painful withdrawal symptoms whenever levels of the substance decline in the bloodstream. This is, in part, what drives addicts to continue abusing drugs or alcohol despite suffering severe negative medical, legal and interpersonal consequences. Carefully controlled, rigorous laboratory studies have proven beyond further dispute that marijuana addiction is associated with a clinically significant withdrawal syndrome. When marijuana-addicted individuals stop using the drug, they experience symptoms of irritability, anger, cravings, decreased appetite, insomnia, interpersonal hypersensitivity, yawning and/or fatigue (Budney et al., 2001; Preuss et al., 2010). In fact, the features and severity of the marijuana withdrawal syndrome are virtually indistinguishable from those of nicotine (cigarette) withdrawal.
A second hallmark feature of addiction is psychosocial dysfunction resulting from repeated use of the substance. The most commonly diagnosed symptoms of psychosocial dysfunction among marijuana addicts include persistent procrastination, bad or guilty feelings, low productivity, low self-confidence, interpersonal or family conflicts, memory problems and financial difficulties (Budney & Moore, 2002; NIDA, 2005). This constellation of symptoms has been collectively referred to as an “amotivational syndrome” (e.g., Hubbard et al., 1999) because marijuana abusers tend to be characteristically languid and often achieve considerably below their true intellectual potentials.
Based on this substantial body of empirical research, the American Psychiatric Association (APA) has long recognized cannabis dependence as a valid and reliable psychiatric disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The DSM is the official psychiatric diagnostic classification system in the U.S. A diagnosis of cannabis dependence has been continuously included in the 3rd and 4th editions of the DSM since 1980 (APA, 1980, 1987, 1994, 2000). In the soon-to-be published 5th edition of the DSM, a cannabis withdrawal syndrome will now also be officially recognized as part of the diagnostic criteria for cannabis dependence.

Medical Harm

In many respects, smoked marijuana has the potential to be as, or more, harmful than cigarettes. Although marijuana does not contain nicotine, it does contain 50 to 70 percent more carcinogenic compounds, including tar, than cigarettes (NIDA, 2005; Hubbard et al., 1999). Marijuana also produces high levels of a particular enzyme which converts certain hydrocarbons into their carcinogenic or malignant forms (NIDA, 2005).
Although gram for gram, marijuana smoke is clearly more carcinogenic than cigarette smoke, it is difficult to predict whether actual incidence rates of induced cancers are likely to be as high as they are for cigarettes. On one hand, cannabis smokers tend to use the drug on fewer occasions than cigarette smokers. On the other hand, they typically inhale larger amounts of the drug per occasion, hold the smoke in their lungs for longer intervals of time, and are unlikely to employ filters. This makes it difficult to compare the predicted magnitudes of the harms. The best estimate from the National Institutes of Health (NIH) is that a person who smokes five marijuana cigarettes per week is likely to be inhaling as many cancer-causing chemicals as one who smokes a full pack of cigarettes every day.1
See U.S. Dept. of Justice, Drug Enforcement Administration, Exposing the myth of medical marijuana: The facts. Available at http://www.justice.gov/dea/ongoing/marijuanap.html.
Like nicotine, cannabis increases heart rate, alters blood pressure, can induce tachycardia (rapid or irregular heartbeat), increases myocardial (heart) stress, decreases oxygen levels in the circulatory system, and exacerbates angina (Hubbard et al., 1999). As a result, a person’s risk of a heart attack is increased four-fold during the first hour after smoking marijuana (NIDA, 2005).
There is no question that regular marijuana use is associated with a wide spectrum of chronic respiratory ailments. A nationally representative study of 6,728 adults found heavy marijuana use to be substantially associated with chronic bronchitis, coughing on most days, wheezing, abnormal chest sounds and increased phlegm (Moore et al., 2005).
Marijuana has undisputed negative effects on cognitive functioning, including memory, learning and motor coordination. These negative effects persist long after the period of acute intoxication, averaging approximately 30 days of residual cognitive impairment (Bolla et al., 2002; NIDA, 2005; Pope et al., 2001). This means that individuals are apt to wrongly believe they are capable of performing critical tasks, such as driving a car, operating heavy machinery, caring for children or solving work-related intellectual problems, when in fact they may be performing in the mildly to moderately impaired range of functioning.
Like any drug, marijuana’s negative effects tend to be most pronounced in elderly persons, individuals with chronic medical illnesses, and those with compromised immune systems. This is of particular concern given that marijuana is being specifically touted for “medicinal” use by elderly patients, cancer patients, and those with immunodeficiency syndromes such as HIV/AIDS (e.g., Munsey, 2010). Rather than benefiting such individuals, marijuana has the serious potential to further suppress or compromise their immune systems and exacerbate the disease process (NIDA, 2005).

Medicinal Effects

Marijuana is a “Schedule I” drug according to the Drug Enforcement Administration (DEA), meaning it has a high abuse potential and no recognized medical indication. However, the Food and Drug Administration (FDA) has approved a particular ingredient within marijuana (THC) in a non-smoked form for certain medical indications, such as for treatment of nausea, vomiting and poor appetite. Recent studies have also supported its use in treating chronic neuropathic pain (e.g., Munsey, 2010).
To date, research indicates that oral THC (when administered at adequate doses) is as effective as smoked marijuana in achieving these therapeutic effects (e.g., Munsey, 2010). Anecdotal testimonials are the only evidence favoring smoked marijuana over oral THC for therapeutic purposes. Further research is called for to determine whether other compounds within marijuana might have medicinal properties as well, but at this juncture any such indications are purely experimental and speculative.
Regardless, smoked marijuana could no more be considered a “medication” than cigarettes or alcohol. Although cigarettes and alcohol have undeniable effects that many people may find palliative (such as alleviating short-term stress), they are very “dirty” drugs. This means they contain dozens, if not hundreds, of other physiologically active compounds which are irrelevant to their palliative effects and may actually work at cross-purposes against those effects. For example, many people believe alcohol and nicotine lower their stress level, but in fact these drugs are proven to increase anxiety, lower stress tolerance and exacerbate insomnia over the longer term. These drugs are also associated with a host of serious medical conditions, including cancer, heart disease, liver disease and respiratory illnesses. For these reasons, physicians would rarely, if ever, “prescribe” these drugs to treat a medical condition.
More research is needed to isolate the potential therapeutic effects of specific compounds within marijuana, and to determine how to administer those compounds in a manner that is medically safe and does not threaten to cause heart, lung and other diseases. Administering the “dirty” form of the drug would never be a legitimate medical end-goal.

Impact on Crime

Two recent meta-analyses (advanced statistical procedures) have concluded that marijuana use during adolescence or young adulthood significantly predicts later involvement in criminal activity and criminal arrests (Bennett et al., 2008; Pedersen & Skardhamar, 2010). The risk of criminal involvement was determined to be between 1.5 and 3.0 times greater for cannabis users than for non-users. 5 The results suggest that, all else being equal, cannabis users are at a statistically increased risk for associating with antisocial individuals, engaging in illegal conduct, and eventually getting a criminal record.

Conclusion

Marijuana is an intoxicating and addictive drug that poses serious medical risks akin to those of nicotine and alcohol. Although some physicians may consider it to have palliative indications, no national or regional medical or scientific organization recognizes marijuana as a medicine in its raw or smoked form.
If marijuana becomes decriminalized or legalized in a given jurisdiction, this does not necessarily require drug court practitioners to abide its usage by their participants. The courts have long recognized restrictions on the use of a legal intoxicating substance (i.e., alcohol) to be a reasonable condition of bond or probation where the offender has a history of illicit drug involvement. If there is a rational basis for believing cannabis use could threaten public safety or prevent the offender from returning to court for adjudication, appellate courts are likely to uphold such restrictions in the drug court context.
Individuals who have a valid medical prescription for marijuana present a more challenging issue, but one that is probably also not insurmountable. Under such circumstances, the judge might subpoena the prescribing physician to testify or respond to written inquiries about the medical justification for the prescription. In addition, the court may be authorized by the rules of evidence or rules of criminal procedure to engage an independent medical expert to review the case and offer a medical recommendation or opinion. Having a Board-certified addiction psychiatrist on hand to advise the drug court judge may provide probative evidence about whether a particular marijuana prescription is medically necessary or indicated.
It remains an open question what degree of deference appellate courts are likely to give to the conclusions of a treating physician. In the absence of clear precedent, the best course of action is to develop a factual record and make a particularized decision in each case about the medical necessity for the prescription and the rationale for restricting marijuana usage during the term of criminal justice supervision.
If judges make these decisions based on a reasonable interpretation of medical evidence presented by qualified experts, it seems unlikely that drug courts — which were specifically designed to treat seriously addicted individuals — could not restrict access to an intoxicating and addictive drug as a condition of criminal justice supervision.

About NADCP

It takes innovation, teamwork and strong judicial leadership to achieve success when addressing drug-using offenders in a community. That’s why since 1994 the National Association of Drug Court Professionals (NADCP) has worked tirelessly at the national, state and local level to create and enhance Drug Courts, which use a combination of accountability and treatment to compel and support drug-using offenders to change their lives.
Now an international movement, Drug Courts are the shining example of what works in the justice system. Today, there are over 2,400 Drug Courts operating in the U.S., and another thirteen countries have implemented the model. Drug Courts are widely applied to adult criminal cases, juvenile delinquency and truancy cases, and family court cases involving parents at risk of losing custody of their children due to substance abuse.
Drug Court improves communities by successfully getting offenders clean and sober and stopping drug-related crime, reuniting broken families, intervening with juveniles before they embark on a debilitating life of addiction and crime, and reducing impaired driving.
In the 20 years since the first Drug Court was founded in Miami/Dade County, Florida, more research has been published on the effects of Drug Courts than on virtually all other criminal justice programs combined. The scientific community has put Drug Courts under a microscope and concluded that Drug Courts significantly reduce drug abuse and crime and do so at far less expense than any other justice strategy.
Such success has empowered NADCP to champion new generations of the Drug Court model. These include Veterans Treatment Courts, Reentry Courts, and Mental Health Courts, among others. Veterans Treatment Courts, for example, link critical services and provide the structure needed for veterans who are involved in the justice system due to substance abuse or mental illness to resume life after combat. Reentry Courts assist individuals leaving our nation’s jails and prisons to succeed on probation or parole and avoid a recurrence of drug abuse and
Today, the award-winning NADCP is the premier national membership, training, and advocacy organization for the Drug Court model, representing over 27,000 multi-disciplinary justice professionals and community leaders. NADCP hosts the largest annual training conference on drugs and crime in the nation and provides 130 training and technical assistance events each year through its professional service branches, the National Drug Court Institute, the National Center for DWI Courts and the National Veterans Treatment Court Clearinghouse.

NADCP publishes numerous scholastic and practical publications critical to the growth and fidelity of the Drug Court model and works tirelessly in the media, on Capitol Hill, and in state legislatures to improve the response of the American justice system to substance-abusing and mentally ill offenders through policy, legislation, and appropriations.
For more information please visit us on the web at www.AllRise.org.

Source: National Association of Drug Court Professionals. Sept. 2010

Filed under: Effects of Drugs (Papers),Medicine and Marijuana,Prevention (Papers) :

 

BANGOR, Me. — The mother got the call in the middle of the night: her 3-day-old baby was going through opiate withdrawal in a hospital here and had to start taking methadone, a drug best known for treating heroin addiction, to ease his suffering.
The mother had abused prescription painkillers like OxyContin for the first 12 weeks of her pregnancy, buying them on the street in rural northern Maine, and then tried to quit cold turkey — a dangerous course, doctors say, that could have ended in miscarriage. The baby had seizures in utero as a result, and his mother, Tonya, turned to methadone treatment, with daily doses to keep her cravings and withdrawal symptoms at bay.
As prescription drug abuse ravages communities across the country, doctors are confronting an emerging challenge: newborns dependent on painkillers. While methadone may have saved Tonya’s pregnancy, her son, Matthew, needed to be painstakingly weaned from it. Infants like him may cry excessively and have stiff limbs, tremors, diarrhea and other problems that make their first days of life excruciating. Many have to stay in the hospital for weeks while they are weaned off the drugs, taxing neonatal units and driving the cost of their medical care into the tens of thousands of dollars.
Like the cocaine-exposed babies of the 1980s, those born dependent on prescription opiates — narcotics that contain opium or its derivatives — are entering a world in which little is known about the long-term effects on their development. Few doctors are even willing to treat pregnant opiate addicts, and there is no universally accepted standard of care for their babies, partly because of the difficulty of conducting research on pregnant women and newborns.
Those who do treat pregnant addicts face a jarring ethical quandary: they must weigh whether the harm inflicted by exposing a fetus to powerful drugs, albeit under medical supervision, is justifiable. “I’ve had pharmacies that have just called back and said: ‘This lady’s pregnant. Why do you want me to fill this scrip? I can’t do that,’ ” said Dr. Craig Smith, a family practitioner in Bridgton, Me. “But when you stop and think about what actually happens during withdrawal and how violent it can be, that would certainly be not in the baby’s best interest.”
Still, even doctors who advocate treating pregnant addicts have had moments of doubt. “At first I was going, ‘Gosh, what am I doing?’ ” said Dr. Thomas Meek, a primary care physician in Auburn, Me. “ ‘Am I really helping these people?’ ”
There are no national figures that document the extent of the problem, but interviews with doctors, researchers, social workers and women who abused painkillers while pregnant suggest that it has grown rapidly, especially in rural regions, where officials say such abuse is most common.
In Maine, which has been especially plagued by prescription drug abuse, the number of newborns treated or watched for opiate withdrawal, known as neonatal abstinence syndrome, at the state’s two largest hospitals climbed to 276 in 2010 from about 70 in 2005. Hospitals in states including Florida and Ohio reported similar increases, and experts said the numbers were probably higher since pregnant women are rarely tested for drug use and many mothers do not admit to abusing opiates.
Tonya, 24, said she was introduced to painkillers like OxyContin, Percocet and Vicodin while working the overnight shift at an industrial bakery an hour from her home. Everyone — including co-workers, the boyfriend she met on the job and their manager — was taking pills, she said. “It was a lot easier to get through life and have energy,” Tonya said at Eastern Maine Medical Center here in January, holding Matthew a month after his birth. He was still being weaned off methadone.
Before she was pregnant, Tonya said, she quickly became addicted, spending all of her money on pills bought on the street. She and her boyfriend, Josh, needed to stave off withdrawal and get through the day, she said. Now that she is in treatment, Tonya, who like most mothers interviewed for this article did not want her last name used, said her focus was on Matthew. “We put him in this situation,” she said, “and we have to help him out of it.”
‘How Little We Know’

Rigorous studies on treating infant withdrawal are scarce, and the American Academy of Pediatrics has not published guidelines since 1998. “It’s really remarkable how little we know about the effect of prescription drugs and even nonprescription drugs on the fetus,” said Dr. Nora D. Volkow, director of the National Institute for Drug Abuse. “There are real roadblocks in terms of helping us advance the field.”
Dr. Mark L. Hudak, a neonatologist in Jacksonville, Fla., is helping to revise the pediatrics academy’s guidelines. “There are commonalities, but it’s not like you can go to a Web site that says, ‘This is what should be used by everyone,’ ” Dr. Hudak said. “No one knows what the best approach is.”
Within states, every hospital that delivers babies exposed to painkillers may have its own approach. Eastern Maine treats affected newborns with tiny doses of methadone, while Maine Medical Center in Portland uses morphine combined with phenobarbital, a barbiturate that prevents seizures. Some hospitals are also experimenting with clonidine, a mild sedative that can relieve withdrawal symptoms.
There is growing debate over treatment for pregnant women addicted to prescription drugs, in light of concerns over the effects on their babies. Many are slowly weaned from their dependence with methadone, the standard of care for decades. Methadone, when taken in prescribed doses, keeps a steady amount of opiate in the body, preventing withdrawal and drug cravings that occur when levels dip. But it, too, can be addictive and cause nagging side effects like drowsiness. And for addiction treatment, it can be obtained only at federally licensed clinics where most users have to report for a daily dose.
A growing number of addicts are instead taking buprenorphine, another drug used to treat addiction that some studies suggest staves off drug cravings as effectively as methadone but is less likely to cause withdrawal in newborns. In rural areas of the nation, where methadone clinics are few, buprenorphine is considered a promising alternative because it can be prescribed by primary care doctors and taken at home. But buprenorphine also appears not to work for some addicts.
Still, a study published in December in The New England Journal of Medicine showed that babies whose mothers had taken buprenorphine required significantly less medication after birth and less time in the hospital than did babies whose mothers were treated with methadone. But researchers cautioned that exposure to buprenorphine in utero can still cause withdrawal symptoms and that further study was needed. “We don’t want it misconstrued that buprenorphine is a miracle drug,” said Hendrée E. Jones, a Johns Hopkins University researcher and the study’s lead author.
Even less is known about longer-term effects on babies exposed to painkillers, though in a second leg of their study, Dr. Jones and her fellow researchers plan to follow the 131 babies in the cohort until they turn 3. A recent study by the Centers for Disease Control and Prevention found that babies exposed to opiates in utero, in this case legally prescribed painkillers, had slightly higher rates of birth defects, including congenital heart defects, glaucoma and spina bifida.
Experts say that since many drug users also smoke and abuse alcohol, not to mention that they face extenuating circumstances like poverty, it is difficult to tease out the effects of each substance on their offspring. “Most of the literature suggests consistently that the drug exposure itself is not the primary concern,” said Karol Kaltenbach, a professor at Jefferson Medical College in Philadelphia who studies addiction in pregnant women. “It’s the cumulative effect of the drug-using lifestyle — poverty, chaos in the home, domestic violence. All those things affect development.”
Not all newborns exposed to opiates have severe enough withdrawal to need medicine; at Maine Medical Center since 2003, about 55 percent of babies exposed to buprenorphine and 80 percent of those exposed to methadone have needed treatment. But it is hard to predict which ones will need it: a newborn whose mother was on a high dose of either drug might need none, while a baby whose mother took a low dose might experience acute withdrawal. Babies known to have been exposed to drugs are often kept in the hospital for at least five days because withdrawal symptoms usually do not set in immediately. Nurses examine them for a checklist of symptoms every few hours, assigning each baby a score that, if high enough, calls for treatment.
“They don’t stop crying, they can’t settle down, they don’t relax,” said Geraldine Tamborelli, nursing director of the birthing unit at Maine Medical Center, which in 2010 diagnosed opiate withdrawal in 121 newborns. “They’re struggling in your arms instead of snuggling into you like a baby that is totally fine.”
In the neonatal intensive care unit at Eastern Maine, Kendra, 3 days old, was sleeping in a dark, silent room one morning, away from the bustle and bright lights that can be especially irritating to babies going through withdrawal. Nurses frequently crept in to observe her, though, and by the afternoon her limbs had stiffened and she was crying excessively and having tremors; it was enough to begin treatment. “This seems to be ramping up fairly quickly for her,” said Dr. Mark Brown, the hospital’s chief of pediatrics, “so the decision was to start treatment more quickly.”
On the pediatric ward, Matthew started fussing while his mother, Tonya, talked to reporters that afternoon in January; his cry had a strange, reedy pitch that nurses say is common to babies with his condition. The small dose of methadone he had received gave him gas and heartburn, for which he was given two stomach medications. He also was on clonazepam, a muscle relaxant and anti-anxiety drug that helped him metabolize the methadone more slowly.
Tonya said that at first she “didn’t believe in” methadone treatment during pregnancy and that doctors had to persuade her that it would not hurt her fetus. She had experienced wrenching withdrawal when she stopped using painkillers after learning she was pregnant, she said, and the doctors had warned her that “when I was feeling that bad, he was feeling 1,000 times worse.” Tonya said that in a previous pregnancy, she quit using drugs altogether and miscarried a month later. “That was the last thing I wanted to happen this time,” she said.
Avoiding Addicts, and Liability
Treating drug-dependent mothers and babies is often lonely work, with little communication among the doctors who take it on. As Dr. Brown said, “My network for people who do this is really very small.”
Dr. Mark R. Publicker, an addiction medicine specialist at Mercy Recovery Center in Westbrook, Me., is on a mission to get more of the state’s doctors to treat pregnant prescription drug abusers and more hospitals to deliver their babies. Only a handful of doctors here treat pregnant women with buprenorphine, Dr. Publicker said, partly because they fear liability and do not want to deal with addicts. The fact that most hospitals will not deliver the babies makes doctors even less likely to treat the women. “It’s mostly ignorance,” Dr. Publicker said. “It’s a concern that it’s a risky proposition and that they’re going to wind up with an ill baby.”
In February, Dr. Smith persuaded Bridgton Hospital, which has only 25 beds, to deliver the babies of women on buprenorphine — a major victory, he said, because until then women in rural southwestern Maine had to drive an hour or more to Maine Medical to deliver. Courtney, a patient of Dr. Smith’s who discovered she was pregnant while in jail for stealing OxyContin from her landlord, said buprenorphine treatment seemed the best of her bleak options. “I just don’t want to mess up,” she said.
Tonya, too, said she was determined to make things right for Matthew, who was five weeks old when she took him home to a trailer outside Bangor. He is off the methadone now and appears healthy, but Tonya still has to go to a methadone clinic in Bangor every day for her dose and resist the pressures to return to illicit drug use. Her boyfriend began using opiates as a young teenager, she said, and his father and grandmother abused OxyContin along with him. “I’m proud that I changed my life,” Tonya said. “But at the same time, when you see your child in pain and you know your child is in pain because of a life decision you made, it’s the hardest thing in the world.”

Source: New York Times April 9th 2011

Filed under: Effects of Drugs (Papers),Social Affairs (Papers) :

Are young smokers risking cognitive impairment as adults? Call it “nicolescence.” It’s that time of life when certain 18-and-unders discover cigarettes. Most adult smokers begin their habit before the age of 19, and a majority of adolescents have tried cigarettes at least once. But for some of them—those who were “born to smoke,” in a sense—early exposure to nicotine may influence adolescent cognitive performance in ways that adult exposure to nicotine does not. Furthermore, early exposure may result in “cognitive impairments in later life.”

These provocative notions are raised by a group of researchers at VU University, Amsterdam, The Netherlands, in a paper for Nature Neuroscience. And while the specifics of glutamate activity they have documented are fascinating, the leaps back and forth between adolescent humans and adolescent lab mice are dizzying. Nonetheless, the bold claims made in the paper prompted the scientists “to reconsider our views on the etiology of attention deficits.”

That may be more than many addiction researchers are willing to countenance, but the study makes an intriguing case for long-term effects on attentional processing. The Dutch researchers exposed adolescent rats to nicotine, assessed visuospatial attention and other markers associated with synaptic activity in the prefrontal cortex, and found impaired measures of attention and signs of increased impulsivity in adulthood after five weeks of abstinence. Adult rats exposed to nicotine for the first time did not show similar long-term consequences.

The molecular underpinnings for this phenomenon appear to be reduced glutamate receptor protein levels in the prefrontal cortex. Glutamate is a neurotransmitter involved in attention, among other cortical tasks. Glutamate levels were “altered specifically by adolescent and not adult nicotine exposure” in the lab animals, the researchers found.

The glutamate receptor mGluR2 is the likely culprit. The researchers report that “a lasting downregulation of mGluR2 on presynaptic terminals of glutamatergic synapses in the prefrontal cortex persists into adulthood causing disturbances in attention…. Restoring mGluR2 activity in vivo in the prefrontal cortex of adult rats exposed to nicotine during adolescence remediated the attention deficit.”

The study concludes: “Not only from a behavioral, but also from a molecular point of view, the adolescent brain is more susceptible to consequences of nicotinic receptor activation.” In other words, there is at least some evidence that the neurotoxic effects of nicotine are potentially more severe in the early developmental stage called adolescence.

The Dutch study is not the only one of its kind. In 2005, Biological Psychiatry published a report on cognition in which adolescent smokers “were found to have impairments in accuracy of working memory performance irrespective of recency of smoking. Performance decrements were more severe with earlier age of onset of smoking.”

And a 2007 study published in Neuropsychopharmocology, based on testing and fMRI scans of 181 male and female adolescent smokers, concluded that “in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention…” Boys were more sensitive than girls to attention deficits involving auditory processing, while girls tended to show equal deficits in both auditory and visual attention tasks.

Counotte, D., Goriounova, N., Li, K., Loos, M., van der Schors, R., Schetters, D., Schoffelmeer, A., Smit, A., Mansvelder, H., Pattij, T., & Spijker, S. (2011). Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence Nature Neuroscience DOI: 10.1038/nn.2770

Source: http://addiction-dirkh.blogspot.com/2011/02/smoking-and-adolescent-attention.html 24th Feb 2011

Filed under: Effects of Drugs (Papers) :

Risk appears to be elevated particularly among frequent and/or long-term users.

SEATTLE — February 9 — Frequent and/or long-term marijuana use may significantly increase a man’s risk of developing the most aggressive type of testicular cancer, according to a study by researchers at Fred Hutchinson Cancer Research Center. The study results were published online Feb. 9 in the journal Cancer.
The researchers found that being a marijuana smoker at the time of diagnosis was associated with a 70 percent increased risk of testicular cancer. The risk was particularly elevated (about twice that of those who never smoked marijuana) for those who used marijuana at least weekly and/or who had long-term exposure to the substance beginning in adolescence. The results also suggested that the association with marijuana use might be limited to nonseminoma, a fast-growing testicular malignancy that tends to strike early, between ages 20 and 35, and accounts for about 40 percent of all testicular-cancer cases.
Since the 1950s, the incidence of the two main cellular subtypes of testicular cancer, nonseminoma and seminoma – the more common, slower growing kind that strikes men in their 30s and 40s – has increased by 3 percent to 6 percent per year in the U.S., Canada, Europe, Australia and New Zealand. During the same time period, marijuana use in North America, Europe and Australia has risen accordingly, which is one of several factors that led the researchers to hypothesize a potential association.
“Our study is not the first to suggest that some aspect of a man’s lifestyle or environment is a risk factor for testicular cancer, but it is the first that has looked at marijuana use,” said author Stephen M. Schwartz, M.P.H., Ph.D., an epidemiologist and member of the Public Health Sciences Division at the Hutchinson Center. Established risk factors for testicular cancer include a family history of the disease, undescended testes and abnormal testicular development. The disease is thought to begin in the womb, when some fetal germ cells (those that eventually make sperm in adulthood) fail to develop properly and become vulnerable to malignancy. Later, during adolescence and adulthood, it is thought that exposure to male sex hormones coaxes these cells to become cancerous.
“Just as the changing hormonal environment of adolescence and adulthood can trigger undifferentiated fetal germ cells to become cancerous, it has been suggested that puberty is a ‘window of opportunity’ during which lifestyle or environmental factors also can increase the risk of testicular cancer,” said senior author Janet R. Daling, Ph.D., an epidemiologist who is also a member of the Center’s Public Health Sciences Division. “This is consistent with the study’s findings that the elevated risk of nonseminoma-type testicular cancer in particular was associated with marijuana use prior to age 18.”
Chronic marijuana exposure has multiple adverse effects on the endocrine and reproductive systems, primarily decreased sperm quality. Other possible effects include decreased testosterone and male impotency. Because male infertility and poor semen quality also have been linked to an increased risk of testicular cancer, this further reinforced the researchers’ hypothesis that marijuana use may be a risk factor for the disease.
Daling first got the idea to explore a possible association between marijuana use and testicular cancer about eight years ago, when she attended a talk by a physician at the University of Washington who presented findings that only two organs, the brain and the testes, had receptors for tetrahydrocannabinol, or THC, the main psychoactive component of marijuana. Since then, a number of other sites have been found to contain THC receptors, including the heart, uterus, spleen and immune-system cells. The male reproductive system also naturally produces a cannabinoid-like chemical that is thought to have a protective effect against cancer. The authors speculate that marijuana use may disrupt this anti-tumor effect, which could be another explanation for the possible link between marijuana and increased risk of testicular cancer.
For the population-based, case-control study, Daling, Schwartz and colleagues interviewed 369 Seattle-Puget Sound-area men, ages 18 to 44, who had been diagnosed with testicular cancer about their history of marijuana use. For comparison purposes they also assessed marijuana use among 979 randomly selected age- and geography-matched healthy controls. (More than 90 percent of the cases and 80 percent of the controls in the study were Hispanic or non-Hispanic white men, due to the fact that testicular cancer is very rare in African-Americans, and because the Seattle-Puget Sound region has a relatively small African-American population.)
Study participants were also asked about other habits that may be correlated with marijuana use, including smoking and alcohol consumption. Even after statistically controlling for these lifestyle factors, as well as other risk factors, such as first-degree family history of testicular cancer and a history of undescended testes, marijuana use emerged as a significant, independent risk factor for testicular cancer. The researchers emphasize that their results are not definitive, but rather open a door to more research questions.
“Our study is the first inkling that marijuana use may be associated with testicular cancer, and we still have a lot of unanswered questions,” Schwartz said, such as why marijuana appears to be associated with only one type of testicular cancer. “We need to conduct additional research to see whether the association can be observed in other populations, and whether measurement of molecular markers connected to the pathways through which marijuana could influence testicular cancer development helps clarify any association that exists,” he said.
In future studies the researchers plan to measure the expression of cannabinoid receptors in both seminomatous and nonseminomatous tumor tissue from the cases in the study, and to see whether variation in the genes for the receptors and other molecules involved in cannabinoid signaling influences the risk of testicular cancer. In the meantime, Schwartz said, “What young men should know is that first, we know very little about the long-term health consequences of marijuana smoking, especially heavy marijuana smoking; and second, our study provides some evidence that testicular cancer could be one adverse consequence,” he said. “So, in the absence of more certain information, a decision to smoke marijuana recreationally means that one is taking a chance on one’s future health.”
The National Cancer Institute, the National Institute on Drug Abuse and funds from the Hutchinson Center supported this research, which also involved researchers from the University of Washington, Vanderbilt University and Cincinnati Children’s Research Foundation. According to the National Cancer Institute, testicular cancer is very rare, accounting for only 1 percent of cancers in U.S. men. About 8,000 men are diagnosed with testicular cancer each year, and about 390 die of the disease annually. It is the most common form of cancer in men between the ages of 15 and 34 and is most common in white men, especially those of Scandinavian descent.

Source: journal Cancer. online Feb. 9 2011 Association of Marijuana Use and the Incidence of Testicular Germ Cell Tumors,”

Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N. PO Box 19024 Seattle, WA 98109

Filed under: Effects of Drugs (Papers) :

“The science is finally in on the link between cannabis use and early onset psychosis. New Australian research has provided the first conclusive evidence that smoking cannabis hastens the appearance of
psychotic illnesses by up to three years….The risks are especially high for young people whose brains are still developing.”

So were the opening lines of ABC Radios Tony Eastley’s AM report on the latest Australian research into Cannabis and psychosis. The study was carried out on an incredibly large sample group and drew on research from scores of international studies.
However, will this report, one in a long line of scientific and ‘evidence based’ papers, actually be embraced or will it be swept away (as many others have) by the relentless and often unchecked rhetoric of the shameless pro-drug lobby and their spin ‘doctors’? One of the most manipulative terms used in the pro-legalisation platform is ‘evidence based science’
and of course such ‘science’ is rarely geared to the detrimental social, familial or long term physical or mental health of individuals; no, it is aimed at trying to convince the understandably unaware public, that drug use and particularly cannabis use, isn’t a problem. It is posited by such peddlers that only ‘problematic drug use’ that may be the problem and that ‘science’ is there to help us manage the problem, not prevent it.

These most recent findings are by no means new. In recent years Professor Jim van Os and his team at the Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network in the Netherlands in another significant study into cannabis and youth psychosis concluded the following…
“Cannabis use … increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of predisposition for psychosis.”2
The publishing on line in the last few days, of findings from researchers at NSW Prince of Wales hospital concluded that:

The results of meta-analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis.3

Yet again, this is not new, other previous and standing research as also found…
It has also been argued that 27% of the population carry a high risk genetic variant which produces a weaker Catechol-O-Methyl Transferase (COMT) enzyme which is responsible for the breakdown of dopamine in the brain…those cannabis users with weaker COMT enzyme are at 10 times greater risk of developing psychosis and,
later in life, of developing schizophrenia…the greater the amount of cannabis consumed correlates to a higher degree of risk of psychosis4

The potential damage of this cannabis induced psychosis was no more apparent than in the recent Tucson massacre at the hands of Jared Lee Loughner. In a commentary from the Institute for Behaviour and Health titled Marijuana, Schizophrenia
and Jared Loughner the following was revealed….
‘Overlooked by most commentators is Loughner’s history of heavy marijuana and alcohol use… Loughner has a serious mental disorder, probably paranoid schizophrenia…One important message that must be heard amidst the chatter over this tragedy is that marijuana is not a harmless recreational drug. The sale and use of marijuana is often trivialized, or even glamorized. Marijuana use is neither trivial nor glamorous. Marijuana use is linked to addiction, to dropping out of high school, to lower educational attainment, to other substance use, and to mental illness. Marijuana use doubles the risk and hastens the onset of schizophrenia. Once schizophrenia emerges, marijuana use adversely impacts the course of the disease. Schizophrenics are about twice as likely to smoke marijuana as individuals without this mental disorder. Marijuana use not only makes the symptoms of this disease
worse, but it reduces the effectiveness of treatments for schizophrenia. Marijuana use predicts an increase in the severity of psychotic symptoms.5

These evidences should be enough in and of themselves to renew efforts to diminish and not promote this pernicious substance, but this is only one of the health risks that Cannabis presents. What is important to note is that this illicit substance, touted as harmless to ‘most’ couldn’t be further from that, and its impact is not
restricted to mental health arena, but can and does inflict serious harm to users as the following outlines…

There is evidence of psychiatric, respiratory, cardiovascular, and bone toxicity associated with chronic cannabis use. Cannabis has now been implicated in the etiology of many major long-term psychiatric conditions including depression, anxiety, psychosis, bipolar disorder, and an amotivational state. Respiratory conditions linked with cannabis include reduced lung density, lung cysts, and chronic bronchitis.
Cannabis has been linked in a dose-dependent manner with elevated rates of myocardial infarction and cardiac arrhythmias. It is known to affect bone metabolism and also has teratogenic effects on the developing brain following perinatal exposure. Cannabis has been linked to cancers at eight sites, including children after in utero
maternal exposure, and multiple molecular pathways to oncogenesis exist.

Conclusion
Chronic cannabis use is associated with psychiatric, respiratory, cardiovascular, and bone effects. It also has oncogenic, teratogenic, and mutagenic effects all of which depend upon dose and duration of use.6

It is time that responsible and health conscious Australians, particularly policy formulators and legislators take head to the scientific evidence that refutes the manipulative rhetoric of a few, if not malevolent, then staggeringly naïve activists; those who seek only to promote the ‘rights’ of a dysfunctional minority at the expense of the mental, social and physical
health of an entire generation. It’s time to prevent, not promote!

Source: www.dalgarnoinstitute.org.au www.nobrainer.org.au Feb.2011

Endnotes
1 http://www.abc.net.au/am/content/2011/s3132596.htm 2/8/2011
2 Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people Cécile Henquet, Lydia
Krabbendam, Janneke Spauwen, Charles Kaplan, Roselind Lieb, Hans-Ulrich Wittchen, Jim van Os (Paper for BMJ Online First bmj.com)
3 Cannabis Use and Earlier Onset of Psychosis A Systematic Meta-analysis Matthew Large, BSc(Med), MBBS, FRANZCP; Swapnil Sharma, MBBS,
FRANZCP; Michael T. Compton, MD, MPH; Tim Slade, PhD; Olav Nielssen, MBBS, MCrim, FRANZCP Arch Gen Psychiatry. Published online February 7,
2011. doi:10.1001/archgenpsychiatry.2011.5
4”Cannabis – suicide, schizophrenia and other ill effects: a research paper on the consequences of acute and chronic cannabis use.” Drug Free Australia March 2009
5 Marijuana, Schizophrenia and Jared Loughner – Commentary; Institute for Behaviour and Health (Jan 2011)
6 ‘Chronic toxicology of cannabis Dr. ALBERT STUART REECE Medical School, University of Queensland, Highgate Hill, Brisbane, QLD, Australia –
Clinical Toxicology (2009) 47, 517–524 Copyright © Informa UK, Ltd. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.1080/15563650903074507
LCLT REVIEW Cannabis toxicology (taken from Introduction summary)

Filed under: Effects of Drugs (Papers) :

Special Report

The young wrestler was sitting on the kitchen floor, his bloody face illuminated by the early-morning light that streamed through a nearby window. In other parts of the world, the shadow of the moon was edging across the rising sun, marking the beginning of a dramatic and well-publicized total eclipse. Will Hollingsworth had talked of little else for the past four days: the last eclipse of the millennium and the apocalypse some believed would follow. He had not slept in more than 100 hours, holed up in his room, paging restlessly through a Bible, his television tuned to news of the eclipse. It was a peculiar obsession for a 20-year-old college student who spent most of his time training to be a world-class athlete. Will didn’t appear intoxicated. To the contrary, he was alert, engaging and philosophical, though strangely fixated on current events.

Now this.

On any other day, he would have been out the door — running for miles along eastern Hillsborough County’s busiest roads, pumping iron at the gym, working out with his old high school wrestling team.

But on this August morning in 1999, there was only the inexplicable blood and the vacant stare that greeted me when I came to make breakfast. “What happened?” I asked my only son. “I’ve been fighting demons,” he replied.

Demons?

“It’s true,” he insisted, gesturing to his bloody face and filthy shirt. “I’ve been fighting demons all night. And I won.”

I followed his gaze through the window into the back yard. There, the torn sod and blood-stained patio marked the spot where he had pounded his face into the ground as his father and I slept, oblivious to the war we were about to wage with an invisible enemy. Will would battle his demons for the next three years. But he would never exorcise them. GHB already had laid claim to his sanity, and there was no one who could tell us how to retrieve it.

Dying To Win

Trinka Porrata is all too familiar with the phenomenon of young men who speak of mortal conflict with demons — men who pound their heads on concrete as they experience the unique and little-known psychosis that accompanies GHB withdrawal. “I can’t tell you how many times I’ve heard about that,” said the retired Los Angeles narcotics detective. “Some of them try to put their heads through plate-glass windows.” Some succeed.

Porrata, founder of Project GHB, has spent seven years throwing a lifeline into cyberspace for addicts desperate to escape the grip of a nutritional supplement promoted as a safe, non-habit-forming sleep aid that claimed to build lean muscle mass. Most have been athletes or bodybuilders, but GHB use cuts across all demographics. “It’s the most unique drug,” she said. “We have a lot of senior citizens hooked on it thinking it’s antiaging. It’s big in the gay community, big in the gym scene, big in the club scene. Yet it’s invisible.”

Porrata said she has had more than 1,800 inquiries from GHB users and their family members since Project GHB went online in December 1999. “We were getting: ‘I thought I was the only person in the world with this problem,’” she said.

Before the debut of Project GHB, anyone looking for information on the chemical discovered a nest of Internet sites featuring glowing testimonials, mail-order supplies and recipes for cooking it at home. Central Florida, with its fitness culture, was a watershed for the craze during the 1990s, before GHB-related products were outlawed.

Tampa had its own cottage industry in the form of Body Life Sciences, a now-defunct company that produced and marketed the supplement under the brand names Revivarant and Revivarant G. GHB seemed to offer something for everyone, depending on the dosage: sedation, exhilaration, sexual stimulation, weight loss and the unsubstantiated promise of massive muscles. It was readily available at health food stores and gyms, where it entered the marketplace as an ostensibly safe, legal alternative to steroids.

In recent years, its ability to induce mild euphoria and amnesia attracted a new kind of customer who employed it as a party drug associated with overdoses and sexual assaults. GHB’s link to “date rapes” and all-night raves quickly overshadowed its widespread use in the athletic community. Yet it is the athletes and bodybuilders, who incorporate it into a daily regimen, who are most at risk of becoming addicted.

“It’s really the frequency of the dose as opposed to the amount of the dose that leads to this very striking psychosis,” said David Kershaw, a psychologist for Hillsborough County’s Mobile Crisis Unit. Kershaw has seen his share of GHB addicts in withdrawal — beginning in late 1999, when the county’s mental health center saw a rash of cases involving muscular young men suffering from hallucinations and paranoia.

One believed he had an invisible tape recorder fastened to his leg. Another saw a swarm of flies covering his body. All were regular users of GHB. “The irony is that despite the fact that they wouldn’t deliberately pollute their bodies like that, they get sucked into using it,” Kershaw said. “The people I see are all athletes, all concerned with being as healthy as they can be.”

One of them was Will.

The Runner Stumbles

Will’s descent into madness was swift and seemingly irreversible.

The first sign that something was amiss came one night in the spring of 1999, when he called to ask his father to come help him change a flat tire. It turned out the tire was flat because Will had drifted off an exit ramp on Interstate 75 and into a tree. Weeks later, another late-night call — this one from an ex-girlfriend, who said she had received an urgent message from Will asking her to pick him up at a gas station near the University of South Florida.

When she arrived, she found the car, with the engine still running, the driver’s door ajar, but no sign of Will. He turned up at another nearby gas station — incoherent, with no memory of how he got there. His father and I were mystified. Will seemed as bewildered as we were. “I keep making mistakes, and I don’t know why,” he said.

He never made the connection between the potion he bought at the local health food store and the bizarre things that happened when he stopped using it. We didn’t know he was using GHB. There were a lot of things we didn’t know.

The Will we knew was exceptionally bright, responsible, hardworking and honest. A good student, a loyal friend and — most striking — a gifted athlete with a passionate dream to be the best of the best — at something.

He was, at one time, the fastest boy in Hillsborough County — sprinting and jumping his way through a medley of track-and-field titles during his middle school years. There was a charisma about the sturdy blond boy whose blistering speed brought stadium crowds to their feet as he entered the homestretch.

When he earned a place on the Brandon High School wrestling team — one of the premiere prep athletic programs in the nation — he told a sports reporter what it meant to soar with the Eagles. “I feel there is no limit to where I can go,” he said in a 1997 newspaper interview. “It is a great team and I don’t think my life will ever be the same.”

Death And Detox

About the time the young wrestler was beginning to unravel in Florida, bodybuilder Mike Scarcella, a former Mr. America, was arrested in Texas, charged with felony possession with intent to distribute GHB.

The U.S. Food and Drug Administration had banned the supplement in 1990 but left loopholes that allowed its analogues — chemical cousins that turn into GHB after ingestion — to be sold for another decade. By all accounts, including his own, Scarcella had been using the supplement for years — first as a muscle-building nightcap, then as a morning pick-me-up. Eventually he was sipping capfuls throughout the day, a classic pattern among athletic users that can lead to physical dependence in a matter of weeks or months. Scarcella was hooked. His May 1999 arrest, which resulted in 10 years’ probation, was not enough to pry him from the grip of GHB.

The 1992 Mr. America continued to use and sell the drug, even as he tried to kick the habit — first on his own, then in hospitals, where doctors had no experience with the bizarre hallucinations and raging psychosis of GHB withdrawal.

Even with a doctor’s help, withdrawal can be deadly. Stroke, heart attack and suicide are among the consequences for addicts in withdrawal, which can start within one to three hours of a missed dose.

Anxiety, restlessness and insomnia can quickly progress to delirium, muscle tremors and delusions.

“They think they’re on fire. They’re moving, thrashing, screaming,” said Karen Miotto, a University of California-Los Angeles addiction psychiatrist who helped develop a GHB detox protocol. “I think GHB is probably harder to get addicted to than some other drugs,” she added. “But once people get addicted, it is far harder to get off than any drug I’ve seen.”

Scarcella’s battle ended in August 2003, when the 39-year-old bodybuilder was admitted to a Texas hospital feeling the first effects of GHB withdrawal. By the 10th day, he had become delusional and suffered what the medical examiner termed “sudden cardiac death.”

Doctors and psychiatrists have been slow to recognize GHB withdrawal. Most know little beyond its reputation as a date-rape or club drug with the potential to deliver a swift, deadly knockout punch. Emergency room physicians have become familiar with the unconscious overdose patients — generally youthful partiers — who are often treated and released.

But they rarely consider GHB use in the muscular, hallucinating patients who are delivered in four-point restraints. “ER doctors don’t really know what to look for,” Kershaw said. Most physicians and mental health professionals also fail to recognize the early stages of withdrawal, when careful detoxification using the right medications might head off a spiral into psychosis. “It really means that the only time they’re going to get help is when they’ve reached the state of hallucinating,” said San Francisco addiction specialist Alex Stalcup. By then, their condition may be far less treatable.
“It’s just heartbreaking.”

Jesus’ Son

The angels appeared in September 1999, shortly after the eclipse that marked the end of life as we knew it.
These were not benevolent guardians, but mute, shadowy creatures only Will could see. What was their purpose? I asked him. “They’re here to watch us,” he said. Not as protectors but observers. They were neither dangerous nor benign. They just WERE, he said. Six weeks had passed since the morning of Will’s bloody battle with the backyard demons.

His father and I had spent the first week taking turns staying home from work with him as he slept round-the-clock, sedated by a physician.

The sleep deprivation that preceded the incident was enough to cause hallucinations, according to a psychologist friend. Perhaps sleep would bring him out of it, she suggested. We knew by this time that GHB had played some role. Will had acknowledged taking the supplement in the week before the eclipse. But he had stopped about three days before, he insisted. When Will finally woke up by week’s end, the crisis seemed to have passed.

He returned to his part-time job as a waiter at a Brandon restaurant and began his junior year at USF. With his sights set on the Olympics since high school, he resumed his regular workouts — and, according to his off-campus roommates, resumed his GHB use. “It takes you to a place you never want to come back from,” Will said.

On Labor Day, he was back home, reading the Bible around the clock. He stopped attending classes, didn’t report for work and did not return to the apartment he shared with three other students. He had stopped taking GHB.
He also had ceased his workouts and stopped eating. He claimed he was going to fast for two weeks — “like Jesus.”

Once again, his father and I took turns working from home, watching, waiting. He was, by law, an adult and could not be forced into an evaluation unless he proved to be a danger to himself or others. He didn’t meet that criterion — not yet. His father took his car keys, just in case. Sept. 17, 1999. It was my turn to watch over Will.

I worked on a news story from my laptop on the dining room table, just outside his bedroom. Each time I checked on him, he was sitting on his couch, reading his Bible. He had not eaten since Sept. 6. Shortly before 6 p.m., Will wandered out of his room and pulled up a chair across from me. My fingers froze on the keyboard as I met his gaze. “What are you working on?” he asked. I knew he couldn’t possibly be interested, but it was the first time in weeks he had made any effort to engage in conversation. I began to explain the story I was writing. Then I saw it, so plainly that for a moment I thought I was the one losing touch with reality.

Will’s gray-green eyes, the windows to his troubled soul, suddenly transformed into black pools of blazing madness. And for the first time, I understood the concept of possession. I was still answering his question when he cut me off in midsentence. “You don’t know who you’re dealing with, do you?” hissed the suddenly dark, dangerous creature.

“No,” I replied, cautiously. “Who AM I dealing with?” He rose from his chair and took a step toward me, his fist clenched, his face contorted with rage. “I am the Lord Jesus Christ, and I want my car keys.” I glanced at the clock. His father was due home any time now.

Will’s lips smiled, but his eyes still glittered with that dark madness. “He’s not going to save you,” he said, as though he had read my mind. The phone rang. Will answered. “Yeah, Dad. She’s right here,” he said, handing me the phone, still smiling that frightening smile. Whatever I had seen in Will’s eyes, his father heard in his voice. “Can you talk?” he asked me. “No.”

“Something is wrong?”

“Yes.”

“Get out of the house,” Will’s father told me. “Get out NOW.” Clearly the time for watching and waiting was over. His father dialed 9-1-1.

That night, the angels made their first appearance as Kershaw and his mobile crisis unit came to commit Will for 72 hours of psychiatric observation under Florida’s Baker Act — the first of nearly a dozen hospitalizations over the next 30 months. It wasn’t a tough call. Will was in “florid psychosis” and claimed alternately to be God, Jesus and Jesus’ son.

Then there were the angels, who would, in time, become Will’s constant companions. Kershaw was among the few professionals we encountered over three years who took serious note when we told him of the GHB link.

“Will’s case prompted me to educate myself on this,” he said. “If I have someone who’s got psychotic symptoms, and they’ve got a history of being a fairly well-functioning athlete with no history of mental illness, one of the first things I think of now is GHB.”

Spontaneous Combustion

GHB was the last thing David Johnson thought of as he searched the Internet for information about “Enliven,” a supplement his 28-year-old son, Tyler, purchased at a health food store near his home in Beebe, Ark.

Tyler, who had graduated weeks before from the University of Arkansas, became restless and “fidgety” on the night of July 15, 2000. His pulse raced, and he began to say things that didn’t make sense, Johnson said. Unknown to Johnson, the young bodybuilder had been taking Enliven for about a year. Now, engaged to be married and about to begin law school, Tyler had decided to stop taking it. That night, he showed his father a bottle of the supplement, labeled as a “100% Pure Cellular Recovery System” that “Renews the Body Naturally.”

What it didn’t say was the active ingredient — 1,4 butanediol, better known as BD — is a solvent that converts into GHB once ingested.

GETTING OFF ‘G’

Withdrawal from GHB is among the most prolonged and severe of any drug and should not be undertaken without medical supervision.

Cardiovascular distress is significant, posing the risk of stroke or heart attack. Spikes in blood pressure from repeated bouts of withdrawal can result in arterial damage and an enlarged heart. Withdrawal grows more severe with each subsequent attempt, “kindling” the nervous system to the point of inducing delirium or seizures.

Patients treated before they reach this stage stand a better chance of successful recovery. Detox begun in early stages of withdrawal, with onset of restlessness and anxiety, works best. Detox generally takes at least two weeks, often requiring heavy doses of sedatives, accompanied by monitoring of blood oxygen levels. David Johnson didn’t know it, but Tyler was in GHB withdrawal.

“I wanted to take him to the hospital, but he told me he was all right and he went to bed,” Johnson said.

The next morning, shortly after dawn, a neighbor discovered Tyler’s body on the Johnsons’ front lawn. He had shot himself in the head. Suicide is an all-too-common outcome in cases of GHB addiction, though the true numbers will never be known. Porrata has seen it over and over.

“It’s like spontaneous combustion, not like they pondered it. They just shoot themselves in the head,” she said.
Detox from GHB can take at least two weeks.

“I think one of the most dangerous periods is after detox, where they are suffering depression, anxiety, and it becomes this protracted withdrawal state,” Miotto said. GHB anxiety is malignant — the frightening dreams at night, the terror during the day as the central nervous system tries to deal with the legacy of a little-understood chemical assault on the brain, Stalcup said. “If I had to go through what I see people going through, I don’t know if I could do it,” he said.

Perhaps the harshest irony, Porrata said, is the people who become addicted to GHB in the pursuit of health and fitness and end up turning to street drugs to counter the effects of withdrawal. Black-market Xanax, Valium and similar drugs tend to be the ones of choice. Alcohol, cocaine, Ecstasy and even crystal methamphetamine aren’t far behind.

Of Dreams And Nightmares

In the weeks and months that followed Will’s first Baker Act, life took on a rhythm of sorts — but not the sort we envisioned.

By day, Will continued to run, lift weights, wrestle and pursue his athletic dreams. By night, he battled the demons that invaded his sleep. The boy who once was a designated driver for friends retreated to his room, alone, to drown the delusions in rum and vodka.His circle of friends shifted from students and athletes to dropouts and drug dealers who could ensure a steady supply of sedatives and anything else that might quiet the voices and visions.

I purchased a dreamcatcher and hung it beside his bed, hoping the mystical Indian legend would offer some comfort.

But nothing could banish the nightmarish images that appeared when he closed his eyes. “You can’t imagine what is happening in the world,” he told me. “Yes, I can.” I had to look no further than the gaping hole in his soul.

Laced with antipsychotics prescribed by his doctors, supplemented by a pharmacopia of his own invention, Will struggled to hold down a job and tried, unsuccessfully, to complete his junior year.

He teetered for months on the brink of madness, alternately stabilizing, then disintegrating into a series of forced hospital stays. We didn’t know whether he continued to use GHB or whether the drug had permanently rewired his brain.

“With Will, when I saw him again and again, I wasn’t sure if the GHB had triggered more of a chronic process with him,” Kershaw said. Each time Will was committed, we asked the nurses and doctors to flag his chart to reflect his GHB use — a request that often was received with blank stares and dismissive waves. Will continued to slip from our grasp, trapped in a world inhabited by demons and angels, a world defined by the absence of light or joy.

We wondered how long he could survive in such a dark and hopeless place. It didn’t help that he had come to believe he possessed the gift of prophesy and claimed to have seen his own death many times. He wouldn’t tell us when this was to occur. All he would say was that it involved fire.

Drowning In Cases

In the beginning, the addicts who flocked to Project GHB for help tended to be young men in their late teens and early 20s. Today, Porrata is seeing older men who have been using for five to 10 years. Most are 30 to 55 years old.
“It’s not the party kids,” she said. “It’s the man in midlife crisis who starts going to the gym and wants to lose a few pounds, look a little better, rekindle things — and someone introduces him to ‘G.’”

But still it is the athletes who concern her the most. “Any place you see steroids, GHB is right in the shadows,” she said. “The sports world won’t admit this drug. It’s like their secret drug, and they won’t give it up.”

Unlike steroids, there is no evidence GHB enhances physique or performance. Still, users subscribe to the myth.

“What makes GHB so attractive to athletes is it’s very difficult to detect. They pass all the routine urine drug screens that you do,” said Tampa addiction specialist David Myers.

One of Myers’ patients — a Major League Baseball player — sipped GHB from a small mouthwash bottle during his games. He told Myers and his team managers that GHB use was widespread in pro sports, including among his teammates.

“He relapsed,” Myers said. “There was no support from team management, and it was clear they were not interested in tackling GHB issues.”

There is some speculation that stepped-up enforcement has limited the drug’s availability. But despite a major Drug Enforcement Administration sting that netted 115 Internet distributors in 84 North American cities in 2002, followed by a $7 million bust this year in Scotland, there is plenty of GHB to go around. With Project GHB and other Internet sources supplying information that wasn’t available to addicts six years ago, many users are taking matters into their own hands, Porrata said. “They’ll die from other drugs,” she said. “And we’ve had so many suicides — so many.”

The Three Demons

Will’s final Baker Act took place Jan. 18, 2002. His slide into psychosis began as it always did: He stopped eating.

This time he said he planned to fast until Easter. When he entered Memorial Hospital’s psychiatric unit that day, he had been fasting for two weeks and had lost nearly 30 pounds. A public defender assigned to Will’s case blocked every effort to give him intravenous fluids and nutrients. If he wanted to starve himself, it wasn’t our business, or his doctor’s, she said. By February, Will was still fasting and began walking into walls. He fell and hit his head.

Then something remarkable happened: After three years of inexplicable madness, someone finally decided to take a look at Will’s brain. A nurse requested a CT scan. It was then that we finally met his demons. There were three of them: inoperable brain lesions whose nature and origin doctor’s couldn’t even guess at. Will was transferred to the medical floor, and for the first time in nearly two months, he received IV fluids and nutrients. Too late.

The neurological collapse began with involuntary flickering of his eyelids, which grew more pronounced each day. His hearing began to fail. He started to lose the use of the right side of his body. Still he would not eat. “Don’t worry,” he said. “I’ll be fine.” “All you have to do is start eating, and they’ll let you out of here,” I pleaded. “Isn’t there someplace you’d rather be?” “Heaven,” he said. On Easter, Will broke his fast with a Cadbury egg. He was transferred to a physical therapy unit, then sent home.

The brain scan was sent to Johns Hopkins University in an attempt to identify the lesions. The young wrestler, once the fastest boy in Hillsborough County, could not get from the bedroom to the bathroom without a walker. His balance was gone, his hearing severely impaired. And his flickering eyes couldn’t focus on a television screen, much less a Bible.
But he could kneel, and he could pray. And that is what Will did each day. “Everything will be fine,” he kept saying. “I’ve seen the future, and I’ll be wrestling.”

One of the saddest things about GHB, Miotto said, is the way the drug affects the mind. “They don’t grasp the level of their impairment,” she said. But the saddest thing about Will’s experience was his ability to grasp just that.

Despite his irretrievably broken mind, he knew what he had lost. He knew it all along. Will had always felt a particular affinity for the homeless. In the years he struggled with GHB psychosis, he actively sought them out to give them money as they picked through garbage bins. “That could be me someday,” he said. Despite his intermittent delusions of grandeur, his goals were humble. “What do you want from life?” I asked him shortly before that last Baker Act.

“I just want to be able to take care of myself,” he said. “To drive a car. To have a place of my own.”
Weeks after Will’s release from the hospital, his doctor evaluated him. He checked his eyes, his ears, his balance. This, he told him, was as good as it was going to get. As for the three still-unidentified brain lesions — things could get worse, he added.

Four days later, on June 3, 2002, my son took a gas can from the garage to the back yard. He doused himself and lit a match. A young man approached me after the memorial service. He said his name was Brandon and that Will had persuaded him to seek treatment for cocaine addiction.

“I’m two years clean and sober now,” he said. “Will saved my life, and I just wanted you to know.”

Source: Researcher Mike Messano contributed to this project. Reporter Jan Hollingsworth can be reached at (813) 865-4436 or jhollingsworth@tampatrib.com.

PRODUCT NAMES

Blue Nitro
Renewtrient
Revivarant
Remforce
Firewater
Enliven
Serenity
Revitalize Plus
Thunder Nectar
Rejoov
Flower Power
Dream On
Weight Belt Cleaner

By JAN HOLLINGSWORTH The Tampa Tribune
Published: Nov. 12, 2006

Source: Project GHB

Filed under: Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers),USA :

By Mary Brett, BSc.

Today’s cannabis is much stronger
In 1971 drugs were classified in the UK,and cannabis was placed into the B category. Since then it has changed out of all recognition. The THC (tetrahydrocannabinol, the psychoactive ingredient) content at that time was under 1%. This rose in 2002 to more than 7%. Specially cultivated varieties like skunk and nederweed can have THC contents of more than 30%.

Even more alarming is the fact that the class A cannabis oils with up to 60% THC are now also downgraded to class C. Although rare in Britain, these powerful mind bending drugs should stay where they were, in their proper place, alongside cocaine and heroin.

Persistence in the cells
THC is rapidly absorbed into the blood and then sequestered into fatty tissue in the body, especially the cell membranes of the brain. Release of THC back into the blood is very slow. Fifty per cent will still be there after a week and 10% a month later. The prolonged presence of the drug in our brain cells, results in the disruption and impairment of the chemical communication system, the neurotransmitters between the cells, for some considerable time.

Dependence and addiction
Because THC mimics and so replaces one of the neurotransmitters, anandamide, it has its own receptor sites. These occur in many different areas of the brain so many systems are affected. These include concentration, memory, learning, motor skills, judgment, reasoning, planning, logical thoughts, reward, pain, sound and colour perception. Tolerance and physical addiction occur and withdrawal symptoms are common when use of the drug ceases, though not so severe as the “cold turkey” of heroin withdrawal due to its persistence in the body.7 The earlier the child starts to use cannabis, the greater the escalation of use. In September 2002, out of 6 million drug addicts in the USA, two thirds were cannabis dependent. More were being treated for cannabis than for alcohol addiction. Psychological addiction has been recognized for many years and is very difficult to treat.

Driving and flying hazards
Psycho-motor skills are affected so cannabis intoxication is a driving hazard In some American studies, cannabis has been implicated as many times as alcohol in accidents, although 10 times as many people drink. In Norway, 56% of drug-impaired drivers who tested negative for alcohol tested positive for THC.12 It has been estimated that in 2001, out of 4 million high school seniors in the US, approximately one sixth admitted to driving under the influence of cannabis. Of these, 38,000 reported crashing as a result. Alcohol was blamed for 46,000 accidents. Airline pilots on flight simulators could not land their planes properly even 24 hours after a joint and had no idea they had a problem. Someone having a joint today should not be driving tomorrow.

Psychiatric risks/schizophrenia/psychosis
Mental illness and cannabis have been linked for a long time15 but 3 papers in the BMJ in November 2002 brought the subject sharply into focus.16 Studies from New Zealand, Australia and Sweden found strong links with a variety of mental disorders including schizophrenia, psychosis, depression and anxiety. A separate Dutch study noted that 50% of psychiatric cases were due to cannabis. Professor Robin Murray of The Institute of Psychiatry has been widely quoted recently in the press, saying that cannabis is the “number one problem facing mental health services in inner cities”. A colleague, Dr Paddy Powers said that cannabis is a factor in 70 to 80% of all psychosis cases. Over 2000 cases of cannabis psychosis in a 2-year period caused an experiment in decriminalization in Alaska to be terminated by public referendum in 1991.

THC increases the amount of the neurotransmitter dopamine released in the brain. The psychiatric symptoms of schizophrenia are mediated by dopamine. This may prove to be the link. A Swedish scientist, Jan Ramstrom, said in 1989, “Cannabis is one of the most psychopathogenic narcotic preparations. It is worth mentioning that the opiates (heroin etc), apart from the development of dependence itself, produce far fewer toxically precipitated psychiatric complications than do cannabis preparations”

Violence
One of the cries of the liberalisers of this drug is, “Better for kids to sit around stoned and peaceful rather than be drunk and violent”. Not so! A New Zealand paper in 2002 showed young male users to be 5 times more likely to be violent than their non-using peers.

Overdosing?
Maybe you can’t overdose on cannabis; tobacco smokers don’t overdose either; in US records for 1999, of 664 marijuana related deaths, 187 of them involved only marijuana. Mentions of marijuana use in emergency room visits has risen in the United States by 176% since 1994, surpassing those of heroin. 110,000 such visits were recorded in 2001.

Personality changes
Even on one joint a month, a “cannabis personality” develops within a year or so. Users become inflexible, can’t plan their days properly, can’t take criticism or criticise themselves. At the same time they feel lonely and misunderstood. Trying to talk sense to them becomes a futile exercise.26 They are more likely to drop out of school, steal, become violent, run away from home or contemplate suicide.27 Adolescents with their immature brains are particularly vulnerable to mind-altering drugs. Personal and emotional development can be severely compromised.28

Cognitive impairment/school performance
Teachers will tell you that school performance begins to decline with those using cannabis. An American paper showed that youths with an average grade D or below, were more than 4 times as likely to have used cannabis in the past year as those with an average grade A. Australian researcher, Dr Nadia Solowij, said, “Use more often than twice a week for even a short period of time, or use for 5 years or more at a level of even once a month, may each lead to a compromised ability to function to their full mental capacity, and could possibly result in lasting impairments”.

A study of municipal workers found those using cannabis on or off the job reported more “withdrawal behaviours”, leaving work without permission, daydreaming, shirking tasks and spending work time on personal matters. All practices that adversely affect productivity and morale, not only for the users but also their colleagues.

Lung disease – emphysema/ bronchitis/cancer
Cannabis smoke contains between 50 and 70% more of the carcinogens found in unfiltered tobacco smoke.32 The amount of tar and levels of carbon monoxide absorbed are 3 to 5 times more than for the same amount of tobacco.33 Pre-cancerous changes have been seen in the airways of 20 to 30 year olds,34 and rare head and neck cancers, formerly only seen in older tobacco smokers are now being seen in young cannabis users. A case of emphysema showing a pair of lungs shot through with holes from cannabis use is yet another item in this sorry saga.

Effects on the reproductive system and children
Cannabis can suppress ovulation in women and if they smoke when pregnant, the baby will be lighter and have a smaller head circumference. A long running study of children in Canada by Peter Fried has discovered deficits in their cognitive functioning at 9. One form of leukaemia is 10 times more common in these offspring.

A reduction in sperm count and the presence of abnormal sperm has been documented for years. Some men complain of impotence. Cannabis smoking in the previous hour has been associated with a fivefold increased risk of heart attack in middle-aged people.

The gateway effect
Australian researchers found that weekly users were 60 times more likely to move on to other drugs, the strongest association being in 14 to 15 year olds. A possible genetic link was dismissed by a study of 300 pairs of same-sex twins in New Zealand. Use of cannabis by one of them before the age of 17 meant that he or she was 2 to 5 times more likely to have drug problems and dependency later in life, than their sibling. Professor Denise Kandel and her team in the USA have researched this topic for the past 20 years or so. They have consistently found that level of usage is a major factor.

Medical Use
Pure synthetic THC, Nabilone, is already available in the UK for the nausea of chemotherapy and the stimulation of the appetite in AIDS patients.51 No-one should have a problem with extracts of cannabis being purified and tested, as they are now in Britain, if, according to the EU rules for medicines they prove to be efficacious, but cannabis, per se, with its 400 chemicals would never pass the tests. Nabilone anyway is by no means the first choice of doctors because of its side effects.54 The warning on it reads, “THC encourages both physical and psychological dependence and is highly abusable. It causes mood changes, loss of memory, psychosis, impairment of coordination and perception, and complicates pregnancy”.

Keith Stroup, an American pot-using lawyer said in 1979, “We will use the medical marijuana argument as a red herring to give pot a good name”.

In conclusion
For a UK government which banned beef-on-the-bone with its infinitesimal risk of transmitting CJD, it is astonishing that they should relax the law on a drug which has been proved to be so damaging.

*************************

This digest is an extract of a much longer paper prepared by Mary Brett, BSc., Head of Personal, Social and Health Education at Dr Challoner’s Grammar School in Amersham, Buckinghamshire, England, and a former Executive Councillor of the National Drug Prevention Alliance. The full paper runs to 9 pages, including 54 technical references. The full paper may be requested from Mrs Brett by emailing her on mary.brett@dsl.pipex.com

*************************

For further extensive references and research digests on cannabis and other drugs, access the NDPA website on www.drugprevent.org.uk – and see also its links to several other sites in a range of countries.

Filed under: Effects of Drugs (Papers),Legal Sector :

Drug Deaths

38,371 people died of drug-induced causes in 2007, the latest year for which data are available. The number of drug-induced deaths has grown from 19,128 in 1999, or from 6.8 deaths per 100,000 population to 12.6 in 2007.1 (These include causes directly involving drugs, such as accidental poisoning or overdoses, but do not include accidents, homicides, AIDS, and other causes indirectly related to drugs.)
There is a drug-induced death in the U.S. every 15 minutes.
Compared to other causes of preventable deaths, drug-induced causes exceeded the 31,224 deaths from injuries due to firearms and the 23,199 alcohol-induced deaths recorded in 2007. In the same year, 34,598 deaths were classified as suicides and 18,361 deaths as homicides.3

Drugged Driving

From a national roadside survey in 2007, one in eight (12.4%) of weekend nighttime drivers tested positive for at least one illicit drug.4
Based on a self-report survey in 2009, approximately 10.5 million Americans reported driving under the influence of an illicit drug during the past year.5
In 2009, one in three drivers killed in motor vehicle crashes who were tested for drugs and the results known, tested positive for at least one medication or illicit drug.6
Among high school seniors in 2008, one in 10 (10.4%) reported that in the two weeks prior to their interview, they had driven a vehicle after smoking marijuana.7

Children

Annual averages for 2002 to 2007 indicate that over 8.3 million youth under 18 years of age, or almost one in eight youth (11.9%), lived with at least one parent who was dependent on alcohol or an illicit drug in the past year.8 Of these, About 2.1 million youth lived with a parent who was dependent on or abused illicit drugs, and almost 7.3 million lived with a parent who was dependent on or abused alcohol.9

School Performance

Significantly fewer youth in school who are current marijuana users report an average grade of “A” (12.5%) compared to those who are not current marijuana users (30.5% report an average grade of “A”).10
College students who use prescription stimulant medications nonmedically typically have lower grade point averages, are more likely to be heavy drinkers and users of other illicit drugs, and are more likely to meet diagnostic criteria for dependence on alcohol and marijuana, skip class more frequently, and spend less time studying. 11

Economic Costs

The economic cost of drug abuse in the US was estimated at $180.9 billion in 2002, the last available estimate. This value represents both the use of resources to address health and crime consequences as well as the loss of potential productivity from disability, premature death, and withdrawal from the legitimate workforce.12
ONDCP seeks to foster healthy individuals and safe communities by effectively leading the Nation’s effort to reduce drug use and its consequences. December 2010
Addiction and Treatment Need
In 2009, 23.5 million persons aged 12 or older needed treatment for an illicit drug or alcohol use problem (9.3 percent of persons in that age group). Of these, 7.1 million persons needed treatment for illicit drug problems, with or without alcohol.13
Of the 23.5 million persons needing substance use treatment, 2.6 million received treatment at a specialty facility in the past year, and of the 7.1 million needing drug treatment, 1.5 million received specialty treatment.14

Acute Health Effects

In 2008, an estimated 2 million visits to emergency departments in US hospitals were associated with drug misuse or abuse, including close to one million (993,379) visits involving an illicit drug. Nonmedical use of pharmaceuticals was involved in 971,914 visits.15 Cocaine was involved in 482,188 visits, marijuana was involved in 374,435 visits, heroin was involved in 200,666 visits, and stimulants (including amphetamines and methamphetamine) were involved in 91,939 visits.

Criminal Justice Involvement

According to a 2009 study of arrestees in 10 major metropolitan areas across the country, drug use among the arrestee population is much higher than in the general U.S. population. The percentage of booked arrestees testing positive for at least one illicit drug ranged from 56 percent to 82 percent. The most common substances present during tests, in descending order, are marijuana, cocaine, opiates (primarily metabolites of heroin or morphine), and methamphetamine. Many arrestees tested positive for more than one illegal drug at the time of arrest.16
According to a 2004 survey of inmates in correctional facilities, 32 percent of state inmates and 26 percent of federal prisoners reported that they used drugs at the time of the offense.17

Environmental Impact and Dangers

There are significant environmental impacts from clandestine methamphetamine drug labs, including chemical toxicity, risk of fire and explosion, lingering effects of toxic waste, and potential injuries. The number of domestic meth lab incidents, which includes dumpsites, active labs, and chemical/glassware set-ups, dropped dramatically in response to the Combat Meth Epidemic Act, (CMEA) of 2005, from nearly 13,000 in 2005 to just over 6,000 in 2007. However, traffickers are devising methods to avoid the CMEA restrictions and domestic meth lab incidents are rising again, reaching 9,800 in 2009.18
Coca and poppy cultivation in the Andean jungle is significantly damaging the environment in the region. The primary threats to the environment are deforestation caused by clearing the fields for cultivation, soil erosion, and chemical pollution from insecticides and fertilizers. Additionally, the lab process of converting coca and poppy into cocaine and heroin has adverse effects on the environment.19
Mexican drug trafficking organizations have been operating on public lands in the U.S. to cultivate marijuana, with serious consequences for the environment and public safety. Propane tanks and other trash from illicit marijuana growers litter the remote areas of park lands from California to Tennessee. Growers often use a cocktail of pesticides and fertilizers many times stronger than what is used on residential lawns to cultivate their crop. These chemicals leach out quickly, killing native insects and other organisms directly. Fertilizer runoff contaminates local waterways and aids in the growth of algae and weeds. The aquatic vegetation in turn impedes water flows that are critical to maintaining biodiversity in wetlands and other sensitive environments.20

Source: Office of National Drug Control Policy. USA Dec. 2010

1 Xu, J; Kochanek, KD; Murphy, SL; and Tejada-Vera, B. Deaths: Final Data for 2007. National Vital Statistics Reports 58/9, Centers for Disease Control and Prevention, National Center for Health Statistics (May 2010).
2 Calculated from Xu, et al. (2010).
3 Xu, et al. (2010).
4 National Highway Traffic Safety Administration, 2007 National Roadside Survey of Alcohol and Drug Use (December 2009).
5 SAMHSA. 2009 National Survey on Drug Use and Health, Detailed Tables (September 2010).
6 National Highway Traffic Safety Administration, Drug Involvement of Fatally Injured Drivers (November 2010).
7 University of Michigan. 2008 Monitoring the Future Study. Unpublished special tabulations (December 2010).
8 SAMHSA. Children Living with Substance-Dependent or Substance-Abusing Parents: 2002-2007 (April 2009).
9 SAMHSA. Children Living with Substance-Dependent or Substance-Abusing Parents: 2002-2007 (April 2009).
10SAMHSA. 2007 and 2008 National Surveys on Drug Use and Health, unpublished special tabulations (September 2010).
11 Arria AM; DuPont RL. Nonmedical Prescription Stimulant Use Among College Students: Why We Need to Do Something and What We Need to Do. Journal of Addictive Diseases. 29;4:417-426. 2010.
12 Office of National Drug Control Policy, The Economic Costs of Drug Abuse in the United States, 1992-2002 (December 2004).
13 Substance Abuse and Mental Health Services Administration [SAMHSA]. 2009 National Survey on Drug Use and Health (September 2010).
14 SAMHSA. 2009 National Survey on Drug Use and Health (September 2010).
15 SAMHSA. Drug Abuse Warning network, 2009 (January 2010).
16 Office of National Drug Control Policy, ADAM II 2009 Annual Report (June 2010).
17 Bureau of Justice Statistics, Drug Use and Dependence, State and Federal Prisoners, 2004 (October 2006).
18 National Drug Intelligence Center [NDIC]. National Drug Threat Assessment 2010 (February 2010).
19 NDIC. National Drug Threat Assessment 2010 (February 2010).
20 NDIC. National Drug Threat Assessment 2010 (February 2010).

Filed under: Effects of Drugs (Papers),USA :

July 30, 2010

We have been monitoring ALL scientific research on marijuana/cannabis since about 1994 (and before that we purchased reference material from NIDA of all previous scientific studies). My husband is a nephrologist and clinical pharmacologist and my son is a rheumatologist. Both of these medical specialties require a depth of knowledge of pharmaceutical drugs that far surpasses that of most other subspecialties. One of the most important aspects of prescribing drugs of any sort is knowing the potential side effects and knowing how the drug will interact with other drugs or foods the individual may be taking. Every person is unique and drugs that are benign to one individual may be deadly for another. Penicillin is an excellent example because though it has saved millions of lives, it is also deadly for some. To date there are more than 20,000 published studies on marijuana and none of them offer proof of its safety or efficacy. That being said, I am attaching a file of documents relating to marijuana being a leading cause of drug-related emergency room episodes.

Fifteen years ago I attended a medical conference in Auckland, NZ with my husband. The doctor sitting next to me at dinner asked what I do. I told him that I was the unpaid head of a non-profit drug prevention organization. He said he didn’t think NZ had a drug problem. The doctor sitting across from us interjected that not only did NZ have a drug problem but that it was impacting the medical system. He said that he was head of the psychiatric unit at Auckland’s main hospital and that he would venture that at least 50% of those admitted for emergency psychiatric problems were there because of marijuana. I had heard that marijuana could cause psychiatric problems because two individuals I knew had kids who would go “round the twist” as they say in Auckland, whenever they smoked pot, and would end up in psychiatric care, but I had no idea is was that severe.

Then, about ten years ago, just after my husband became director of transplant for Legacy Hospital Systems, we went to dinner with one of the administrators and his wife. The wife asked what I do and I told her. She then volunteered that she was head of a triage unit in a psychiatric ward at another hospital and that it was her opinion that at least 65% of those admitted for emergency psychiatric problems were there because of marijuana.

re ingesting cannabis. One does not always know the potency of the cannabis being used or how much is in the product. Below is an exchange between a doctor who ingested “space cakes” and the editor of High Times Magazine. You will see that Ed Rosenthal (then the editor) acknowledges that marijuana can cause problems for even experienced users.

Marijuana is such an insidious drug that it may be years before we see the full extent of its potential to do harm. But a couple of things I think are VERY important and that is that marijuana has become a major factor in infertility (see Science Magazine for starters), and it destroys brain cells.

I am also attaching a document put together in 1999 (when there were only about 10,000 studies on marijuana) by a drug prevention specialist out of Canada. This document is called The Marijuana Connection and it categorizes the studies by side effect.

Source: Marijuana Research Review July 2010

Constituents of Cannabis Sativa L. (Marijuana)

In a document entitled “Constituents of Cannabis Sativa L. (Marijuana)” published by the University of Mississippi, Research Institute of

Pharmaceutical Sciences, Department of Pharmaceutics” (Ross SA, Elsohly MA. Constituents of Cannabis Sativa L. XXVIII A review of the natural

constituents: 1980-1994. J. Pharm Science. 1995;4:1-10, it states that marijuana contains 483 substances, 66 of which are cannabinoids. No

other plant contains cannabinoids.

Up to January, 2001, over 15,000 scientific papers have been published on cannabis and its constituents and many reviews have been written on

cannabis constituents and cannabinoid chemistry. A total of 483 natural constituents have been isolated and/or identified in Cannabis sativa

L., and they have been delineated as follows:

Cannabinoids 66
Nitrogenous Compounds 27
Amino acids 18
Proteins, Glycoproteins, Enzymes 11
Sugars & related compounds 34
Hydrocarbons 50
Simple Alcohols 7
Simple Aldehydes 12
Simple Keytones 13
Simple Acids 21
Fatty Acids 22
Simple Esters & Lactones 13
Steroids 11
Terpenes 120
Non-Cannabinoids Phenols 25
Flavonoids 21
Vitamins 1
Pigments 2
Elements 9

Filed under: Effects of Drugs (Papers) :

During the last quarter of the 20th century recreational use of
cannabis increased greatly across the world.1 Cannabis consumption
came to be seen as a normal leisure activity, and was regarded
as safe even by the medical establishment.2 However, in recent
years there has been considerable controversy over the use of
cannabis, with, for example, the UK government repeatedly
reviewing its safety.3 This concern has arisen from large prospective
epidemiological studies which have reported that use of
cannabis increases the risk of schizophrenia-like psychosis.4,5
However, these studies have not collected detailed data on the
patterns of use or potency of the cannabis used, which may be
important factors moderating the associated risk.6
The principal constituents of cannabis are D9-tetrahydrocannabinol
(D9-THC) and cannabidiol. The former is the main
psychoactive ingredient and in experimental studies it produces
transient psychotic symptoms and impaired memory in a dose dependent
manner.6,7 In contrast, cannabidiol does not induce
hallucinations or delusions, and it seems to antagonise the cognitive
impairment and psychotogenic effects caused by D9-THC.6
Until the early 2000s the most freely available type of cannabis
in the UK was cannabis resin (‘hash’), which had approximately
70% of the ‘street’ market, followed by traditional imported herbal
cannabis and then sinsemilla (‘skunk’). Cannabis resin contains
2–4% D9-THC and a similar proportion of cannabidiol, whereas
herbal cannabis contains a similar percentage of D9-THC but no
cannabidiol.8,9 However, sinsemilla (skunk) has increasingly taken
over the UK market and its THC concentration, and to a lesser
extent that of imported herbal cannabis, has been consistently
rising. For example, seizures of cannabis on the streets of England
in 2008 by the police showed that sinsemilla had a market share
of more than 70%, and had reached a D9-THC concentration of
12–18% with virtually no cannabidiol.8,9

Smith has suggested that such high-potency cannabis might be
especially harmful to mental health.10 We therefore compared
patterns and types of cannabis use in people experiencing their
first episode of psychosis and in a healthy control sample.
Specifically, we sought to test the hypothesis that daily use of
high-potency cannabis is associated with a particularly high risk
of psychosis.

Method
Sample
We approached all patients aged 18–65 years who presented with a
first episode of psychosis to the Lambeth, Southwark and Croydon
adult in-patient units of the South London & Maudsley Mental
Health National Health Service (NHS) Foundation Trust between
December 2005 and October 2008. We validated clinical diagnosis
by administering the Schedules for Clinical Assessment in
Neuropsychiatry (SCAN).11 Patients who met ICD–10 criteria
for a diagnosis of psychosis (codes F20–F29 and F30–F33)12 were
invited to participate in the study; cases with a diagnosis of
organic psychosis were excluded. During the same period we
recruited a healthy control group (n = 174) from the local
population living in the area served by the Trust, by means of
internet and newspaper advertisements, and distribution of
leaflets at train stations, shops and job centres. Cannabis was
not mentioned in these advertisements. Particular attention was
directed to attempting to obtain a control sample similar to the
patient sample in age, gender, ethnicity, educational qualifications
and employment status. Those who agreed to participate were
administered the Psychosis Screening Questionnaire,13 and
excluded if they met criteria for a psychotic disorder or reported
a previous diagnosis of psychotic illness.
Ethical permission was obtained from the Trust and the
Institute of Psychiatry research ethics committee. All study
participants signed a consent form allowing publication of data
originating from the study.

Background
People who use cannabis have an increased risk of
psychosis, an effect attributed to the active ingredient D9-
tetrahydrocannabinol (D9-THC). There has recently been
concern over an increase in the concentration of D9-THC in
the cannabis available in many countries.

Aims
To investigate whether people with a first episode of
psychosis were particularly likely to use high-potency
cannabis.

Method
We collected information on cannabis use from 280 cases
presenting with a first episode of psychosis to the South
London & Maudsley National Health Service (NHS) Foundation
Trust, and from 174 healthy controls recruited from the local
population.

Results
There was no significant difference between cases and
controls in whether they had ever taken cannabis, or age at
first use. However, those in the cases group were more
likely to be current daily users (OR = 6.4) and to have smoked
cannabis for more than 5 years (OR = 2.1). Among those who
used cannabis, 78% of the cases group used high-potency
cannabis (sinsemilla, ‘skunk’) compared with 37% of the
control group (OR 6.8).

Conclusions
The finding that people with a first episode of psychosis had
smoked higher-potency cannabis, for longer and with greater
frequency, than a healthy control group is consistent with
the hypothesis that D9-THC is the active ingredient
increasing risk of psychosis. This has important public health
implications, given the increased availability and use of highpotency
cannabis.

Source: The British Journal of Psychiatry (2009)
195, 488–491. doi: 10.1192/bjp.bp.109.064220

Filed under: Effects of Drugs (Papers) :

Historian looks at resistance to the “NIDA paradigm.”

The history of addiction as a brain disease “looks a lot like the history of atoms or germs, insofar as these were older and controversial ideas for which scientific confirmation later became available,” writes historian David Courtwright, author of Forces of Habit: Drugs and the Making of the Modern World.

In a recent issue of the social science journal BioSocieties, Courtwright surveys the history of the disease paradigm of drug addiction, and, in doing so, brings into focus several key dilemmas related to what former National Institute on Drug Abuse (NIDA) director Alan Leshner once characterized as the “quintessential biobehavioral disorder.”

The scientific evidence available to us at present largely supports a statement like Leshner’s. Researchers have documented long-term changes in brain structure and function due to drug abuse, and neuroimaging technologies have resulted in maps of the abnormal neuronal activity addicts exhibit. Courtwright cites the discovery of the endogenous opioid system, the mapping of receptor pathways, and the growing understanding of the mesolimbic dopamine reward pathway as evidence of clinical confirmation of theories about addictive disease that has been floating around in one form or another for many years.

Why then, Courtwright asks, does the medical profession largely stay clear of issues having to do with our law enforcement-driven drug war? Why are clinical professionals not on the front lines of revolt over this issue? “If addiction was beyond the individual’s control, then criminal punishment was as inappropriate as jailing a schizophrenic who wandered into an emergency room,” the author writes.

The most obvious reason for this conundrum, says Courtwright, is that “the brain disease model has so far failed to yield much practical therapeutic value.” The disease paradigm has not greatly increased the amount of “actionable etiology” available to medical and public health practitioners. “Clinicians have acquired some drugs, such as Wellbutrin and Chantix for smokers, Campral for alcoholics or buprenorphine for heroin addicts, but no magic bullets.” Physicians and health workers are “stuck in therapeutic limbo,” Courtwright believes. “The drug-abuse field is characterized by, at best, incomplete and contested medicalization.”

Moreover, unlike the current situation in the case of, say, diabetes or schizophrenia, “at least four important groups continue to wrestle for control of the addiction field.” (Medical personnel, police, social scientists, and political officials.) Social scientists, in particular, are frequently skeptical about the NIDA disease paradigm “as part of a broader post-World War II pattern of resistance against biological explanations of behavior, genetic research and the neo-Darwinian renaissance.”

Social scientists and neuroscientists “still live in their own gated academic communities,” Courtwright alleges. “There is a lot more at stake in the brain disease debate than our understanding of addiction.”

However, these problems do not mean that valuable findings in one area–addictive disease theory–cannot produce innovations in other research fields as well. In fact, such spinoffs happen all the time. Courtwright points to advancements in our understanding of evolution: “Michael Kuhar has argued that, because the brain co-evolved with neurotransmitters, it can usually manage its internal chemistry quite well. But it did not co-evolve with drugs, understood as recently introduced and wholly exogenous super-neurotransmitters that can override the brain’s control mechanisms.”

The author also cites spinoffs in economic studies: “The permanent alteration of neurons and the development of addiction in some, but not all, users also helped explain the commercial and tax appeal of drugs, insofar as they were nondurable goods with relatively inflexible demand curves. Even non-addicted users tended to consume more over time, because of tolerance.”

In the end, it is just possible to contemplate some sort of fusion, or meeting of the minds, over the disease model. As Courtwright speculates, “it may turn out that the tension between the personality and brain disease models is more apparent than real.” He cites as evidence such connections as the fit between impulsive, thrill-seeking behavior and an associated paucity of dopamine D2 and D3 receptors in the midbrain region. The result? Such people “have less inhibition of dopamine, and experience more reward when stimulated by risky behavior.” A nice fit. And the number of nice fits between social science and brain science continues to accumulate.

“If the brain disease model ever yields a pharmacotherapy that curbs craving, or a vaccine that blocks drug euphoria, as some researchers hope,” Courtwright says, “we should expect the rapid medicalization of the field. Under those dramatically cost-effective circumstances, politicians and police would be more willing to surrender authority to physicians.”

Graphics Credit: http://alcoholanddrugabuse.org

SOURCE:HTTP://ADDICTION-DIRKH.BLOGSPOT.COM/2010/06/ WEDNESDAY, JUNE 23, 2010

Filed under: Education Sector (Papers),Effects of Drugs (Papers) :

White House ‘drug czar’ Gil Kerlikowske lays out his most thorough arguments yet against marijuana legalization. They help clear up confusion over White House drug policy, and can serve as talking points for parents and officials.
The Obama White House has finally laid out its most thorough, reasoned rebuttal to arguments for marijuana legalization – countering a campaign that is gaining alarming momentum at the state level.
The president’s tough position was delivered in early March by his “drug czar,” Gil Kerlikowske, in a private talk before police chiefs in California – which is ground zero for this debate.
“Marijuana legalization – for any purpose – is a nonstarter in the Obama administration,” said Mr. Kerlikowske, a former police chief himself.
It’s almost certain that California voters will be asked in a November ballot initiative whether to allow local governments to regulate and tax marijuana (similar to taxes on sales of alcohol). Other states are considering similar proposals, which are really a backdoor way to legalize pot.
(For a Monitor news story on the California ballot initiative, click here)
Thirteen states have decriminalized the use or possession of small amounts of marijuana, which is not the same as legalizing it. Selling it is still illegal except in states where it is used for medical purposes. And under federal law, any sort of marijuana use or sale is a criminal offense.
The drug czar’s remarks are worth notice for two reasons. First, they provide needed talking points for those who oppose legalization but who can’t seem to make their message resonate in the face of a well-financed, well-organized pro-marijuana effort. Second, they help clear up confusion about the White House policy on legalization.
When Attorney General Eric Holder announced last year that US law enforcement officials would neither raid nor prosecute medical marijuana dispensaries or those using them, states got mixed signals. Mr. Holder explained it as a matter of the best use of scarce federal law enforcement resources, which he didn’t want to expend in the now 14 states that have approved some use of medical marijuana.
But “a lot of people believe the administration is somewhat in favor of the decriminalization of marijuana,” says Scott Kirkland, police chief for El Cerrito, in the San Francisco Bay area. In California, the public, city council members, city managers, even police chiefs have “misinterpreted” the administration’s position, says Mr. Kirkland, the spokesman for marijuana issues for the California Police Chiefs Association.
The drug czar couldn’t have been more plain. On medical marijuana, which has strong public backing in opinion polls, the former Seattle police chief said that “science should determine what a medicine is, not popular vote.” As Kerlikowske pointed out, marijuana is harmful – and he has the studies to back it up. Read the footnotes in his speech; they’re sobering, especially No. 8.
(For a previous Monitor editorial on the perils of legalizing pot, click here)
Legalization supporters argue that no one has ever died from an overdose of this “soft” drug. But here’s what “science” has found so far: Smoking marijuana can result in dependence on the drug.
More than 30 percent of people who are 18 and over and who used marijuana in the past year are either dependent on the drug or abuse it – that is, they use it repeatedly under hazardous conditions or are imparied when they’re supposed to be interacting with others, such as at work. This is according to a 2004 study in the Journal of the American Medical Association.
Pot is also associated with poor motor skills, cognitive impairment (i.e., affecting the ability to think, reason, and process information), and respiratory and mental illness.
The recent “Pentagon shooter,” John Patrick Bedell, was a heavy marijuana user. The disturbed young man’s psychiatrist told the Associated Press that marijuana made the symptoms of his mental illness more pronounced. Mr. Bedell’s brother, Jeffrey, told The Washington Post that marijuana made his brother’s thinking “more disordered” and that he had implored him to stop smoking pot, to no avail.
Kerlikowske also effectively knocked down the argument that regulating and taxing marijuana is a great way for states to make money in these deficit-dreary times. Indeed, NORML, the lead group in the legalization movement, is set to launch a digital ad campaign in Manhattan’s Times Square next week: “Money CAN grow on trees!”
It’s a claim that’s too good to be true, just as the exclamation point implies. Look at the nation’s experience with regulated alcohol. America collects nearly $15 billion a year in federal and state taxes from alcohol. But Kerlikowske says that covers less than 10 percent of the “social costs” related to healthcare, lost productivity, and law enforcement. And what about lost lives? Let’s not add marijuana to the mix of regulated substances.
“The costs of legalizing marijuana would outweigh any possible tax that could be levied,” Kerlikowske explains. In the United States, illegal drugs already cost an estimated $180 billion annually in social costs, according to the Office of National Drug Control Policy. That number would increase as marijuana became more widely and easily available.
The Dutch – so often praised by marijuana advocates – have had to greatly ratchet back the number of legal marijuana outlets because of crime, nuisance, and increased pot usage among youth. Los Angeles, too, now sees the need to scale back the number of private dispensaries of medical marijuana. Many California towns have looked at L.A. and are saying “no” to dispensaries.
The California Board of Equalization, which administers the state’s sales tax, estimates $1.4 billion of potential revenue from a marijuana tax. Found money? Its reasoning is based on either “a series of assumptions that are in some instances subject to tremendous uncertainty or in other cases not valid,” according to an independent study by the RAND Corporation.
What’s too bad about the drug czar’s speech is that it was made behind closed doors at a venue not accessible to the press, then quietly put on the administration’s website. Given the confusion over the message, the White House needs to be far more outspoken about this.
President Obama himself needs to get more involved than simply letting his drug czar reveal this critical stance below the radar. As a high-profile parent, he can help other parents who are struggling to prevent their children from going down the rabbit hole of drug use. If one message can resonate in this debate, it’s that America’s young people are most vulnerable to the threat of legalization.
They are particularly sensitive to the price of pot (and prices will come down if pot is legalized). They’re the most influenced by societal norms (and public approval is growing). And they’re the ones most heavily engaged in studying and learning – a process that pot smoking can impair.
Individuals who reach age 21 without using drugs are almost certain to never use them. But according to a study by a leading source on young people and drugs, Monitoring the Future, marijuana use among teens has increased in recent years, after a decade of decline. Teens perceive less risk in use – not surprising when states approve of it as medicine. Risk perception greatly influences drug use among young people.
The risks of marijuana – and the wisdom of knowing that joy and satisfaction are not found in a drug – are lessons that Mr. Obama could effectively teach the nation. But even so, it can’t stop there.
The momentum, for now, is with those who want to legalize marijuana. They have been generously financed by a few billionaires, including George Soros, and make strategic use of the Internet and media.
It will take clear-thinking parents, teachers, local officials, faith leaders, and law enforcement officers to convincingly articulate why the march to legalization must be stopped. They can, if they use the kinds of reasonable and fact-based arguments that the nation’s drug czar has just laid out.
(To read Gil Kerlikowske’s speech, click here.)
Kerlikowske also effectively knocked down the argument that regulating and taxing marijuana is a great way for states to make money in these deficit-dreary times. Indeed, NORML, the lead group in the legalization movement, is set to launch a digital ad campaign in Manhattan’s Times Square next week: “Money CAN grow on trees!”
It’s a claim that’s too good to be true, just as the exclamation point implies. Look at the nation’s experience with regulated alcohol. America collects nearly $15 billion a year in federal and state taxes from alcohol. But Kerlikowske says that covers less than 10 percent of the “social costs” related to healthcare, lost productivity, and law enforcement. And what about lost lives? Let’s not add marijuana to the mix of regulated substances.
“The costs of legalizing marijuana would outweigh any possible tax that could be levied,” Kerlikowske explains. In the United States, illegal drugs already cost an estimated $180 billion annually in social costs, according to the Office of National Drug Control Policy. That number would increase as marijuana became more widely and easily available.
The Dutch – so often praised by marijuana advocates – have had to greatly ratchet back the number of legal marijuana outlets because of crime, nuisance, and increased pot usage among youth. Los Angeles, too, now sees the need to scale back the number of private dispensaries of medical marijuana. Many California towns have looked at L.A. and are saying “no” to dispensaries.
The California Board of Equalization, which administers the state’s sales tax, estimates $1.4 billion of potential revenue from a marijuana tax. Found money? Its reasoning is based on either “a series of assumptions that are in some instances subject to tremendous uncertainty or in other cases not valid,” according to an independent study by the RAND Corporation.
What’s too bad about the drug czar’s speech is that it was made behind closed doors at a venue not accessible to the press, then quietly put on the administration’s website. Given the confusion over the message, the White House needs to be far more outspoken about this.
President Obama himself needs to get more involved than simply letting his drug czar reveal this critical stance below the radar. As a high-profile parent, he can help other parents who are struggling to prevent their children from going down the rabbit hole of drug use. If one message can resonate in this debate, it’s that America’s young people are most vulnerable to the threat of legalization.
They are particularly sensitive to the price of pot (and prices will come down if pot is legalized). They’re the most influenced by societal norms (and public approval is growing). And they’re the ones most heavily engaged in studying and learning – a process that pot smoking can impair.
Individuals who reach age 21 without using drugs are almost certain to never use them. But according to a study by a leading source on young people and drugs, Monitoring the Future, marijuana use among teens has increased in recent years, after a decade of decline. Teens perceive less risk in use – not surprising when states approve of it as medicine. Risk perception greatly influences drug use among young people.
The risks of marijuana – and the wisdom of knowing that joy and satisfaction are not found in a drug – are lessons that Mr. Obama could effectively teach the nation. But even so, it can’t stop there.
The momentum, for now, is with those who want to legalize marijuana. They have been generously financed by a few billionaires, including George Soros, and make strategic use of the Internet and media.
It will take clear-thinking parents, teachers, local officials, faith leaders, and law enforcement officers to convincingly articulate why the march to legalization must be stopped. They can, if they use the kinds of reasonable and fact-based arguments that the nation’s drug czar has just laid out.
Source: www.csmonitor.com  By the Monitor’s Editorial Board / March 12, 2010

Filed under: Effects of Drugs (Papers),Law (Papers),USA :

There has been a considerable scientific effort over the past three decades in to identifying and understanding the core features of alcohol and drug dependence. This work really began in 1976 when the British psychiatrist Griffith Edwards and his American colleague Milton M. Gross collaborated to produce a formulation of what had previously been understood as ‘alcoholism’ – the alcohol dependence syndrome.
The alcohol dependence syndrome was seen as a cluster of seven elements that concur. It was argued that not all elements may be present in every case, but the picture is sufficiently regular and coherent to permit clinical recognition.   The syndrome was also considered to exist in degrees of severity rather than as a categorical absolute. Thus, the proper question is not ‘whether a person is dependent on alcohol’, but ‘how far along the path of dependence has a person progressed’.   The following elements are the template for which the degree of dependence is judged:

Narrowing of the drinking repertoire

A normal drinker’s consumption and choice of drink varies from day to day and week to week, with the drinking being patterned by varying internal cues and external circumstances.   The dependent person may drink to the same extent whether it is workday, weekend or holiday, irrespective of whether he is alone or in company, and whatever his mood. With advanced dependency, the drinking may become timetabled to maintain high alcohol levels.
Increased salience of the need for alcohol over competing needs and responsibilities
As dependence advances, the person gives priority to maintaining their intake. Their partner’s distressed complaints are ignored, income is used to support their drinking rather than provide for the family, and the need for drink may become more important for the person with liver damage than consideration of survival. A person who used to have moral standards now begs, borrows and steals to pay for drinking.

An acquired tolerance of alcohol

A given amount of alcohol will have a smaller effect on the dependent person than on a naïve drinker due to changes in brain function arising from repeated consumption of alcohol. Tolerance is also shown by the dependent person being able to sustain an alcohol intake and go about their business at blood alcohol levels that would incapacitate the non-tolerant individual.   However, in later stages of dependence this tolerance declines and the drinker is incapacitated by quantities of alcohol that he would previously hold easily.

Withdrawal symptoms

These vary from a mild shaking of the hands in the morning through to convulsions and the life-threatening illness of delirium tremens (confusion, hallucinations, tremor). As dependence increases, so does the frequency and severity of the symptoms. Symptoms of withdrawal may occur during the day as blood alcohol levels drop.    The four key symptoms are tremor, nausea, sweating and mood disturbance. A person may wake in the morning with soaking sweats, or they may vomit in the morning. In the early stages, a person may feel a ‘bit edgy’, but as dependence develops, they may experience terrible agitation and depression, or may show phobic reactions. Other symptoms include muscle cramps, sleep disturbance, hallucinations and grand mal seizures.

Relief or avoidance of withdrawal symptoms by further drinking

In the earlier stages of dependence, the person may feel at lunchtime that the first drink of the day ‘will help me straighten up a bit’.   At the other extreme, a person may require a drink every morning before they can get out of bed. They may try to maintain steady alcohol levels which they may have learnt to recognise as being comfortable above the danger level for withdrawal.

Subjective awareness of compulsion to drink

The person may become aware of their ability to lose control: ‘If I have one or two, I won’t stop’. They may start to experience and express their craving for alcohol. Cues for craving include the feeling of intoxication, incipient withdrawal, mood or situational cues (e.g. seeing a drinking friend). They may constantly think about alcohol when experiencing withdrawal.

Reinstatement after abstinence

If a severely dependent drinker is abstinent for a year and then attempts to return to social drinking, it is likely that within a few days they will be back to an intensity of withdrawal experience which had previously taken many years of drinking to develop. Dependence has memory.
There is no signpost to a person becoming dependent. Whilst a severely dependent person is easy to recognise, it can be difficult to detect a problem in the early stages.    Clearly, it is essential to be able to diagnose early problems, before drinking gets out of hand and there is a precipitous decline in the quality of life that accompanies increasing dependence.
In the latter stages of dependence, there may be rapidly mounting intensity of morning distress, appalling shakes and suicidal thoughts and delirium tremens. Gross and incapacitating intoxication becomes common.
The person is intoxicated after a couple of drinks, there is a gross and repeated amnesia (they may disappear for several days but not remember where), and there are desperate attempts to avoid withdrawal by topping up.   Drinking makes the person very ill – this is partly due to mounting intensity of morning distress, but also due to various alcohol-induced physical problems (e.g. liver disease). Psychiatric disorders may become common at this stage

Source: www.wiredin.org.uk 2009

Filed under: Effects of Drugs (Papers),Prevention (Papers) :

Two NIDA-funded studies identify health risks that  underscore the importance of curbing marijuana abuse.

BY PATRICK ZICKLER, NIDA Notes Contributing Writer                             

A large new epidemiological study suggests that marijuana smoke can cause the same types of respiratory damage as tobacco smoke. Significant associations between marijuana smoking and a variety of respiratory diseases also have been confirmed by an extensive review of clinical literature.

MONITORING THE EFFECTS OF TOBACCO AND MARIJUANA

Dr. Brent Moore and colleagues at Yale University, the National Cancer Institute, and the University of Vermont evaluated data from a nationally representative sample of 6,728 adults. Their analysis indicated that a history of more than 100 lifetime episodes of smoking marijuana, with at least one episode in the past month, increased an individual’s risk of chronic bronchitis, coughing on most days, wheezing, chest sounds without a cold, and increased phlegm.

“The most significant difference between tobacco smoke and marijuana smoke is their principal active ingredients—nicotine in tobacco and delta-9-tetrahydrocannabinol (THC) in marijuana. Beyond that, marijuana contains at least as much tar and half again as many carcinogens as smoke from conventional tobacco,” says Dr. Moore. “Quitting marijuana smoking may benefit respiratory health as much as quitting cigarettes, in addition to the clear and considerable health, psychological, and social benefits of no longer abusing an illicit drug.”

The information Dr. Moore and his colleagues analyzed was gathered through the third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988 and 1994. Participants included 4,789 nonsmokers of either tobacco or marijuana; 1,525 smokers of tobacco but not marijuana; 320 smokers of both marijuana and tobacco; and 94 who smoked marijuana only. On average, marijuana abusers had smoked the drug on 10 of the preceding 30 days, with 16 percent reporting daily or almost daily smoking. Tobacco smokers consumed roughly the same number of cigarettes—averaging 19.2 per day—whether or not they also smoked marijuana. Survey participants answered questions about their experiences of a range of respiratory symptoms and were examined for signs of respiratory abnormalities.

 

 

The researchers concluded that tobacco smokers who also smoked marijuana had a higher prevalence of most respiratory symptoms than tobacco-only smokers. Compared with tobacco-only smokers, however, those who also smoked marijuana were less likely to have had pneumonia during the previous year or to show spirometric evidence of obstructive pulmonary disorder. Commenting on this finding, Dr. Moore says that it is important to note that the marijuana smokers in the sample were significantly younger (average age 31.2 years) than the tobacco smokers (average age 41.5 years). “The marijuana-related respiratory effects correspond to a relatively young population, and NHANES III did not ask participants older than age 59 about drug use,” he adds. “It is likely that respiratory effects will be higher in older marijuana smokers, and, because of the high prevalence of tobacco use among marijuana smokers, there appears to be an increased risk for illness due to cumulative effects of smoking both drugs.”

MARIJUANA’S LONG-TERM PULMONARY EFFECTS

Further evidence of marijuana’s respiratory toxicity emerged from a study conducted by Dr. Donald Tashkin at the University of California, Los Angeles. Dr. Tashkin conducted an extensive review of clinical and epidemiological research to determine the extent to which chronic marijuana smoking might lead to long-term pulmonary effects and diseases similar to those caused by tobacco. Unlike the NHANES III data examined by Dr. Moore, the studies evaluated by Dr. Tashkin made it possible to assess a possible association between marijuana smoking and respiratory cancers.

The results of animal and cell culture studies are mixed with respect to the carcinogenic effects of THC, some studies showing that THC promotes lung cancer growth and others showing an anti-tumoral effect on a variety of malignancies. Although the results of epidemiological studies are also mixed, a large, recently completed case-control study has failed to find a direct link between marijuana use (including heavy use) and lung, throat, or other head and neck cancers. “Nevertheless, there is evidence that suggests precarcinogenic effects in respiratory tissue,” Dr. Tashkin says. “Biopsies of bronchial tissue provide evidence that regular marijuana smoking injures airway epithelial cells, leading to dysregulation of bronchial epithelial cell growth and eventually to possible malignant changes.” Moreover, he adds, because marijuana smokers typically hold their breath four times as long as tobacco smokers after inhaling, marijuana smoking deposits significantly more tar and known carcinogens within the tar, such as polycyclic aromatic hydrocarbons, in the airways. In addition to precancerous changes, Dr. Tashkin found that marijuana smoking is associated with a range of damaging pulmonary effects, including inhibition of the tumor-killing and bactericidal activity of alveolar macrophages, the primary immune cells within the lung.

Taken together, Dr. Tashkin’s survey of clinical and epidemiological studies and Dr. Moore’s assessment of self-reported and clinically observed effects provide an extensive catalog of respiratory and pulmonary damage associated with marijuana smoking. Smokers are subject to:

·         Coughing and phlegm production on most days;

·         Wheezing and other chest sounds;

·         Acute and chronic bronchitis;

·         Injury to airway tissue, including edema (swelling), increased vascularity, and increased mucus secretion;    

·         Impaired function of immune system components (alveolar macrophages) in the lungs.

Moore, B.A., et al. Respiratory effects of marijuana and tobacco use in a U.S. sample. Journal of General Internal Medicine 20(1):33-37, 2005. [Full Text]

Tashkin, D.P. Smoked marijuana as a cause of lung injury. Monaldi Archives for Chest Disease 63(2):93-100, 2005. [Abstract]

Hashibe, M., et al. Marijuana use and aerodigestive tract cancers: a population-based case control study. Cancer Epidemiology, Biomarkers & Prevention (In Press).

Source:NIDA Notes > Vol. 21, No. 1  Oct.2006

 

 

 

 

Filed under: Effects of Drugs (Papers),Medicine and Marijuana,Social Affairs (Papers) :

Background: Cannabis is the most widely used illegal drug worldwide. Long-term use of cannabis is known to cause chronic bronchitis and airflow obstruction, but the prevalence of macroscopic emphysema, the doseresponse relationship and the dose equivalence of cannabis with tobacco has not been determined.

Methods: A convenience sample of adults from the Greater Wellington region was recruited into four smoking groups: cannabis only, tobacco only, combined cannabis and tobacco and non-smokers of either substance. Their respiratory status was assessed using high-resolution CT (HRCT) scanning, pulmonary function tests and a respiratory and smoking questionnaire. Associations between respiratory status and cannabis use were examined by analysis of covariance and logistic regression.

Results: 339 subjects were recruited into the four groups. A dose-response relationship was found between cannabis smoking and reduced forced expiratory volume in 1 s to forced vital capacity ratio and specific airways conductance, and increased total lung capacity. For measures of airflow obstruction, one cannabis joint had a similar effect to 2.5–5 tobacco cigarettes. Cannabis smoking was associated with decreased lung density on HRCT scans. Macroscopic emphysema was detected in 1/75 (1.3%), 15/92 (16.3%), 17/91 (18.9%) and 0/81 subjects in the cannabis only, combined cannabis and tobacco, tobacco alone and nonsmoking groups, respectively.

Conclusions: Smoking cannabis was associated with a dose-related impairment of large airways function resulting in airflow obstruction and hyperinflation. In contrast, cannabis smoking was seldom associated with macroscopic emphysema. The 1:2.5–5 dose equivalence between cannabis joints and tobacco cigarettes for adverse effects on lung function is of major public health significance.

INTRODUCTION

Cannabis is used by an estimated 160 million people worldwide.1 Concerns regarding its pulmonary effects arose from the observation that it is qualitatively similar to tobacco, with the exception of their respective tetrahydrocannabinol (THC) and nicotine components.2 This observation led to a series of cross-sectional and longitudinal studies which showed that long-term cannabis smoking results in chronic bronchitis3–5 and airflow obstruction with impaired large airways function.6 However, other studies have failed to find an effect of cannabis smoking on lung function.7 These studies were limited by the unavailability of CT scanning to determine the presence of emphysema which a recent case series suggests may be associated with cannabis use.8 Importantly, it has not yet been possible to determine the dose-response relationship of long-term cannabis smoking with adverse respiratory effects using objective measures of pulmonary structure and function, or the dose equivalence of cannabis with tobacco consumption. In this study, lung function tests, high resolution CT scans and detailed questionnaires were used to determine the association between cannabis smoking (with and without tobacco) on pulmonary structure, function and symptoms. This study was undertaken in New Zealand because of the high prevalence of cannabis smoking and the infrequent practice of combining cannabis and tobacco.9

METHODS

Study population

Phase I: Random sample

Participants in the Wellington Respiratory Survey were randomly selected from the electoral register, equally distributed by sex across the five 10-year age groups from 25 to 75 years.10 11 Subjects were sent a single page postal questionnaire seeking demographic, respiratory and smoking history data. Those who completed and returned their questionnaires were invited to undertake a detailed interviewer administered questionnaire and investigative modules. Owing to the inadequate number of subjects who smoked cannabis in this random population sample, it was necessary to recruit a convenience sample for the study (see fig E2 in the online supplement available at http://thorax.bmj.com/supplemental). The results therefore pertain only to the convenience sample.

Phase II: Convenience Sample

A convenience sample of adults aged 18–70 years was recruited from the Greater Wellington area using newspaper and radio advertisements and through informal contacts. The stated purpose of the study was to investigate the health of cannabis smokers.

Smoking categories

Participants were recruited into four smoking categories: (1) cannabis only; (2) tobacco only; (3) combined cannabis and tobacco; and (4) non-smokers of either substance. Inclusion criteria for cannabis smokers and tobacco smokers were a lifetime exposure of at least 5 joint-years of cannabis or at least 1 pack-year of tobacco, respectively. A joint-year of cannabis was defined as smoking one joint per day for 1 year and a packyear of tobacco was equivalent to smoking 20 tobacco cigarettes per day for 1 year. Non-smokers had a lifetime exposure of,1 packyear of tobacco and 20 joints of cannabis.

Subjects were excluded if they had chronic lung disease (such as asthma, chronic bronchitis or cystic fibrosis) diagnosed by a doctor before the age of 16, were pregnant, were heterozygous or homozygous for a1-antitrypsin deficiency or they had used a substance of abuse other than cannabis, tobacco and alcohol .12 times in their lifetime. Subjects who claimed to be non-smokers were excluded as controls if they tested positive for urinary THC or cotinine.

Lung function tests

Participants underwent extensive pulmonary function testing using two Jaeger Master Screen Body volume constant plethysmography units (Masterlab 4.5 and 4.6 Erich-Jaeger, Wurtzberg, Germany). Tests performed included forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), maximum mid-expiratory flow (MMEF), slow vital capacity (SVC), total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC), specific airways conductance (sGaw) and carbon monoxide transfer factor (TLCO). Lung function tests were carried out before and after the administration of 400 mg salbutamol inhaled via a spacer device. TLCO measurements were corrected for haemoglobin and carboxyhaemoglobin and for lung volume to give the carbon monoxide transfer coefficient (TLCO/VA). Reference equations were those derived by the European Community for Coal and Steel.12

The lung function tests were conducted in accordance with American Thoracic Society 13 14 and European Respiratory Society15 guidelines and equipment was calibrated daily. Subjects were asked to refrain from caffeine and carbonated drinks for 6 h before testing and smokers were asked to refrain from tobacco for 2 h and cannabis for 6 h before testing. Shortacting bronchodilators were withheld for 6 h and long-acting bronchodilators for 36 h prior to testing. Testing was not carried out within 3 weeks of a respiratory tract infection.

CT scanning

Subjects were scanned, without contrast, using a single scanner (GE Prospeed, General Electrical Medical Systems, YMS, Japan) by two radiographers specifically trained in the study protocol. Scans were obtained at full inspiration with a breath hold time of 4.5 s (1 mm thickness high resolution axial images performed at 1 cm intervals with a 5126512 matrix, kVp 120, Ma .120).

The three images obtained at levels 1 cm above the superior margin of the aortic arch, 1 cm below the carina and 3 cm above the top of the diaphragm were used for measurements of lung density using a density mask programme. The trachea and main stem bronchi were excluded from the measurements of lung area, and lung tissue was separated from the chest wall using a density of 2300 to 21200 Hounsfield Units (HU) to calculate the total area of lung tissue per slice. The area below 2950 HU was expressed as a percentage of total lung area for that slice (RA950) and as the mean of three slices. The apical slice of the HRCT scan was analysed as a separate variable as it has been shown to be a better discriminator between controls and subjects with chronic obstructive pulmonary disease (COPD).10

All lung slices were subjectively analysed by two radiologists, blinded to the patient’s smoking history, for the presence and severity of emphysema, the type and distribution of any emphysematous change and any other morphological changes in the lung.

Other tests

Blood samples were taken from all participants for measurement of haemoglobin, carboxyhaemoglobin and a1-antitrypsin levels. A urine sample was collected for measurement of THC and the tobacco metabolite cotinine for the purpose of validating the subject groups. Atopy was defined by a positive skin prick test to at least one common allergen or a serum IgE level .100 kU/l.

Questionnaires

Participants completed a detailed respiratory questionnaire incorporating validated questions from the Compendium of Respiratory Standard Questionnaires (CORSQ).16 Questions were asked to determine smoking history, passive smoking exposure, respiratory symptoms, family history, occupation and known respiratory illnesses. Wheeze was defined as a whistling sound in the chest, either high or low pitched, at any time. Cough was considered significant if it occurred more than six times a day. Phlegm production referred to mucus production from the chest and excluded mucoid discharge from the nose. To meet the criteria for chronic bronchitis, phlegm production had to occur on most days for at least 3 months of the year for two consecutive years. Chest tightness was defined as a tight or heavy feeling in the chest. Passive smoking exposure was calculated using a modified version of the system used in the Po River Delta epidemiological study.17 Exposure was calculated for home, work and social places by multiplying hours per day 6days per week 6intensity. The three values were summed and multiplied by years of exposure to give a total exposure. Family history was a dichotomous variable defined as the presence or absence of a first degree relative with a family history of COPD, asthma, emphysema or chronic bronchitis. The occupational histories were coded using the New Zealand Standard Classification of Occupations 1999. Occupations associated with a higher risk of COPD were identified from the literature and subjects were assigned a ‘‘duration at risk’’ value in years. Socioeconomic status was derived from the New Zealand deprivation score, a composite of nine variables including income, employment and home ownership. Ethnicity was derived by priority coding of the responses into three groups; Maori, European and ‘‘other’’. The questionnaire was administered in a standardised manner by trained interviewers.

Subjects also completed a detailed questionnaire regarding their lifetime use of cannabis, which was a modified version of that used in previous studies.6 Information was obtained regarding amount, frequency, type and method of cannabis use and inhalation characteristics. The most common method of using cannabis in New Zealand is smoking a joint, in which cannabis is rolled in the form of a cigarette without the addition of tobacco.9 If subjects smoked cannabis in a form other than a joint (eg, pipes or bongs), they were asked to estimate the number of cannabis joints to which that would equate. This conversion allowed cannabis use for all participants to be quantified in terms of the total number of joints smoked. If subjects shared joints they were asked to estimate the proportion of the joint they actually smoked themselves. The total number of joint-years of cannabis smoked was calculated from the questionnaire. Subjects were additionally asked to calculate how many joints they would obtain per gram of cannabis. Both questionnaires were piloted before use.

Statistical analysis

For categorical variables, respiratory symptoms and the presence of macroscopic emphysema on CT scans, the association between cannabis and tobacco smoking, each treated as categorical predictor variables, and the presence or absence of the respiratory symptom and macroscopic emphysema was examined by logistic regression. As well as testing whether each of cannabis or tobacco smoking was associated with the symptom or CT scan result, adjusted each for the other, an interaction term was assessed to determine if the presence of cannabis smoking altered the association with tobacco smoking (ie, if cannabis smoking was an effect modifier as well as a confounding variable). With the relatively small number of subjects we were unable to adjust these associations for the other variables describing characteristics of the subjects. Odds ratios (ORs) for an association are reported together with 95% confidence intervals. Where an interaction term was significant at p=0.05, the effect of smoking cannabis on smokers of tobacco is also given.

For continuous variables, CT scan findings and pulmonary function tests, the association between cannabis and tobacco smoking was examined by analysis of covariance (ANCOVA), again treated as categorical predictor variables, together with testing for an interaction term between cannabis and tobacco smoking. These analyses were adjusted for age, sex, height, family history, passive smoking, ethnicity, atopy and years of working in an at-risk occupation. Type III sums of squares were used to check for the importance of cannabis and tobacco smoking each adjusted for the other. The adjusted difference between smokers of cannabis or tobacco smokers and nonsmokers of each substance is reported, together with how this difference was modified for tobacco smokers who also smoked cannabis where an interaction term between cannabis and tobacco smoking was significant at p=0.05. Normality assumptions were reasonably well met for the analyses.

As we found that smokers of cannabis and tobacco smoked less tobacco than tobacco only smokers, we also carried out ANCOVA treating cannabis and tobacco smoking as joint-years and pack-years, respectively, as detailed in the Methods section. For these analyses we adjusted for age, sex and height. Type III sums of squares were again used to evaluate the effect of each of cannabis and tobacco smoking adjusted for the other. The coefficients describing these associations show the number of units change in the particular pulmonary function variable for the amount smoked per extra joint-year for cannabis and packyear for tobacco.

RESULTS

Subject characteristics

Four hundred and forty-two volunteers presented to the clinic for screening, 103 of whom did not meet the inclusion criteria, leaving 339 for recruitment into the four smoking groups: cannabis only (n=75); combined cannabis and tobacco (n=91); tobacco only (n=92); non-smokers of either substance (n=81) (Participant flow diagram for inclusion of subjects can be found online at http://thorax.bmj.com/supplemental, figure E2). Urine testing confirmed a history of the absence of cannabis or tobacco smoking in the respective control groups. The characteristics of the participants are shown in table 1. The mean age of the four groups was similar and most of the participants were men. The distribution of ethnic groups was broadly representative of the distribution in the general population of New Zealand. Socioeconomic status was higher in the non-smoking group and the tobacco smoking group than in both cannabis smoking groups.

In the cannabis only group (n=75), all subjects reported smoking joints as the predominant form of cannabis consumption. Nine of these subjects (12%) reported having previously added tobacco to cannabis in the preparation of the joint, but in none of these subjects was this routine practice. In addition to smoking joints, 54 (72%) reported that they had also smoked cannabis by another method such as bongs or pipes.

In the combined cannabis and tobacco group (n=91), all subjects reported smoking joints as the predominant form of cannabis consumption. Twenty of these subjects (22%) reported adding tobacco to cannabis in the preparation of the joint. In addition to smoking joints, 72 (79%) reported that they had also smoked cannabis by another method such as bongs or pipes.

Cannabis smokers used similar amounts of cannabis whether or not they were also tobacco smokers. However, tobacco smokers who smoked cannabis smoked less tobacco than those who smoked tobacco alone, with a difference of 7.4 pack-years (95% CI 3.4 to 11.4).

As cannabis is purchased by weight and supplies are monitored with care, subjects were able to calculate the number of joints they obtained per gram of cannabis. They reported that the most common amount of cannabis purchased was a NZ$20 foil of median weight 1.1 g (range 1–5) from which the median number of joints obtained was 3 (range 1– 7.5). From these figures it was possible to calculate that the median amount of cannabis contained in one joint was 0.37 g, with considerable variability between subjects. As a reference, the standard weight of a tobacco cigarette is 1 g.

Associations between cannabis and tobacco use and measures of pulmonary structure, function and symptoms

Descriptive statistics for cannabis and tobacco use and measures of pulmonary structure, function and symptoms are shown in table 2. The statistical analysis of the effects of cannabis and tobacco use on these respiratory measures are summarised in table 3. The main effects represent the differences between smokers of cannabis and non-smokers of cannabis, and smokers of tobacco and non-smokers of tobacco, respectively.

Respiratory symptoms

Wheeze was associated with cannabis smoking, OR 1.3 (1.0 to 1.6), and tobacco smoking, OR 1.4 (1.1 to 1.9) with no evidence of an interaction. Chest tightness was associated with cannabis smoking, OR 1.4 (1.1 to 1.7), but not with tobacco smoking, OR 1.1 (0.9 to 1.3). Cough was associated with cannabis smoking, OR 1.5 (1.1 to 2.0), and tobacco smoking, OR 1.9 (1.4 to 2.6), however there was evidence of an interaction. The apparent effect of being a combined cannabis and tobacco smoker was to attenuate this association. For example, in tobacco smokers who also smoked cannabis the association with cough had an OR of 1.0 (0.7 to 1.4), indicating that for combined smokers of tobacco and marijuana there was no association with cough. Chronic bronchitis, defined as daily sputum production for at least 3 months of the year for greater than 2 years duration, was associated with cannabis use, OR 2.0 (1.4 to 2.7), and tobacco use, OR 1.6 (1.2 to 2.2). The presence of asthma diagnosed after the age of 16 years was associated with cannabis use, OR 1.7 (1.0 to 2.9), but not tobacco, OR 1.2 (0.7 to 1.9).

Lung function tests

Table 3 shows the main effects of cannabis and tobacco on the lung function tests. There was no statistically significant interaction between cannabis and tobacco smoking on TLC and TLCO/VA but, for FEV1/FVC, FEV1, MMEF and sGaw, there was a statistically significant interaction. Both cannabis and tobacco smoking were associated with a reduction in the FEV1/FVC ratio, but the effect of cannabis was only of marginal statistical significance. The effect of cannabis smoking in those who smoke tobacco was to attenuate this effect by 0.8% (95% CI –1.8% to 3.4%). Cannabis smoking had no effect on FEV1 but tobacco smoking reduced it. The effect of cannabis smoking on those who smoke tobacco was to attenuate this effect by 0.13 litres (95% CI – 0.08 to 0.36). Cannabis had no statistically significant effect on MMEF and tobacco smoking reduced it. The effect of cannabis on smokers was to attenuate this effect by 14.9 l/s (95% CI –10.5 to 40.2). Cannabis increased TLC with marginal statistical significance but tobacco had no effect on TLC. Neither cannabis nor tobacco had a statistically significant effect on RV or FRC. Cannabis and tobacco use reduced sGaw, although the effect was of marginal statistical significance for tobacco. Although the interaction term was statistically significant, cannabis smoking did not further reduce sGaw in those who smoked tobacco (–0.02 (95% CI –0.18 to 0.14)). For TLCO/VA (adjusted), cannabis had no effect while tobacco smoking reduced this measurement.

High-resolution CT scanning

Cannabis smoking was associated with an increased percentage of low density lung tissue both on the apical slice and the mean of the three slices but tobacco smoking showed no such association and there was no evidence of an interaction (table 3). Tobacco smoking was associated with the presence of macroscopic emphysema (OR 5.7 (95% CI 2.1 to 15.6)) while cannabis smoking was not (OR 1.0 (95% CI 0.7 to 1.4)). An interaction term could not be calculated for macroscopic emphysema. In the two tobacco smoking groups (with and without cannabis) there was no difference in the distribution of emphysema (centrilobular versus paraseptal). The one cannabis only subject with macroscopic emphysema had a 437 joint-year history.

Cannabis and tobacco use as continuous variables

Cannabis use, analysed as joint-years, predicted FEV1/FVC ratio, sGaw, FRC and TLC, but was not associated with FEV1, TLCO/VA or MMEF. Tobacco use was also associated with FEV1/ FVC ratio, FRC and sGaw but not with TLC. The regression coefficients describing some of the associations are shown in table 4. The interpretation of these coefficients is the number of units change for the respiratory response variable per unit change in joint-years of cannabis or pack-years of tobacco smoked. For example, the FEV1/FVC ratio, expressed as a percentage, decreased by 1.5% for each 10 pack-years of tobacco smoking. One pack-year of tobacco was equivalent to 7.9, 4.4 and 4.1 joint-years for the effect on FEV1/FVC, FRC and sGaw, respectively. As 1 pack-year represents 20 cigarettes per day for 1 year, it could be calculated that one joint was equivalent to 2.5–5 tobacco cigarettes for the effect on FEV1/FVC, FRC and sGaw.

DISCUSSION

This study has identified the nature and magnitude of the effects of cannabis smoking on respiratory structure, function and symptoms. There was a dose-response relationship of cannabis smoking with airflow obstruction, impaired large airways function and hyperinflation. For measures of airflow obstruction, one joint of cannabis had a similar effect to that of 2.5–5 tobacco cigarettes. In contrast, cannabis smoking was uncommonly associated with macroscopic emphysema, which was present almost entirely in the tobacco smoking groups.

There are several methodological issues relevant to the interpretation of the results. The first was the inability to identify a sufficient number of cannabis smokers from the random population sample. Despite starting with an initial postal questionnaire of 3500 adults, only 19 met the criteria for smoking at least 5 joint-years with no other illegal drug use and no chronic respiratory disorder such as asthma in childhood. It was apparent that it was not possible to use a random population sample for a study of this nature and, as previously,6 a convenience sample was used. While this approach incurred the risk of selection bias by preferentially attracting people concerned about their respiratory health, this applies equally to all subject groups. We applied strict exclusion criteria for other illegal drug use due to their potential respiratory effects.18 This meant that many potential participants were ineligible, particularly the heaviest cannabis users who were more likely to have used other drugs. As a result, these criteria preferentially excluded such heavy users, suggesting that the effects observed may represent a conservative estimate.

The requirement for tobacco smokers to have a history of at least 1 pack-year was based on the data that tobacco smokers need to smoke in excess of this amount to develop abnormal lung function.19 The requirement for cannabis smokers to have a history of at least 5 joint-years was based on the data that one cannabis joint results in three to five times higher levels of carbon monoxide and tar deposition, respectively,20 thereby achieving an a priori equivalence between the lower limit of cannabis and tobacco smoking levels. It also ensured that experimental users who did not smoke cannabis habitually were excluded.

Cannabis remains illegal in New Zealand although participants were willing to volunteer under the assurance of strict confidentiality. All subjects in the groups with no cannabis or no tobacco use had negative samples for THC or cotinine, demonstrating the honest reporting of the subjects in this regard. A further problem is that cannabis use is often difficult to quantify precisely due to smokers sharing joints, different inhalation techniques and different ways of smoking cannabis including joints, pipes and bongs. In order to standardise use, subjects were asked to estimate the ‘‘joint equivalent’’ used by these methods to enable cannabis use to be expressed as jointyears of use. In our community the median amount of cannabis in a joint was 0.37 g, although there was considerable variability in the amount of cannabis in joints prepared by different subjects. By comparison, the average amount of tobacco in a commercial cigarette of standard length is 1 g.

Although the calculation of joint-years was based on subjects’ self-reports, there is evidence that cannabis use is more accurately reported than other drugs21 and self-reports have been shown to correlate well with urinary THC levels.22 Influential factors in increasing the validity of self-reported drug use include privacy, anonymity and credibility of the study. Every effort was made to create a relaxed and confidential environment to increase the accuracy of reporting, and all subjects gave informed consent.

The practice of combining cannabis and tobacco within a joint is relatively uncommon in New Zealand.9 In our sample of cannabis only smokers, 12% had combined their cannabis with tobacco on some occasions although it was not routine practice in any of these subjects. As a result, the small quantities of tobacco used by cannabis only smokers were unlikely to significantly affect the results.

As this study was exploratory, caution must be used in interpreting the presence or absence of associations. In particular, we analysed a number of measures of pulmonary structure, function and symptoms without any adjustment for the inflation of type I error that may ensue. For some variables where we failed to find associations, this may reflect a relative lack of statistical power for any individual analysis.

The most important finding was that one joint of cannabis was similar to 2.5–5 tobacco cigarettes in terms of causing airflow obstruction. This dose equivalence is consistent with the reported 3–5-fold greater levels of carboxyhaemoglobin and tar inhaled when smoking a cannabis joint compared with a tobacco cigarette of the same size.20 This pattern is likely to relate to the different characteristics of the cannabis joint and the way in which it is smoked. Cannabis is usually smoked without a filter23 and to a shorter butt length,24 and the smoke is a higher temperature. Furthermore, cannabis smokers inhale more deeply,20 hold their breath for longer20 and perform the Valsalva manoeuvre at maximal breath hold.25

Our findings have extended previous observations that the principal physiological impairment with long-term cannabis smoking is on large airway function6 by demonstrating a doseresponse relationship for sGaw. Similarly, a dose-response relationship was observed with measures of airflow obstruction and hyperinflation which are a consequence of the large airways impairment. Previous research has shown that this large airways impairment is probably due to the inflammation and oedema that occurs in the tracheobronchial mucosa of cannabis smokers,26 as well as mucus hypersecretion.27 It is well recognised that an increase in airway resistance leads to hyperinflation.28 These effects are also likely to contribute to the increased prevalence of symptoms of wheezing, cough and sputum production associated with cannabis smoking, resulting in the twofold increased prevalence of chronic bronchitis. These findings are unlikely to be due to pre-existing disease as subjects were excluded if they had chronic lung disease diagnosed by a doctor before the age of 16 years.

Another novel finding was the effect of cannabis smoking— but not tobacco smoking—on lung density, which has been proposed as a marker of emphysema.29 30 However, we and others have observed that decreased lung density may not be specific to emphysema10 31–34 and correlates more closely with markers of airflow obstruction and hyperinflation.11 As a result, we have interpreted our lung density findings as being predominantly due to the effect of cannabis smoking on airflow obstruction and hyperinflation rather than causing emphysema. This interpretation is consistent with our finding that macroscopic emphysema was present almost entirely in the tobacco smoking groups. Furthermore, tobacco—but not cannabis use—was associated with a significant reduction in TLCO, the most specific lung function measure of emphysema in subjects with airflow obstruction.35 Thus, while a case series has shown that heavy cannabis smoking may cause macroscopic emphysema at a young age with a characteristic apical paraseptal pattern,8 our findings would suggest that this is not a common complication with the amount of cannabis smoked in New Zealand. Importantly, it suggests that cannabis does not cause emphysema when smoked in sufficient quantities to cause airflow obstruction, hyperinflation and chronic bronchitis.

Finally, we observed that, whereas cannabis smokers used similar amounts of cannabis whether or not they were tobacco smokers as well, tobacco smokers who used cannabis smoked less tobacco than those who smoked tobacco alone. Similarly, a study from the USA reported that, whereas cannabis users more often smoked tobacco, they were less likely than never cannabis users to be heavy long-term users of tobacco, as defined by a level of .30 pack-years.36 However, this lesser amount of tobacco in combined users did not result in reduced adverse respiratory effects compared with tobacco only smokers because of the additional effects of the cannabis use.

In conclusion, these findings suggest that the predominant effects of cannabis on pulmonary structure, function and symptoms are in causing the symptoms of wheezing, cough, chest tightness and sputum production, large airways obstruction and hyperinflation, but not emphysema. The dose equivalence of 1:2.5–5 between cannabis joints and tobacco cigarettes in causing airflow obstruction is of major public health significance.

ACKNOWLEDGEMENTS

The authors thank the subjects who participated in the study and Denise Fabian, Avrille Holt, Patricia Heuser, Eleanor Chambers, Andrew Kingzett-Taylor and the radiology and administrative staff of Pacific Radiology Ltd for their contribution to this study.

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Source: From thorax.bmj.com on March 3, 2011 – Published by group.bmj.com

Filed under: Cannabis/Marijuana,Drug use-various effects,Effects of Drugs (Papers),Health :

The human brain is also a system of subsystems and there is now overwhelming evidence that the development of the human brain continues well into adolescence up to age 20. We know that the brain is vulnerable to toxic substances that can cause cognitive dysfunctions in adults. There is substantial literature on the consequences of acute and chronic marijuana exposure in adults, including measures of cognitive and behavioral effects, as well as some measures of alterations in brain function, primarily in the domains of learning and memory. There have been relatively few studies, however, of the effects of exposure to marijuana during development,
Some have reported that a delay in adolescent brain development is common when alcohol and or other drug usage including marijuana – begins at a young age. Some frequent users feel a lack of initiative and concern about the future, find it hard to become or stay motivated, and think things will take care of them selves, (Wapner, Roger, 1995). As a result, the normal maturation process is interrupted. Development of coping skills, a code of ethics, acceptance of responsibility, and other signs of maturity frequently cease or regress. A frequent user’s emotional development may be delayed when he starts using, and may take much longer to develop once the user has become clean and sober for an extended period of time. Drug misuse usually leads to denial. Denial is one of the hallmarks of chemical dependency. Frequent users not only deny that their drug use is a problem; they may begin using denial to pretend other problems do not exist either. Forgotten birthdays, missed social engagements, and unmet commitments are all no big deal . (Wapner, Roger, 1995)
Jonathon Shedler and Jack Block (University of California, Berkeley) have done extensive studies of teenagers, which included abstainers, occasional users, and frequent users. Frequent users are described (by family and peers) as not dependable or responsible, not productive or able to get things done, guileful and deceitful, opportunistic, unpredictable and changeable in attitudes and behavior, unable to delay gratification, rebellious and nonconforming, prone to push and stretch limits, self-indulgent, not ethically consistent, not having high aspirations, and prone to express hostile feelings directly. (Shedler and Block, 1990)
Marijuana Effects
The specific effects of marijuana, however, vary greatly, depending on the quality and dosage of the drug, the personality and mood of the user, the user s past experiences with the drug, the social setting, and the user s expectations.
Considerable consensus exists however among regular users that when marijuana is smoked and inhaled, a state of slight intoxication results. This state is one of mild euphoria distinguished by increased feelings of well-being, heightened perceptual acuity, and pleasant relaxation, often accompanied by a sensation of drifting or floating away. Sensory inputs are intensified. Often a person’ s sense of time is stretched or distorted, so that an event that lasts only a few seconds may seem to cover a much longer span. Short-term memory may also be affected, as one notices that a bite has been taken out of a sandwich but does not remember having taken it. For most users, pleasurable experiences, including sexual intercourse, are reportedly enhanced. When smoked, marijuana is rapidly absorbed and its effects appear within seconds to minutes but seldom last more than 2 to 3 hours (Butcher, Mineka, & Hooley, 2004).
Marijuana may lead to unpleasant as well as pleasant experiences. For example, if a person uses the drug while in an unhappy, angry, suspicious, or frightened mood, these feelings may be magnified. With higher dosages and with certain unstable or susceptible individuals, marijuana can produce extreme euphoria, hilarity, and over talkativeness, but it can also produce intense anxiety and depression as well as delusions, hallucinations, and other psychotic-like experiences. Evidence suggests a strong relationship between daily marijuana use and the occurrence of self-reported psychotic symptoms (Tien & Anthony, 1990).

One study exploring past substance use history in incarcerated murderers reported that among men who committed murder, marijuana was the most commonly used drug. One-third indicated that they used the drug before the homicide, and two-thirds were experiencing some effects of the drug at the time of the murder (Spunt et al., 1994).
Marijuana does not lead to extreme physiological dependence, as heroin does. It can, however, lead to psychological dependence, in which the person experiences a strong need for the drug whenever he or she feels anxious or tense. In fact, recent research has reported that many marijuana use abstainers reported having withdrawal-like symptoms such as nervousness, tension, sleep problems, and appetite change (Budney, Hughes, et al., 2001; Kouri and Pope, 2000). One recent study of substance abusers reported that marijuana users were more ambivalent and less confident about stopping use than were cocaine abusers (Budney, Radonovich, et al., 1998).
Self Diagnosis
1. Does your periodic marijuana use and intoxication interfere with your performance at work or school?
2. Is your periodic marijuana use and intoxication physically hazardous in situations such as driving a car?
3. Do you or have you had legal problems as a consequence of arrests for marijuana possession?
4. Do you or have you had arguments with spouses or parents over the possession of marijuana in the home or its use in the presence of children?
If you answered Yes to any one of the above you may meet criteria for a diagnosis of Cannabis Abuse and I would recommend that you undergo an alcohol/ substance abuse evaluation by a Certified Substance Abuse Counselor (CSAC) and comply with all treatment recommendations.
If you are having psychological or physical problems associated with compulsively using marijuana, such as:

1. Craving;
2. Withdrawal symptoms;
3. Irritability;
4. Sleeplessness; and/ or
5. Anxiety
– when trying to quit, then a diagnosis of Cannabis Dependence should be considered rather than Cannabis Abuse. Likewise, I would recommend that you undergo an alcohol/ substance abuse evaluation by a Certified Substance Abuse Counselor (SAC) and comply with all treatment recommendations.
Multiple Addictions
In 2001, marijuana was a contributing factor in more than 110,000 emergency department visits in the United States. In a survey of drug-related visits to the emergency room (DAWN Report, 2001), 16 percent of drug-related visits were for marijuana abuse. Many of these emergency room visits, as one might suspect, involved the use of other substances along with marijuana. If you had trouble answering Yes to one of the above self-diagnosis questions, because you have used alcohol and/ or other drugs along with marijuana and you cannot contribute your problems to marijuana alone, then you may meet the criteria for Poly-substance Dependence and or Poly-behavioral Addiction, see below. other addictions co-exist, the initial therapeutic intervention for any addiction needs to include an assessment for other addictions. National surveys revealed that very high correlation exists between cannabis abuse and/ or other substance abuse and behavioral addictions.
Poor Prognosis
We have come to realize today more than any other time in history that the treatment of Cannabis Dependence and other lifestyle diseases and behavioral addictions related to gambling, food, sex, and/ or religion, (etc.) are often a difficult and frustrating task for all concerned. Repeated failures abound with all of the addictions, even with utilizing the most effective treatment strategies. But why do 47% of patients treated in private addiction treatment programs (for example) relapse within the first year following treatment (Gorski, T., 2001)? Have addiction specialists become conditioned to accept failure as the norm? There are many reasons for this poor prognosis. Some would proclaim that addictions are psychosomatically- induced and maintained in a semi-balanced force field of driving and restraining multidimensional forces. Others would say that failures are due simply to a lack of self-motivation or will power. Most would agree that lifestyle behavioral addictions are serious health risks that deserve our attention, but could it possibly be that patients with multiple addictions are being under diagnosed (with a single dependence) simply due to a lack of diagnostic tools and resources that are incapable of resolving the complexity of assessing and treating a patient with multiple addictions?
Diagnostic Delineation
Thus far, the DSM-IV-TR has not delineated a diagnosis for the complexity of multiple behavioral and substance addictions. It has reserved the Poly-substance Dependence diagnosis for a person who is repeatedly using at least three groups of substances during the same 12-month period, but the criteria for this diagnosis do not involve any behavioral addiction symptoms. In the Psychological Factors Affecting Medical Condition s section (DSM-IV-TR, 2000); maladaptive health behaviors (e.g., unsafe sexual practices, excessive alcohol, drug use, and over eating, etc.) may be listed on Axis I, only if they are significantly affecting the course of treatment of a medical or mental condition. Since successful treatment outcomes are dependent on thorough assessments, accurate diagnoses, and comprehensive individualized treatment planning, it is no wonder that repeated rehabilitation failures and low success rates are the norm instead of the exception in the addictions field, when the latest DSM-IV-TR does not even include a diagnosis for multiple addictive behavioral disorders. Treatment clinics need to have a treatment planning system and referral network that is equipped to thoroughly assess multiple addictive and mental health disorders and related treatment needs and comprehensively provide education/ awareness, prevention strategy groups, and/ or specific addictions treatment services for individuals diagnosed with multiple addictions. Written treatment goals and objectives should be specified for each separate addiction and dimension of an individuals life, and the desired performance outcome or completion criteria should be specifically stated, behaviorally based (a visible activity), and measurable.
New Proposed Diagnosis
To assist in resolving the limited DSM-IV-TRs diagnostic capability, a multidimensional diagnosis of Poly-behavioral Addiction, is proposed for more accurate diagnosis leading to more effective treatment planning. This diagnosis encompasses the broadest category of addictive disorders that would include an individual manifesting a combination of substance abuse addictions, and other obsessively-compulsive behavioral addictive behavioral patterns to pathological gambling, religion, and/ or sex / pornography, etc.). Behavioral addictions are just as damaging – psychologically and socially as alcohol and drug abuse. They are comparative to other life-style diseases such as diabetes, hypertension, and heart disease in their behavioral manifestations, their etiologies, and their resistance to treatments. They are progressive disorders that involve obsessive thinking and compulsive behaviors. They are also characterized by a preoccupation with a continuous or periodic loss of control, and continuous irrational behavior in spite of adverse consequences.
Poly-behavioral addiction would be described as a state of periodic or chronic physical, mental, emotional, cultural, sexual and/ or spiritual/ religious intoxication. These various types of intoxication are produced by repeated obsessive thoughts and compulsive practices involved in pathological relationships to any mood-altering substance, person, organization, belief system, and/ or activity. The individual has an overpowering desire, need or compulsion with the presence of a tendency to intensify their adherence to these practices, and evidence of phenomena of tolerance, abstinence and withdrawal, in which there is always physical and/ or psychic dependence on the effects of this pathological relationship. In addition, there is a 12 – month period in which an individual is pathologically involved with three or more behavioral and/ or substance use addictions simultaneously, but the criteria are not met for dependence for any one addiction in particular (Slobodzien, J., 2005). In essence, Poly-behavioral addiction is the synergistically integrated chronic dependence on multiple physiologically addictive substances and behaviors (e.g., using/ abusing substances – nicotine, alcohol, & drugs, and/or acting impulsively or obsessively compulsive in regards to gambling, food binging, sex, and/ or religion, etc.) simultaneously.
Multidimensional Treatment
Since chronic lifestyle diseases and disorders such as diabetes, hypertension, alcoholism, drug and behavioral addictions cannot be cured, but only managed – how should we effectively manage poly-behavioral addiction?
The Addiction Recovery Measurement System (ARMS) is proposed utilizing a multidimensional integrative assessment, treatment planning, treatment progress, and treatment outcome measurement tracking system that facilitates rapid and accurate recognition and evaluation of an individual s comprehensive life-functioning progress dimensions. The ARMS hypothesis purports that there is a multidimensional synergistically negative resistance that individual s develop to any one form of treatment to a single dimension of their lives, because the effects of an individual ‘s addiction have dynamically interacted multi-dimensionally. Having the primary focus on one dimension is insufficient. Traditionally, addiction treatment programs have failed to accommodate for the multidimensional synergistically negative effects of an individual having multiple addictions, (e.g. nicotine, alcohol, and obesity, etc.). Behavioral addictions interact negatively with each other and with strategies to improve overall functioning. They tend to encourage the use of tobacco, alcohol and other drugs, help increase violence, decrease functional capacity, and promote social isolation. Most treatment theories today involve assessing other dimensions to identify dual diagnosis or co-morbidity diagnoses, or to assess contributing factors that may play a role in the individual s primary addiction. The ARMS theory proclaims that a multidimensional treatment plan must be devised addressing the possible multiple addictions identified for each one of an individual s life dimensions in addition to developing specific goals and objectives for each dimension.
Conclusion
This article was not written with the intent to demonize or glorify the most widely used illicit and top US cash crop (U.S. growers produce nearly $35 billion worth of marijuana annually, making the illegal drug the country’s largest cash crop, bigger than corn and wheat combined, an advocate of medical marijuana use said in a study released on 18 Dec. 06, WASHINGTON), Reuters. Nor was it written to advocate the use or non-use of marijuana whether legally for medicinal purposes or illegally.
There are numerous articles readily available that already accomplish that mission. It is my hope though, that the 10 to 15 percent of individuals that have multiple complex problems involving marijuana usage will find the help that they need. Considering the wide range of addictive behaviors in our world today, one should always take into account an individual s ethnic, cultural, religious, and social background prior to making any clinical judgments, and it would be wise to not over-pathologize in this area. However, since successful treatment outcomes are dependent on thorough assessments, accurate diagnoses, and comprehensive individualized treatment planning – Poly-behavioral Addiction needs to be identified to effectively treat the complexity of multiple behavioral and substance addictions.
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Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits, April 2006
Substance Abuse and Mental Health Services Administration, Mortality Data from the Drug Abuse Warning Network, 2001 (PDF), January 2003.
Substance Abuse and Mental Health Services Administration, Treatment Episode Data Set (TEDS) Highlights 2004 (PDF), February 2006
Federal Bureau of Investigation, Crime in the United States, 2005, September 2006
National Drug Intelligence Center, National Drug Threat Assessment 2007, October 2006
Bureau of Justice Statistics, Drug Use and Dependence, State and Federal Prisoners, 2004, October 2006
United States Sentencing Commission, 2005 Sourcebook of Federal Sentencing Statistics, June 2006
National Drug Intelligence Center, National Drug Threat Assessment 2007
James Slobodzien, Psy.D. CSAC, is a Hawaii licensed psychologist and certified substance abuse counselor who earned his doctorate in Clinical Psychology. The National Registry of Health Service Providers in Psychology credentials Dr. Slobodzien. He has over 20-years of mental health experience primarily working in the fields of alcohol/ substance abuse and behavioral addictions in medical, correctional, and judicial settings. He is an adjunct professor of Psychology and also maintains a private practice as a mental health consultant.

Filed under: Effects of Drugs (Papers) :

A large multi-cohort analysis has investigated factors affecting long-term response to potent antiretroviral therapy. Four to six years after starting anti-HIV treatment, higher rates of AIDS and mortality were seen in injection drug users and in those who had had AIDS-defining events or CD4 cell counts less than 25 cells/mm3 before starting therapy. The study, conducted by the Antiretroviral Therapy Cohort Collaboration, was published in the December 15th issue of the Journal of Acquired Immune Deficiency Syndromes.

Previous studies have found that rates of AIDS-related illness and death are higher in people who begin antiretroviral therapy with lower CD4 cell counts. Poorer response has also been found in injection drug users (IDUs) compared to other patients. However, most studies to date have looked at response over relatively short time periods. In this study, the Antiretroviral Therapy Cohort Collaboration (an international alliance of investigators from sixteen cohort studies of people with HIV – see www.art-cohort-collaboration.org) analysed data from 20,379 HIV-positive adults who had been on anti-HIV drugs for up to six years.

Participating cohorts were included if they had enrolled at least 100 treatment-naïve patients, 16 years of age or older, who had begun treatment with a combination of at least three antiretroviral agents. People with baseline viral loads less than 1000 copies/ml were excluded as possibly not treatment-naïve. This yielded a total of 20,379 patients from twelve European and North American cohorts. (A prognostic model based on this same data set was recently published – see the aidsmap report here)

Baseline characteristics were as follows: median age, 36; median CD4 cell count 224 cells/mm3; median month of therapy initiation, February 1999. Before treatment initiation, 2737 patients (23%) had already had a diagnosis of AIDS; 3231 (16%) were presumed infected due to IDU.

Of the initial regimens, 66% were NRTI/PI, 24% NRTI/NNRTI, 7% NRTI only, 2% triple-class; and 2% other (NRTI-sparing, or including T-20). The majority of participants (88%) began on a three-drug regimen.

Over a total of 61,798 person-years of follow-up, 1844 participants developed at least one AIDS-defining event, and 1005 died. AIDS-defining events and deaths were analysed by: baseline CD4 cell count (<25, 25 to 49, 50 to 99, 100 to 199, 200 to 349, and >350 cells/mm3), baseline viral load (<100,000 or ≥100,000 copies/ml), presumed mode of transmission (IDU or other), and AIDS diagnosis before baseline (yes or no). Consistent with previous studies, lower baseline CD4 cell counts were consistently the strongest predictor of poorer outcomes. The effect was strongest for the lowest baseline counts, and tended to decline with length of time on therapy for all strata of CD4 count. Beginning therapy at a baseline CD4 cell count between 200 and 349 continued to show a benefit until the four-year mark. Compared to those beginning at >350 cells/mm3 (the comparator group), the hazard ratio for progression to AIDS at one to two years on therapy was 1.5 (95% confidence interval [CI]: 1.0 to 2.3), 1.4 at two to three years (95% CI: 1.0 to 2.1), and 1.0 at four to six years (95% CI: 0.6 to 2.0). For each time period, hazard ratios were progressively higher for each lower CD4 stratum. For baseline CD4 counts <25 cells/ mm3, the hazard ratio for developing AIDS was 3.7 at one to two years (95% CI: 2.2 to 6.1), 2.4 at two to four years (95% CI: 1.5 to 3.8), and 2.3 at four to six years (95% CI: 1.0 to 2.3). At four to six years, the hazard ratio for mortality was 2.5 (95% CI: 1.2 to 5.5) for baseline CD4 counts <25 cells/ mm3. For people presumed infected through IDU, at four to six years on HAART, the hazard ratio for AIDS was 1.6 (95% CI: 0.8 to 3.0) and the hazard ratio for mortality was higher at 3.5 (95% CI: 2.2 to 5.5). Note that cause of death was not analysed and was not necessarily directly due to HIV; mortalities due to hepatitis-related liver disease, overdose, trauma and other causes were not excluded. Mortality rates were still lower than would be expected in the absence of anti-HIV therapy. Diagnosis of AIDS before the initiation of anti-HIV treatment also continued to predict AIDS-defining events at four to six years, with a hazard ratio of 2.3 (95% CI: 1.2 to 4.4); the predictive value for mortality ceased to be significant. HIV viral load (greater than, or less than, 100,000 copies/ml) was not a significant predictor of progression or death at any time point. The study was limited by declining numbers of patients in follow-up after longer periods on antiretroviral treatment. At the end of the fourth year of anti-HIV therapy, 6838 participants were still being followed (23% of the original cohort); only 791 (4%) were followed for more than six years. As most original patients were still being followed up at the time of analysis, the researchers "do not believe that informative censoring is likely to be an important source of bias." However, results may have been confounded by socioeconomic and other factors which caused people to begin treatment late in the course of HIV progression. Larger hazard ratios for mortality than for development of AIDS were seen in several groups, which may be evidence of such confounding. Also, race and ethnicity were not included in the analysis due to lack of sufficient data. The researchers concluded that "rates of AIDS and death were persistently higher in patients infected [through injection drug use]", and that "although the prognostic value of baseline CD4 count and a prior AIDS diagnosis declined with time, patients who were severely immunodeficient when they started therapy experienced higher rates of AIDS and death up to 6 years later." They believe these results may "strengthen the case for screening for HIV, because delaying treatment… has long-term disadvantages." Reference Antiretroviral Therapy Cohort Collaboration. Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collaborative analysis of cohorts of HIV-1–infected patients. J Acquir Immune Defic Syndr 46 (5):607-615, 2007. Source: Wednesday, January 2, 2008
http://www.aidsmap.com/en/news/8ACEB690-26EB-4583-BF14-A4353CE335EC.asp

Filed under: Effects of Drugs (Papers) :

“Drug [including alcohol] addictions are medical diseases which deserve parity in national healthcare programmes…” states scientist and professor Carlton Erickson, as he reveals the neurobiological research.
Although this article was first printed in Addiction Today journal in 2002, the vast majority of alcohol and drug workers remain unaware of these vital facts. Read on…
Public and professional stigma against addictive diseases is a major social problem when dealing with conditions which have traditionally been dealt with by behavioural and spiritually-based programmes. Reducing this stigma is critical, as negative attitudes damage the level and quality of patient care – and funding for prevention, education and research.
For far too many years, the “field” of drug addiction treatment and prevention has drifted aimlessly, based on insufficient research evidence that addictions are brain diseases and about the pharmacology of addicting drugs. Much of the confusion is based on an incomplete understanding of the differences between intentional drug abuse and pathological drug dependence, the “new term for addiction”.
There is also a great deal of misinformation about the pharmacology of addicting drugs. This picture is changing rapidly, based on new neuroscience (brain) research which strongly indicates that the pleasure pathway – the medial forebrain bundle – of the brain is affected by all addictions, particularly in the pharmacological qualities of euphoria, craving and a theoretical concept of “drug need”.
This is the psychological correlate of behavioural “impaired control”. The neuroanatomical and neurochemical bases of drug need have yet to be demonstrated in the laboratory. But the research technology, such as brain scans, is now at hand to test the theories.
Everyone who cares about the victims of addiction must become more scientifically literate about the implications of new research findings, and ‘spread the news’ that biomedical research is on the threshold of proving what recovering people already know – that drug dependencies are medical diseases which deserve parity in present and future national healthcare programmes. Drug dependence must also be ‘handled’ differently from drug abuse in terms of responsibility and culpability in law enforcement.
This article covers the latest research on the neurobiology of dependence, including how the brain’s pleasure pathway works. It covers the differences between chemical abuse and chemical dependency, the latest therapies for drug dependency, and research methodologies which promise even more exciting breakthroughs in understanding “addictions” in the future. This information has important implications for prevention and education of the public about the true causes of drug problems, and how society can best deal with such problems.

SOLUTIONS
The solution. First, get rid of “Spam”: an acronym for stigma, prejudice, anger and misunderstanding. All of these lead to myths – widely-held, inaccurate beliefs – as compared to research-generated facts.
And there are some dangerous myths in this world. These include the myths that club drugs and marijuana are not addicting… that everyone who uses cocaine or heroin is addicted… that caffeine is highly addicting… that the form of a drug and how it is taken affects its “addiction potential”… and that alcoholics can stop drinking, since all they have to do is go to AA meetings.

TWO CRITICAL DEFINITIONS.
brain
It is vital that professionals carry out assessments to distinguish between chemical abuse and dependence. As the cover story by Norman Hoffman in the last issue of Addiction Today emphasises, assessment directly affects what type of treatment is most effective for each client, and thus their care plan, choice of treatment unit and outcome results. To distinguish between the two is the most humane, most cost-effective and most professional course of action.
Chemical abuse is intentional overuse of substances in cases of celebration, anxiety, despair or ignorance. It is about people making bad choices about the use of drugs. It declines with adverse consequences, supply reduction or change in drug-use environment. Drug abusers have a major economic impact on society; for example, it is estimated that property theft to fund drug habits accounts for at least £2billion a year in the UK.
The criteria for chemical abuse, according to the DSM-IV diagnostic and statistical manual, are:
1) a maladaptive pattern of drug use leading to impairment or distress, presenting as one or more of the following over a 12-month period –
• recurrent use leading to failure to fulfill obligations
• recurrent use that is physically hazardous
• recurrent drug-related legal problems, and
• continued use despite social/interpersonal problems
2) the symptoms have never met the criteria for chemical dependence.
Dependence is “impaired control” over drug use, probably caused by a dysfunction in the brain’s pleasure pathway. This is the disease of addiction, an “I can’t stop without help” disease. It requires formal therapy and/or 12 steps and might require anti-craving drug therapy. The DSM-IV criteria for chemical dependence are:
1) a maladaptive pattern of drug use, leading to impairment or distress, presenting as three or more of the following over a 12-month period –
• tolerance to the drug’s actions
• withdrawal (generally, physical withdrawal)
• drug is used more than intended
• there is an inability to control drug use
• effort is expended to obtain the drug
• important activities are replaced by drug use, and
• drug use continues despite negative consequences
2) two types of dependence can occur –
• physiological dependence, including tolerance and withdrawal, and
• non-physiological dependence, excluding tolerance and withdrawal.
The terms “physical addiction” and “psychological addiction” are no longer valid, since the DSM-IV term includes both psychological and physical components.

DOES DRUG ABUSE LEAD TO DEPENDENCE?
A five-year follow-up of 1,300 men and women (Schuckit et al 2001) found that only 3% of abusers met criteria for dependence five years after being diagnosed as abusers. But many people believe that abuse usually leads to dependence. Instead, the two conditions appear to be separate; abuse may be a milder disorder not usually progressing to dependence.

RISK OF DEPENDENCE.
Data from the National Co-morbidity Survey of 8,100 men and women aged 15-24 years old (Wagner & Anthony 2002) showed that different drugs are associated with different rates of dependence. In the 10 year study, 15-16% of cocaine users become dependent, 12-13%of alcohol users and 8% of marijuana users. Of those who became dependent on cocaine, 5-6% became dependent in the first year of use. Fully 80% of people who became dependent on cocaine over the 10 years had become dependent in the first three years. These are only single studies which deserve more replication, but they are interesting in that they begin to break down some myths that people have about the onset of dependence in users and abusers.

EARLY vs LATE ONSET.
So, although it “looks” as if most people evolve from abuse to dependence, people can become dependent during their first year of using drugs, including alcohol. People in recovery seem to understand that some people become “instantly” dependent with the very first use of the drug; most reports concern early onset with the use of alcohol and cocaine. There is only one explanation, and it lies in the physiology of the medial forebrain bundle, or MFB, also known as the mesolimbic dopamine system.
The neurobiological model of “impaired control” characteristics.
A key point is that the “dependence” brain areas are in the part of the brain that governs unconscious thought. Dependence is not a “lack of will power” because
• the main problem with dependence lies in the MFB
• problems with the frontal cortex portion of the MFB produce a pathological impairment of decision-making.
Dependence is not mainly under conscious control.

BASIC NEUROBIOLOGY: NEUROTRANSMITTERS INVOLVED IN DEPENDENCE.

Dependence is probably due to a functional dysregulation – meaning: they aren’t working right! – of one or more neurotransmitter chemicals in the MFB. These include dopamine (which is affected by cocaine, amphetamines or alcohol), serotonin (alcohol or LSD), endorphins (alcohol or opioids such as heroin), gamma-aminobutyric acid (alcohol or benzodiazepines – antianxiety agents), glutamate (alcohol) and acetylcholine (nicotine or alcohol).
The dysregulation could be related to too much or too little neurotransmission, abnormal breakdown of neurotransmitters or abnormal receptor function. How does it come about? Is it due to genetic ‘malfunctions’, to drug-induced changes, or to other aspects of the environment? Neurobiological research points to genetics and drug-induced changes as being primary causes of dependence, whereas the environment is a major, though secondary, contributor to drug abuse and thus dependence.

THE RATIONALE BASED ON GENETICS.Abnormal genes lead to abnormal proteins. This results in abnormal transmitter-synthesising enzymes, abnormal transmitter-breakdown enzymes, or abnormal receptors. This is the cause of neurotransmitter dysregulation in the pleasure pathway. Impaired control appears to be due to this brain-chemistry disruption. It is the reason that scientists and clinicians now believe that dependence is a chronic medical brain disease.

SUMMARY.
Addicting drugs seem to ‘match’ the transmitter system that is not normal. To treat such individuals, detoxification – weaning people off the drug of choice – is the first step. Then, ideally, abstinence-based treatments are attempted, which traditionally have the greatest chance of success. But abstinence is not for everyone, so more treatment choices are becoming available through scientific research. For some, continued use of a similar drug (such as methadone for heroin- dependent people) or the initial drug (nicotine patches for people who stop smoking) is the choice, because some people report that they “need” a chemical to “feel normal” – in other words, to overcome the non-normal transmitter system.

TODAY’S TREATMENT OPTIONS.
More options create greater chances for helping people. Today’s options include some or all of the following:
• traditional – 12-step programmes/abstinence
• talk – inpatient/outpatient/aftercare
• misunderstood but useful – harm reduction, including methadone
• new – brief motivational counselling, cognitive behavioural therapy, motivational enhancement therapy, ‘significant others’ therapy, vouchers
• medical treatment – new medications to enhance abstinence, anticraving medications, methadone, buprenorphine, vaccines, drugs to alleviate withdrawal.
So, if addictions are a medical disease, why do we treat them behaviourally? What is the similarity between behavioural or talk therapies and pharmacotherapies in the way they work? Simple. Behavioural therapies probably change brain chemistry! If this is a brain disease, and people get better in behaviourally-based therapies, then brain chemistry has to change. Recent brain-scan research is confirming this rational conclusion.

DISRUPTING NERVE CELLS: EXPLANATION.

The basis of chemical dependence is dysregulation of nerve cell transmission – (see picture on the right) and there is an excellent description of this on the author’s university website here. Also, most drugs used to treat mental disorders, including chemical dependence, have their most basic action on individual nerve cells
Carlton Erickson PhD is a research scientist who has been studying the effects of alcohol on the brain for over 30 years. He is the Pfizer Centennial Professor of Pharmacology and director of the Addiction Science Research and Education Center, College of Pharmacy, University of Texas. He has published over 150 scientific and professional articles, has co-edited and co-authored books and is associate editor of the scientific journal Alcoholism: Clinical and Experimental Research. He is also a recipient of the Betty Ford Center Visionary Award 2000. He has spoken to about 70,000 professionals and people in recovery since 1978 and presents every two years at the UK/European Symposium on Addictive Disorders.
Source : www.addictiontoday.org. Sept. 17th 2008

Filed under: Effects of Drugs (Papers) :

By Mary Brett

In the last few years increasing concern has been expressed about the association of cannabis with mental illness. The number of cannabis users is going up. In the USA in some age groups, almost as many people are smoking cannabis as cigarettes. Children are starting to use the drug at an increasingly early age, more and more studies are emerging which link cannabis use with psychological and social problems, demand for treatment for cannabis users is rising and there is a change in the THC content of some cannabis varieties. Selectively bred strains such as skunk and nederweed have much greater percentages of THC than did the marijuana of the sixties and seventies.

Jan Ramstrom, the Swedish psychiatrist and expert on substance abuse who wrote Adverse Health Consequences of Cannabis Use (2003) said, “ At present we find ourselves in a curious situation where researchers and clinicians are becoming even more concerned, while the general public, not least in Europe, seems to grow less concerned”.

He also said, “It is worth mentioning that the opiates (heroin etc), apart only from the development of dependence, produce far fewer toxic psychiatric complications than do cannabis preparations”

Two fundamentally different psychotic manifestations are involved.

Toxic psychosis:
Cannabis-induced psychotic disorder, recognised as a diagnostic unit in the DSM 1V (Diagnostic and Statistical Manual of Mental Disorders) is caused by the toxic effects of the drug and involves a group of brain damage syndromes. The symptoms are caused by cannabis consumption and subside when drug use ceases. The use of anti-psychotic medicines to eliminate any residual symptoms means most patients make a full recovery unless he or she resumes the taking of cannabis or indeed other drugs. Symptoms of delirium often dominate, i.e. bewilderment and memory disturbance. Paranoia, hallucinations and aggression alternating with euphoria also occur. There is usually an absence of any heredity factor.

Functional psychosis:
“Functional” in this sense applies to the absence of organic damage. Cullberg 2000, said that there probably is some organic damage, possibly taking the form of some subtle vulnerability as yet unknown. This category covers schizophrenia and schizophrenia-like psychosis which usually runs a chronic course. Symptoms of delirium are absent and there is often a feeling of outside interference with thought. Often the person has a “premorbid personality” with extreme reserve, loss of interest and bizarre suspicious ideas.

To quote Jan Ramstrom again, “…what we are dealing with here are the most profound disturbances known to psychiatry; even when they are short-lived, such disturbances can leave marks on those affected and on their families which may remain for many years or even be of life-long duration.…..there is both an abuse condition and a serious mental disorder. These “dual disorders” are among the most difficult to assess in the whole of psychiatry. Moreover, conditions of this type not rarely make demands on the most costly resources available in the field of psychiatric care”.

Early Studies.
Papers as early as the 1970s saw researchers connecting cannabis consumption with psychosis.

1972. Tennant and Groesbeck studied American soldiers in Europe and found large numbers abusing drugs mostly hashish. Between 1968 and 1971, the number of acute psychotic reactions, not necessarily leading to schizophrenia increased from 16 in 1968 to 77 in 1971, an almost 5-fold increase in 4 years. They concluded that hashish smoking was the major contributor.

1974. Chopra and Smith described 200 patients admitted to a Calcutta psychiatric hospital between 1963 and 1968 with psychotic symptoms following cannabis use. Most cases were preceded by the ingestion of large quantities. One third had no previous psychiatric history and the symptoms were the same regardless of their history. The most potent cannabis preparations resulted in psychotic reactions in the shortest period of time.

1974. DA Treffert allowed 4 schizophrenic patients, all on anti-psychotic medicine to act as their own controls. Having been warned not to, all of them smoked cannabis occasionally. All of them experienced deterioration in their condition, sometimes with very serious consequences. This clearly demonstrated that there was a direct association between relapses into pot smoking and serious deterioration in the schizophrenia condition.

1974. Breakey and others pointed to some sort of association between drug use, including cannabis, and the onset of schizophrenic illness. He considered that cannabis and other drugs could precipitate latent schizophrenia, but also thought that cannabis could do this in cases where the illness would not occur otherwise. They based this conclusion on the fact that the drug induces schizophrenia on average 4 years earlier than the onset in other types of schizophrenia. The onset was also more sudden, and the premorbid personality always better than a comparative group of non-drug using schizophrenics.

1976. Thacore and Shukla made a clear attempt to demonstrate the occurrence of a specific cannabis-provoked functional psychosis.

Other papers around this time, giving support to the findings include, Talbott and Teague 1969, Weil 1970, Bernardson and Gunne 1972 and Harding and Knight 1973.

So even as long ago as the early seventies some researchers were trying to ring alarm bells about the possible psychological problems of cannabis use.

The eighties brought another crop of papers on the subject.

1981. MB Holmberg found that 10% of 16 year-old consumers of large quantities of drugs, almost exclusively cannabis, by the age of 27, would have a record of psychosis. This was much higher than the 3% in the normal population.

1985. Bier and Haastrup looked at psychological admissions over one year in a Copenhagen hospital. Thirty patients had cannabis-provoked psychosis. They then estimated that 15 in a population of 100,000 would be admitted each year with psychosis either precipitated or caused by cannabis.

1986. Negrette and others concluded that interaction between cannabis smoking and schizophrenia had the following characteristics. Cannabis smokers have more relapses, more hospital visits, the positive symptoms of schizophrenia are more dramatic and the patients are less susceptible to neuroleptic medication.

1986. Ghodse said there was clear evidence from countries where heavy cannabis use is common, that cannabis causes a short-term toxic psychosis. This was supported by laboratory experiments.

Among the large body of reports from researchers and clinicians at this time are the following: Palsson, Thulin and Tunving 1982, Rottamburg et al 1982, Tsuang et al 1982, Carney 1984, Brook 1984, Tunving 1985 and Hollister 1986.

However the most important publication at this time was the large study of Swedish conscripts by Andreasson, Allebeck et al in 1987.

Forty-five thousand conscripts had their drug-taking details taken at entry, aged 18 or 19. The levels of schizophrenia were then recorded over the next 15 years. Those on admission who claim to have taken cannabis on more than 50 occasions were found to be 6 times more likely to be diagnosed with schizophrenia in the following 15 years than those who had never consumed the drug. When confounding factors were taken into account, the risk became smaller but remained statistically significant.

Although the study attracted some criticisms, Negrette, the doyen in this field judged the connection to be reasonable taking other previous studies into account, while accepting there were some weaknesses. Andreasson in 1989 and Allebeck in 1993 strengthened their position by further research. They examined the medical records of 112 cannabis-dependent and schizophrenic patients. The findings in all significant respects confirmed the original study.

Further support came from the analysis of records of 100 schizophrenic patients between 1973 and 1977 randomly chosen by Dalman et al in 2002. A large measure of consistency was established with respect to regions, hospitals and timescale as well as the diagnostic criteria for schizophrenia, DSM-1V.

Over twenty years later in 2002, Zammit and others re-analysed the results. In the light of new research into the development of schizophrenia, they were able to discount more of the original objections.

Research continued in the nineties.

1990. Tien and Anthony conducted an epidemiological analysis of drug and alcohol use and concluded that there was an association between cannabis use and psychosis. Daily use over a year suggested a 2.4 times greater risk than non-users, any use related to a risk of 1.3 times. The daily risk figure remained significant after adjustment for other substance abuse and baseline psychiatric diagnosis.

1991. Chaudry et al studied cannabis psychosis following bhang ingestion. Bhang drinkers in Pakistan were found to have mania and paranoid features. Treated with anti-psychotic medicines, the majority recovered completely in 5 days. None had residual symptoms.

1991. Johnson, from his own long experience and a review of the current literature, estimated that 10% of all of those who had used cannabis more than once, experienced either delirium or psychosis. Later estimates confirmed this figure, notably Thomas in 1996 who sent questionnaires to young new Zealanders. Johns as recently as 2001 supported this claim.

1995. Wylie observed a group of British consumers of Dutch cannabis with a high THC content. He recorded a “wave of psychosis and confusional states”. The risk therefore becomes greater the more often cannabis is used and the greater its strength.

1998. Hall concluded that cannabis can cause psychotic like symptoms during intoxication, can lead to a “cannabis psychosis” to increase the relative risk of schizophrenia, and affect the clinical course of established schizophrenia.

Other studies which deserve mention are: Thornicroft 1990, Eikmeir et al 1991, Mathers et al 1991, Rolfe et al 1993, Kristensen 1994, McBride and Thomas 1995, Castle and Ames 1996, Hambrecht and Hafner 1996 and Fowler 1998.

A paper by J Giedd et al in 1999 on development of the adolescent brain must be mentioned here. They conclude that the brain does not finish its development till the mid twenties or beyond. So the warning is that drug abuse could alter the normal course of the maturing of the brain in the teenage years. Research by Giedd on this subject is on-going.

Since the year 2000 there has been a flood of publications. 2002. Louise Arsenault et al assessed 1100 New Zealand children at 11, 15, 18 and 26. Young adults smoking cannabis at the age of 15 were at a greater risk of developing schizophrenia or a schizophrenia-like illness by the age of 26. The risk was 10% times compared to 3% for non-users. Use at 15 was a stronger risk factor for schizophreniform disorder than use by the age of 18.

2002. The Nemesis Study by Van Os et al studied 4045 psychosis-free Dutch people and 59 who had a psychotic disorder, taken at random from 60 localities. They concluded that it must be considered proven that smoking cannabis can provoke a functional (non-toxic) schizophrenia-like psychosis. They replicated the Swedish study of Andreasson. It was of shorter duration and had fewer participants, but not the weaknesses. There was a baseline assessment and 2 follow up sessions, after 1 and 3 years, by questionnaire and clinical interviews. The study showed that individuals using cannabis at baseline were almost 3 times more likely to manifest psychotic symptoms at follow up. After confounding factors were taken into account the risk remained significant. A dose-response relationship was also found. The risk factor for the heaviest users rose to 6.8. They concluded: “cannabis use is an independent risk factor for the emergence of psychosis in psychosis-free persons and that those with an established vulnerability to psychotic disorders are particularly sensitive to its effects, resulting in poor outcome”.

2002. Nunez and Gurpegui compared 26 patients with cannabis-induced psychosis to 35 with acute schizophrenia. All used cannabis, they were repeatedly urine tested. They concluded that cannabis when continuously and heavily used can induce a psychotic disorder distinct from acute schizophrenia.

2002. Hiroshi Ujike found genetic abnormalities in the genes for the cannabinoid receptors on the brain cells of schizophrenics compared to non-schizophrenics. This implies a potential malfunction of their marijuana-linked circuitry, perhaps making them more vulnerable to schizophrenia.

Many people have argued and it seems logical that if the use of cannabis has increased then so must the incidence of schizophrenia.

2003. Boydell et al found that there was indeed a continuous and statistically significant rise in the incidence of schizophrenia between 1965 and 1997. It had doubled over the last 3 decades. The increase was greatest in people under 35.

2003. The Christchurch Health and Development Study. Fergusson et al looked at 1200 children from birth to the age of 21. The cannabis-dependent youngsters developed psychotic symptoms more often than those who were non-dependent. Individuals with cannabis-dependence disorder at 18 had a 3.7-fold increased risk of psychosis than those with no dependence disorder. At 21 the risk fell to 2.3 times.

They conclude that: “the findings are clearly consistent with the view that heavy cannabis use may make a causal contribution to the development of psychotic symptoms since they show that, independently of pre-existing psychotic symptoms and a wide range of social and contextual factors, young people who develop cannabis dependence show an elevated rate of psychotic symptoms”.

Another paper on the development of the brain appeared at this time.

2003. Chambers et al reviewed literature regarding the neurocircuitry underlying motivation, impulsivity and addiction. They focused on studies investigating adolescent neurodevelopment.

They found that adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity and addiction. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. This has significant implications for understanding adolescent behaviour, addiction vulnerability and the prevention of addiction in adolescence and adulthood.

2004. Veen et al. One hundred and thirty-three Dutch patients with schizophrenia were interviewed. There was a strong association between the use of cannabis and an earlier age of first psychotic episode in male schizophrenics. On average they were 6.9 years younger than non-using patients.

2004. D’Souza et al. Various doses of THC were administered to 22 healthy subjects, screened for any vulnerability to schizophrenia. Some of them developed symptoms resembling schizophrenia for 30 minutes to 1 hour. There were no side effects after 1, 3 and 6 months. The study findings go along with several other lines of evidence that suggest a contribution of cannabis and/or abnormalities in the brain cannabinoid receptor system to the pathophysiology of schizophrenia.

2004. Arendt et al. Findings: 1439 heavy cannabis users seeking treatment for abuse problems in Denmark were compared to 9122 abusers of other substances.

Conclusion: Co-morbid psychiatric disorders are common among heavy cannabis users seeking treatment. Some psychiatric disorders occur more frequently in this group compared to users of other substances.

2005. Isaac and Holloway did their research in PICUs (Psychiatric Intensive Care Units). There was a high rate of cannabis abuse (71.3%) among the PICU population. Patients with cannabis abuse spent longer as their psychosis was more severe. They were also younger at first hospital admission. The conclusion was that cannabis abusers have more severe psychotic illness especially in schizophrenia. There are additional problems of weight gain.

2004. Frischer et al from Keele University monitored 3% of the population of England and Wales. The number of people using drugs and having mental illness rose by 62% between 1993 and 1998. (230 GP practices were looked at). Men accounted for 79% and women 44%.

The average age affected fell from 38 to 34. The number of cases of 25 to 34 year olds more than doubled. Drug abuse and psychosis were up by 147%, paranoia by 144% and schizophrenia by 128%.

They said, “A long-term, well funded, innovative campaign aimed at publicising the real mental health risks associated with drugs including cannabis needs to be in place as soon as possible”.

2004. Stephanis et al looked at 3500 19-year olds in Greece. Conclusions: These results add credence to the hypothesis that cannabis contributes to the population level of expression of psychosis. In particular, exposure early in adolescence may increase the risk for the sub-clinical positive and negative dimensions of psychosis, but not for depression.

2005. Favrat et al. Clinical trials of THC on psychomotor function and driving performance were conducted on 8 occasional cannabis users with no history of psychosis. Low doses were used. Two young men reacted badly. One 22 year-old showed severe anxiety and psychotic symptoms 90 minutes later, and was unable to do the tests. The other, also 22, was unable to do the tests for several hours, and experienced very unpleasant symptoms.

The doses were administered under clinical conditions and were much lower than would normally be found in a modern joint. The importance of this research is that oral administration of the THC caused significant psychotic reactions. Oral medicines are becoming increasingly available and doctors should be aware of these findings.

2005. Ferdinand. The “Zuid Holland” Study, a 14 year follow up study of 1580, initially 4 to16 year olds, drawn randomly from the Dutch population. (Because cannabis use is generally condoned in Holland, false negative reports of cannabis use may occur less frequently. This adds to the value of this study). Findings: Cannabis use in individuals who did not have psychotic symptoms before they began using cannabis, predicted future psychotic symptoms, the risk was almost 3 times greater. Also psychotic symptoms in those who had never used cannabis before the onset of psychotic symptoms also predicted future cannabis use.

Conclusion: The results either imply a common vulnerability with varying order of onset or a bi-directional causal relationship between cannabis use and psychosis.

2005. Van Os et al. Nearly 2500 young people between the ages of 14 and 24, with or without predisposition to psychosis were studied. Adjustment was done for confounding factors such as alcohol, cigarettes and other drugs. There was a dose-response relationship with increasingly frequent use of cannabis.

Conclusions: Cannabis use in young people moderately increased the risk of developing psychotic symptoms. The risk for onset of symptoms was much higher in young people with a predisposition for psychosis. Predisposition psychosis at baseline did not predict cannabis use at follow up. This rejects the self-medication hypothesis i.e. that psychotic patients take drugs to relieve the symptoms of the illness.

2005. Fergusson et al. This was a 25 year longitudinal study of 1055 New Zealand children from birth. Conclusions: “Even when all factors were taken into account, there was a clear increase in rates of psychotic symptoms after the start of regular use, with daily users of cannabis having rates that were over150% those of non-users. These findings add to a growing body of evidence from different sources, all of which suggest that heavy use of cannabis may lead to increased risks of psychotic symptoms and illness in susceptible individuals”.

Several review articles have also appeared in the last few years.

2001. Johns. Conclusion: “Heavy cannabis misuse leads to the risk of psychotic episodes and aggravates the symptoms and course of schizophrenia. For any psychiatric patient, risk management and care planning is incomplete without a thorough assessment of substance abuse”. 2003. Degenhardt and Hall. Conclusion: “Cannabis use does not appear to be causally related to the incidence of schizophrenia but its use may precipitate disorders in persons who are vulnerable to develop psychosis and worsen the course of the disorder among those who have already developed it”.

2004. Arsenault et al. A review of 5 papers was undertaken: The Swedish Conscript cohort, Andreasson 1987 and Zammit et al 2002. The Dutch Nemesis Sample, Van Os 2002. The Christchurch Study, Fergusson et al 2003. The Dunedin Study, Arsenault 2002. The overall conclusion: “A twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis smoking would reduce the incidence of schizophrenia by around 8% assuming a causal relationship. Cannabis is a component cause for psychosis, part of a complex constellation of factors”.

2004. Rey et al. Conclusion: The weight of evidence points in the direction of early and regular use of cannabis having substantial negative effects on psychosocial functioning and psychopathology.

2004. Drewe et al. This article appeared in response to the potential legalization of cannabis in Switzerland. Conclusion: “An increase in consumption would be expected therefore there would probably be an increase in the prevalence of psychosis, not only acute toxic but also chronic psychosis. Schizophrenic psychoses would be expected to be triggered at an earlier age so there could be deleterious consequences not only for many currently healthy individuals but for disablement pensions”.

2004. Raphael and Wooding. Conclusion: “Of primary importance is the fact that cannabis use does have a number of significant associated harms. It is not a soft or safe option and its notable co-morbidity with psychotic and non-psychotic illnesses make it a significant and growing public health issue – a fact increasingly reflected in both the national and international scientific literature”.

Other reviews deserving mention include: Leweke et al 2004, Witton and Murray 2004, John Macleod et al 2004 and Smit et al 2004.

Professor Robin Murray of the Institute of Psychiatry, London, drew attention to the fact in 2003 that recent evidence had demonstrated that THC increases the release of dopamine, thus increasing its level in the brain. Psychotic symptoms in conditions like schizophrenia are mediated by dopamine.

Two important papers are awaiting publication in scientific journals.

Caspi et al. in a paper to be published in Biological Psychiatry, have found variants in a gene (COMT) which is involved in dopamine transmission. It was found to moderate the influence of adolescent cannabis use on the development of adult psychosis. One in four people carries this gene. The research was carried out on 803 men and women born in Dunedin, New Zealand in 1972 and 1973. They were enrolled at birth. The gene comes in 2 variants, methionine and valine, and everyone has two copies of the gene. If a person inherits 2 methionine types, the rate of psychotic illness is 3%, the normal rate for non-users. However if a person has 2 valine variants, the rate rises to 15% for those who have used cannabis in their teens. Dr Caspi said, “Research has shown that the valine gene variant and cannabis affect the brain’s dopamine system in similar fashion, suggesting that they deliver a “double dose” that can be damaging”.

Markus Leweke and others from the University of Cologne in Germany addressed The International Cannabis and Mental Health Conference in Melbourne in August 2004.

The brain’s “natural cannabis” is a substance called anandamide. Much higher levels of this chemical were found in the brains of schizophrenics experiencing their first psychotic episode and before they had embarked on medication for their condition, and also the brains of people with psychotic symptoms and a strong susceptibility to schizophrenia.

Surprisingly the more severe the schizophrenia, the lower the levels of anandamide. They postulated that anandamide may actually be produced to control psychotic symptoms and dampen them down. THC binds to anandamide receptors. It makes these receptor sites less sensitive and may disrupt the system in other ways as well.

An article appeared in New Scientist in August 2004.

In 2004 Marijuana and Madness was published by Cambridge University Press. The editors were, Professor David Castle of The Mental Health Research Unit, Melbourne, and Professor Robin Murray of The Institute of Psychiatry in London.

Twenty-nine contributors to 13 chapters are listed. Many of them have been mentioned in this article. The review from the journal “Addiction” says:

“Each chapter is well written and well presented…There is little doubt that the chapters are expertly written…Marijuana and madness illustrates clearly the benefits of a multi-disciplinary perspective in providing the tools for answering a complex question”.

Mary Brett, retired biology teacher and former Head of Health Education Dr Challoner’s Grammar School Amersham Bucks. May 9th 2005.

Filed under: Effects of Drugs (Papers) :

The high prevalence of co-morbidity between drug use disorders and other mental illnesses does not mean that one caused the other, even if it appeared first. In fact, establishing causality or directionality is difficult for several reasons. Some symptoms of a mental disorder may not be recognized until the illness has substantially progressed, and imperfect recollections of when drug use/abuse started can also present timing issues. Still, three scenarios deserve consideration:
1. Drugs of abuse can cause abusers to experience one or more symptoms of another mental illness. The increased risk of psychosis in some marijuana abusers has been offered as evidence for this possibility.
2. Mental illnesses can lead to drug abuse. Individuals with overt, mild, or even subclinical mental disorders may abuse drugs as a form of self-medication. For example, the use of tobacco products by patients with schizophrenia is believed to lessen the symptoms of the disease and improve cognition (“Smoking and Schizophrenia: Self-Medication or Shared Brain Circuitry?”).
3. Both drug use disorders and other mental illnesses are caused by overlapping factors such as underlying brain deficits, genetic vulnerabilities, and/or early exposure to stress or trauma.
All three scenarios probably contribute, in varying degrees, to how and whether specific comorbidities manifest themselves.
Overlapping Conditions– Shared Vulnerability
High Prevalence of Drug Abuse and Dependence Among Individuals With Mood and Anxiety DisordersHigh Prevalence of Mental Disorders Among Patients With Drug Use Disorders

Higher Prevalence Smoking Among Patients With Mental Disorders

Because mood disorders increase vulnerability to drug abuse and addiction, the diagnosis and treatment of the mood disorder can reduce the risk of subsequent drug use. Because the inverse may also be true, the diagnosis and treatment of drug use disorders may reduce the risk of developing other mental illnesses and, if they do occur, lessen their severity or make them more amenable to effective treatment. Finally, because more than 40 percent of the cigarettes smoked in this country are smoked by individuals with a psychiatric disorder, such as major depressive disorder; alcoholism; post-traumatic stress disorder (PTSD); schizophrenia; or bipolar disorder, smoking by patients with mental illness contributes greatly to their increased morbidity and mortality.
Data in top two graphs reprinted from the National Epidemiologic Survey on Alcohol and Related Conditions (Conway et al., 2006).
Data in bottom graph from the 1989 U.S. National Health Interview Survey (Lasser et al., 2000).
Common Factors
Overlapping Genetic Vulnerabilities. A particularly active area of comorbidity research involves the search for genes that might predispose individuals to develop both addiction and other mental illnesses, or to have a greater risk of a second disorder occurring after the first appears. It is estimated that 40-60 percent of an individual’s vulnerability to addiction is attributable to genetics; most of this vulnerability arises from complex interactions among multiple genes and from genetic interactions with environmental influences. In some instances, a gene product may act directly, as when a protein influences how a person responds to a drug (e.g., whether the drug experience is pleasurable or not) or how long a drug remains in the body. But genes can also act indirectly by altering how an individual responds to stress or by increasing the likelihood of risk-taking and novelty-seeking behaviors, which could influence the development of both drug use disorders and other mental illnesses. Several regions of the human genome have been linked to increased risk of both, including associations with greater vulnerability to adolescent drug dependence and conduct disorders. The rate of smoking in patients with schizophrenia has ranged as high as 90 percent.
Involvement of Similar Brain Regions.
Some areas of the brain are affected by both drug use disorders and other mental illnesses. For example, the circuits in the brain that use the neurotransmitter dopamine–a chemical that carries messages from one neuron to another– are typically affected by addictive substances and may also be involved in depression, schizophrenia, and other psychiatric disorders.
Indeed, some antidepressants and essentially all antipsychotic medications target the regulation of dopamine in this system directly, whereas others may have indirect effects. Importantly, dopamine pathways have also been implicated in the way in which stress can increase vulnerability to drug addiction. Stress is also a known risk factor for a range of mental disorders and therefore provides one likely common neurobiological link between the disease processes of addiction and those of other mental disorders.
The overlap of brain areas involved in both drug use disorders and other mental illnesses suggests that brain changes stemming from one may affect the other. For example, drug abuse that precedes the first symptoms of a mental illness may produce changes in brain structure and function that kindle an underlying propensity to develop that mental illness. If the mental disorder develops first, associated changes in brain activity may increase the vulnerability to abusing substances by enhancing their positive effects, reducing awareness of their negative effects, or alleviating the unpleasant effects associated with the mental disorder or the medication used to treat it.
Smoking and Schizophrenia: Self- Medication or Shared Brain Circuitry?
Patients with schizophrenia have higher rates of alcohol, tobacco, and other drug abuse than the general population. Based on nationally representative survey data, 41 percent of respondents with past-month mental illnesses are current smokers, which is about double the rate of those with no mental illness. In clinical samples, the rate of smoking in patients with schizophrenia has ranged as high as 90 percent.
Various self-medication hypotheses have been proposed to explain the strong association between schizophrenia and smoking, although none have yet been confirmed. Most of these relate to the nicotine contained in tobacco products: Nicotine may help compensate for some of the cognitive impairments produced by the disorder and may counteract psychotic symptoms or alleviate unpleasant side effects of antipsychotic medications. Nicotine or smoking behavior may also help people with schizophrenia deal with the anxiety and social stigma of their disease.
Research on how both nicotine and schizophrenia affect the brain has generated other possible explanations for the high rate of smoking among people with schizophrenia: The presence of abnormalities in particular circuits of the brain may predispose individuals to schizophrenia; increase the rewarding effects of drugs like nicotine; or reduce an individual’s ability to quit smoking. The involvement of common mechanisms is consistent with the observation that both nicotine and the medication clozapine (which also acts at nicotine receptors) can improve attention and working memory in an animal model of schizophrenia. Clozapine is effective in treating individuals with schizophrenia. It also reduces their smoking levels. Understanding how and why patients with schizophrenia use nicotine is likely to help us develop new treatments for both schizophrenia and nicotine dependence.
The Influence of Developmental Stage
Adolescence–A Vulnerable Time. Although drug abuse and addiction can happen at any time during a person’s life, drug use typically starts in adolescence, a period when the first signs of mental illness commonly appear. It is therefore not surprising that co-morbid disorders can already be seen among youth. Significant changes in the brain occur during adolescence, which may enhance vulnerability to drug use and the development of addiction and other mental disorders. Drugs of abuse affect brain circuits involved in reward, decision making, learning and memory, and behavioral control, all of which are still maturing into early adulthood. Thus, understanding the long-term impact of early drug exposure is a critical area of co-morbidity research.
The brain continues to develop into adulthood and undergoes dramatic changes during adolescence. One of the brain areas still maturing during adolescence is the prefrontal cortex– the part of the brain that enables us to assess situations, make sound decisions, and keep our emotions and desires under control. The fact that this critical part of an adolescent’s brain is still a work in progress puts them at increased risk for poor decisions (such as trying drugs or continuing abuse). Thus, introducing drugs while the brain is still developing may have profound and long-lasting consequences.
The high rate of co-morbidity between drug abuse and addiction and other mental disorders argues for a comprehensive approach to intervention that identifies, evaluates, and treats each disorder concurrently.
Early Occurrence Increases Later Risk. Strong evidence has emerged showing early drug use to be a risk factor for later substance abuse problems; additional findings suggest that it may also be a risk factor for the later occurrence of other mental illnesses. However, this link is not necessarily a simple one and may hinge upon genetic vulnerability, psychosocial experiences, and/or general environmental influences. A recent study highlights this complexity, with the finding that frequent marijuana use during adolescence can increase the risk of psychosis in adulthood, but only in individuals who carry a particular gene variant (see sidebar, “The Influence of Adolescent Marijuana Use on Adult Psychosis Is Affected by Genetic Variables”).
The Influence of Adolescent Marijuana Use on Adult Psychosis Is Affected by Genetic Variables

Percentage of Individuals Meeting Diagnostic Criteria for Schizophreniform Disorder at Age 26

Source: Caspi A, Moffitt TE, Cannon M, et al., 2005.
The above figure shows that variations in a gene can affect the likelihood of developing psychosis in adulthood following exposure to cannabis. The Catechol-O-Methyltransferase gene regulates an enzyme that breaks down dopamine, a brain chemical involved in schizophrenia. It comes in two forms: Met and Val. Individuals with one or two copies of the Val variant have a higher risk of developing schizophrenic-type disorders if they used cannabis during adolescence (dark bars). Those with only the Met variant were unaffected by cannabis use. These findings hint at the complexity of factors that contribute to co-morbid conditions; however, more research is needed.
Source: NIDA Jan.2009

Filed under: Effects of Drugs (Papers) :

CASE REPORT

Cannabinoid hyperemesis syndrome: Clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse

Siva P Sontineni, Sanjay Chaudhary, Vijaya Sontineni, Stephen J Lanspa
Online Submissions: wjg.wjgnet.com World J Gastroenterol 2009 March 14; 15(10): 1264-1266
wjg@wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.1264 © 2009 The WJG Press and Baishideng. All rights reserved.
Siva P Sontineni, Sanjay Chaudhary, Vijaya Sontineni,
Stephen J Lanspa, Department of Medicine, Creighton
University, Suite 5850, 601 N 30th Street, Omaha, NE 68131,
United States
Author contributions: Sontineni SP provided the patient’s data,
organized, conceptualized and contributed to the manuscript
writing and final approval; Chaudhary S collected the patient
data, reviewed the literature and contributed to the manuscript
writing; Sontineni V reviewed the literature and compiled the
references; Lanspa SJ supervised, provided critical review
and obtained financial support from the division; All authors
approved the final manuscript.
Correspondence to: Siva P Sontineni, MD, Department
of Internal Medicine, 601 N 30th St Suite 5850, Creighton
University Medical Centre, Omaha, NE 68131,
United States. ssontineni@gmail.com
Telephone: +1-402-4158319 Fax: +1-402-2804220
Received: October 25, 2008 Revised: February 8, 2009
Accepted: February 15, 2009
Published online: March 14, 2009

Abstract

Cannabis is a common drug of abuse that is associated with various long-term and short-term adverse effects.
The nature of its association with vomiting after chronic abuse is obscure and is underrecognised by
clinicians. In some patients this vomiting can take on a pattern similar to cyclic vomiting syndrome with
a peculiar compulsive hot bathing pattern, which relieves intense feelings of nausea and accompanying
symptoms. In this case report, we describe a twentytwo year-old-male with a history of chronic cannabis
abuse presenting with recurrent vomiting, intense nausea and abdominal pain. In addition, the patient
reported that the hot baths improved his symptoms during these episodes. Abstinence from cannabis led
to resolution of the vomiting symptoms and abdominal pain. We conclude that in the setting of chronic
cannabis abuse, patients presenting with chronic severe nausea and vomiting that can sometimes be
accompanied by abdominal pain and compulsive hot bathing behaviour, in the absence of other obvious
causes, a diagnosis of cannabinoid hyperemesis syndrome should be considered.
© 2009 The WJG Press and Baishideng. All rights reserved.

INTRODUCTION
Cannabis has been used recreationally for millennia and is the third most commonly used drug after tobacco
and alcohol[1,2]. Research into the neurobiology of the compound has led to the discovery of an endogenous
cannabinoid system. The therapeutic potential of cannabinoids has been recognized and these compounds are
utilized as anti-emetics[3-5]. Recently, a distinct syndrome in chronic cannabis abusers characterized by recurrent
vomiting associated with abdominal pain and a tendency to take hot showers has been increasingly recognised.
This clinical manifestation is paradoxical to the previously identified therapeutic role of cannabinoids as antiemetics.
We describe the case of a young male seeking repeated emergency room care with recurrent nausea
and vomiting.

CASE REPORT
A 22-year male presented with recurrent episodes of nausea, refractory vomiting, and colicky epigastric pain
for one week. The symptoms were characterized by treatment-resistant nausea in the morning, continuous
vomiting, and colicky epigastric abdominal pain. Each episode lasted 2 to 3 h and increased with food intake.
He often had two or more episodes a day during the symptomatic period. He had been treated for the severe
nausea and vomiting in the emergency room on two occasions in the preceding two months. He also reported
having learned to help himself by taking a hot bath each time the symptoms appeared, which dramaticallyimproved his symptoms. This habit had become a compulsion for him for symptom relief with each episode
of hyperemesis. On physical examination his mucous membranes were dry, his pulse rate was 102/min and
blood pressure was 140/100 with positive orthostasis. The remainder of the physical examination was unremarkable.
His complete blood count and comprehensive metabolic panel were unremarkable. In addition, serum
amylase and lipase levels were within the normal range. His urine drug screen was positive for tetrahydrocannabinol
(THC). Abdominal X-ray series and ultrasonography were within normal limits.
Oesophagogastroduodenoscopy revealed Grade 2 distal oesophagitis and hiatal hernia. On further interviewing,
he admitted to consistent marijuana abuse for the past 6 years, often smoking cannabis every hour or
two on a daily basis. The patient and his mother did not recall any significant past illnesses or recurrent vomiting
when he was a child. He was treated with intravenous fluids with steady improvement in symptoms, and metoclopramide,
pantoprazole and morphine for the abdominal pain. It was explained that marijuana was the cause
of his symptoms and he was advised not to resume marijuana abuse. On subsequent follow-up, he had abstained from cannabis and remained symptom-free.

DISCUSSION
Cannabis is one of the most commonly abused drugs worldwide. Over the past decade, marijuana has
remained the most commonly used illicit substance with close to 50% of high school seniors admitting use at
some time[1]. It is estimated that each year 2.6 million individuals in the USA become new users and most are
younger than 19 years of age[6].
The long-term and short-term toxicity of cannabis abuse is associated with pathological and behavioural
effects. However, cannabis has also been suggested to have therapeutic properties with anticonvulsive,
analgesic, antianxiety and anti-emetic activities. Cannabis has also been used to treat anorexia in patients with
acquired immunodeficiency syndrome[3-5]. The actions of cannabis are mediated by specific cannabinoid
receptors. The first of the cannabinoid receptors-CB-1- was identified in 1990 and this finding revolutionized the
study of cannabinoid biology. Since then, a multitude of roles for the endogenous cannabinoid system has been
proposed. A large number of endogenous cannabinoid neurotransmitters or endocannabinoids have been
identified, and the CB-1 and CB-2 cannabinoid receptors have been characterized[7]. The CB-1 receptors exert
a neuromodulatory role in the central nervous system and enteric plexus[8]. Cannabinoid type 2 receptors
have an immunomodulatory effect and are located on tissues such as microglia[5]. The presence of other
receptors, transporters, and enzymes responsible for the synthesis or metabolism of endocannabinoids are
being recognised at an extraordinary pace. Cannabinoids have a wide variety of effects on the body systems and
physiologic states (Table 1) due to their actions on the receptors as well as direct toxic effects.
The anti-emetic effect of cannabinoids is largely mediated by CB-1 receptors in the brain and the
intestinal tract, although some of their effect may also be receptor-independent. However, in this report,
we were presented with the paradoxical effect of hyperemesis in a susceptible chronic cannabis abuser.
Such a paradoxical response has previously only been demonstrated following acute toxicity to an intravenous
injection of crude marijuana extract[9]. Proposed mechanisms of cannabinoid hyperemesis include
toxicity due to marijuana’s long half-life, fat solubility, delayed gastric emptying, and thermoregulatory and
autonomic disequilibrium via the limbic system[10].
Cannabinoids are known to impair peristalsis in a dosedependent manner[11,12], which can theoretically override
the centrally mediated anti-emetic effects, thus leading to hyperemesis. It is not known why the hyperemesis
syndrome surfaces after several years of cannabis abuse. The effects of cannabinoids on the functions of the
thermoregulatory and autonomic mechanisms of the brain can lead to behavioural changes[10]. Such effects
might be the underlying mechanism for the compulsive hot bathing behaviour. There is also a supposition that
the syndrome could represent a type of cyclic vomiting.
Cyclic vomiting syndrome (CVS) in adults is now very well recognized, and it has been proposed that marijuana
contributes to CVS[13]. However, unlike the other forms of CVS, patients with cannabinoid hyperemesis are not
likely to have a history of migraine or other psychosocial stressors and the peculiar behaviour of hot showers is
Cognitive and mental health
Impaired memory
Impaired attention, organization and integration of complex information
Association with schizophrenia
Increased risk for depression
Pulmonary
Carcinogenic effect
Obstructive lung disease
Increased propensity toward infections
Acute and chronic bronchitis
Behavioural
Weapon possession and physical fighting
Unwanted and unprotected sexual encounters
Unwanted pregnancies
School dropout
Amotivational syndrome
Impairment of driving skill and coordination
Endocrine
Decreased testosterone, sperm motility and production, disruption of
ovulatory cycle
Pregnancy
Low birth weight
Problems with attention, memory and higher cognitive function
Cardiovascular
Stroke
Dose-dependent increase in HR
Orthostasis
Decreased exercise tolerance
Precipitation of angina or myocardial infarction unique to this syndrome.

Allen et al[10] first noted this condition in a group of nineteen patients from Australia with chronic
cannabis abuse and cyclical vomiting illness. An earlier case report by de Moore et al[17] described a chronic
cannabis abuser with psychogenic vomiting, which was complicated by spontaneous pneumomediastinum.
Subsequent reports have identified similar clinical presentations[7-9,18]. Given the high prevalence of chronic
cannabis abuse worldwide and the paucity of reports in the literature, clinicians need to be more attentive to the
clinical features of this underrecognised condition.

REFERENCES
1 National Institutes of Health website: NIDA Info Facts:
Marijuana. National Institute on Drug Abuse. Available
from: URL: http//www.nida.nih.gov/Infofacts/marijuana.
html. Accessed January 23, 2008
2 Baker D, Pryce G, Giovannoni G, Thompson AJ. The
therapeutic potential of cannabis. Lancet Neurol 2003; 2: 291-298
3 Walsh D, Nelson KA, Mahmoud FA. Established and
potential therapeutic applications of cannabinoids in
oncology. Support Care Cancer 2003; 11: 137-143
4 Tramèr MR, Carroll D, Campbell FA, Reynolds DJ, Moore
RA, McQuay HJ. Cannabinoids for control of chemotherapy
induced nausea and vomiting: quantitative systematic
review. BMJ 2001; 323: 16-21
5 Davis M, Maida V, Daeninck P, Pergolizzi J. The emerging
role of cannabinoid neuromodulators in symptom
management. Support Care Cancer 2007; 15: 63-71
6 Foley JD. Adolescent use and misuse of marijuana. Adolesc
Med Clin 2006; 17: 319-334
7 Childers SR, Breivogel CS. Cannabis and endogenous
cannabinoid systems. Drug Alcohol Depend 1998; 51: 173-187
8 Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah
TW, Porreca F, Makriyannis A, Malan TP Jr. The cannabinoid
agonist WIN55,212-2 suppresses opioid-induced emesis in
ferrets. Anesthesiology 2001; 94: 882-887
9 Vaziri ND, Thomas R, Sterling M, Seiff K, Pahl MV, Davila
J, Wilson A. Toxicity with intravenous injection of crude
marijuana extract. Clin Toxicol 1981; 18: 353-366
10 Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid
hyperemesis: cyclical hyperemesis in association with
chronic cannabis abuse. Gut 2004; 53: 1566-1570
11 Pertwee RG. Cannabinoids and the gastrointestinal tract.
Gut 2001; 48: 859-867
12 McCallum RW, Soykan I, Sridhar KR, Ricci DA, Lange
RC, Plankey MW. Delta-9-tetrahydrocannabinol delays the
gastric emptying of solid food in humans: a double-blind,
randomized study. Aliment Pharmacol Ther 1999; 13: 77-80
13 Abell TL, Adams KA, Boles RG, Bousvaros A, Chong SK,
Fleisher DR, Hasler WL, Hyman PE, Issenman RM, Li BU,
Linder SL, Mayer EA, McCallum RW, Olden K, Parkman
HP, Rudolph CD, Taché Y, Tarbell S, Vakil N. Cyclic
vomiting syndrome in adults. Neurogastroenterol Motil 2008;
20: 269-284
14 Roche E, Foster PN. Cannabinoid hyperemesis: not just a
problem in Adelaide Hills. Gut 2005; 54: 731
15 Boeckxstaens GE. [Cannabinoid hyperemesis with the
unusual symptom of compulsive bathing] Ned Tijdschr
Geneeskd 2005; 149: 1468-1471
16 Chepyala P, Olden KW. Cyclic vomiting and compulsive
bathing with chronic cannabis abuse. Clin Gastroenterol
Hepatol 2008; 6: 710-712
17 de Moore GM, Baker J, Bui T. Psychogenic vomiting
complicated by marijuana abuse and spontaneous
pneumomediastinum. Aust N Z J Psychiatry 1996; 30: 290-294
18 Chang YH, Windish DM. Cannabinoid hyperemesis relieved
by compulsive bathing. Mayo Clin Proc 2009; 84: 76-78
S- Editor Li LF L- Editor Kerr C E- Editor Yin DH
Essential for diagnosis:
History of regular cannabis use for years
Major clinical features of syndrome
Severe nausea and vomiting
Vomiting that recurs in a cyclic pattern over months
Resolution of symptoms after stopping cannabis use
Supportive features
Compulsive hot baths with symptom relief
Colicky abdominal pain
No evidence of gall bladder or pancreatic inflammation
Table 2 Clinical diagnosis of cannabinoid hyperemesis

Source: 1266 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol March 14, 2009 Volume 15 Number 10
www.wjgnet.com

Filed under: Effects of Drugs (Papers) :

There were 1810 deaths from benzodiazepine overdose 1990–1996 according to Home Office Statistics and there are an estimated 1600 benzodiazepine-related traffic accidents with 110 deaths each year in the UK.
C.H. Ashton, Emeritus Professor of psychopharmacology, Newcastle UniversityThe current number of benzo addicts in the UK is estimated at one and a half million although no official figures exist. Many more people are ingesting benzos and are on their way to addiction. Many other ex-addicts have withdrawn but remain damaged. There is no treatment for benzo damage. Post-benzo sufferers are often left to struggle alone, stigmatised and excluded by the Health Service that made them ill.
Mick Behan, Parliamentary Researcher, Submission to the Health Select Committee Enquiry into the Influence ofthe Pharmaceutical Industry 2004

“It is estimated that 1.5 million people’s lives have been destroyed by involuntary tranquilliser addiction leading to long periods of mental ill health. A man whom I met recently had been on tranquillisers for 45 years. Those people want to work, but cannot do so. As far as I am aware, the only primary care trust that has introduced a withdrawal programme is Oldham. Will the Secretary of State encourage his Department and the Department of Health to
study the Oldham model with the aim of getting some of those people off prescription drugs and back to work? That would improve their quality of life, and would reduce the benefits bill as well.”
Jim Dobbin (Heywood and Middleton) (Lab/Co-op) Hansard 31 March 2008

Manslaughter by gross negligence
“Negligence is generally defined as failure to exercise a reasonable level of precaution given the circumstances and so may include both acts and omissions. The defendants in such cases are often people carrying out jobs that require special skills or care, such as doctors who fail to meet the standard which could be expected from them and cause death. In R v Bateman (1925) 19 Cr App.R. 8, the Court of Criminal Appeal held that gross negligence
manslaughter involved the following elements:

1. the defendant owed a duty to the deceased to take care
2. the defendant breached this duty
3. the breach caused the death of the deceased
4. the defendant’s negligence was gross, that is, it showed such a disregard for the life and safety of others as to amount to a crime and deserve punishment.”

Negligence
“Failure to exercise the care toward others which would reasonably be expected of a person in the circumstances,or taking action which a reasonable person would not. Failure to exercise care, resulting in injury to others.”

On 23 February 2009 the Archer report on the 4,800 or so haemophiliacs who were infected with hepatitis C (and around 1,200 who were also infected with HIV) through blood transfusions in the late 1970s and early 1980s was made public. The report plainly sets out the pattern of negligence and injustices of successive governments.
The inquiry was privately funded by donations and received no support from government, either financial or through evidence. At the time of the inquiry’s launch, in February 2007, there had been 1,757 deaths and the number is increasing. The inquiry was set up by Lord Morris of Manchester and chaired
by the former solicitor general, Lord Archer. The report runs to 113 pages and Lord Archer told the press conference that the infection of the haemophiliacs was “the worst treatment disaster in the history of the NHS” and a “horrific human tragedy”. But has there been an even greater disaster with nearly fifty years of tranquilliser over-prescribing by doctors?
As with tranquillisers, the blood scandal campaigners have been religiously rejected by the Department of Health over the years and although some have received a small degree of compensation (tranquilliser victims have received none), little has in fact been done to help them or their families. Some UK families have had nothing because their HIV-infected breadwinners died before 2003. Others live anxious and needy lives because they have been unable to work. Canada and Ireland on the other hand acted much more quickly with more generous financial help and assistance with mortgages and insurance. The report has urged the government to offer a more substantial compensation package with survivors and their families but the Department of Health has so far offered only sympathy and a promise to look at the findings. No-blame assistance could be given though it is nearly 20 years since Virginia Bottomley, as health minister, promised that the needs of haemophiliacs would be kept under constant review. That review has sunk without trace.
The Department of Health also looked at the findings of the 2004-5 Health Select Committee report on the Pharmaceutical Industry, which included criticism of the provision for prescribed Tranquilliser addicts, but then rejected almost all of them. Sympathy is cheap but action and recognition costs money and impacts on the image of the NHS and politicians. The DoH is blame averse and addicted to the avoidance of responsibility and the recognition of avoidable scandals. Charles Dickens summed it up very well:
‘Regard our place [The Circumlocution Office] from the point of view that we only ask you to leave us alone and we are as capital a Department as you will find anywhere…It’s like a limited game of cricket. A field of outsiders are always going to bowl in at the Public Service, and we block the balls…Clennam asked what became of the bowlers? The airy young Barnacle replied, that they grew tired, got dead beat, got lamed, got their backs broken,
died off, gave it up, went in for other games.’ Charles Dickens, Little Dorrit, pp 736, 737

The reality of Benzodiazepines
Benzodiazepines are much more than a question of harm done by the medical profession. There is the crucial fact that successive governments of both parties allowed them to do it. Government and medical dismissal of patient experience as relatively minor and short-term is nothing more than a repetition of false assertions, the original source of which (if it was ever known), has been lost. What cannot be rationally doubted, is the fact that benzodiazepines are frequently seriously
damaging—something which might not be immediately apparent, judging by the truly enormous quantities that doctors have prescribed over the years, both in the UK and in other countries. There were warnings from very early in the life of these drugs that this was so, but the drug companies successfully fought off the findings for nearly thirty years until benzodiazepines were old news. Benzodiazepines might well help some people in the short-term, owing to their properties as hypnotics, anticonvulsants, muscle relaxants, amnesics and anxiolytics. But benzodiazepines have potentially incredibly serious adverse effects made even worse by polypharmacy, excessive dosages and long-term use. Benzodiazepines were largely sold to doctors as being much less toxic than their predecessors the barbiturates but they are a long way from being safe drugs. High doses of benzodiazepines lead to over-sedation. Benzodiazepines impact on the ability to think, make decisions,
and to remember. They make it much harder to learn new information. There are people who have withdrawn from benzodiazepines who find they have lost whole years and decades of their lives. In the elderly, these effects can lead to a false diagnosis of Alzheimer’s disease. In spite of this fact, many occupants of old people’s homes and in the community are regularly prescribed benzodiazepines. The primary effect of benzodiazepines is one of addiction. With regular use for only a few months
or even weeks the body comes to depend on them both psychologically and physically for normal
functioning. As a consequence of this dependence, tolerance develops, so that larger doses are needed to produce the same initial effects. There is clear evidence showing that hypnotic effects are no longer effective after a few weeks and anxiolytic effects after only a few scant months. People unknowingly continue taking them mainly to prevent withdrawal effects. If dosage is insufficient once tolerance has
developed, or if the drug is completely stopped, withdrawal symptoms then develop. This is an important reason why the long-term prescribed feel so ill all the time. The Department of Health stubbornly and perversely ignores this basic scientific truth and has illogically introduced an instalment prescription plan. Quite how doling out prescriptions over days will benefit addicted patients is a question it refuses to
answer. It looks like action and to government that is probably enough of a recommendation, but doctors tempted to give it a try, may well find the ‘problem’ becoming much more noticeable in their surgeries as a result. At present there are over a million long-term prescribed benzodiazepine users in the UK. Several
studies, including those carried out by Newcastle University, have shown from computerised prescribing records, that there are 180 or so such patients in every GP practice. These long-term patients, while continuing their drug use, often suffer from adverse effects and from withdrawal effects afterwards —for
a sizeable proportion this is permanent. Long-term use is commonly accompanied by increasingly diverse illnesses.
“Withdrawal symptoms can last months or years in fifteen percent of long-term users. In some people chronic use has resulted in long-term, possibly permanent disability.” C.H. Ashton 2003

Professor C.H. Ashton, unlike those who advise government behind the scenes, ran an effective benzodiazepine withdrawal clinic from 1982–1994 at Newcastle University. She has described the morbidity in the first 50 consecutive patients who attended. They had been taking prescribed “therapeutic” doses of benzodiazepines for between five and twenty years and had decided to withdraw because they did not feel well while taking the drugs. Of these, 20% suffered from agoraphobia and/or
panic attacks, 10% had had neurological investigations (three for Multiple Sclerosis) and 18% had had gastrointestinal investigations. Backing up the argument that long-term benzodiazepines lead to other prescriptions, she said that 62% of the first group had been prescribed other psychotropic drugs since starting benzodiazepines, the most common being antidepressants. In addition, 28% had been prescribed two benzodiazepines, thereby doubling the addiction potential and the possibility of side effects. Professor Ashton has said categorically that the symptoms which led to the investigations and the polypharmacy, were not the reason for starting benzodiazepines, but developed during long-term use. She has said on several occasions, that there is a likelihood that health for everyone does not
necessarily return to normal after prescriptions cease.

“From the current evidence it appears that the symptoms that are most likely to be long-lasting are anxiety and insomnia, cognitive impairment, depression, various sensory and motor phenomena, and gastrointestinal problems. Tranquilliser drugs undoubtedly cause thought deficits and impair coping abilities. There may be an extended period after the taking of benzodiazepines has ceased when former patients find stressful situations difficult to deal
with, though of course many still taking the drugs have the same experience as well. Something as basic as queuing in a shop, or answering the phone, can often seem a frightening and stressful situation. Complete recovery may require the individual to learn new strategies to replace the years of coping through drugs. For some people whose economic and social circumstances, have been severely impacted, this learning may prove to be
inordinately difficult and sometimes impossible.”
C.H. Ashton, 2003
On any patient leaflet you will find advice saying that anxiety occurring after withdrawal is due to pre-existing symptoms recurring. Indeed it is normally cited by the profession as a reason why most doctors continue prescriptions. Patients who were not prescribed the drugs for clinical anxiety (and that is the majority) know that the self-serving ‘symptoms recurring argument’ is untrue. This can be a Catch
22 situation. Depression is common in long-term benzodiazepine users and patient experience points to the drugs being the cause. Depression also appears when patients withdraw. There may be pharmacological reasons for this but who would not be depressed by the realisation of what had been done to them by what they thought was a safe medicine? Depressive symptoms may appear for the very first time after withdrawal—often some weeks later, and may be severe and protracted for a long
time. Suicide has been reported in some studies. Government maintains a supreme indifference to this benzodiazepine research. Instead it continues a parrot-like repetition of the need to prevent addiction occurring in the first place, ignoring the plight of many thousands of people disabled through medical prescribing.
It will be difficult for most people to believe that members of a highly regarded profession could inflict such damage, but the fact is that most doctors have an affinity with potions, and with the rise of drug company influence, they developed an affinity with the manufacturers of them.

“Doctors prescribe by nature. I had a patient who told me that her doctor had warned her that if she came off her medication she might die. I just saw another patient who was on seventy tablets a day. There are doctors out there who are absolutely committed to prescribing, and if the patient doesn’t get better, they just up the dose.”
Dr Robert Lefever, Director of the Promis Recovery Centre in Kent

It was the psychopharmacalogical era beginning in the late fifties that led to the explosion of medically-induced ill health. Benzodiazepines were pushed by their manufacturers as appropriate for virtually anything. Doctors followed the logic of this advert religiously: “In the face of ill health there is anxiety and where there is anxiety either as a complicating factor or as a cause of illness itself, there is a place for LIBRIUM.”
Today, in spite of this undeniable fact, the UK Department of Health rigidly maintains an illusion that the drugs are always prescribed for clinical anxiety and therefore suffering patients fall within the psychiatric sphere of responsibility. That way, it can say that any psychological problems while taking benzodiazepines or following withdrawal, are due to pre-prescription symptoms returning. They will not engage with the fact that patients, who were given the drugs for other reasons, are as likely to experience the same psychological difficulties as those who were given them for clinical anxiety. Physical side-effects are ignored. It has been claimed that benzodiazepines are the most researched drugs in the world but much of the early research was basic and superficial to say the least, and would not meet today’s standards.

Long-term research has never taken place, either then or subsequently. Patients who took the drugs for years—many for decades—therefore have their claims of health damage ignored and rejected in the face of zero scientific evidence that it did not happen. Between the introduction of benzodiazepines and 2004, Home Office and other figures suggest 17,000 deaths associated with benzodiazepines but as with all official statistics, they may well be an underestimate. In reply to a question from the Parliamentary Health Committee in 2004, Professor Alasdair Breckenridge, the Chairman of the UK drugs regulator stated that he thought there had been
approximately 170 deaths. As Professor Heather Ashton said at the time, this represented 1% of the total and was a gross under-representation on the part of the regulator. There are people who have taken the drugs and claim to have experienced no untoward effects or problems during ingestion or in withdrawal. On one side of the argument about the benefit of benzodiazepines and possible symptoms, there is Professor David Nutt of Bristol University, who believes the downside of benzodiazepines has been over-emphasised and that medics are being unduly
constrained in their use. Nutt outlines his position on benzodiazepines in his paper “The Psychopharmacology of Anxiety”. He recommends prescribing practices that directly contradict the 1988 CSM Guidelines on prescribing and what the Department of Health says is its position. Professor Nutt takes every opportunity to air these views, most recently in a lecture to students and medical staff at Newcastle University. Professor Heather Ashton agrees that some people can withdraw from benzodiazepines with few if any symptoms and that there are probably many reasons why. Personality may play a part and this ultimately has a physical basis, shaped by genetics and environment which determines the “wiring up” of the brain—e.g. the synaptic connections which mediate the ways that individuals have learnt to cope
with anxiety and stress. There is evidence that anxious people have fewer GABA/benzodiazepine receptors in the emotional areas of the brain than more stolid people—so perhaps those without withdrawal symptoms had more GABA receptors to utilise. They may not develop so much benzodiazepine tolerance (down-regulation of GABA/benzodiazepine receptors) and so suffer less rebound of GABA under activity related to withdrawal symptoms. The distribution and sensitivity of these
receptors may vary so that some people may have more physical symptoms in withdrawal while others experience more psychological symptoms. She also says that the nature of withdrawal may depend partly on the type of benzodiazepine used. Withdrawal symptoms are usually worse in those using short acting
and/or potent benzodiazepines such as lorazepam, alprazolam, and clonazepam even if these are withdrawn slowly
A crucial ingredient, seldom if ever, ever mentioned in relation to benzodiazepine withdrawal, is the factor of polypharmacy, which Professor Ashton agrees may also play a part. She says that over 60% of the long-term dependent she saw in her National Health Service Withdrawal Clinic, had also been prescribed other drugs, usually antidepressants, along with the benzodiazepines. Antidepressants, antipsychotics, and morphine-based painkillers, all have side-effects themselves—with symptoms not dissimilar to benzodiazepine withdrawal. Any discussion by anyone on the subject of benzodiazepine withdrawal is therefore necessarily incomplete, if it does not take into account the fact that for many people, benzodiazepine prescriptions led to other drug prescriptions—many of them producing physical dependence. It is often a situation of withdrawing from multi-drug use, rather than single drug use. So, the experience of people who have taken (or who are still taking) benzodiazepines and indeed other mind-altering drugs, varies. There are a number of reasons for the individuality of response, not least, differences in human physical make-up, length of prescription and differences in personal circumstances. A person working in a job, which does not require high-level intellectual thought, or constant decision-making, for instance, may find it altogether easier to avoid the impact of benzodiazepines on cognition.
But there needs to be some sort of true representation for the stories of the very large numbers of UK citizens whose existence has been needlessly harmed and sometimes destroyed by prescribed benzodiazepine addiction. Benzodiazepines are not the only treatment to destroy health and lives as the recent Vioxx disaster and the haemophilia scandal testify. There are strong common elements between
the stories—pharmaceutical company deceit, regulatory inaction, and dogged medical belief in benefit, is common to all. But it is the scale of benzodiazepine prescribing and its longevity that makes this story unique. Benzodiazepines have been prescribed in their billions to millions of patients, based on a jigsaw
of poor and non-existent research, pharmaceutical power, amateur regulation, medical ignorance and disdain, and organised government cover-up.
How are statistics of large benefit and little harm arrived at? What rigorous investigation is it based on? Is it, for instance, based on the absence of complaint to doctors, regulators or drug companies? Is it based on collected endorsements from patients? Or is based on neither of these? Is it, in fact, not a statistic at all—merely another plank in the house built by the indoctrinators? But the desire to believe is strong. It is a sad but observable fact that we look beyond positive claims and assurances only after we have personally met the hidden downside of drugs that ‘help millions’, through our own experience.

Socio-economic cost of benzodiazepine addiction
Benzodiazepines have been a near 50 year horror story for tens of thousands of people in the UK but this medical disgrace has never been addressed. Weak, belated and spasmodic warnings have been issued over the years and they have had the unfortunate side-effect for patients, of allowing government and the benzodiazepine manufacturers to further draw a veil over the historic and ongoing impact of
inappropriate prescribing in the public mind. It is possible to make an argument that much of the medical profession does not fully realise what it has done, given the speed of consultations, the failure of regulators to pass on the horror stories they
have been told, and the distance between the patient in the doctor’s surgery and the patient’s actual life outside it. But above all, it is the chemical ability of benzodiazepines to produce apparent mental instability and engender a belief, not only in doctors but also in patients, that this drug-produced harm is genuine illness that has led to the greatest medical damage. The belief has been fostered among
doctors (and unwittingly by the patients), that the drugs and consequent ones have been necessary. It is simply not true that benzodiazepine injury has ever been addressed.
There are still far too many prescribed addicts in the UK and thousands of former addicts who took the drugs long-term, and as a result are living with ruined health which cannot be rebuilt. Many are living in poverty because of the effects of benzodiazepines. Whole lives have been lost and cannot be relived. Families have
disintegrated, never to reunite. The real severity of benzodiazepine damage has never been officially recognised. In the face of it the Department of Health believes that repeated utterance of statements such as ‘we take the problem seriously’ or ‘our priority is to prevent addiction occurring in the first place’ makes it true for actual and
former patients and is adequate support for those badly in need of it. The debate on benzodiazepines has largely centred on addiction versus efficacy, but addiction
can be seen as only part of the picture—mostly important in relation to the fact that once addicted, patients keep taking them— the far more serious side of the issue centres around what continued addiction often leads to, and its dire effects on general health, thinking abilities, and life. There are extensive costs to the patient and to society, caused by benzodiazepines but not studied by medicine, because their nature is not seen as medical. There are costs produced by benzodiazepines which are medical but which have never been researched, and which are therefore not
recognised by medicine

There are costs to the National Health Service of medical investigations for symptoms which are in reality a result of the effects of benzodiazepines. These costs must be very high indeed, if patient reporting is taken into account, but they are officially unquantified. Investigations for MS, ME, IBS, Arthritis and Thyroid deficiency and other ‘ghost illnesses’ are common—usually the results are negative.
For people taking benzodiazepines and particularly the elderly, there is a much increased risk of accidents. The cause of the accidents, whether occurring in the home, on the road, at work or in a care home is routinely not recognised, but has a cost for the individual beyond the cost to the NHS. There is a great deal of evidence that the unborn are severely affected by the addiction of the mother. The link between benzodiazepines and foetal harm was denied in Parliament in 1999 but it
undoubtedly occurs.
“The developing foetus can be congenitally malformed; it can have heart attacks in the womb. We also know that the newborn baby born to somebody taking benzodiazepines will have difficulty breathing and they would have floppy muscles—what doctors call a ‘floppy baby’ and they may be unduly cold because the temperature regulation, which is so important to a baby, is disrupted…Well I think if any doctor is prescribing benzodiazepines to a pregnant woman, he should check his indemnification status because it is in fact illegal prescribing.”
Robert Kerwin, Professor of Psychopharmacology at the Maudesley Hospital in London, ‘Face the Facts’, BBC Radio 4 1999

Prescribed benzodiazepines can lead to loss of control over actions which means in practice that drug-induced violence occurs in the home involving partners and children. Unwanted pregnancies are another side-effect of the drugs. Inhibition reduction leads to anti-social acts such as theft and vandalism. People end up in gaol because the impact on thought and emotion is not recognised. As Professor Ashton says:
“Benzodiazepines can occasionally cause paradoxical aggression and have been associated with baby-battering, wife-beating and grandma-bashing. They can also cause depression and can precipitate suicide in depressed patients. They should not be used in depression although they are still commonly prescribed long-term for depressed and anxious patients. They can also cause emotional blunting and apathy, with inability to cope with the needs of children and family, an effect bitterly regretted by many long-term users.”

Benzodiazepines cause job loss either whilst taking them or while attempting to withdraw. Not everyone loses their job of course but a significantly large number do, and it is not surprising, given the deadening effects of the addiction and the high number and severity of possible withdrawal effects. This effect on the individual and on families is totally ignored by government. In 2004 the Chief Medical
Officer, Professor Liam Donaldson, reminded doctors of their continuing over-prescribing. He referred to the cost to the NHS of the drugs themselves, but made no mention of the costs to the individual. There is a large financial impact to the state generally, which benzodiazepine addiction is responsible for. People who are unable to work pay no taxes or national insurance. Their spending power is curtailed and therefore they pay less VAT. Addicted and unemployed the benzodiazepine dependent make very little contribution to the economy. Although many iatrogenic benzodiazepine addicts are to all intents and purposes disabled, few receive disability benefits. Thousands do receive incapacity benefit at a lower figure, because of the length of their ‘illness’, and this is of course a drain on the national economy. Many iatrogenic victims have not worked for decades. Perhaps the biggest loss for a proportion of the dependent (and who knows how big this proportion is) is the loss of choice. They cannot choose to buy a house or might lose a house because of
the drug effects. They cannot take holidays or buy a new car. They cannot socialise or take up hobbies because of induced anxiety and the inability to concentrate and think clearly. Some discover after they have withdrawn from the drugs that they never left the house or indeed a room, for years because of benzo-induced agoraphobia—prisoners because of drug prescriptions. There is much exhortation from government these days about the need to build up personal pensions to maintain a secure lifestyle in retirement—we are all living longer and the state is becoming
more hard-pressed to finance pensioners. There are thousands, addicted for decades to benzodiazepines, who feel assaulted anew when they hear that message. Through state avoidance of responsibility for health protection, they had no chance to build up a personal pension, leaving them entirely dependent on the state for the future. What a supreme irony it is then, that at a time when the state is telling everyone that the state pension is completely inadequate and that they should save for a personal one, there are many condemned to poverty through state inactivity and denial.
The most insidious effect of the drugs in the estimation of many is the effect the drugs have had on their family. The family was not prescribed the drugs but it was as certainly and indelibly marked as the taker. The lack of emotional response due to benzodiazepines is something a child does not understand and may never understand, even as an adult. The life chances of children of the unemployed
and sick iatrogenic addict are necessarily reduced and their emotional needs may remain unsatisfied, leading to problems for them later in life. It can be very difficult afterwards to re-establish relationships between a formerly addicted parent and children. Where does the patient find closure in the face of orchestrated denial, lack of government recognition and help, and a spirit within the medical profession that sees each new drug as a wonder drug, taking decades each time before it exercises control? The three components of continuing good health are psychological, physical and social. Benzodiazepines have a three-pronged negative effect on health—the effects of taking of them, the realisation afterwards of the impact they had on a life and the realisation for the individual that they are powerless to achieve recognition. It is a deep and genuine kind of grief which is not in the annals of medicine. Within the present political, legal and medical structures, there is little hope of closure.

A Selection of Informed Comments on Tranquillisers
“Thousands of people could not possibly invent the bizarre symptoms caused by therapeutic use of benzodiazepines and reactions to their withdrawal. Many users have to cope, not only with a frightening range of symptoms, but also with the disbelief and hostility of their doctors and families. It is not uncommon for patients to be “struck off” if they continue to complain about withdrawal symptoms. Even when doctors are concerned and understanding about the problem, they often have little knowledge of withdrawal procedure, even less about
treatment…”
Trickett S, Withdrawal from Benzodiazepines, Journal of the Royal College of General Practitioners 1983; 33: 608

“The medical profession took nearly 20 years from the introduction of benzodiazepines to recognise officially that these minor tranquillisers and hypnotics were potentially addictive. The ‘happiness pills’, which had been propping up a fair proportion of the adult population since the early 1960s, were found to have an unexpectedly bitter aftertaste: doctors and patients alike were unprepared for the problems of dependence and withdrawal that are
now known to be common even with normal therapeutic doses.”
Editorial (Anon), The Benzodiazepine Bind, The Lancet, 22 September 1984, 706

“There’s certainly a problem, the NHS are concerned. The NHS spends about £40 million per annum on these drugs. There are a substantial number of people who do suffer from this problem long-term. I know that the withdrawal symptoms can be agonising for some people and can be very difficult indeed.”
John Patten, Health Minister, 1984

“In the UK, 11.2% of all adults take an anti-anxiety drug at some time during any one year. But over a quarter of these people (3.1% of all adults) are chronic users, taking such medication every day. Even at a conservative estimate, 20% of these will develop symptoms when they attempt to withdraw. That means a quarter of a million people in the UK. The sooner the medical profession faces up to its responsibilities towards these iatrogenic
addicts, the sooner it will regain the confidence of the anxious members of our community.”
M.H. Lader, Anna C. Higgitt, Management of benzodiazepine dependence, Update 1986, Brit J Addiction, 1986, 81, 7–10

“The benzodiazepines are probably the most addictive drugs ever created and the vast army of enthusiastic doctors who prescribed these drugs by the tonne have created the world’s largest drug addiction problem.”
Dr Vernon Coleman, ‘The Drugs Myth’, 1992

Dear Mr Haslam,
Thank you for your recent letter regarding Benzodiazepine Tranquillisers. Dawn Primarolo and myself have been taking up cases and have advised on how best the groups involved might organise a parliamentary lobby and keep attention on these issues. We have also tried to assist through both Parliamentary Questions and raising the matter on the floor of the House, in pushing the Government to accept its own responsibilities and to take action now to ensure that it does not happen again.

This is something we will be returning to both in the House and in terms of our own future policy development. I am passing your letter to Paul Boateng who, as the legal affairs spokesman, has specific responsibility for the litigation side of what is a national scandal.
David Blunkett MP, Shadow Secretary of State for Health,
24 February 1994

“…the risks [of benzodiazepines] were always obvious and…the providers of medicine between them, readily let this happen.”
Charles Medawar, Social Audit, Power and Dependence 1991

They [benzodiazepines] are very effective at relieving anxiety, but we now know that they can be addictive after only four weeks regular use. When people try to stop taking them they may experience unpleasant withdrawal symptoms which can go on for some time. These drugs should be only used for short periods, perhaps to help during a crisis. They should not be used for longer-term treatment of anxiety.
The Royal College of Psychiatrists, July 2001

“Benzos are responsible for more pain, unhappiness and damage than anything else in our society.”
Phil Woolas MP, Deputy Leader of the House of Commons and Local Government Minister, Oldham Chronicle, February 12 2004

Parallels
“My family believe my brother was murdered, and I stick by that.”
Brother of Blood Transfusion Victim, Daily Telegraph, February 23, 2009
Interviewer: I don’t want to sensationalise this Susan but, in the last couple of minutes, you’ve actually accused doctors of murder. Campaigner Sue Bibby: Well I think that they do have a case to answer – it would be very nice if one or two of them would actually stand up and speak.
Talk Radio UK Interview on Tranquillisers with Mike Dicken and Susan Bibby
December 5, 1998

Is one scandal greater than the other, a larger case of inertia and unconcern? A scandal is a scandal, both are sizeable and have involved a large number of deaths, both have involved government inaction, but the 48 year benzodiazepine scandal must be seen as the greater if only for its longevity and absence of recognition. The heyday of vast tranquilliser over-prescribing took place in the 1970s and 1980s. The 4,800 or so haemophiliac victims received their contaminated blood at that time. But the tranquilliser scandal rolled on and new addicts are still, without warnings, being created today.

“The Department of Health fails even to collect figures that might be considered unpalatable.”
Alice Miles, The Times, July 4 2007

“[Benzodiazepines] have been prescribed for sports injuries, muscle spasms, premenstrual tension, exam nerves, depression, general malaise and much else…”
Professor C.H. Ashton, Bristol and District Tranquilliser Project AGM, October 2005

The benzodiazepine story has many unique qualities and the Department of Health has developed a policy of no-admission and steadfast denial. Instead of action it has:
•Routinely insisted that its priority is “to prevent addiction occurring in the first place” in the face of much evidence of injury and the fact that those injuries have been occurring for nearly half a century. Crucially, it also maintains that doctors must be free to exercise clinical judgement, even when that judgement (as in the case of David Nutt) is likely to increase addiction and harm.

•It has made no effort to commission research into the wide variety of injuries reported by patients and sticks rigidly to the message that tranquilliser addiction is a mental health problem when in fact it is a problem of chemical addiction with physical responses to that addiction.

•It has left campaigners to provide detailed information on the scale and nature of the problem but has not accepted it; neither has it made any attempt to investigate and provide its own data.

•It has always insisted that treatment and withdrawal assistance is available when it has been shown to be non-existent and in the knowledge that prescribers who addicted patients have little interest in the addiction or the expertise to assist.

•It has consistently evaded all responsibility for the situation, preferring historically to blame it on prescribers, though lately it has moved towards the blaming of patients and stigmatising them as drug misusers. Medical and government defence of the benzodiazepine scandal has moved through several stages, not necessarily in this order and not necessarily one at a time. Sometimes previous positions are
resurrected:

•The drugs are not addictive
•And if they are, it is because of an addictive personality
•Patients ask for them
•Patients bully doctors into prescribing
•The drugs are cheap to provide for government
•Doctors have no time to assist in withdrawal/doctors find it very difficult
•There are no alternatives to pills in UK healthcare
•Aware or former iatrogenic addicts are merely seeking compensation
•It’s all down to defective genes
•It’s all in the past, it was regrettable but we have learned lessons
•Patients abuse the drugs and must be controlled
•Benzo campaigners select their evidence

In 1988 the Committee on the Safety of Medicines issued 4 week prescribing Guidelines to doctors but these were never seriously followed up and the CSM had no remit to discover whether they were being followed. There was no plan to audit the number of patients on individual prescriber lists who had already exceeded the Guidelines and offer withdrawal assistance. Hence there are tens of thousands of
people today who have been taking tranquillisers for decades without knowledge that their life is being harmed.

“GPs will be asked to trawl through their patients’ records to identify those most at risk of developing cardiovascular disease and call them in for an assessment, the National Institute for Health and Clinical Excellence proposed today.
The Guardian in June 2007

Hearing the victims of the haemophilia scandal speak is like a rerun of the tranquilliser scandal: “I would just like to see someone apologise, but they won’t do it because they think they will be subject to criminal actions.” “One of the reasons the government had been so successful in keeping the whole thing silent was because there
were so few people willing to stand in public and campaign.” “People say move on with your life, but that’s hard if you have had no resolution and you are surviving on £59 a
week.” “We need an apology, just the acknowledgement that this happened and it shouldn’t have happened. I don’t think they realise how much that means to people.”
“People need to be able to live comfortably without having to go cap in hand to the local authority or a fund whenever they need the slightest thing. All we are asking for is to be able to live with decency and dignity.”

Tranquilliser victims
“[But] for a large proportion of those on incapacity benefit—half of them claiming for five years or longer—the benefit is a (cheap) compensation for the fact that they have no future. And never will have…”
Yvonne Roberts, Where’s the Benefit? The Guardian, February 6 2008

Tranquilliser victims have received no recognition, no support, no apologies, no compensation and no closure—and this in spite of the fact that so many of them cannot work, have no pensions or security and live with ruined health because there is no agonist for the damage inflicted. Many victims do receive state benefits and the government refuses to investigate how many of those on benefits are there because of the drugs, but benefits are not large and do not represent security. In fact because the Department of Works and Pensions, reliant on Department of Health information, does not take benzodiazepine injury seriously, the victims live constantly with the fear of losing those benefits. The Archer report acknowledges how the extraordinary financial burden of long term ill-health had been placed upon people who had lost their jobs, lost their insurance and, as has so often been the case, lost the breadwinners in their families. There has been no such acknowledgement in the case of tranquillisers. In this horror story the victims have been left to their own devices.

•Government has allowed health, social and economic destruction through addiction to take place and still allows it.
•Government knows what has happened and avoids recognition of it.
•Government has left many to wither on benefits and has made no attempt at rehabilitation.
•Government now believes as part of its political struggle with other parties that such people can continue to remain unrecognised and can be viewed in exactly the same light as every other benefit claimant.

Tranquilliser Quotes

“…apart from people’s physical health going down (although luckily, some people seem to be able to stand up to that), they are described by their families as being “Jekyll and Hyde”. Agoraphobia (not being able to go out) is a very, very common symptom which very few people actually have before they’re given the drugs – sometimes they might have it, but mostly they don’t have it until they’ve been put on the drugs. This of course makes them [the
patients] incapable of doing anything much. They can’t go out to the local shops, they can’t look after their children properly; they are very distressed by this and feel it’s their own fault. Usually they go back to the GP and the GP will say: “Oh you’re an anxious personality and that’s what’s wrong with you,” and they usually give them more benzodiazepines, or other antidepressant drugs as well.
Sue Bibby Talk Radio UK Interview with Mike Dicken and Susan Bibby December 5, 1998

“In fact the drug was poisoning my central nervous system. Emotionally I felt numb…Those pills cheated me of myadult life – I lived like a robot…”

“….After 30 years of tranquillisers mixed with a variety of anti-depressants, the mother-of-six says the drugs have left her physically and mentally handicapped. Over the years Mrs Dixon’s health has deteriorated and she has suffered a host of problems including panic attacks, muscle weakness, mood swings, bowel problems, nausea and severe pelvic pain. Her condition has left her unable to leave her home for the past 10 years and watch her children
and 20 grandchildren growing up….”

“One Barnet woman, who wanted to remain anonymous, says she was left housebound after being addicted to benzodiazepines for more than 20 years. She was originally prescribed the drugs for a stomach upset, but now suffers thyroid problem, asthma, ME and leg pain so severe she can hardly walk – all of which she attributes to the drugs.”
Hendon & Finchley Times August 2003

“I was prescribed Lorazepam at 16. I am now aged 44 and have been off tranquillisers for two years, after a GP suggested that I had perhaps been on them too long! After suffering most of my life with Agoraphobia and Panic Attacks, I cannot believe that this drug is still manufactured. It is high time the drug companies were held accountable and something positive was done. How many people have to lose their quality of life and battle so hard, with little help to regain it, before someone says stop.”
The Tranquilliser Trap, May 2001

“If the government knows these drugs to be harmful why are they allowing them to be dispensed? Why have they not implemented resources to help patients come off the drugs? It takes more than a guideline…the problem will not go away…indeed it will not ‘die’ off which is one method some GPs are using to reduce their prescriptions, i.e. they are waiting for those patients who have been addicted for 20+ years to die because it is easier to give a 2
minute prescription rather than seeing a demanding patient for 20 minutes a visit every day until they get what they demand.”
The Tranquilliser Trap, May 2001

“I believe I am one of the longest addicts of Lorazepam, I started taking them in 1974 following a car accident and finished taking them in 2000 (26 years). I was 18 when I was first prescribed them and the effect upon my life has been devastating, like others I thought I was going out of my mind, a fact my doctor was only too willing to agree with…I am forty five and I can’t remember what it was like when I was 18, I can’t remember a time when my life was
not governed by fear. I may function in society, but that does not mean I can lead a normal life. However I find that the medical profession believes that now I no longer take these drugs that I am back to full fitness…I was offered no support from anywhere and yet if I was a Heroin addict, I would have had masses of help and support.” The Tranquilliser Trap, May 2001

“There are people out there…who are hooked, unknowingly, unwillingly, and they feel that society has ‘chucked them overboard’. They feel they no longer belong anywhere. They feel they’ve lost such a lot, that they can no longer regard themselves as fully human.”The Tranquilliser Trap, May 2001

Source: Published in Daily Dose 4th April 2009 Colin Downes-Grainger 25 .02.2009

Filed under: Effects of Drugs (Papers) :

BackgroundStreet drugs known as ‘ecstasy’ have been sold for
about 20 years in the UK. The active substance that
such tablets contain – or purport to contain – is
3,4-methylenedioxymethamphetamine (MDMA).
Shortly after consumption, MDMA releases
chemicals in the brain that tend to bring about
a sense of euphoria, exhilaration and increased
intimacy with others. It is thought to be the third
most commonly used illegal drug in the UK after
cannabis and cocaine, with estimates suggesting
that between 500,000 and 2 million tablets are
consumed each week. Most people who take
ecstasy also use other legal and illegal drugs,
sometimes at the same time. Ecstasy is commonly
taken in nightclubs and at parties and is very often
associated with extended sessions of dancing.
Along with the pleasurable effects sought by users
of MDMA, it has become clear that the drug can
cause a range of unintended harms. In the short
term, a range of adverse events have been reported
– some fatal – and consumption of MDMA may
also have long-term consequences, especially with
regard to users’ mental health.
Objectives
This review aims to address the question: ‘What
are the harmful health effects of taking ecstasy
(MDMA) for recreational use?’ It does not examine
the harmful indirect and/or social effects, such as
effects on driving and road traffic accidents and
the consequences of any effect MDMA may have on
sexual behaviour.

Previous research syntheses
(Level I evidence)
For each identified Level I synthesis, it was difficult
to ascertain the exact methods adopted and
evidence included. Three reviews reported worse
performance for ecstasy users compared to controls
in a variety of neurocognitive domains (attention,
verbal learning and memory, non-verbal learning
and memory, motor/psychomotor speed, executive
systems functioning, short- and long-term
memory). A fourth study reviewed self-reported
depressive symptoms and found that ecstasy users
had increased levels compared to controls. The
final synthesis was primarily concerned with the
acute intoxication effects of ecstasy rather than
health harms. In all analyses, the effect sizes seen
were considered to be small.
Controlled observational
studies (Level II evidence)
Of the 110 controlled observational studies
included, there was one prospective study, the
Netherlands XTC Toxicity (NeXT) study, which
recruited a cohort of participants likely to start
using ecstasy and followed them for a year. Those
who started using ecstasy were then compared to
a group of matched controls who had remained
ecstasy-naïve. Ecstasy-exposed participants had
poorer performance in some memory tests,
although the absolute test scores for both cohorts
were comfortably within the normal range.
Other tests suggested an association between
ecstasy exposure and certain aspects of sensation seeking,
but there was no evidence of an effect on
depression or impulsivity. The cumulative dose of
ecstasy consumed was small (median 3–6 tablets).
The remaining Level II evidence consisted of cross sectional
studies only. Data were directly pooled
for seven individual outcomes. Six were common
measures of immediate and delayed verbal recall,
in which ecstasy users performed significantly
worse than polydrug controls. Effect sizes appeared
to be small, with the mean scores for each group
falling within the normal range for the instrument
concerned. No difference was seen between ecstasy
users and polydrug and drug-naïve controls in the
remaining measure, IQ.
A total of 915 outcome measures were grouped
into broad outcome domains as suggested in
the literature and after consultation with expert
advisers. For 16 of these meta-outcomes, there
were sufficient data for meta-analysis: immediate
and delayed verbal and visual memory, working
memory, sustained and focused attention, three
measures of executive function (planning, response
inhibition and shifting), perceptual organisation,
self-rated depression, memory, and anxiety and
impulsivity measured objectively and subjectively.
Ecstasy users performed significantly worse than
polydrug controls on all outcome domains with
the exception of executive function (response
inhibition and shifting) and objective measures of
impulsivity. Fewer comparisons were possible with
drug-naïve controls, with statistically significant
effects seen for verbal and working memory and
self-rated measures of depression, memory and
impulsivity. With both control groups, former
ecstasy users frequently showed deficits that
matched or exceeded those seen among current
users.
The small effect sizes seen were not consistently
modified by any study-level demographic variables.
There was little evidence of a dose–response
effect: studies reporting heavier average use
of ecstasy did not provide more extreme effect
measures than those consisting of lighter users,
and there was no demonstrable effect of length
of abstinence from ecstasy. When assessing the
impact of inter-arm differences on results, no
consistent effect was seen for imbalances in age
or gender. However, in several cases, it appeared
that imbalances in intelligence between cohorts
may have been important. Use of other drugs also
appeared to modify effects: alcohol consumption
proved the most consistent effect modifier, with
increased exposure in ecstasy-exposed populations

apparently reducing the magnitude of deficits
across a range of neurocognitive outcomes.
For the remaining outcome domains, there
were insufficient data for quantitative synthesis
and the results were summarised narratively.
For psychopathological symptoms, there was a
significant deficit for ecstasy users compared to
polydrug controls in the obsessive–compulsive
domain only, with greater deficits seen in
comparison to drug-naïve controls. In a few studies,
ecstasy users have been shown to have higher
levels of subjectively rated aggression than drug naïve
controls. It was not possible to draw clear
conclusions about the possible effects of ecstasy
consumption on dental health, loneliness, motor
function or sleep disturbance.
Case series and case reports
(Level III evidence)
Registry data from the np-SAD and GMR are not
directly comparable due to differences in data
sources and recording of drug use. The GMR
(1993–2006) suggests that there were, on average,
17 deaths a year where ecstasy was recorded as the
sole drug involved (2.5% of all deaths ascribed to a
single drug) and another 33 per year where it was
reported as co-drug use. Ecstasy-associated deaths
appear to have increased up to 2001 but to have
stabilised thereafter. In the 10 years to 2006, the
np-SAD recorded an average of 50 drug-related
deaths in which ecstasy was present (69 in 2006; 5%
of the total for the year). Ecstasy was believed to be
the sole drug implicated in an average of 10 deaths
annually over the same time period. According to
this registry, the typical victim of an ecstasy death
is an employed white male in his twenties, who
is a known drug user co-using a number of other
substances. Nearly half of ecstasy-related deaths
occur on a Saturday or Sunday night.
Published case series and case reports document
a wide range of fatal and non-fatal acute harms,
often very selectively. Two major syndromes
are most commonly reported as the immediate
cause of death in fatal cases: hyperthermia (with
consequences including disseminated intravascular
coagulation, rhabdomyolysis and acute liver and
renal failure) and hyponatraemia (commonly
presenting with confusion and seizures due to
cerebral oedema). Ecstasy users presenting with
hyponatraemia have invariably consumed a large
amount of water. We found 41 deaths relating to
hyperthermia reported in the literature and 10
from hyponatraemia (all women).
Other acute harms associated with fatal cases
include cardiovascular dysfunction, neurological
dysfunction (seizures and haemorrhage) and
suicide. Acute renal failure and sub acute liver
failure can occur without association with
hyperthermia. All these presentations were also
seen in non-fatal cases, alongside an additional
range of symptoms including acute psychiatric
effects, urinary retention and respiratory
problems including pneumothorax and
pneumomediastinum.
There are difficulties in estimating taken dose
of MDMA from the available literature, and it is
not clear why some people seem to have acute,
even fatal, reactions to doses that are commonly
tolerated in others.
Discussion
The evidence we identified for this review
provides a fairly consistent picture of deficits in
neuro-cognitive function for ecstasy users compared
to ecstasy-naïve controls. Although the effects
are consistent and strong for some measures,
particularly verbal and working memory, the effect
sizes generally appear to be small: where single
outcome measures were pooled, the mean scores of
all participants tended to fall within normal ranges
for the instrument in question and, where multiple
measures were pooled, the estimated effect sizes
were typically in the range that would be classified
as ‘small’.
However, there are substantial shortcomings in the
methodological quality of the studies analysed.
Because none of the studies was blinded, observer
or measurement bias may account for some of
the apparent effect. There is a suggestion of
publication bias in some analyses, and we saw clear
evidence of selective reporting of outcomes.
Selection bias is an inevitable problem: due to the
observational nature of all relevant evidence, there
is no guarantee that the cohorts being compared
were not subject to differences in areas other than
exposure to ecstasy. This effect will have been
exaggerated in those studies comparing ecstasy exposed
participants to drug-naïve controls; in
these instances, it is impossible to isolate the effect
of ecstasy exposure from the impact of other
substances. Within-study imbalances in intelligence
and the use of other substances, particularly
alcohol, appeared to explain some of the effects
seen. We suggest that the apparently beneficial
Methods
The following databases were searched using
a comprehensive search syntax: MEDLINE,
EMBASE, PsycINFO (run 19 September 2007)
and Web of Knowledge (run 7 October 2007).
The search outputs were considered against pre specified
inclusion/exclusion criteria; the full text
of all papers that could not confidently be excluded
on title and abstract alone was then retrieved and
screened. Only studies published in English were
included. Meeting abstracts were included only
if sufficient methodological details were given
to allow appraisal of study quality. Studies were
categorised according to a hierarchy of research
design, with systematic research syntheses (Level
I evidence) being preferred as the most valid and
least open to bias. Where Level I evidence was
not available, controlled observational studies
(Level II evidence) were systematically reviewed. If
neither Level I nor Level II evidence was available,
uncontrolled case series and case reports (Level
III evidence) were systematically surveyed. Data
extraction was undertaken by one reviewer and a
sample checked by a second.
Synthesising Level II evidence posed substantial
challenges due to the heterogeneity of the included
studies, the number and range of outcome
measures reported, the multiplicity of comparisons
(differing ecstasy exposures, differing comparator
groups) and outcomes, repeated measures and
the observational nature of the data. Analyses
were stratified for current and former ecstasy
users, with separate analyses for control groups
using other illegal drugs but not ecstasy (polydrug
controls) or controls naïve to illegal drugs (drug naïve
controls). Random-effects meta-analyses were
used throughout. Heterogeneity was also explored
through study-level regression analysis (meta regression).
Where a sufficient number of studies
had reported identical outcomes, they were meta analysed
on their original scale. Other outcome
measures were grouped into broad domains
and effect sizes expressed as standardised mean
differences in order to combine data derived from
multiple instruments. Objective and self-reported
outcome measures within each domain were
analysed separately.
For the Level III evidence, only narrative synthesis
was possible.
Results
Of 4394 papers identified by our searches, 795
were reviewed in full and 422 met the inclusion
criteria. Five systematic syntheses, 110 controlled
observational studies and 307 uncontrolled
effect of alcohol consumption may be explained
in two ways: either alcohol may mitigate the
hyperthermic effects of ecstasy in the acute setting,
attenuating damage to the brain, or ecstasy users
who co-use alcohol may represent a population of
more casual ecstasy takers than those who tend not
to drink.
Although the NeXT study suggests that small
deficits in memory may be secondary to ecstasy
exposure, all other included studies were
cross-sectional in nature; without evidence of
the temporal relationship between exposure
and outcome, it is difficult to draw any causal
inferences.
We did not find any studies directly investigating
the quality of life of participants, and we found
no attempts to assess the clinical meaningfulness
of any inter-cohort differences. The clinical
significance of any exposure effect is thus
uncertain; it seems unlikely that these deficits
significantly impair the average ecstasy user’s
everyday functioning or quality of life. However,
our methods are unlikely to have identified
subgroups that may be particularly susceptible
to ecstasy. In addition, it is difficult to know how
representative the studies are of the ecstasy-using
population as a whole. Generalising the findings is
therefore problematic.
Ecstasy is associated with a wide range of
acute harms, but remains a rare cause of death
when reported as the sole drug associated with
death related to drug use. Hyperthermia and
hyponatraemia and their consequences are the
commonest causes of death, but a wide range of
other acute fatal and non-fatal harms are reported.
Due to the poor quality of the available evidence, it
is not possible to quantify the risk of acute harms in
any meaningful way.
Research recommendations
Large, population-based, prospective studies are
required to examine the time relationship between
ecstasy exposure and neuro-cognitive deficits and
psychopathological symptoms.
Further research synthesis of the social and other
indirect health harms of ecstasy would provide a
more complete picture. Similar synthesis of the
health harms of amphetamines generally would
provide a useful comparison.
Future cross-sectional studies will only add to the
evidence-base if they are large, as representative as
possible of the ecstasy-using population, use well validated
outcome measures, measure outcomes
as objectively as possible with researchers blind
to the ecstasy-using status of their subjects, report
on all outcomes used, and provide complete
documentation of possible effect modifiers.
Cohorts should be matched for baseline factors,
including IQ and exposure to alcohol.
The heterogeneity of outcome measures used by
different investigators is unhelpful: consensus on
the most appropriate instruments to use should be
sought. Investigators should collect data directly
reflecting the quality of life of participants and/or
attempt to assess the clinical meaningfulness of any
inter-cohort differences.
A registry of adverse events related to illegal
intoxicants presenting to medical services (akin to
the ‘yellow card’ system for prescription medicines)
would enable useful estimation of the incidence of
harmful effects of ecstasy in comparison to other
substances.
Future case reports of acute harms of ecstasy are
unlikely to contribute valuable information to the
evidence-base. Where novel findings are presented,
care should be taken to report toxicological
findings confirming the precise identity of the
substance(s) consumed by the individual(s) in
question.

Source: Rogers G, Elston J, Garside R, Roome C, Taylor
R, Younger P, et al. The harmful health effects
of recreational ecstasy: a systematic review of
observational evidence. Health Technol Assess
2009;13

Filed under: Effects of Drugs (Papers) :
An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption.

Approximately 36% of East Asians (Japanese, Chinese, and Koreans) show a characteristic physiological response to drinking alcohol that includes facial flushing , nausea, and tachycardia [1] . This so-called alcohol flushing response (also known as “Asian flush” or “Asian glow”) is predominantly due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2) [2]. Although clinicians and the East Asian public generally know about the alcohol flushing response (e.g., http://www.echeng.com/asianblush/), few are aware of the accumulating evidence that ALDH2-deficient individuals are at much higher risk of esophageal cancer (specifically squamous cell carcinoma) from alcohol consumption than individuals with fully active ALDH2. This is particularly unfortunate as esophageal cancer is one of the deadliest cancers worldwide [3], with five-year survival rates of 15.6% in the United States, 12.3% in Europe, and 31.6% in Japan [4] Our goal in writing this article is to inform doctors firstly that their ALDH2-deficient patients have an increased risk for esophageal cancer if they drink moderate amounts of alcohol, and secondly that the alcohol flushing response is a biomarker for ALDH2 deficiency. Because of the intensity of the symptoms, most people who have the alcohol flushing response are aware of it. Therefore clinicians can determine ALDH2 deficiency simply by asking about previous episodes of alcohol-induced flushing. As a result, ALDH2-deficient patients can then be counselled to reduce alcohol consumption, and high-risk patients can be assessed for endoscopic cancer screening. Based on the sizes of the Japanese, Chinese, and Korean populations and the expected frequency of ALDH2-deficient individuals in each [1], we estimate that there are at least 540 million ALDH2-deficient individuals in the world, representing approximately 8% of the population. In a population of this size, even a small reduction in the incidence of esophageal cancer could result in a substantial reduction in esophageal cancer deaths worldwide.

Summary Points

ALDH2 eficiency resulting from the ALDH2 Lys487 allele contributes to both the alcohol flushing response and an elevated risk of squamous cell esophageal cancer from alcohol consumption.
Knowledge of the flushing response is useful clinically, as it allows doctors to identify their ALDH2-deficient patients in a simple, cost-effective, and non-invasive manner.
Doctors should counsel their ALDH2-deficient patients to limit alcohol consumption and thereby reduce the risk of developing esophageal cancer.
In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in esophageal cancers due to a reduction in alcohol drinking would translate into a substantial number of lives saved.

A Primer on the Genetics of Alcohol Metabolism

Ethanol is first metabolized primarily by alcohol dehydrogenase (ADH) into acetaldehyde (Figure 2), a mutagen and animal carcinogen that causes DNA damage and has other cancer-promoting effects [5–7]. Acetaldehyde is subsequently metabolized to acetate, mainly by the enzyme ALDH2 [8]. In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys) [9]. The Glu allele (also designated ALDH2*1) encodes a protein with normal catalytic activity, whereas the Lys allele (ALDH2*2) encodes an inactive protein. As a result, Lys/Lys homozygotes have no detectable ALDH2 activity. Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold [8].

Alcohol consumed by ALDH2-deficient individuals is metabolized to acetaldehyde, which accumulates in the body due to absent ALDH2 activity and results in facial flushing, nausea, and tachycardia [2]. These unpleasant effects are the result of diverse actions of acetaldehyde in the body, including histamine release [10]. Because of the intensity of this unpleasant response, ALDH2 Lys/Lys homozygotes are unable to consume significant amounts of alcohol. As a result, they are protected against the increased risk of esophageal cancer from alcohol consumption [11]. This observation also provided evidence for a causative role for ethanol in esophageal cancer, and a key role for acetaldehyde in mediating this effect [11].
ALDH2 Lys/Glu heterozygotes experience a less severe manifestation of the flushing response due to residual but low ALDH2 enzyme activity in their cells. As a result, some are able to develop tolerance to acetaldehyde and the flushing response and become habitual heavy drinkers, due in part to the influence of societal and cultural factors (see below). Therefore, paradoxically, it is the more common low-activity ALDH2 heterozygous genotype that is associated with greatest risk of esophageal cancer from drinking alcohol.

Evidence That ALDH2 Deficiency Increases the Risk of Alcohol-Related Squamous Cell Esophageal Cancer
Following the first study [12], which was conducted in the Japanese population, case control studies in Japan and Taiwan have consistently demonstrated a strong link between the risk of esophageal squamous cell carcinoma and alcohol consumption in low-activity ALDH2 heterozygotes, with odds ratios (ORs) ranging from 3.7 to 18.1 after adjustment for alcohol consumption. Moreover, most studies show ORs of over 10 for increased risk in heterozygotes who are heavy drinkers [13,14]. An independent meta-analysis has also confirmed an increased risk, even among moderate drinking heterozygotes [11]. In the Japanese and Taiwanese studies, a strikingly high proportion (58%–69%) of the excessive risk for esophageal cancer is attributable to drinking by low-activity ALDH2 heterozygous individuals [13,14].
Consistent with the results of case control studies, prospective studies in cancer-free alcoholics have also shown that the relative hazard for future upper aerodigestive tract (UADT) cancers in low-activity ALDH2 heterozygotes is approximately 12 times higher than in individuals with active ALDH2 [15]. (The UADT includes the oral cavity, pharynx, larynx, and esophagus.) In addition, alcohol consumption in low-activity ALDH2 heterozygotes has been associated with other cancer-related outcomes, including the presence of multiple areas of esophageal dysplasia (i.e., premalignant lesions) and multiple independent UADT cancers [13].
It is important to note that ALDH2 deficiency does not influence esophageal cancer risk in non-drinkers [11]. Furthermore, the magnitude of the ALDH2-associated esophageal cancer risk depends on the relative importance of alcohol versus other risk factors in a given population. In rural areas of China, where there is a high rate of esophageal cancer but alcohol drinking plays a less important role than in Japan and Taiwan, there is a more modest positive association (ORs, 1.7 to 3.1) between low-activity ALDH2 heterozygotes and esophageal cancer risk (e.g., [16]).
Acetaldehyde Is Responsible for Facial Flushing and Esophageal Cancer Risk in ALDH2-Deficient Individuals Top
Acetaldehyde is responsible for the facial flushing and other unpleasant effects that ALDH2-deficient individuals experience when they drink alcohol [10]. Importantly, there is now direct evidence that ALDH2-deficient individuals experience higher levels of acetaldehyde-related DNA and chromosomal damage than individuals with fully active ALDH2 when they consume equivalent amounts of alcohol, providing a likely mechanism for the increased cancer risk. A study in Japanese alcoholics [17] showed that the amount of mutagenic acetaldehyde-derived DNA adducts (Figure 4) in white blood cells was significantly higher in ALDH2-deficient heterozygotes than in individuals with active ALDH2 (Table 1). In this study, while the two groups were matched for alcohol consumption, the ALDH2-deficient group consumed slightly less alcohol on average than the controls. Also, ALDH2 heterozygotes who drank alcohol had higher levels of white blood cells with chromosomal damage than drinkers with active ALDH2 [18]. Because of these as well as other data, the 2007 International Agency for Research on Cancer Working Group on alcohol and cancer specifically noted the substantial mechanistic evidence supporting a causal role for acetaldehyde in alcohol-related esophageal cancer [19].

Five Key Papers in the Field
Harada et al., 1981 [2] The first documentation of the relationship between ALDH deficiency and the flushing reaction.

Yoshida et al., 1984 [9] Identification of the amino acid variant responsible for ALDH deficiency.

Yokoyama et al., 1996 [12] The first evidence demonstrating that ALDH2-deficient individuals have a dramatically elevated risk of esophageal cancer when they drink alcohol.

Yokoyama et al., 2003 [25] Demonstrates that an updated flushing questionnaire containing two simple questions is approximately 90% sensitive and specific for identifying ALDH2-deficient individuals.

Baan et al., 2007 [19] Summary of the conclusions from the 2007 International Agency for Research on Cancer Working Group on the Consumption of Alcoholic Beverages. This is the first report to conclude that ethanol in alcoholic beverages is carcinogenic to humans. The report also adds the female breast and colorectum to the list of sites for alcohol-related carcinogenesis and notes substantial mechanistic evidence linking acetaldehyde to esophageal cancer risk based on studies from ALDH2-deficient individuals.

While the UADT is exposed to acetaldehyde from alcoholic beverages [20] and tobacco smoke, increasing evidence points to the metabolism of ethanol by microorganisms in the oral cavity as an important source of acetaldehyde in saliva and, by extension, in the esophagus. Acetaldehyde levels in saliva are 10–20 times higher than in blood, due to the local formation of acetaldehyde by oral microorganisms [21]. Importantly, ALDH2 heterozygotes had two to three times the acetaldehyde levels in their saliva compared to fully active ALDH2 individuals after a moderate dose of oral ethanol [22].

Social and Cultural Factors Modulate Alcohol Drinking by ALDH2 Heterozygotes

Alcohol consumption is a social activity, and as such can be strongly influenced by cultural and social forces. In Japan, where the risk of alcohol-related esophageal cancer in ALDH2 heterozygotes has been most well documented, going out drinking after work with colleagues is an essential element of Japanese business society, and the idea of group harmony is particularly powerful. The percentage of heavy drinking men who are low-activity ALDH2 heterozygotes has risen substantially in the last few decades, in parallel with the proliferation of business society in Japan and increases in per capita alcohol consumption. Harada et al. [23] first reported that the frequency of inactive ALDH2 was very low (only 2%) in Japanese alcoholics in 1982. In a later study using archival DNA samples, Higuchi et al. [24] determined that in 1979, 3% of Japanese alcoholics were ALDH2 heterozygotes, compared with 8% in 1986 and 13% in 1992. In a more recent study, approximately 26% of heavy drinking (consuming more than about 400 g of ethanol per week) men in Tokyo were ALDH2 Lys487 heterozygotes [35]. In other East Asian countries, estimates of the percentage of alcoholics who are low-activity ALDH2 heterozygotes range from 17% in Taiwan in 1999 [26] to 4% in Korea in 2007 [27]. Taken together, these observations indicate that the inhibitory effect of heterozygous ALDH2-deficiency on alcohol consumption can be strongly influenced by local social and cultural factors which may change over time.

There are many East Asians now living in Western societies, particularly at universities and in metropolitan areas. A sub-population of special concern is ALDH2-deficient university students who may face peer pressure for heavy drinking and binge drinking. Furthermore, anecdotal evidence indicates that some young people view the facial flushing response as a cosmetic problem and use antihistamines in an effort to blunt the flushing while continuing to drink alcohol [28]. This practice is expected to increase the likelihood of developing esophageal cancer.

Education and Early Detection Can Reduce the Global Health Burden of Esophageal Cancer

Clinicians who treat patients of East Asian descent need to be aware of the risk of esophageal cancer from alcohol consumption in their ALDH2-deficient patients. Importantly, clinicians can determine whether an individual of East Asian descent is ALDH2 deficient simply by asking whether they have experienced the alcohol flushing response. In the Japanese population, ALDH2 deficiency can be identified accurately based on the answers to a flushing questionnaire consisting of two questions (see Box 1) about previous episodes of facial flushing after drinking alcohol [25]. The two questions can be easily included as part of a standard clinical interview. In a Japanese male population, the flushing questionnaire had a 90% sensitivity and 88% specificity [25] and a positive predictive value of 87% (based on the tabulated data in [25]). The flushing questionnaire gave a similarly high sensitivity (88%) and specificity (92%) when administered to Japanese women [29].

Clinical Tests To Assess ALDH2 Deficiency Due To the ALDH2 Lys487 Allele
1. The Flushing Questionnaire

The flushing questionnaire consists of two questions: (A) Do you have a tendency to develop facial flushing immediately after drinking a glass (about 180 ml) of beer?; (B) Did you have a tendency to develop facial flushing immediately after drinking a glass of beer in the first one or two years after you started drinking? For both questions, the choice of answers are: yes, no, or unknown.
If an individual answers yes to either question A or B, they are considered to be ALDH2 deficient [25]. The addition of question B is important because some individuals can become tolerant to the facial flushing effect.
The questionnaire that was tested referred to a small (about 180 ml) glass of beer. However, it seems likely that similar results would be obtained if the question were asked about beer or other beverages containing a similar amount of alcohol (about two-thirds of a glass of wine or shot of hard liquor).

2. The Ethanol Patch Test

The ethanol patch test is performed as follows: 0.1 ml of 70% ethanol is pipetted onto a 15 × 15 mm lint pad fixed on an adhesive tape. The patch is attached to the inner surface of the upper arm for a 7-minute period and then removed. A patch area that shows erythema 10–15 minutes after removal is judged as positive. The sensitivity, specificity, and positive predictive value for inactive ALDH2 are more than 90% in Japanese youth [34].

Once ALDH2-deficient patients have been identified, they should be informed about their elevated risk of developing esophageal cancer risk from drinking alcohol. As can be seen from Figure 5, ALDH2 deficiency increases esophageal cancer risk at all three drinking levels, but the slope of the line relating alcohol consumption to esophageal cancer risk is steeper in ALDH2-deficient individuals. Clinicians might therefore use this graph to explain the increased risk when counseling their ALDH2-deficient patients to reduce alcohol consumption.

Alcohol consumption amounts: low, 1–8.9 units/week; moderate, 9–17.9 units/week; high, ≥18 units/week; where 1 unit = 22 g of ethanol. The referent (OR = 1) is never/rare drinkers (<1 unit/week) of either genotype. Odds ratios were adjusted for age, frequency of drinking strong alcohol beverages, pack-years of smoking, and intake of fruit and green-yellow vegetables, based on a multiple logistic regression model. Error bars are 95% confidence intervals. The graph is based on the data in [25].
doi:10.1371/journal.pmed.1000050.g005
The ORs in Figure 5 are adjusted for smoking. However, patients should also be informed that smoking further increases the esophageal cancer risk in a synergistic manner with alcohol [30]. As noted above, cigarette smoking dramatically increases acetaldehyde levels in saliva, and ALDH2-deficient individuals have a reduced capacity to clear salivary acetaldehyde.
For patients at high risk of esophageal cancer, doctors should also consider endoscopy for early cancer detection. A health risk assessment tool to select candidates for endoscopic cancer screening, including data on alcohol flushing as well as alcohol consumption, smoking, and dietary habits, is currently being developed and validated [31]. Using a version of the health risk assessment that includes the flushing questionnaire as a major component, it has been estimated that approximately 58% of esophageal cancers in the Japanese population could be detected by screening only the individuals with the top 10% risk scores [31].
When detected early, esophageal cancer can be treated by endoscopic mucosectomy, a standard and relatively non-invasive procedure. However, once the cancer has grown large enough to penetrate the submucosal layer, the likelihood of lymph node metastasis increases significantly [32]. Only about 20% of esophageal cancer patients survive three years after diagnosis [3], emphasizing the importance of disease prevention.
ALDH2-deficient university students may have their first experiences with heavy drinking while at university. Therefore, it is particularly important for university health professionals to be aware of the relationship between ALDH2 deficiency, facial flushing, and alcohol-related cancer risk. Informing ALDH2-deficient young people of their risk of esophageal cancer from alcohol drinking represents a valuable opportunity for cancer prevention. However, most of the data on the accuracy of the flushing questionnaire have come from individuals over 40 years old. To assess ALDH2 deficiency in young people with little experience of alcohol consumption, an ethanol patch test (see Box 1) can be used [13]. In the patch test, ethanol is applied to the skin, where it is metabolized to acetaldehyde. (Both ADH and ALDH can be detected in skin fibroblasts [33].) If the acetaldehyde is not further metabolized to acetate, it causes vasodilation, which is detected visually as localized erythema. Like the flushing questionnaire, the ethanol patch test is simple and inexpensive to perform, and the sensitivity, specificity, and positive predictive value for inactive ALDH2 have been shown to be more than 90% in Japanese youth [34].

How Many Cancers Could Be Prevented by Reducing Alcohol Consumption in ALDH2-Deficient Individuals?
Finally, it is important to consider how many esophageal cancer cases might be prevented if ALDH2-deficient individuals reduced alcohol consumption. To address this question, the tabulated data of [35] were used to recalculate the population-attributable risk by Bruzzi’s method [36]. The results of this calculation indicate that if moderate or heavy drinking ALDH2 heterozygotes were instead only light drinkers, 53% of esophageal squamous cell carcinomas might be prevented in the Japanese male population.

Source: PLoS Med 6(3): e1000050. doi:10.1371/journal.pmed.1000050
Published: March 24, 2009

 

Filed under: Effects of Drugs (Papers) :

Effects on Neurocognitive Functioning
Maternal cannabis use during pregnancy has subtle effects on offspring’s neurocognitive functioning.

Beginning at age three to four, children of mothers who used cannabis heavily while pregnant have demonstrated deficits in memory, verbal and perceptual skills, and verbal and visual reasoning after adjusting for potentially confounding variables (Day et al., 1994; Fried & Watkinson, 1990).

Impaired performance in verbal and quantitative reasoning and short-term memory has also been found among six-year-old children whose mothers reported smoking one or more marijuana cigarettes per day, after controlling for significant covariates (Goldschmidt, Richardson, Willford, & Day, 2008).

In children around the age of nine, prenatal cannabis exposure has been linked with impaired abstract and visual reasoning, poor performance on tasks reflecting
executive functioning (i.e., visual-motor integration, nonverbal concept formation, and problem solving), and deficits in reading, spelling, and achievement, independent of various covariates (Fried, Watkinson & Gray, 1998; Fried & Watkinson, 2000; Goldschmidt, Richardson, Cornelius, & Day, 2004; Richardson, Ryan, Willford, Day & Goldschmidt, 2002)

Vulnerability in visual-cognitive functioning has been shown to persist into early adolescence among those offspring heavily exposed to cannabis (Fried, Watkinson, & Gray, 2003). Findings from brain imaging studies of young adults aged 18–22 indicate that in utero cannabis exposure negatively impacts the neural circuitry involved in aspects of executive functioning, including response inhibition and visuospatial working memory (Smith, Fried, Hogan, & Cameron, 2004, 2006).

These findings are particularly noteworthy as they demonstrate the long-term impairing effects of prenatal exposure to cannabis on offspring’s neurocognitive functioning.Global intelligence does not appear to be impacted by prenatal cannabis exposure (Fried et al., 1998, 2003).

When children reach age six, the effects of maternal cannabis use during pregnancy become much more evident. Compared to offspring of non-users, children born to cannabis users— particularly heavy users—have been found to be more hyperactive, inattentive, and impulsive (Fried, Watkinson, & Gray, 1992; Leech, Richardson, Goldschmidt, & Day, 1999), even after controlling for extraneous variables.

At age 10, prenatally exposed children display increased hyperactivity, inattention, and impulsivity, and show increased rates of delinquency and externalizing problems as reported by their mothers and teachers, compared to those children who were not exposed prenatally to cannabis (Fried et al., 1998; Goldschmidt, Day, & Richardson, 2000).

In children aged 13–16, however, some aspects of attention (i.e., flexibility, encoding and focusing) appear to no longer be affected by cannabis exposure (Fried et al., 2003).

There is accumulating evidence that suggests prenatal cannabis exposure may contribute to the initiation and frequency of subsequent substance use during
adolescence. Porath and Fried (2005) reported that 16- to 21-year-old offspring (particularly males) of cannabis users were at increased risk, in a dose-related
manner, for the initiation of cigarette smoking and cannabis use, and daily cigarette smoking, compared to offspring of non-using mothers, independent of potential prenatal confounds. Similar results were noted by Day, Goldschmidt, and Thomas (2006); compared to offspring of non-users, youth of mothers who heavily used cannabis while pregnant not only reported using this substance more frequently at age 14, but they also initiated use at an earlier age. This result was significant even after controlling for potential confounds.

Effects on Mental Health
There is emerging evidence linking in utero cannabis exposure to depressive and anxious symptomatology. After controlling for prenatal exposure to other drugs and risk factors for childhood depression, offspring of maternal cannabis users expressed significantly more depressive and anxious symptoms at age 10 compared to children of non-users (Gray, Day, Leech, & Richardson, 2005; Leech, Larkby, Day, & Day, 2006).

Mechanisms of Action
The mechanisms responsible for the effects of prenatal cannabis exposure are not well understood. Cannabinoids are able to cross the placental barrier and may affect the expression of key genes for neural development, leading to neurotransmitter and behavioural disturbances (Gomez et al., 2003). The presence of cannabinoid receptors in the placenta and fetal brain may also mediate adverse actions of prenatal cannabis exposure (Park, Gibbons, Mitchell, & Glass, 2003), as these receptors are associated with aspects of brain functioning including cognition and memory (Kumar, Chambers, Pertwee, 2001). Animal studies have documented that cannabinoids can lead to changes in dopamine activity and impaired functioning of the hypothalamus-pituitaryadrenal axis (Kumar et al., 2001), which may affect mood and neurobehavioural outcomes in offspring. It is also possible that an underlying genetic factor may account for both the lifestyle habits of the pregnant mother (i.e., cannabis use) and her child’s neurodevelopment and behaviour.

Conclusions and Implications
Evidence does suggest that prenatal exposure to cannabis (particularly heavy exposure) has subtle adverse effects, beginning at approximately three years of age, on subsequent cognitive functioning, behaviour, substance use, and mental health in offspring. Cannabis-related deficits in the cognitive domain could impair a child’s academic functioning and may require educational remediation, enrichment or placement to help protect against future learning problems.

Prevention efforts directed towards reducing maternal cannabis use during pregnancy could have significant effects in reducing such cognitive impairment. Prevention and intervention programs aimed at reducing prenatal cannabis exposure could also help reduce the percentage of youth who experience mental health conditions and other comorbid problem behaviours, such as substance use and delinquency. It has been reported that at least half of all pregnancies in North America are unplanned (Walker, Rosenberg, & Balaban, 1999). That, combined with the fact that nearly 7% of American women of childbearing age (15–44 years) reported past-month use of marijuana and hashish in 2005 (SAMHSA, 2006) indicates the potential risk for offspring to be prenatally exposed to cannabis.

Cannabis use is a preventable prenatal risk factor; the findings reviewed from the literature suggest that it is prudent to advise pregnant women, and women thinking of becoming pregnant, of the risks associated with cannabis use during pregnancy.

Source Clearing the Smoke on Cannabis . Maternal Cannabis Use During Pregnancy http://www.ccsa.ca/ 2009

Filed under: Effects of Drugs (Papers) :

Jordan Diplock, Irwin Cohen, and Darryl Plecas
School of Criminology and Criminal Justice,
University College of the Fraser Valley, Abbotsford, British Columbia, Canada
Abstract
The truth about the risks and harms associated to personal marijuana use is rarely a feature of the ongoing debate over the legal status of the drug, with advocates on both sides at fault. Some consensus over the potential harms needs to be reached before any meaningful discussion can occur on this issue. This article reviews research published between 2000 and 2007 and suggests that there are many risks associated to marijuana use with regards to impairment, academic and social development, general and mental health, and continued drug use. Although some findings highlight very serious concerns for users, the numbers that become adversely affected by marijuana use do not represent the majority of users. A debate on the legal status of marijuana based on the facts about the risks and harms of this drug will greatly aid in determining the appropriate actions to address personal marijuana use around the world.
Keywords: Academic Performance; Gateway; Harms; Health; Impairment; Marijuana; Mental Health; Risks
Introduction
The debate over the personal use of marijuana in North America and around the world is extremely contentious with supporters for decriminalization and legalization, and others who assert the importance of strict prohibition. The exceptionally adversarial nature of this debate is likely one of the main obstacles to determining the most appropriate way to address marijuana use within society. As a result of interested parties remaining resolute in their particular positions, the marijuana debate often becomes characterized by selective reporting or the misuse or misinterpretation of the available information. In addition, the popular debate rarely transcends ideological arguments on marijuana’s potential harms. With proponents of legalization championing marijuana as a benign drug and prohibitionists stressing its dangerousness, the debate often fails to consider the totality of the empirical research evidence. The purpose of this review is to discuss the harms associated with marijuana use from an objective viewpoint to provide a basis for the development of further research on how to best address the issues of marijuana use.
As research on marijuana use and its effects is constantly providing additional information, the full extent of the effects of marijuana on users will likely not be known conclusively in the near future. This should not be regarded negatively, as it is the nature of research that future studies improve upon the methodologies and results of previous research. For example, in 1997, The Independent, a popular British newspaper, was a strong supporter of the decriminalization of marijuana in the United Kingdom. In part, this support led to a pro-cannabis march that pressured the government to downgrade the classification of marijuana . Ten years later, that newspaper printed a public apology for its leadership role in the legalization campaign with a headline stating “If only we had known then what we can reveal today”. This example demonstrates the importance of considering new evidence and being willing to refine one’s position based on the best available information. By reviewing the current research on the potential harms associated with marijuana use, this review intends to synthesize the best evidence to inform the debate.
Ensuring that one considers the most current research on marijuana use is not only important because of the changing nature of academic research, but also because the drug under study has changed over the years. In other words, marijuana does not refer to cannabis with a particular level of -Tetrahydrocannabinol (THC). Over time, the level of THC in marijuana has changed; typically, it has increased. However, because there have been very few studies on the changes in potency of marijuana over the years, it cannot be confirmed conclusively that marijuana users in the 1970s were typically consuming a different drug than today’s users. The information that does exist suggests that, on average, marijuana users today are exposed to higher levels of THC than in past decades. Research on potency trends of seized marijuana between 1980 and 1997 concluded that average THC levels of marijuana seized in the United States increased from less the 1.5% in 1980 to approximately 3% in the early 1990s, to over 4% in 1997 . Moreover, in an article published by the Drug Enforcement Administration (DEA), Newell reported that average THC concentrations in marijuana from 36 samples seized in the state of Florida in 2002 were over 6%. These levels were determined to be at par with the averages reported by the Marijuana Potency Monitoring Project . In Canada , the Royal Canadian Mounted Police [RCMP] reported that on average seizures of marijuana in Canada had THC concentrations over 10%. Seizures in Europe of imported marijuana typically had THC levels between 2% and 8%, but the potency of hydroponically-grown “skunk” may be as high as double that of the imported marijuana . However, it must be kept in mind that the nature of marijuana production and distribution is such that a regular user would likely be exposed to marijuana of various different concentration levels of THC. As the majority of marijuana production remains the industry of criminals, many of whom use hydroponic operations and compete with each other to produce the most and the ‘best’ marijuana, there is no reason to believe that the quality of street marijuana has remained consistent over time.
In addition to levels of THC, the understanding of the number of different constituents of marijuana and their potential to interact with each other changes over time. ElSohly and Slade reported that the number of known natural compounds in marijuana increased from 423 to 489 between 1980 and 2005. Of those numerous chemicals, 70 were Cannabinoids, 9 of which were discovered since 1980 . The changes in knowledge about the complex chemical makeup of marijuana further complicate the study of the potential dangers of its use.
Because marijuana is used around the world by approximately 160 million people, there has been a great deal of research conducted on its effects on users . The use of marijuana results in a variety of changes within the user’s body that can have a range of effects . Given this, the focus of this review is limited to the research evidence on potential harms associated with marijuana use in the areas of: impairment; academic and social development; general physical health; mental health; and continuing drug use. Although there is also a substantial body of research on the medical use of marijuana for particular patients, a review and discussion of the research on medical marijuana is not included in this study. This exclusion is not meant to suggest that marijuana is universally accepted as a safe or effective treatment for any illness, as Voth has clearly demonstrated that the wider debate over the use of marijuana extends into the issue of the drug’s medical use. The discussion presented in this review will concentrate on the use of marijuana within the general population and the empirical evidence for how marijuana use effects the general population in the five previously listed areas.

Methodology
To ensure that this review considered the most current research, information was collected from articles published from 2000 to 2007. Articles were identified by searching a number of databases, including Medline, Pub.Med, PsychINFO, and Google Scholar. To ensure a more complete search, a variety of keywords were combined with ‘marijuana’ to search the databases. In particular, these keywords related to the five aforementioned areas. An extremely partial list of keywords included ‘impairment’, ‘academics’, ‘heart disease’, ‘respiratory’, ‘cancer’, ‘psychosis’, and ‘gateway’.
Once an article was identified, it was assessed for appropriateness based on a review of the article’s title and abstract. One potential limitation of this review was that only full-text-available articles written in English were considered for this review. However, in order to expand the number of articles considered, both original research studies and articles that reviewed topics related to the harms of marijuana use were included. In order to ensure objectivity in the selection process, the inclusion or rejection of articles occurred without consideration of authorship or the conclusions or recommendations made by the authors. Given this, the articles considered in this review represented the continuum of current research on the harms that may be associated with marijuana use. Because of the scope of this topic and the amount of literature on marijuana use, the articles included in this review do not represent all available research on the effects of marijuana use. However, because many of the articles included in this review included extensive reviews of previous literature, the areas of focus for this review were well represented.
Finally, when considering the evidence presented in this review, it is critical to keep in mind that many of the studies based their results and conclusions on self-reported effects of marijuana use by the users themselves. While self-report studies are extremely valuable, they are susceptible to a variety of methodological problems, such as social desirability effects, errors in memory, exaggeration, and deception, which must be considered when evaluating results or conclusions . In addition, it is also extremely difficult to link or establish a direct causal relationship between drug use and other specific behaviours as it is likely that behaviours or outcomes are the result of multiple factors, rather than exclusively one factor, such as drug use.
Marijuana Related Impairment
One of the important debates in the research literature is the effect of marijuana use on cognitive and motor skills. Several studies have focused on determining whether there are any negative effects on cognitive or motor skills within hours of marijuana use . A number of studies have more specifically focused on the effect of marijuana use on abilities related to operating a motor vehicle . In addition to studies of short-term impairment, research has been conducted on long-term impairments associated with prolonged marijuana use .
Short-term Impairment
Impairment immediately after the consumption of marijuana may be a concern for users and the community at large. Short-term impairment has generally been assessed anywhere from 5 – 10 minutes to several hours after use. Testing the effects of marijuana on working and episodic memory determined that focusing attention and response accuracy were impaired immediately after smoking marijuana, even marijuana with less than 4% THC. The authors concluded that the marijuana resulted in difficulty maintaining a coherent train of thought and disruptions to selective filtering processes, both of which impaired memory. Similarly, another study reported that acute marijuana intoxication was accompanied by impairment of brain function related to goal-oriented activities. Further, it was suggested that marijuana consumption inhibited impulse and anger control in some users implying a possible link between marijuana use and violent or antisocial behaviour in some individuals . However, impaired attention was not found in a study of marijuana’s effects on auditory focused attention tasks where participants responded to a tone by pressing a button as quickly as possible. Results of an examination of brain functioning hours after using marijuana found that heavy marijuana users did not present impaired abilities on simple spatial working memory tasks, as deficits were compensated for by employing regions of the brain not commonly used during such tasks.
Although the research reported that short-term cognitive impairment could occur among marijuana users, the level of impairment and its seriousness was not significant. However, this does not suggest that there are no or few short-term risks of impairment. Instead, this conclusion may be due to the small sample sizes of only 10 to 12 participants in the studies examined . In effect, the sample sizes in these studies limited the ability to draw any firm conclusions about the range or seriousness of short-term cognitive impairments associated with marijuana consumption.
Researchers also examined the relationship between marijuana induced cognitive impairment and common abilities, activities, or behaviours, such as operating a motor vehicle. Ramaekers and co-workers concluded that decision-making, planning, tracking, reaction time, and impulse control were impaired by high-potency marijuana. Although the 20 subjects were considered only light users, substantial impairment of executive and motor functioning for a period of at least six hours was found. Although the 13% THC level in the marijuana used in this study was higher than the averages reported by the DEA and RCMP , this study demonstrated that serious impairment lasting for many hours was common when consuming high potency forms of marijuana.
Operating a motor vehicle can be dangerous at any time. However, doing so while impaired by marijuana significantly increases the risks of accident. Although some studies revealed that recent marijuana use was a causal factor for only a small proportion of accidents, short-term marijuana impairment does contribute to serious motor vehicle accidents To better determine marijuana impairment among drivers, standardized field sobriety tests have been designed to detect impairment by marijuana in a manner similar to alcohol. Research on field tests concluded that, as expected, impairment increases with the level of THC . Even low levels of THC can moderately impair driving abilities, but driving is severely impaired when either higher levels of THC marijuana is consumed or marijuana with lower levels of THC is consumed with even small amounts of alcohol . Considering the research examined for this review on the relationship between marijuana consumption and impairment, there appears to be a strong consensus that marijuana use has a negative and potentially harmful effect on driving.
Long-term Impairment
There are few studies on the long-term impairment of chronic marijuana consumption compared to the acute effects of marijuana use. Still, some researchers examined the potential for impairment as a result of long-term use, even during periods of abstinence . From the results of one study of older participants (33-50 years old), it appeared that, although heavy marijuana users showed impaired cognitive abilities after a week of abstinence, there were no noticeable impairments after twenty-eight days of abstinence . When compared to a control group, long-term marijuana using teens (aged 16 – 18) had equivalent task performance on a go/no-go task after twenty-eight days of abstinence . However, marijuana users committed more errors on cognitive tests and showed increased brain processing effort during the inhibition task . When comparing early-onset users to late-onset users, even after twenty-eight days of abstinence, early-onset frequent marijuana users had a greater likelihood of suffering a range of cognitive functioning impairments, in particular verbal IQ, compared to late-onset and non-users .
One interesting finding about long-term marijuana users was that there was an increase in brain activity in more regions of the brain when performing a variety of cognitive tests when compared to non-users. The researchers concluded that this finding was the result of the brain working harder and differently to overcome the deficits resulting from the marijuana use . In addition to working harder and differently, significantly increased blood volumes in various regions of the brain have been discovered , even after a period of abstinence of six to thirty-six hours. The researchers indicated that it remained unknown how these changes affected brain functioning and whether these changes were permanent, long-lasting, or temporary. However, these findings do suggest that there is a potential for some type of long-term brain impairment. Nonetheless, with the exception of impairments caused by psychosis and other mental illnesses discussed later in this review, when considering the totality of the research literature on the relationship between marijuana use and long-term cognitive or motor impairment, there appears to be little evidence to support the assertion that serious impairment is a likely result from long-term marijuana use, especially after a period of abstinence.
The Effects of Marijuana Use on Academic and Social Development
As marijuana is the drug of choice for many young people, it is necessary to understand whether marijuana has any negative effects on academic performance and the transition from adolescence to adulthood. The evidence for both immediate impairment and the possibility of longer-term impairment supports the notion that marijuana use may have negative consequences on the development of young users. In a consideration of academic performance and graduation, a number of studies have focused on the relationship between marijuana use and absenteeism , I.Q. , and academic achievement . By examining the lifestyles of adults who reported being heavy marijuana users in their youth, other researchers have attempted to assess the effects of marijuana use on social development . The following section provides a discussion of the literature in these areas.
Marijuana and School Performance
There are many factors that contribute to academic achievement, such as general intelligence, interest/curiosity, motivation, lifestyle, and social relationships/networks. Since the adolescent human brain is still developing, it is possible that recreational marijuana use may disrupt ‘normal’ development, which may manifest in, among other things, poorer school performance. Survey research revealed that students who were absent on the day of a school-based survey were more likely to use marijuana, alcohol, and cigarettes than students who were present. Although it is unsupportable to conclude that one specific day of absence from school was caused by or related to marijuana use, this study provides some small support for the more impressive findings of Lynskey and Hall’s review of cross-sectional studies on marijuana and school-related issues. Their review of over 50 research studies concluded that marijuana appeared to have a strong relationship with absenteeism, lack of retention, and not graduating.
An examination of the relationship between academic achievement and drug use in a diverse sample of 18,726 students concluded that marijuana use, when examined alone, was statistically significantly related to lower standardized test scores in math, science, reading, and social studies. Average scores on the math comprehension test for marijuana users were further below the mean than on any other test, while reading comprehension appeared to be affected the least. However, when marijuana was combined with alcohol or cigarettes, the results were much less robust. In effect, both regular smoking and alcohol intoxication explained much more of the variance, thus reducing the influence of marijuana on test scores. The explanation provided for this finding was the relatively small number of students who reported ever being under the influence of marijuana at school compared to the number of students who regularly used alcohol and/or cigarettes at school . Similarly, a study by Diego and colleagues found that grade point averages decreased as the reported frequency of marijuana use increased. Marijuana use had a larger negative correlation with grade point average as frequency of use increased than alcohol or cigarettes. While these findings suggested a link between marijuana use and academic achievement, the research could not establish a direct causal relationship or the direction of the relationship. Nonetheless, for the most part, social scientists agree that marijuana use is detrimental to school performance .
Since marijuana has been linked to short-term impairment and a decrease in school performance, some researchers have studied the effects of marijuana on IQ (29). However, measuring the direct effects of marijuana use on IQ has been difficult as there is rarely a baseline measure of a subject’s IQ prior to their initiation into marijuana use. One longitudinal study that had baseline measures of IQ prior to the subject ever using marijuana reported a statistically significant decrease in IQ score among individuals who smoked five or more marijuana cigarettes per week. On average, a 4.1 point decrease was measured between the time the subject was 9 – 12 years old (no prior use) and 17 – 20 years old (current and/or past use). However, when considering the degree of marijuana use for the sample of 70 marijuana users, only those characterised as heavy users showed any decreases in IQ compared to slight users, former users, and non-users who demonstrated increases in IQ . These results suggested that marijuana use has an effect on general intelligence but is more severe for regular and chronic marijuana users.
Marijuana Use and Later Social Development
Success in adulthood is related to a wide range of developmental and social variables throughout childhood and adolescence. It has been hypothesised that many of these contributing dynamics could be negatively affected by the use of marijuana. For example, some people contend that one of the possible outcomes of marijuana use is chronic low motivation. In effect, the hypothesis is that marijuana use among young people contributed to the development of low motivation which has long-term effects on school and employment performance. In their research, however, Lynskey and Hall concluded that there was little evidence to support the low motivational syndrome hypothesis because the majority of supportive evidence was based on older uncontrolled studies of case histories and observational reports, while controlled field or laboratory studies did not find compelling evidence of such a syndrome. Moreover, long-term (over 20 years), regular marijuana use among males was not associated with any specific negative socio-demographic effects such as alcohol or nicotine abuse or dependence, hospitalizations, and health-related quality of life .
However, other researchers have found several adverse associations between marijuana use and social development. A study of the relationship between marijuana use in 2,842 high school students and later occupational attainment concluded that marijuana had some differential negative associations with occupational attainment for males and females . Specifically, for males, self-reported abstinence or low frequency use of marijuana had no effect on occupational attainment, although high prestige jobs typically had a greater percentage of non-users or former low frequency users. However, for male users, after a certain threshold level was passed, success in occupational attainment decreased with increased early marijuana use. The threshold for this relationship in this study was ambiguous as the linear relationship began with the category associated to between 3 and 39 occasions of marijuana use in one year. Among females, early marijuana use was found to have strong negative outcomes on occupational attainment, but the pattern was different from that of males, lacking the easily identifiable threshold and negative linear relationship .
Green and Ensminger examined the effects of marijuana use on a variety of social variables among a cohort of 530 African Americans. Frequent adolescent marijuana use was associated with poorer academic achievement, a lack of stable employment, and family dysfunction. These results suggested that using marijuana 20 or more times during adolescence was associated with being unemployed, unmarried, and becoming a parent while unmarried. Early marijuana use was also linked to dropping out of school and continued marijuana use as an adult . Although this study was specific to African Americans, when considered with other studies on occupational attainment and school performance, these results contribute to the body of literature indicating that marijuana use among young people can have a detrimental outcome on their future. However, these findings do not confirm a causal relationship between marijuana use and poor performance in school or life. Still, the evidence does suggest that, even in the absence of a direct causal link, the use of marijuana during adolescence, for many young people, is often accompanied by other factors, such as the development of delinquent peer associations or a general lack of commitment to pro-social activities and institutions, which can lead to problems with social development.
General Health Consequences of Marijuana Use
The use of marijuana introduces foreign substances into the body and produces a number of chemical changes in the user’s brain and body. Given this, there is a large amount of literature focusing on the physical effects of marijuana. To begin, there is little evidence to suggest that marijuana use poses a serious risk for an overdose death or its infrequent use is related to the development of long-term health problems . Given this research, the majority of health-related studies focused on the potential harmful health outcomes associated with long-term and heavy marijuana use. One of the most widely studied issues is the relationship between smoking marijuana and the development of respiratory ailments .
In addition, the short-term and long-term effects of marijuana use on the circulatory system have also been extensively studied . Other researchers have focused on potential reproductive harms , the effects of marijuana use on the immune system , and the risks for cancers . There is also a burgeoning research literature on the degree to which marijuana users can develop a dependency and experience withdrawal symptoms . The following section will review the research literature on these important issues.
Respiratory Ailments Related to Marijuana Use
The most common way of using marijuana is by smoking it. A direct consequence of this method of consumption is that smoke must enter the airways and lungs of the user. As a result, researchers are interested in the amount and type of harm that smoking marijuana has on the respiratory system of users. This is particularly important because marijuana smoke contains many of the same poisons found in tobacco smoke. Given this, research has focused on determining whether the respiratory outcomes of smoking marijuana are similar or worse than those associated with smoking tobacco . Taylor et al. reported that respiratory symptoms were significantly more prominent in marijuana-dependent users than in non-users. The sample consisted of 21 year old subjects from the 1970s who self-reported short histories of smoking marijuana . The associated self-reported respiratory problems included wheezing, shortness of breath after exercise, nocturnal chest tightness, and early morning phlegm and mucus. These symptoms, which are typically indicative of chronic bronchitis, were also found to be associated with smoking marijuana in other research .
In their review of the research literature, Taylor and Hall argued that marijuana should be considered as damaging to the airways as tobacco and that there was a strong possibility that smoking marijuana was a contributing factor to the development of chronic lung disease. Further research concluded that long-term marijuana smoking was also associated with an increase in airflow obstruction and obstructive lung disease. A comparison of the effects of marijuana cigarettes to tobacco cigarettes concluded that one marijuana cigarette can have the obstructing effects on the lungs equal to that of two to five tobacco cigarettes. Lower lung density and increased total lung capacity were also recorded for marijuana smokers, but macroscopic emphysema was not found to be a common symptom . These findings suggested that serious negative respiratory outcomes should be expected for regular marijuana smokers, regardless of the marijuana’s THC levels, even among youth or young adults.
Since many of the detrimental effects on the respiratory system are the direct result of smoking, there have been several studies examining whether vaporizers provide a less harmful way to consume marijuana . Based on self-reported respiratory symptoms after using vaporizers to inhale marijuana cannabinoids, Earleywine and Barnwell concluded that vaporizers did provide some measure of safety, especially as the amount of marijuana inhaled increased. Hazekamp et al. reached a similar conclusion.
While the use of vaporizers may reduce or eliminate some of the respiratory ailments for users, the THC in marijuana may pose a respiratory risk. In response to the presence of THC, human airways experience cellular changes, especially to mitochondrial energetics, which are responsible, in part, for the health of cells and their energy production . Sarafina et al. described these changes as deleterious effects, as changes to the mitochondria of lung cells affects the viability and functioning of those cells. These changes were more significant with higher concentrations of THC and longer exposure times . In effect, as a result of THC in the lungs and airways, the risk of adverse pulmonary conditions is substantially increased by the potential for damage to the airway epithelial cells .
Potential Harms of Marijuana Use on the Heart and Circulatory System
One direct outcome from using marijuana is an immediate increase in heart rate. It is estimated that marijuana use increases the heart rate 20% to 50% immediately following consumption . This has led researchers to examine the short and long-term implications of marijuana use on the heart and the circulatory system. The majority of research in this area relies on case studies . Although the conditions documented in the research literature may be serious, it must be kept in mind that there is little evidence to suggest that the outcomes discussed in the case studies are typical or the norm for marijuana users.
Based on their case study of a 34-year-old man who reported heart fluttering and near syncope after marijuana use, Rezkalla and coworkers suggested that marijuana was a likely contributor to the decrease in coronary blood flow and ventricular tachycardia experienced by their subject. Another study described two cases; one in which a man with a history of heart problems suffered arrhythmia precipitated by marijuana use, the second described a young patient who suffered an onset of myocardial infarction. The researchers concluded that marijuana was a serious concern for those who may be predisposed to heart-related illnesses. Similarly, Caldicott et al. documented the case of a young patient who suffered a heart attack after marijuana use, despite having no other identifiable risk factors for a cardiac event.
Findings may be more informative when referring to larger samples that identify cardiac risks associated with marijuana use. One study concluded that, although it was less common than other stressors, marijuana use was a trigger for myocardial infarction . In this study , the risk of onset of myocardial infarction increased approximately five-fold in the first hour after use.
The conclusion of existing research is that marijuana use may, in rare instances, trigger a heart attack. However, it is important to recognise that the evidence in support of this conclusion may be confounded by the subject’s participation in a wide range of other unhealthy habits that may also contribute to a greater or lesser degree to a heart attack. Still, there is some evidence to conclude that marijuana is harmful to the heart and researchers, such as Aryana and Williams (, have stated a belief that heart problems related to marijuana use may be more common than is currently recognized. In addition, they warned that as the population of marijuana users aged, continued use may increase the risk for a number of adverse cardiovascular issues, such as tachyarrhythmia, acute coronary syndrome, vascular complication, and congenital heart defects .
Consequences of Marijuana Use on Reproduction and Pregnancy
There is a growing body of literature on the effects of drug use on sperm and egg development and the short and long-term outcomes for the foetus. This literature focuses on the relationship between drug use and implications for fertility and healthy, successful pregnancy. For example, several studies have investigated the effects of marijuana use on male sperm fertility and female hormones . Scheul et al. found that the presence of THC in the reproductive fluids of both males and females could inhibit the ability of sperm to complete fertilization. Other research reported that THC inhibited male fertility by binding to sperm cells and impairing sperm functions. In females, marijuana was found to disrupt the endocrine system and produce an estrogenic effect, which can have detrimental effects on specific elements of the female reproductive system . It should be noted, however, that the effects were more the result of the contaminants of smoking the drug than the psychoactive chemicals . In addition, marijuana use negatively affected female reproductive hormones which could lead to delayed ovulation . In considering these studies, the conclusion is that marijuana use may have some negative effects on human reproduction and that these outcomes are increased for those already at risk for infertility or other reproductive conditions.
Research also examined the degree to which marijuana use by pregnant mothers affected the unborn foetus and whether maternal marijuana use led to negative outcomes for the child. Kuczkowski reported that THC crosses the placental barrier, but that there was no confirmation that it had a teratogenic effect. In other words, there is no evidence that marijuana use by a pregnant mother contributes or causes birth defects or malformations. However, research by Wang et al. determined that some impairment was present in foetuses exposed to marijuana. This finding led the researchers to conclude that some long-term emotional and behavioural implications existed for children exposed to marijuana while in the womb.
Fried and Smith’s review of literature concluded that the effects of prenatal exposure to marijuana were subtle, with little evidence supporting growth or behavioural effects prior to age three. Others concluded that there was a statistically significant association between prenatal exposure to marijuana and later use; however, they concluded that there were many other potential factors that could have contributed to later marijuana use among those exposed to the drug while in the womb. One common theme among the research conducted to date was that they all called for more study on this issue. Although further research is needed in this area, to date, no substantial dangers have been confirmed to be associated to smoking marijuana while pregnant. However, marijuana smoke contains hazardous chemicals and materials, many of which exist in tobacco smoke. Therefore, just as health providers caution that tobacco should not be used by pregnant mothers, the caution should extend to marijuana use.
Marijuana Use as a Potential Threat to the Immune System
THC from marijuana may act upon the immune system similarly to the way it does on cells in the reproductive system . If the immune system is compromised by the use of marijuana, there may be significant implications for health care systems around the world . The relationship between marijuana use and deficiencies of the immune system is based, in part, on the findings that THC inhibits the ability of T-cells and alveolar macrophages to protect the body from foreign pathogens . Alveolar macrophages are a main defence against infections in the lungs. A review of the research literature in this area by Copeland et al. suggested, however, that it might require high doses of THC to substantially impair immune system functioning. Still, when considering the number of respiratory problems associated with smoking marijuana, and the possibility of serious carcinogenic properties in the drug, compromising the immune system may further compound the harms of marijuana use, especially among those already suffering from weakened immune systems.
Cancer Causing Effects of Marijuana
Because marijuana smoke contains many of the same harmful carcinogens as tobacco smoke, there is a possibility that marijuana use may be associated with the onset of various types of cancers, especially lung cancer as the most common method of consuming marijuana is by smoking it . To date, however, the research does not support the association between marijuana use and cancer. In their study, Hashibe and colleagues failed to find substantial evidence for an association between marijuana use and lung or upper areodigestive tract cancers. A review of research on lung cancer and marijuana use by Mehra et al. revealed many of the methodological difficulties in attributing outcomes specifically to smoking marijuana. For example, in many instances, marijuana users also smoke tobacco, there is the challenge of determining proper thresholds for marijuana use, and the research has typically included only small sample sizes. Mehra et al. suggested that because the plausibility of an association between marijuana smoking and cancer is so apparent, improved studies are required to test this possible link. Other research has reached similar conclusions about the link between marijuana use and cancer . Although a 1999 study by Zhang and colleagues reported a potential for marijuana use to increase the risk of squamous cell carcinoma of the head and neck, the evidence for a link between marijuana use and head and neck cancers has been limited and conflicting . In a recent study, marijuana was not found to increase the risk of head and neck cancer, although the duration of use under study might have been too limited to rule out the possibility of a longer-term effect . Another large-sample study concluded that marijuana was not associated to oral squamous cell carcinoma. There was also no link between maternal or paternal marijuana use and risk of childhood acute myeloid leukaemia .
Although there is currently no evidence to confirm that marijuana use increases the risk for any type of cancer, there will likely be continued research. Already, there are many researchers who believe that the changes to a variety of cells in the body caused by marijuana use may contribute to the development of cancers including lung cancer, oral cancers, and breast cancer .
Marijuana Dependency and Withdrawal
Despite the commonly held belief that marijuana use does not lead to addiction, existing research has often referred to a dependency on the drug . Although many people use marijuana on a regular basis, Looby and Earleywine reported that fewer than half of all daily users exhibited the behaviours necessary to meet the established criteria for being classified as drug dependent. These criteria include tolerance, withdrawal, taking the drug for longer periods of time or larger doses than intended, inability to stop or reduce use, increasing the time spent obtaining the drug and recovering from its effects, ignoring other important activities, and continuing use despite undesirable consequences. The authors argued that frequent use does not necessarily result in dependence, but that it may be a contributing factor. Their research suggested that negative effects of marijuana use, such as dissatisfaction with life, low motivation, and unhappiness, were more related to dependence on the drug than regular use . When considering the results of this research with findings from Copersino et al. on withdrawal symptoms, strong support is established for the idea that a proportion of frequent marijuana users suffer negative effects resulting from a dependency.
In terms of factors that most likely contribute to the development of a marijuana dependency, Hall reported that initiation to drug use at an early age was the most significant. However, in terms of public policy, if THC levels are indeed increasing and continue to increase, there will likely be a growing number of users who find themselves dependent on marijuana. Furthermore, as the National Institute on Drug Abuse’s definition of addiction focuses on the “uncontrollable, compulsive craving, seeking and use of drugs”, the physical effects of dependency and withdrawal may be only part of the problem, as addiction can occur without physical signs of dependency. This may prove more problematic if future research establishes additional negative health consequences of long-term use as users may experience more difficulty abstaining from use even in the face of exacerbating social and health problems.
Marijuana Use and Mental Health
In addition to some potentially serious physical health problems, marijuana use has also been associated with mental health problems. The link between marijuana use and psychosis or later schizophrenia has possibly received the most attention in the research literature. This body of research focuses on the role of marijuana in triggering psychosis the risk of developing schizophrenia among those who suffered marijuana-induced psychoses, the dangers of marijuana use for those already suffering from psychosis , and a number of hypotheses on whether marijuana use contributes to the presence of psychoses or schizophrenia or whether mental health issues contribute to the onset of marijuana use To a lesser degree, researchers have also investigated the relationship between marijuana use and depression and anxiety .
Marijuana-Precipitated Psychosis and Schizophrenia
An association between marijuana use and the onset of psychosis recently emerged as a serious concern. Given this, it is necessary to understand the potential for marijuana to contribute to psychosis and what proportion of marijuana users are at risk for developing psychosis. Research suggests that 8% to 10% of all cases of psychosis may be triggered by the use of marijuana Others concluded that marijuana use was linked to psychosis independent of any previous mental pathology. Given this, there is a growing consensus that, although it is relatively rare, marijuana induced psychosis is a potential threat to users, specifically to those who are already vulnerable for this type of mental affliction In order to explain this relationship, Caspi et al. reported that there may be an interaction between the chemicals typically present in marijuana and a number of ‘susceptible’ genes in the user that contributes to the onset of marijuana-induced psychosis and schizophrenia.
Research findings suggested that if marijuana use triggered psychosis, it might be a risk factor for schizophrenia in determining whether those who suffered from an episode of marijuana-induced psychosis were at risk of developing later schizophrenia, a group of such individuals was compared to a group of people referred for schizophrenia-spectrum disorders for the first time who had no history of marijuana psychosis . Although suffering from some recognized methodological problems, this study found that marijuana-induced psychosis was an important risk factor for developing schizophrenia and that it often had an earlier age of onset compared to those who self-reported no marijuana use. In partial support, Solowij and Michie found similarities between the cognitive effects of marijuana use and the cognitive endophenotypes of schizophrenia. This suggested that there was little reason to believe that marijuana is a direct cause of schizophrenia, but that marijuana likely aggravates pre-existing susceptibilities to schizophrenia . This hypothesis may explain why those prone to suffering from marijuana-related psychosis are also more susceptible to later schizophrenia.
One of the complications for fully understanding marijuana’s association with psychosis and later schizophrenia is that people with mental illness may continue to use the drug. The effects of marijuana use in patients who had recently suffered from psychosis were studied to determine whether symptoms were prolonged and worsened by the drug . Findings suggested that those who continued to use marijuana were at a greater risk of having more symptoms and a continuous course of mental illness . It could not be confirmed from the study, however, if marijuana caused the symptoms to worsen or the degree to which marijuana directly contributed to the symptoms.
There were a number of relational hypotheses tested in the research literature . The most common hypotheses were that: marijuana use caused psychosis and schizophrenia without any existing predisposition; marijuana use triggered the onset of these symptoms in people who were previously vulnerable; marijuana use exacerbated the symptoms in those already suffering; and those already suffering from these symptoms were more likely to self-medicate with marijuana. Although the current state of the research does not support the hypothesis that the relationship between marijuana and psychotic symptoms is one of self-medication , other hypotheses found more support.
The strongest support was for the second and third hypotheses. However, the causal hypothesis remains debatable. Degenhardt and Hall found that cases of schizophrenia in the general population did not rise with an increase in reported marijuana use, thus weakening the case for the causal hypothesis. Although further research is needed to more fully understand the causal association between marijuana use and psychosis, based on the research to date, psychosis and later schizophrenia as a result of marijuana use is a risk for a small portion of the marijuana using population.
Depression and Anxiety Among Marijuana Users
Although psychosis and schizophrenia were researched more than other mental health issues associated with marijuana use, there is a body of research on other issues such as depression, anxiety, and violence. Research found that increased marijuana use among high school students was associated with increased self-reports of depression. However, others found that past-year marijuana use was not a significant predictor of future development of depression. Similarly, research by Bonn-Miller et al. found that marijuana use was a predictor of anxiety symptoms, but not of depression. Again, it remains a challenge to determine whether marijuana use is a cause of these symptoms or if the symptoms play a contributing role in marijuana use.
Marijuana’s Role in Continuing Drug Use
The discussion of potential harms of marijuana use presented thus far indicated that marijuana poses a number of potential risks to the general population of users and some specific negative outcomes for a relatively small subgroup. The risk or actual harms associated with marijuana use can be seriously compounded by the use of other drugs and can become overshadowed by the dangers associated with becoming addicted to ‘harder drugs’. Moreover, there has long been the suggestion that marijuana can act as a ‘gateway’ for much harder drug use. It would appear that the probability that marijuana acts as a gateway to other illicit drugs is much higher than the other way around . According to Fergusson and Horwood , when adjusting for other common covariate factors such as childhood, family, and life-style factors, regular marijuana use (fifty or more times in a year) was strongly related to the onset of further illicit drug use. However, others found that the opportunities presented by the lifestyle accompanying marijuana use were just as likely as the actual use of marijuana to predict the use of other illicit drugs. Currently, there is no evidence to prove or disprove that any biological effects of marijuana use increases the likelihood of using other illicit drugs, although researchers continue to test this hypothesis . Based on twin studies, it is well established that marijuana use is a strong predictor of future illicit drug use regardless of the familial and environmental similarities between twins .
Still, since the majority of marijuana users do not continue on to other illicit drugs , it is important to understand what factors distinguish between those who do and those who do not go on to use harder drugs. The appropriate policy and control responses may be very different depending on whether the relationship was based on the biological effects of marijuana use or on the lifestyles that accompanied marijuana and other illicit drug use. Currently, it can be concluded that, for those who use marijuana, there is a risk of using other illicit drugs. However, without a better understanding of what causes or correlates with an increased risk, it is impossible to determine what effects changes to marijuana’s current legal status would have on patterns and rates of drug use.
Conclusions
The debate over the most appropriate policy to have with respect to the personal use of marijuana has generally been polarized because of differing positions on the drug’s harms. In addition to the unknown extent of the potential for harm caused by existence and interaction of over 800 natural chemical components of marijuana, including 70 cannabinoids, it can be concluded that marijuana does pose some considerable confirmed risks to users. Some concern over marijuana is merited by findings regarding its ability to create short-term impairment, specifically on driving ability. Academic performance and social development appear to be negatively affected by marijuana use, but the causal role that the drug plays in the lack of future success of young people remains unconfirmed. As expected, smoking the drug contributes to considerable harm to the lungs and airways. Even though the use of vaporizers removes the contaminants of combustion and reduces some major respiratory problems, THC exposure to the lungs appears to be unhealthy. The immune system is also compromised by the use of marijuana, specifically the ability of the lungs to defend against foreign pathogens. Although cancers, heart problems, and threats to human reproduction are not common among marijuana users, most experts contend that further investigation is required, and the potential for risk should not be dismissed. The development of psychosis and later schizophrenia should also remain a concern for a small proportion of those who use marijuana. Dependency and regular, long-term use of the drug are also factors that likely exacerbate the potential for the majority of the harms previously identified in this review. Of course, these harms are often compounded by the fact the marijuana users have an increased likelihood of continuing on to other illicit drugs.
It is important to remain cognizant of the fact that the harms associated with marijuana use, though very serious in some cases, are not experienced by the majority of users, although prolonged regular use will generally put a person at a greater risk than occasional use. The debate over marijuana use requires advocates of both decriminalization and prohibition to concede that marijuana is neither harmless, nor is it particularly dangerous to the majority of users. It should be acknowledged by all that the lives of a small proportion of the population will be seriously disrupted by marijuana use.
With an understanding of the potential harms associated to marijuana use forming the basis of the debate, politicians, policymakers, and citizens can begin to answer the important questions that will form the basis for discussing policy options. For example, what can be learned from other jurisdictions about ways to respond to the social and personal harms associated with marijuana use? What lessons can be learned from the experiences with alcohol that might apply to marijuana? Are there other or better approaches than prohibition to manage the problems that marijuana use creates? Further research will also be required to better understand whether decriminalization promotes increased use. In other words, would the decriminalization of marijuana create better opportunities to regulate the drug, or would it result in greater social harm?
To date, the research evidence shows that marijuana has a number of associated harms. In some cases, these harms are worse than those associated with regulated substances such as alcohol or tobacco. Based on the course of research, it is likely that future studies will further refine our understanding of the harms of marijuana use. However, because marijuana continues to be a popular recreational drug, it is necessary that researchers disseminate their latest findings in a wide range of ways in order for the public to have the best information at their disposal about the harms and risks associated with using marijuana.

Source: Journal of Global Drug Policy and Practice Vol. 3. Issue 2 Summer 2009

Filed under: Effects of Drugs (Papers) :
Context: Cannabis is the most widely used illicit drug
in the developed world. Despite this, there is a paucity
of research examining its long-term effect on the human
brain.
Objective: To determine whether long-term heavy cannabis
use is associated with gross anatomical abnormalities
in 2 cannabinoid receptor–rich regions of the brain,
the hippocampus and the amygdala.
Design: Cross-sectional design using high-resolution
(3-T) structural magnetic resonance imaging.
Setting: Participants were recruited from the general
community and underwent imaging at a hospital research
facility.
Participants: Fifteen carefully selected long-term (_10
years) and heavy (_5 joints daily) cannabis-using men
(mean age, 39.8 years; mean duration of regular use, 19.7
years) with no history of polydrug abuse or neurologic/
mental disorder and 16 matched nonusing control subjects
(mean age, 36.4 years).
Main Outcome Measures: Volumetric measures of
the hippocampus and the amygdala combined with measures
of cannabis use. Subthreshold psychotic symptoms
and verbal learning ability were also measured.
Results: Cannabis users had bilaterally reduced hippocampal
and amygdala volumes (P=.001), with a relatively
(and significantly [P=.02]) greater magnitude of
reduction in the former (12.0% vs 7.1%). Left hemisphere
hippocampal volume was inversely associated with
cumulative exposure to cannabis during the previous 10
years (P=.01) and subthreshold positive psychotic symptoms
(P_.001). Positive symptom scores were also associated
with cumulative exposure to cannabis (P=.048).
Although cannabis users performed significantly worse
than controls on verbal learning (P_.001), this did not
correlate with regional brain volumes in either group.
Conclusions: These results provide new evidence of exposure-
related structural abnormalities in the hippocampus
and amygdala in long-term heavy cannabis users and
corroborate similar findings in the animal literature. These
findings indicate that heavy daily cannabis use across protracted
periods exerts harmful effects on brain tissue and
mental health.
Arch Gen Psychiatry. 2008;65(6):694-701
THERE IS CONFLICTING
evidence regarding the
long-term effects of regular
cannabis use. Although
growing literature suggests
that long-term cannabis use is associated
with a wide range of adverse health
consequences,1-4 many people in the community,
as well as cannabis users themselves,
believe that cannabis is relatively
harmless and should be legally available.
With nearly 15 million Americans using
cannabis in a given month, 3.4 million
using cannabis daily for 12 months or
more, and 2.1 million commencing use every
year,5 there is a clear need to conduct
robust investigations that elucidate the
long-term sequelae of long-term cannabis
use.
The strongest evidence against the notion
that cannabis is harmless comes from
the animal literature6-9 in which longterm
cannabinoid administration has been
shown to induce neurotoxic changes in the
hippocampus, including decreases in neuronal
volume, neuronal and synaptic density,
and dendritic length of CA3 pyramidal
neurons. Although such work suggests
that exposure to cannabinoids may be neurotoxic
in animals, much less is known
about the neurobiologic consequences of
long-term cannabis exposure in humans.
Only a handful of brain imaging studies
have been conducted in human cannabis
users, with inconsistent findings reported.
Early cannabis research using
pneumoencephalography10 reported cerebral
atrophy in a small sample (N=10)
of cannabis users, but further studies using
computed tomography11-13 did not detect
any abnormalities, despite the potential
confounds of polydrug use, comorbid neurologic/
psychiatric diagnoses, and a lack
of appropriate comparison groups.

More Author Affiliations: ORYGEN
Research Centre (Drs Yu¨ cel,
Whittle, and Lubman) and
Melbourne Neuropsychiatry
Centre, Department of
Psychiatry, The University of
Melbourne and Melbourne
Health (Drs Yu¨ cel, Whittle,
Fornito, and Pantelis),
Melbourne, Australia; School of
Psychology and Illawarra
Institute for Mental Health,
University of Wollongong,
Wollongong, Australia
(Dr Solowij and
Ms Respondek); and
Schizophrenia Research
Institute, Sydney, Australia
(Dr Solowij).
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recent structural magnetic resonance imaging (MRI) studies
have also reported contradictory findings, ranging from
no global or regional changes in brain tissue volume or
composition14-16 to gray and white matter density changes,
either globally17 or in focal regions, most notably in the
hippocampal and parahippocampal areas.18,19 However,
these previous studies used imaging techniques with relatively
coarse spatial and anatomical resolution and typically
focused on samples with multiple substance use or
comorbid psychiatric disorders and on only moderate levels
of cannabis use (ie, _2 joints per day). Indeed, despite
strong evidence of neurotoxicity in the animal literature,
6-9 to our knowledge, no neuroimaging study has
examined the neurobiologic sequelae of long-term heavy
cannabis use while controlling for the important confounds
of polydrug abuse and co-occurring psychiatric
disorders.
In this study, we used high-resolution 3-T MRI to assess
volumetric changes in 2 cannabinoid-rich regions
of the brain (the hippocampus and the amygdala) known
to be susceptible to the neurotoxic effects of cannabis exposure
in a sample of long-term heavy users carefully
screened for polysubstance abuse and mental disorders.
Given the growing literature regarding an association between
cannabis use and the development of psychosis20
and cognitive impairment,16,21 we also assessed for subthreshold
psychotic symptoms and verbal learning ability
in this otherwise psychologically healthy sample.
METHODS
PARTICIPANTS
Male cannabis users with long histories of regular and heavy
cannabis use (n=15) and nonusing healthy male volunteers
(n=16) matched on age, estimated premorbid intelligence (National
Adult Reading Test),22 years of education, and state and
trait anxiety (Spielberger State-Trait Anxiety Inventory)23 were
recruited from the general community via a variety of advertisements
(Table). Cannabis users had lower Global Assessment
of Functioning scale scores and greater depressive symptoms
(as measured using the Hamilton Depression Rating Scale)24
than the comparison group; however, there were no current
or lifetime histories of diagnosable medical, neurologic, or psychiatric
conditions as assessed using the Structured Clinical Interview
for DSM-IV Axis I Disorders, Patient Edition.25 All the
control subjects also underwent a Structured Clinical Interview
for DSM-IV Axis I Disorders, Non-Patient Edition.25 Subthreshold
psychotic symptoms were probed using the Scale for the
Assessment of Positive Symptoms26 and the Scale for the Assessment
of Negative Symptoms.27 Regarding alcohol use, the
groups did not differ in levels of current consumption, lifetime
use, or history of abuse or dependence; and no participant
drank more than 24 standard alcoholic drinks per week.
Significantly more cannabis users were also tobacco smokers
(_2=22.9, P_.001) (Table). For all users, cannabis was the primary
drug of abuse, with only limited experimental use of other
illicit drugs (generally _10 lifetime episodes).
PROCEDURE
Participants were assessed on 2 occasions, usually 1 week apart.
In the first test session, participants completed demographic,
clinical, and substance use history assessments. In the second
test session, they completed the Rey Auditory Verbal Learning
Test (RAVLT) and underwent structural MRI.
Participants were asked to abstain from using substances for
at least 12 hours before each test session, and cannabis users
reported abstaining from cannabis for a mean of 21.3 hours before
the first test session (median, 14 hours; range, 10-72 hours)
and a mean of 19.8 hours before the second test session (median,
17 hours; range, 12-48 hours). Urine samples were obtained
from users on 4 occasions and from controls on 2 occasions
to corroborate self-reported abstinence. Specifically, for
cannabis users, samples were obtained on the evening before
each test session and on the day of testing. For controls, samples
were collected only on the day of testing. Examination of these
samples demonstrated that all but 1 cannabis user had cannabinoid
metabolites (11-nor-_9-tetrahydrocannabinol-9-
carboxylic acid creatinine normalized) detected in urine samples
from the first test session, and levels were generally high
(evening: median, 467 ng/mg [range, 0-2320 ng/mg]; day of
testing: median, 447 ng/mg [range, 0-11 293 ng/mg]). From the
second test session, 2 users returned a 0 reading; otherwise,
cannabinoid metabolite levels were again high (evening: median,
456 ng/mg [range, 0-3511 ng/mg]; day of testing: median,
389 ng/mg [range, 0-4470 ng/mg]). The levels of urinary
cannabinoid metabolites generally corroborate the selfreported
patterns of heavy cannabis use in the sample. All but
2 control subjects returned a 0 reading for cannabinoid metabolites
across both test sessions. The 2 controls with positive
urine samples reported only minimal and very occasional
exposure to cannabis. The median level of cannabinoid metabolites
in controls at the first test session was 0 ng/mg (range,
0-184 ng/mg) and at the second test session was 0 ng/mg (range,
0-180 ng/mg).
STRUCTURAL MRI
The MRI data were obtained using a 3-T scanner (Intera; Phillips
Medical Systems NA, Bothell, Washington) at the Symbion
Clinical Research Imaging Centre, Prince of Wales Medical
Research Institute, Sydney. A 3-dimensional volumetric
spoiled gradient–recalled echo sequence generated 180 contiguous
coronal slices. The imaging parameters were as follows:
echo time, 2.9 milliseconds; repetition time, 6.4 milliseconds;
flip angle, 8°; matrix size, 256_256; and 1-mm3 voxels.
Hippocampal, amygdala, whole brain, and intracranial volumes
were measured using established reliable protocols28-31
and were delineated by a trained rater (S.W.) masked to group
information. Specifically, the hippocampal boundaries were as
follows: posterior, the slice with the greatest length of continuous
fornix; medial, the open end of the hippocampal fissure
posteriorly, the uncal fissure in the hippocampal body, and the
medial aspect of the ambient gyrus anteriorly; lateral, the temporal
horn of the lateral ventricle; inferior, the white matter inferior
to the hippocampus; superior, the superior border of the
hippocampus; and anterior, the alveus was used to differentiate
the hippocampal head from the amygdala. The anterior border
was the most difficult to identify consistently and was aided
by moving between slices before and after the index slice. The
amygdala boundaries were as follows: posterior, the appearance
of amygdala gray matter above the temporal horn; superolateral,
the thin strip of white matter that separates the amygdala
from the claustrum and the tail of the caudate; medial, the
angular bundle, which separates the amygdala from the entorhinal
cortex; superomedial, the semilunar gyrus; inferior, the
hippocampus; inferolateral, the temporal lobe white matter and
the extension of the temporal horn; and anterior, the slice anterior
to the appearance of the optic chiasm. Whole brain volumes
were estimated using the Brain Extraction Tool method32
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to separate brain from nonbrain tissue. After brain/nonbrain
segmentation, each voxel was classified into gray matter, white
matter, or cerebrospinal fluid using FAST Model statistical software.
33 Only gray and white matter were used in the estimate
of whole brain volumes. The intracranial cavity was delineated
from a sagittal reformat of the original 3-dimensional data
set. The major anatomical boundary was the dura mater below
the inner table, which was generally visible as a white line.
Where the dura mater was not visible, the cerebral contour was
outlined. Other landmarks included the undersurfaces of the
frontal lobes, the dorsum sellae, the clivus, and the posterior
arch of the craniovertebral junction.
Interrater and intrarater reliabilities were assessed by means
of the intraclass correlation coefficient (ICC) (absolute agreement)
using 15 brain images from a separate MRI database established
specifically for this purpose and that has previously
been delineated by another expert rater. For the hippocampus,
interrater ICC reliabilities were 0.92 (right) and 0.91 (left)
and intrarater ICC reliabilities were 0.98 (right) and 0.95 (left).
For the amygdala, interrater ICC reliabilities were 0.85 (right)
and 0.88 (left) and intrarater ICC reliabilities were 0.93 (right)
and 0.97 (left). Once reliability was established, the rater (S.W.)
delineated the regions of interest for the images acquired from
the present study.
STATISTICAL ANALYSES
Whole brain volume, age, educational level, and estimated IQ
were not significantly different between the 2 groups and were,
therefore, not used as covariates (Table). Regional gray matter
volumes for the hippocampus and amygdala were corrected for
the effect of the intracranial cavity using a previously described
formula34 and were analyzed using analyses of variance,
with hemisphere (left or right) and region (hippocampus
and amygdala) as within-subject factors and group as the
between-subject factor. Main effects and interactions were evalu-
Table. Demographic, Clinical, Drug Use, and MRI Volumetric Measures
Measure
Long-term Cannabis Users
(n=15)
Nonusing Control Subjects
(n=16) P Valuea
Age, mean (SD), y 39.8 (8.9) 36.4 (9.8) .31
IQ, mean (SD) 109.2 (6.3) 113.9 (8.1) .09
RAVLT score, mean (SD)
Sum of 5 learning trials 43.8 (8.8) 57.4 (10.1) _.001
20-min delay 8.9 (4.1) 12.3 (3.7) .009b
Educational level, mean (SD), y 13.4 (3.2) 14.8 (3.7) .28
GAF scale score, mean (SD) 72.0 (11.2) 80.8 (9.4) .02
HAM-D score, mean (SD) 5.87 (3.2) 2.56 (1.9) _.001b
STAI, mean (SD)
State anxiety 34.3 (9.8) 32.9 (9.4) .67
Trait anxiety 39.3 (9.7) 39.0 (8.2) .92
SAPS score, mean (SD) 8.1 (7.9) 0.6 (1.2) _.001b
SANS score, mean (SD) 11.7 (8.5) 1.4 (1.4) _.001b
Cannabis use
Duration of regular use, mean (SD) [range], yc 19.7 (7.3) [10-32] NA NA
Age started regular use, mean (SD) [range], yc 20.1 (6.9) [12-34] NA NA
Current use, mean (SD), d/mod 28 (4.6) NA NA
Current use, mean (SD), cones/mod,e 636 (565) NA NA
Cumulative exposure, past 10 y, mean (SD)f 77 816 (66 542) NA NA
Cumulative exposure, lifetime, mean (SD)f 186 184 (210 022) 12.7 (12.2) _.001
Estimated episodes of use, median (range) 62 000 (4600-288 000) 11 (0-30) _.001
Alcohol use, mean (SD), standard drinks/wk 9.6 (6.1) 6.8 (5.0) .19
Tobacco use, mean (SD), cigarettes/d 16.5 (8.9) 7.5 (9.2) .20
Brain volumes, mean (SD), mm3
Intracranial cavity 1 546 237 (94 018) 1 607 590 (136 386) .14
Whole brain 1 310 780 (90 778) 1 374 123 (105 673) .09
Hippocampus .002g
Left hemisphere 2849 (270) 3240 (423)
Right hemisphere 2949 (244) 3348 (400)
Amygdala .01g
Left hemisphere 1766 (98) 1878 (190)
Right hemisphere 1601 (143) 1744 (158)
Abbreviations: GAF, Global Assessment of Functioning; HAM-D, Hamilton Depression Rating Scale; MRI, magnetic resonance imaging; NA, not applicable;
RAVLT, Rey Auditory Verbal Learning Test; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms;
STAI, State-Trait Anxiety Inventory.
aTwo-tailed t test unless otherwise indicated.
bMann-Whitney test.
cRegular use was defined as at least twice a month.
dCannabis users had used at this level for most of their drug-using history.
eA cone is the small funnel into which cannabis is packed to consume through a water pipe in a single inhalation. Without the loss of sidestream smoke, the
quantity of tetrahydrocannabinol delivered by this method is estimated as equating 3 cones to 1 cigarette-sized joint. Thus, the cannabis users in this study
smoked the equivalent of 212 joints per month, or approximately 7 joints per day.
fExpressed as cones for users and as episodes for controls. Estimates of lifetime exposure beyond 10 years in these very long-term users became skewed and
unreliable; hence, the 10-year estimate was used in correlational analyses.
gRegion_group analysis of variance.
(REPRINTED) ARCH GEN PSYCHIATRY/VOL 65 (NO. 6), JUNE 2008 WWW.ARCHGENPSYCHIATRY.COM
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©2008 American Medical Association. All rights reserved.
Downloaded from www.archgenpsychiatry.com , on June 3, 2008
ated using Greenhouse-Geisser–corrected degrees of freedom,
with _=.05. Effect sizes, expressed as Cohen d, are also reported
for pairwise contrasts. Only effects involving group (cannabis
users vs nonusers) and associations with cannabis use
parameters are reported because this was the primary focus of
the present study. Group comparisons of performance on the
RAVLT and measures of subthreshold psychotic symptoms
(using the Scale for the Assessment of Positive Symptoms and
the Scale for the Assessment of Negative Symptoms) were conducted
using independent-samples t tests or Mann-Whitney tests
for nonnormally distributed data. Pearson product moment correlational
analyses were conducted to examine the behavioral
(ie, symptom and cognitive) relevance of any identified group
differences in regional brain volumes and the association
between these brain changes and parameters of cannabis use.
These analyses were necessarily exploratory given the limited
sample size.
RESULTS
GROUP CONTRASTS
In the analysis of regional gray matter volumes, there
was a significant main effect of group (F1,29=12.98,
P=.001) and a region_group interaction (F1,29=6.25,
P=.02). This result and the post hoc pairwise analyses
demonstrated reduced hippocampal volumes in cannabis
users (F1,29=11.14, P=.002 corrected; a reduction of
12.1% in the left and 11.9% in the right hippocampus
relative to controls), with a very large effect size (Cohen
d: left hippocampus, 1.17; and right hippocampus,
1.27) (Figure 1). Cannabis users also had smaller
amygdala volumes (F1,29=7.31, P=.01 corrected; a
reduction of 6.0% in the left amygdala and 8.2% in the
right amygdala relative to controls), with large effect
sizes (Cohen d: left amygdala, 0.80; and right amygdala,
0.99). The region _ group interaction reflects that the
overall reduction in hippocampal volume was relatively
(and significantly) greater than the reduction in amygdala
volume (12.0% in the hippocampus vs 7.1% in the
amygdala). In the analysis of subthreshold psychotic
symptoms, cannabis users reported significantly higher
positive symptoms (Scale for the Assessment of Positive
Symptoms; z=−3.57, P_.001) and negative symptoms
(Scale for the Assessment of Negative Symptoms;
z=−3.66, P_.001) than nonusing controls. Regarding
verbal learning, cannabis users displayed significantly
poorer performance than controls on the RAVLT measures
(sum of words recalled across the 5 learning trials:
z=−3.97, P_.001; and free recall after a 20-minute
delay: z=−2.61, P=.009).
CORRELATIONAL ANALYSES
There was a significant inverse association between left
hippocampal volume and cumulative cannabis exposure
during the previous 10 years (r=−0.62, P=.01; accounting
for 38% of the variance in left hippocampal volume)
(Figure 2A). When 1 participant with relatively
higher cumulative cannabis exposure and small hippocampal
volume was excluded, 22% of the variance was
still accounted for despite falling short of significance in
the reduced sample (r=−0.47, P=.09). There was also an
association between left hippocampal volume and positive
symptoms (r=−0.77, P_.001) (Figure 2B) and between
positive symptoms and cumulative cannabis exposure
(r=0.52, P=.048) (Figure 2C). The associations
between left hippocampal volume and cumulative cannabis
exposure and between left hippocampal volume and
positive symptoms remained after controlling for the effects
of global functioning (Global Assessment of Functioning
scale) and depressive symptoms (Hamilton Depression
Rating Scale). No other associations were found
between other brain volumetric measures, cannabis use,
and psychotic symptoms, and they did not vary as a function
of alcohol or tobacco use. Measures of RAVLT performance
did not correlate with hippocampal or amygdala
volumes in either controls or cannabis users.
COMMENT
To our knowledge, this is the first human study of longterm
heavy cannabis users to demonstrate marked
exposure-related hippocampal volume reductions.
These findings corroborate previous animal research,6-9
suggesting that long-term heavy cannabis use is associated
with significant and localized hippocampal volume
reductions that relate to increasing cumulative cannabis
exposure. In addition, the present findings are consis-
tent with the view that cannabis use increases the risk
of psychotic symptoms and informs the debate concerning
the potential long-term hazardous effects of cannabis
in this regard. The bilateral reduction in amygdala
volume is a novel but not unexpected finding given the
dense concentration of cannabinoid receptors in this
region.35
Although these findings are consistent with those of
a previous study,18 it is difficult to directly compare these
results with those of other human studies given that past
work used MRI with lower magnetic field strength and
spatial resolution and did not conduct region-of-interest–
based analyses (eg, performed whole-brain voxel-based
analyses18). Tzilos et al14 conducted the only other study,
to our knowledge, that investigated cannabis users with
a relatively long history of use (specifically, an average
duration of use of 22.6 years, or 18.9 years of daily use)
and their study is, therefore, most comparable with the
present study. Although they found no effects of longterm
cannabis use on hippocampal volume, the authors
acquired their images at a lower field strength and with
a coarser spatial resolution (1.5 T with 3-mm-thick slices
vs 3 T with 1-mm-thick slices in the present study), an
important consideration given the size of the brain structures
investigated. Moreover, their region of interest was
less specific to the hippocampus relative to the present
measure because they also included the parahippocampal
gyrus. Furthermore, there was a relatively large age
discrepancy between their users and controls (38.1 vs 29.5
years), and the minimum duration of exposure to cannabis
was considerably lower in their sample (as little as
1 year of cannabis exposure), but, overall, their sample
reported an average of 20 100 lifetime episodes of use.
In contrast, the minimum duration of exposure to cannabis
in the present sample was 10 years, with an average
of 62 000 episodes of use. Thus, despite a similar mean
duration of use, the present sample used more than 3 times
as much cannabis, which may explain the finding of a
dose-response relationship between hippocampal volume
and cumulative cannabis use. Further highresolution
MRI work is necessary to characterize precisely
the dosage of cannabis required for significant brain
changes to occur.
The pattern of use in the present sample is consistent
with heavy cannabis use patterns that have previously
been reported in other Australian studies. For example,
Copeland and colleagues36 reported median daily intake
of 8 cones (the small funnel into which cannabis is packed
to consume through a water pipe in a single inhalation)
in an Australian sample of cannabis users seeking treatment
for cannabis dependence, ranging up to 125 cones
per day in the heaviest user, with 11% reporting cannabis
smoking throughout the day. The heaviest user herein
reported smoking 80 cones per day (approximately 25
joints smoked throughout the day). This pattern of cannabis
use is not dissimilar to the heaviest cannabis users
from other studies of non–treatment-seeking samples of
Australian cannabis users.37,38
Despite the large magnitude of effects observed, it remains
unclear whether these volumetric reductions
reflect neuronal or glial loss, a change in cell size, or a
reduction in synaptic density (eg, dendritic arborization),
all of which have been reported in rodent studies.
6-9 For example, Scallet and colleagues9 found striking
tetrahydrocannabinol-induced residual decreases in
the mean volume of hippocampal neurons and their nuclei
and a 44% reduction in the number of synapses up
to 7 months after the last exposure to tetrahydrocannabinol.
Moreover, Landfield and colleagues7 administered
tetrahydrocannabinol 5 times a week for 8 months
(approximately 30% of the rat lifespan, and comparable
in frequency and duration to the present sample) and
found significant tetrahydrocannabinol-induced decreases
in neuronal density in the hippocampus. Such
findings may help explain the mechanisms underlying
gross hippocampal and amygdala volume loss seen in this
sample of long-term heavy cannabis users.
Left Hippocampal Volume, mm3
In the present study, hippocampal volume in the cannabis-
using group was inversely correlated with cumulative
exposure to the drug in the left, but not right, hemisphere.
Previous functional imaging studies16,39 have found
reduced left hippocampal activation during cognitive performance
in cannabis users, and there is evidence to suggest
that hippocampal abnormalities in psychiatric disorders
such as schizophrenia are more prominent in the
left hemisphere.40 These findings converge to suggest that
the left hippocampus may be particularly vulnerable to
the effects of cannabis exposure and may be more closely
related to the emergence of psychotic symptoms. In this
context, it is interesting that we found a significant inverse
correlation between left hippocampal volume and
positive symptoms. Cannabis use was also positively correlated
with positive symptoms, suggesting that there are
complex associations among exposure to cannabis, hippocampal
volume reductions, and psychotic symptoms.
Given these relationships, it is possible that the exposurerelated
hippocampal reduction may reflect heavy cannabis
use in response to preexisting or developing psychotic
symptoms. However, there is limited empirical
support for long-term self-medication of subthreshold psychotic
symptoms with cannabis and stronger support for
the induction of psychotic symptoms subsequent to cannabis
exposure.20 As such, it seems more likely that prolonged
heavy use of cannabis induced subthreshold psychotic
symptoms and that both of these factors are
associated with hippocampal volume loss. These symptoms
were subthreshold because these cannabis-using participants
were carefully screened for current and past history
of mental disorders. Furthermore, the fact that the
mean age of the present cannabis-using sample was nearly
40 years suggests that these symptoms are unlikely to reflect
a prodrome. One speculation is that the present participants
were less genetically vulnerable to developing
a psychotic disorder subsequent to cannabis use,41,42 allowing
them to smoke heavily for many years. Future longitudinal
work assessing the emergence of hippocampal
reductions and psychotic symptoms with continued exposure
to cannabis, and how these are related to polymorphic
variations in susceptibility genes for psychotic
disorders, will prove useful in better characterizing these
relationships.
Given that cannabis users had significantly greater depressive
symptom scores than controls and that there is
an association between depression and hippocampal volume
reduction,43 it could also be argued that depressive
symptoms may be another mediating factor in the relationship
between cannabis use and hippocampal volume
reduction. However, there are a variety of important
considerations that make this unlikely. First, there
was no significant association between hippocampal volumes
and depressive symptom scores. Second, the relationship
between left hippocampal volume and quantity
of cannabis used was maintained after statistically
controlling for depressive symptoms. Finally, the overwhelming
evidence suggests that hippocampal reductions
in major depressive disorder tend to occur in the
more persistent forms of the disorder (eg, multiple episodes,
repeated relapses, or long illness duration).43,44 This
was not the case in the present sample of cannabis users,
who scored less than 6.0 on the Hamilton Depression
Rating Scale, had never been diagnosed as having
major depression, and did not seek treatment for any depressive
disorder.
Cannabis users showed poorer performance on measures
of verbal learning, consistent with previous findings.
Although some functional imaging studies have
found reduced left hippocampal blood flow and activation
during verbal (and visual) learning tasks in cannabis
users, we found no correlation between RAVLT
performance measures and hippocampal volume in either
controls or cannabis users. It is likely that anatomical volume
is a less sensitive measure than brain activation for
identifying correlations with behavioral performance. This
is a particularly pertinent consideration given that the
performance measures on the RAVLT are likely to reflect
the operation of numerous cognitive processes not
necessarily related to hippocampal function. Future work
using experimental tasks designed to more specifically
probe memory functions mediated by the hippocampus
may be useful in this regard.
The bilateral reduction in amygdala volume is a novel
but not unexpected finding given the dense concentration
of cannabinoid receptors in this region.35 There were
no cognitive, psychotic, or depressive symptom associations
with reduced volume in the amygdala. However,
this region has been significantly implicated in cannabinoid-
associated emotional and reward-related learning
and memory processes.47,48 Given that these aspects of
learning have not been examined in human cannabis users,
they would seem to serve as a potentially informative
avenue forward to help elucidate the functional relevance
of such volumetric reduction in the amygdala.
The relationship between long-term cannabis use and
brain abnormalities is complex. Although a limitation of
this study may be the residual effects of cannabis in light
of the fact that the cannabis users in this study were required
to be cannabis free for only 12 to 24 hours before
MRI, such issues are likely to be more pertinent for studies
examining more dynamic aspects of brain functioning
(eg, activations and cognition).49 The present structural
findings are unlikely to relate to the recent effects
of cannabis use because we are unaware of any evidence
that suggests that the hippocampus and amygdala can
change in volume by 6% to 12% in short periods. However,
although we maintain that the present results reflect
brain changes associated with long-term heavy cannabis
use rather than the consequences of recent exposure,
further longitudinal work is required to assess whether
such changes are reversible across more protracted periods
of abstinence.
Another limitation of this study is the relatively small
sample size, although the sample was exceptionally unique
in that participants were very long-term and heavy cannabis
users (mean of 5-7 joints per day for _10 years)
without polydrug use or co-occurring neurologic or diagnosable
mental disorders. As such, we conducted the
first, to our knowledge, “pure” examination of the effects
of heavy and protracted exposure to cannabis in humans.
The large effect sizes of the main findings suggest
that these results are robust and reproducible. These findings
are further strengthened by the observed dose-
response relationships between hippocampal volume reductions
and cumulative cannabis use.
There is ongoing controversy concerning the longterm
effects of cannabis on the brain.  These findings
challenge the widespread perception of cannabis as having
limited or no neuroanatomical sequelae. Although
modest use may not lead to significant neurotoxic effects,
these results suggest that heavy daily use might indeed
be toxic to human brain tissue. Further prospective,
longitudinal research is required to determine the
degree and mechanisms of long-term cannabis-related
harm and the time course of neuronal recovery after abstinence.
Correspondence: MuratYu¨ cel, PhD,MAPS,ORYGENResearch
Centre, 35 Poplar Rd (Locked Bag 10), Melbourne,

Murat Yu¨ cel, PhD, MAPS; Nadia Solowij, PhD; Colleen Respondek, BSc; Sarah Whittle, PhD; Alex Fornito, PhD;
Christos Pantelis, MD, MRCPsych, FRANZCP; Dan I. Lubman, MB ChB, PhD, FRANZCP
Source: Arch.Gen.Psychiatry.  Vol.65  June 2008
 

 

Filed under: Effects of Drugs (Papers) :


A summary of recent scientific findings on the real and adverse impacts of marijuana.

For Further information please contact

Michael Robinson
Executive Director
Drug Free Australia
PO Box H135
Hurlstone Park NSW 2193
Phone 02 9591 8850
Email : info@drugfreeaustralia.org.au

The following summary is a collation of material from a wide source of medical reviews and scientific journals with emphasis on reputable scientific studies rather than editorial commentaries. The following has been collated into the following points for a concise guide

The over-riding principle on which to decide what is in the patient’s best interests must be medical science over rumour or anecdotal opinion.

OVERVIEW

While supporters of marijuana use put forward anecdotal stories and psuedo-science of rumours, myths and snake-oil hype,

… the seriously ill, trusting in the care of medical professionals demand the highest standards of medicine be adhered to, not diverted from.

… Medicine must be based on science.

… As a proposed medical substance, marijuana should be subject to the same level of scientific scrutiny as any other new medicine being suggested for use, when it is it fails the test.

In short, modern medicine is based on fact, not fiction!

15 Reasons to reject marijuana use for the seriously ill include

1) Unacceptable Side Effect Profile.

At the symptom level the toxicity of the oral formulation is almost prohibitive with most cannabis naive patients reporting unacceptable side effects including psychological dysphoria “bad trips.”

This study contains the very interesting observations as follows:

“Although there is an aura that marijuana is a “safe” drug, the untoward psychological (eg. panic, anxiety, depression, psychosis) and medical complications (eg. bronchitis, malignancies, sexual dysfunction) associated with its use are well documented.”

Source: Levin FR “Pharmacotherapy for Marijuana Dependence: A Double blind, placebo
controlled pilot study of divalproex sodium.” Am J Addiction 13: 21-23 (2004)

one journal addressed the clinical consequences of marijuana use. The introductory paper stated

… “that in addition to marijuana abuse/dependence, marijuana use is associated in some studies with impairment of cognitive function in the young and old, fetal and developmental consequences, cardiovascular effects…, respiratory/pulmonary complications… impaired immune function…and risk of developing head, neck, and/or lung cancer. ….” The summary stated further that “…research presented at this workshop suggests that marijuana use is not without health hazards and, within the limits of the available data, is associated with significant adverse consequences affecting almost every physiological system.”

Source: Journal of Clinical Pharmacology 2002;42:7S-10S

….a letter from NIDA’s Marijuana Research Center dated January of 2001 stated that

it had more than 15,000 research papers in its marijuana bibliography. However, it must be noted that because of the many negative consequences associated with marijuana smoking there is a reluctance to do clinical trials on humans. Further, because it remains an illicit drug there is also reticence to spend limited research dollars to determine the interaction of an illicit drug with prescription pharmaceuticals. Nevertheless, research on compounds found in marijuana is ongoing and has lead to the development of a number of prescription drugs with several others currently being accessed. However, smoking marijuana as a medicinal remedy is an unnecessary danger to patients …

Source: Reference: J Clin Pharmacol 2002;42:7S-10S, Khalsa et al
Risk of Heart Attacks increase 4 fold within 1 hour of smoking cannabis

Harvard School of Public Health and Boston’s Beth Israel Deaconess Medical Center that smoking “Marijuana Raises Heart Risks.” The study on which this was based was also published in July of 2001.

Source:Mittleman et al, Triggering Myocardial Infarction by Marijuana, Circulation, (103), 2001.

Now, a report in Forensic Science International, by researchers Bachs & Mørland, of the National Institute of Forensic Toxicology in Oslo, Norway, report on six cases of “cardiovascular death in young adults” …….., the authors reference several other cases of cardiovascular incidents related to cannabis use. The studies reported in this article indicate that using marijuana can increase the risk of stroke and bleeding in the brain, which can result in death.

Source: Thomas Geller, MD; Laura Loftis, MD; David S. Brink, MD; Pediatrics, March 2004
Link to Mental Illness including depression and psychotic episodes tripled by cannabis use

There are now more and more research studies that link mental illness to cannabis use. The following studies are all useful sources

Sources: American Journal of Psychiatry, March 2004
Van Us J, Dutch Study, American Journal of Epidemiology, 2002.
“Cannabis Abuse as a Risk Factor for Depressive Symptoms”
Am J. Psychiatry, 158:12, December 2001. Bovasso

Cancers, Lung Infections and Lung Damage.
“The constituents of cannabis and tobacco smoke include a similar range of pro-inflammatory and carcinogenic substances.”
“The way marijuana is inhaled as opposed to the way tobacco is inhaled means that smoking a ‘joint’ of cannabis results in exposure to significantly greater amounts of combusted material than with a tobacco cigarette.” Regarding the use of waterpipes (bongs) to ameliorate smoking hazards, the paper states: “There appears to be no significant reduction in risk with this modified inhalation technique. There is also a link between psychiatric illness and cannabis use, indicating that this particular subgroup may be at particular risk of respiratory disease with prolonged exposure to both tobacco and cannabis smoke.”

Reference: Internal Medicine Journal 2003;33:310-313, Taylor and Hall.

Smoking marijuana just once or twice a day for a number of years could lead to serious lung disease.

Source: Reported in Join Together March 2000 from Thorax, Journal of British Thoracic Society.
Smoking marijuana can cause cancer

“many people may think marijuana is harmless, but it is not”, Zhang said in a statement. “The carcinogens in marijuana are much stronger than those in tobacco. the big message here is the marijuana, like tobacco, can cause cancer.” Zhang studied 173 patients diagnosed with head and neck cancer, and compared them to 176 cancer free control patients. Those who said they habitually smoked marijuana were more likely to be in the group with head and neck cancers. And the more they smoked , the bigger the risk.

Source: Dr Zhag , Jonsson cancer center University of California,
Reported in journal of cancer Epidemiology Biomarker and prevention Dec 1999.

Researchers report in the July 2000 issue of the “Journal of Immunology” that tetrahydrocannabinol (THC), the major psychoactive component of marijuana, can promote tumor growth by impairing the body’s anti-tumor immunity system.
Source: Roun et al. Biological Psychology Laboratory at Maclean Hospital Limited in haemorrhage Notes Vol. 15, No. 1

Aggravation of pain and muscle spasticity (the opposite of treatment for those suffering AIDS, M.S., Asthma)

Marijuana will not stop Multiple Sclerosis Pain

In findings that contradict earlier research, a team of scientists reports that marijuana does not improve the often painful symptoms of multiple sclerosis (MS). .A previous study in mice indicated that marijuana might help to relieve these painful spasms. However, the amount of the drug used in mice would not be tolerated in humans, the researchers explain. While their study included just 16 patients, it is the largest randomized, controlled clinical trial to investigate the use of marijuana to treat MS.

“Compared to placebo, neither THC nor plant-extract treatment reduced spasticity,” Dr. Joep Killestein from the VU Medical Center in Amsterdam, the Netherlands, told Reuters Health.

Source: Neurology 2002;58:1404-1407.

Smoking can double risk of MS

Smokers are 181 times more likely to develop multiple sclerosis than non smokers according to Dr Trond Riise.

Professor Riise said: “This is the first time that smoking has been established as a risk factor.., hopefully these results will help us learn more about what causes Ms by looking at how smoking affects the onset of the disease.

Source: Dr Trond Riise,University of Bergen Norway reported by ASH Oct 2003

“… since anandamide acts on nerves in the trachea and lungs and is quickly eliminated from the body, an inhaler could potentially control the cough without any side effects. Piomelli says don’t smoke marijuana for asthma, because it could trigger lung constriction and make the problem worse.
Source: Piomelli et al. University of California. Published in Nature . Nov 2000.
2) Inadequate Empirical Evidence

The level of the evidence for its use for the various indications seems to be based at best on preliminary or pilot data. All too often support for marijuana is on anecdotal comment and not scientifically valid data but commonly little more than opinion or anecdotal material.

3) Lack of Comparative Data

This is particularly obvious in the case of the indication for vomiting where there are no comparative trials with the standard serotonin-3 antagonists such as drugs of the ondansetron family. In the case of pain relief, the effects of cannabis appear to be about the same as a moderate dose of codeine, with the notable addition of generally unacceptable side effects.

4) Complexity of the Endocannabinoid System

There are at least two major cannabis receptors and probably three. Their pharmacology is not completely worked out. It is well known that a high concentration of receptors exists on both neurones in the hypothalamus and all of the immune cells of the body. One of the key target groups for whom “medical marijuana” is frequently recommended is AIDS patients. Hence the generally immunosuppressive effects of the cannabinoids should be of major concern in such patients whose immunocompromise is known to be finally lethal.

A third element of this system if the enteric nervous system, which has as many neurones as the brain and spinal cord namely 100 million. Cannabis receptors have been defined in this nervous system, and disorders of bowel function are well known in cannabis addicted patients. This should also worry us – that there is another 100 million neurones whose cannabinoid sensitivies and pharmacology is largely unexplored.

It is also of interest that one of the family of several endocannabinoid molecules 2-acylglycerol, has been noted to change cellular specificity and apparent phenotype of cultured cells from adipocyte to fibroblast. Such radical changes of cellular phenotype imply that usual safety studies will be difficult to guarantee if cellular perturbations of such major degree are involved.

5) Immunosuppression

This immunosuppression is a huge issue in its own right. It is matter of enormous clinical and theoretical interest and implications, and has begun to be explored in great detail in the laboratories of north America. Indeed a senior professional organization has now been formed in the USA to examine this in its own right as it relates to both cannabis and other illicit agents. It is called the Society for Neuroimmune Pharmacology. The effects of this are in fact counter productive indicating that the whole plant marijuana product should never be administered to anyone, let alone someone who is already sick or immune compromised.

Study Finds Marijuana Ingredient Promotes Tumour Growth, Impairs Anti-Tumour Defences

Researchers report in the July 2000 issue of the “Journal of Immunology” that tetrahydrocannabinol (THC), the major psychoactive component of marijuana, can promote tumour growth by impairing the body’s anti-tumour immunity system. While previous research has shown that THC can lower resistance to both bacterial and viral infections, this is the first time that its possible tumour-promoting activity has been reported.

The authors also suggest that smoking marijuana may be more of a cancer risk than smoking tobacco. The tar portion of marijuana smoke, compared to that of tobacco, contains higher concentrations of carcinogenic hydrocarbons, including benzapyrene, a key factor in promoting human lung cancer. And marijuana smoke deposits four times as much tar in the respiratory tract as does a comparable amount of tobacco, thus increasing exposure to carcinogens.

Source: Roun et al. Biological Psychology Laboratory at Maclean Hospital Limited in haemorrhage Notes Vol. 15, No. 1

Cannabis increases tumour growth via several mechanisms including:

1) tars contain many chemicals which are directly tumour stimulating (anthracene’s, nitrosamines, hydrocarbon: higher tar content than
cigarettes);

2) immunosuppressive, reduces immune surveillance and anti-tumour activities of lymphocytes and natural killer cells;

3) altered cytokine production such that permissive cytokines are produced rather than immunostimulatory ones;

4) altered prostaglandin production.

Furthermore these effects occur both by receptor (CB1 and CB2) mediated and receptor independent mechanisms.

All of which means that you CANNOT in good conscience give THC to either AIDS patients or cancer patients, or recommend cannabis for human use.

Source:The PubMed studies

6)
Availability of non-psychoactive congeners

(i.e. there are currently better alternatives and scientific research continues to develop better medicines)

Both cannabidiol and dexanabinol (HU-210) share many of the supposedly beneficial effects of THC but are not psychoactive. As this area is better studied it is likely that many such agents are likely to be made available. With the unacceptably high level of side effects noted in these patients, it would appear to be thoroughly premature to precipitately launch into the making of THC available at this time. A multitude of studies have demonstrated currently available medicines are superior to cannabis.

Source:NeuroReport, Vol. 13, No. 5, 16 April 2002.
Source: Eija Kalso, Associate professor. Pain Clinic, Helsinki University Hospital, Finland BMJ.3212-3.. July 7th 2001

7) Unacceptability of the smoked form of delivery

The toxicity of the smoked form to the aerodigestive tracts, including its association with chronic bronchitis and emphysema and asthma has been agreed upon by major colleges of thoracic medicine worldwide including the Australian and New Zealand Thoracic Society and the British Lung Foundation. Cancer of the mouth, throat, tongue, larynx pharynx have also been noted. Interestingly a high rate of bladder cancer has been noted in some series as cannabinoids are excreted by the urinary route.

Smoking can double risk of MS

Smokers are 181 times more likely to develop multiple sclerosis than non smokers according to Dr Trond Riise.

Source:Dr Trond Riise,University of Bergen Norway reported by ASH Oct 2003
Passive inhalation of cannabis smoke
The blood samples from the passive subjects taken up to 3 hrs. after the start of exposure to cannabis smoke showed a complete absence of cannabinoids. In contrast, their urine samples taken from passive sample up to 6 hrs. after exposure showed significant concentrations of cannabinoid metabolites (less than or equal to 6.8 ng ml-1). These data, taken with the results of other workers, show passive inhalation of cannabis smoke to be possible.

Souce:Law B, Mason PA, Moffat AC, King LJ, Marks V. PMID: 6149279 [PubMed – indexed for MEDLINE]
Cannabis Poisoning
A paediatrician Dr John Goldsmith has come out publicly with a survey he has done in North Island Hospital in NZ. emergency units where babies under the age of 2.5 years are admitted for cannabis poisoning .

Source: Dr John Goldsmith North Island Hospital ,New Zealand, 2002

8) Unacceptability of the oral form of Delivery
As it is not easily possible to titrate the oral dose exactly a very high rate of unpleasant and dysphoric side effects has been noted. This would appear also to be a sub-optimal route of delivery.

9) The Complexity of bringing drugs to market

The complexity and cost of bringing drugs to market has been noted many times, and is said to cost up to the billions of dollars. Furthermore this is understood never to have been done in Australia. Hence it is only prudent for Australian regulatory authorities including Governments to await formal pharmaceutical trials in nations and entities which have recognized pharmaceutical industries such as Europe and North America. It is prudent not to attempt to bypass this process for litigant as well as compassionate reasons. To inflict upon sick people, the adverse effects of marijuana could be interpreted by the public and the courts as a negligent act of the government who have an over riding responsibility to protect the public from claims that cannot and have not been sustained in evidence.

10) Aging and Stem Cells

With all the recent debate in relation to embryonic stem cells, the central, pivotal and essential role of stem cells which occur in the adult organism appears to have been radically overlooked. Obviously patients addicted to many drugs look prematurely and severely aged. Experimental studies have established for many years that all the illicit drugs of abuse cause single cell programmed death. This appears to occur in an additive and indeed multiplicative manner. One of the worst offenders is THC. It is also established that all the illicit drugs cause an inhibition of stem cell growth. This is well described in the brain and hypothalamus, but also affects other tissues. The combined effects of increased rate of cell death, and reduced rate of cell renewal may potentially be very serious and urgently require further study. This should concern many Governments given the increasing burden of aging on health budgets in many nations. The very real prospect of accelerated aging – especially of vulnerable patients such as those suffering from AIDS should precipitate a major community outcry against all but the most scrupulous clinical use of the appropriately researched cannabinoids.

11) Basic Neuropharmacophysiology

THC actually acts to inhibit synaptic transmission. Receptors exist on the PRE-synaptic side of the synapse and appear to act to turn off neurotransmission. This is known to scientists as “retrograde neurotransmission.” This is of course entirely consistent with the clinical syndrome we see of so-called “dope-heads.” This of course is the major reason it is used – the “downer” or sedative effect.

But the basis of its neuropharmacology should give us great pause indeed, for we appear to be shutting down the brain functions. It should also be added that there is a very close relationship between the opiate and cannabinoid receptor at the molecular level on the cell membrane. Both are 7-transmembrane loop-helix-loop GTP coupled plasma membrane receptors, coupled to inhibitory effects on adenyl cyclase and DNA transcription in the cell nucleus via similar intracellular transduction cascades.

Both are associated with immunosuppression, programmed cell death, and stem cell inhibition. Both occur in similar parts of the brain particularly in the hypothalamus and limbic circuits; both appear to share significant cross-talk at the plasma membrane level. In other words the so-called “gateway hypothesis” which was demonstrated and proven in the Christchurch New Zealand cohort, and was thought to be based on social and values based activities, almost certainly extends also to the molecular and cell membrane level.

12) Sundry Toxicities

Toxic effects on the following systems are accepted even by major cannabis advocates such as Wayne Hall.:

‘In fact the serious adverse effects of Cannabis have been known for some time now. Including adolescent developmental problems, permanent cognitive impairment as well as involvement in and the development of psychosis’.

Source:Hall W, Solowij N, “Long-term Cannabis use and Mental Health” 1997 British Journal of Psychiatry, August,1997 171:107-8

‘Caused disturbance to neural connectivity. However, it seems Cannabis can precipitate or exacerbate a schizophrenic tendency in a characteristic manner’.
Source:Hall W, Solowij N, “Long-term Cannabis use and Mental Health” 1997 British Journal of Psychiatry, August, 171:107-8
Hall A, Degenhardt, “Cannabis and Psychosis” Australian National Drug and Alcohol Research Centre, Presented
at The Inaugural International Cannabis and Psychosis Conf. 1999, Melbourne 16-17 February 1999

Chronic Symptoms of Cannabis Psychosis
‘Patients are left with the well-recognised and permanent symptoms of memory loss, apathy, loss of motivation and, paranoid ideation. ….. there is accumulating evidence of the psychological consequences of using Cannabis’.

Source: Hall W, Solowji N, Lemon J, The health and psychological consequences Monograph Series no 25.
Canberra:Australia Government Publishing Service, 1994 of Cannabis use. Nat. Drug Strategy
a) Driving

More than one in five drivers who died on NZ roads 1995-1997 had been smoking cannabis in the-hours before they crashed. The study found 82 of a sample of 386 drivers had cannabis in their bloodstreams and 54 per cent of the cannabis smokers were over the legal alcohol limit.

Source: Institute of Environmental Science and Research (ESR) in New Zealand. Jan 2000.

Marijuana use can render the user unfit to drive for more than 24 hours and adversely affect cognitive impairment for up to 28 days
Source: Bolla, K.I., et al. Dose-related neurocognitive effects of marijuana use. Neurology 59(9):1337-1343, 2002.

b) Gene toxicity
Genetic anomalies tied with marijuana—activated brain chemicals appear linked to schizophrenia, Japanese researchers report.
This result provides genetic evidence that marijuana use can result in schizophrenia or a significantly increased risk of schizophrenia.
The researchers described their findings in the scientific journal Molecular Psychiatry.

Source:Hiroshi Ujike,Okayama university Japan- Reported in UPI Science News, New York 2002

c) Hormonal and reproductive toxicities
d) Likely effect on cancer

e) Amotivational syndrome

f) Depression

Frequent Marijuana Use Associated With Depression and Anxiety in Teen Girls

Teens, especially girls, who use marijuana frequently are more likely to suffer from depression and anxiety, say Australian researchers.
Teens who used marijuana weekly or more often had twice the risk of experiencing depression and anxiety. The risk of depression and anxiety was greatest among females who used marijuana daily – they had five times the risk of being depressed or anxious than their non-using peers.

Source: George C. Patton; Carolyn Coffey; John B. Carlin; Louisa Degenhardt; Michael Lynskey; Wayne Hall;
British Medical Journal, November 23, 2002
g) Psychosis
its effect to exacerbate supposedly underlying tendencies is agreed upon: several recent papers, including some from Netherlands, also document the occurrence of this severe disorder in patients without pre-existing personal or family history. In this connection it is worth noting that in the laboratory psychosis can be predictably produced in 100% of animals by the combined use of amphetamines and cannabis.

Marijuana and Schizophrenia

In one of the earliest studies that associates marijuana use with schizophrenia, 45,570 Swedish conscripts were asked to report their frequency of cannabis use. Over the 15 year follow up period, conscripts who had used cannabis more than 50 times before conscription had a six times higher risk for development of schizophrenia than non-users. Those who used cannabis 11 to 50 times had a three-fold increase in risk.

Source: Quoted in Taylor H: Analysis of the Medical Use of Marijuana and its Societal Implications.
Journal of the American Pharmaceutical Association 1998; 38: 220-7
h) Cardiovascular

Vasoconstriction occurs in many tissue beds, along with a faster heart rate. This has been associated with heart attack in some recent series, and organ infarction. It is of particular concern in the long term to think that such changes are likely occurring in the brain, along with accelerated cell death. The studies reported in this article indicate that using marijuana can increase the risk of stroke and bleeding in the brain, which can result in death.

Source: Thomas Geller, MD; Laura Loftis, MD; David S. Brink, MD; Pediatrics, March 2004
13) Comments on specific indications:

a) Where it is recommended to be used with prochlorperazine for vomiting. It is likely inferior to ondansetron etc. Side effect profile unacceptable. Seldom used clinically even where it is available to be prescribed.

b) Pain relief. Equal to codeine, plus the nasty side effects. codeine and other alternatives preferred.

c) Appetite stimulation. Minimal effect in published studies. However may be associated with other functions later on. Seems to be associated with morbid obesity developing in a number of heavy users in later decades. (This would appear to include several well-known cannabis advocates). Given that we known that obesity itself is a terrible health disadvantage, this alone should give us great cause. Overweight is also associated with at least 12 cancers, and according to a New England Med J article in 2003, the overall elevated cancer risk in the overweight is 156% of normal, with up to 450% for some tumours such as liver.

The authors reported that “participants reported ‘negative’ subjective effects… [irritable, miserable, bad drug effects, negative mood states] during days after smoking marijuana, but not after oral THC.” They noted that previous studies had found that both dronabinol and smoked marijuana increased “total daily calorie intake and produced abstinence symptoms upon discontinuation of their use.” [NOTE: caloric intake does not remedy wasting syndrome]
The doses of dronabinol and smoked marijuana used in the study were based on the researchers’ previous studies in which they found 20 mg of dronabinol had similar effects to marijuana cigarettes with a potency of 3.1% THC.

In conclusion, the authors note “This finding may have important clinical implications because it suggests that oral delta-9 THC is as effective as smoked marijuana…”

d) M.S. Likely to be acting as an immunosuppressant which should worry us enormously especially in AIDS patients.

e) Epilepsy. Some studies demonstrate also pro-epileptic effects. However there are lots of anticonvulsant drugs on the market currently which have a lesser side effect profile than THC.

f) Glaucoma. It is said that the intra-ocular pressure is lowered after systemic administration only at doses which depress the heart action. Very good drugs already exist for this disorder. A topically applied eye drop may have a role. Whether THC or one of the non-psychoactive cannabinoids would be most suitable remains to be determined.

Reference: Hart et al, Psychopharmacology (2002) 164:407-415

MARIJUANA SMOKING VS. CANNABINOIDS FOR GLAUCOMA THERAPY: A REVIEW

Abstract

This review encompasses the clinical effects, including toxicological data, of marijuana and many constituent compounds on the eye and the remainder of the body.

A perspective is given on the use of marijuana and the cannabinoids in the treatment of glaucoma. The conclusion is reached that although it is undisputed that smoking of marijuana plant material causes an intraocular pressure fall in 60 to 65% of users, continued use at a rate needed to control glaucomatous intraocular pressure leads to substantial systemic pathological changes. Development of drugs based upon the cannabinoid molecule or its agonists, for use as topical or oral antiglaucoma medications, seems to be worthy of further pursuit. Among the latter chemicals are some that have no known adverse psychoactive side effects.

Source: Keith Green, Ph.D., D.Sc., Department of Ophthalmology, Department of Physiology & Endocrinology,
Medical College of Georgia, Augusta, Georgia
14) Addictive and Habit Forming Potential
The addictive capacity of cannabis is now accepted and has been established in the scientific literature at least since the publication of the DSM IV of the American Psychiatric Association in 1994; and has been verified many times in papers since that time. The fact that this is now accepted throws into question its clinical use, for the drug itself is associated with uncontrolled use. Combined with its gateway action in terms of introducing the user to other drugs, this should be a point of major concern for all regulatory authorities, simply because addiction implies that it is not able to be regulated in the normal manner of other therapeutic agents.

15) The T.G.A.

If marijuana is in fact effective, economical and ultimately appropriately suitable to be prescribed to patients then it should pass the demands of Australia’s medical regulatory bodies …. including The Therapeutic Administration. Botanical or crude plant marijuana has not.

Refer to Cannabis with care? Booklet for further details on this concern as well as others

Copies available from Drug Free Australia. PO Box H135 Hurlstone Park NSW 2193
Or email info@drugfreeaustralia.org.au

Here is just one of the many examples of Australian and International professional bodies who oppose marijuana use.

AMERICAN ACADEMY PEDIATRICS STATEMENT

American Academy of Pediatrics Vol. 113 No. 6 June 2004 p.1825 – 1826

Recommendations

1. The American Academy of Pediatrics opposes the legalization of marijuana.

2. The American Academy of Pediatrics supports rigorous scientific research regarding the use of cannabanoids for the relief of symptoms not currently ameliorated by existing legal drug formulations.

CONCLUSION.

In short true compassion for our ill patients necessitates and indeed morally obliges appropriate and disciplined medical care for them.

The normal physiological action of cannabinoids in terms of the inhibition of brain function by retrograde neurotransmission is of major concern to all those concerned with preserving and promoting the neurological and normal brain function of adolescents and young adults, and thus maximizing the neurological potential and intellectual property of the on-coming generation.

If cannabinoids are shown to have a place in evidence based medical therapeutics in the future then, given the well established high side effect profile of these agents, and their horrific long term cumulative toxicities, it is appropriate that patients only be exposed after careful and replicated disciplined and independently controlled clinical trials with appropriate dose forms, or appropriate agents, most likely not THC itself.

It is also appropriate that comparative studies with established and accepted safe agents also be performed.

Issues of genotoxicity, weight gain, immunosuppression, impaired concentration while driving, gateway action at both the molecular and social level, premature aging including suppression of stem cell activity and renewal, and depression of brain function and neurogenesis and psychological toxicity appear to be particularly germane and of very real clinical concern, and the subject of on-going research at this time.

Filed under: Effects of Drugs (Papers) :

By Ann Stoker, B.A., NDPA.

CANNABIS – INFORMATION

Cannabis information for parliamentary briefings, leaflets and general articles needs to be clearly stated and simple – but with scientific references to source materials. The general public, and young people in particular, have been, and are being, given misinformation, insufficient information or totally incorrect information in many of the leaflets issued by other agencies. Most of these leaflets repeat messages from large organisations such as DrugsScope, (an organisation which was formed from the merging of two other groups ISDD and SCODA) or Connexions. ISDD had been disseminating out of date information for years yet an offer of help with updating the ISDD information on cannabis by a biology teacher specialising in the subject was refused.

HARMFULNESS OF CANNABIS

Given the known harmfulness of cannabis it would be unethical to try to replicate some of the small scale studies which showed significant harm from the use of the substance, The claim that millions worldwide use cannabis is no reason to ignore the harm which the small studies identify, and there are other quite large scale studies showing different elements of possible harm. In the USA there were 77,000 admissions to hospital emergency rooms in 1998 due to the use of cannabis. In the last year or two more and more psychiatrists and doctors have been publicising the fact that thousands of people are suffering from mental illness due to their use of cannabis. In the National Health Service in Britain there is a ‘yellow card scheme’ where GPs who come across even a few examples of contra-indications to prescribed drugs send in the card to flag up ‘caution’. These cautions are taken very seriously since the widespread prescribing of certain drugs could result in another situation Like thalidomide if not identified early on. This scheme could be adopted to note any physical or mental illness which doctors believe is due to their patient’s use of cannabis. We should take notice of any studies showing harm in so many areas from the use of cannabis. The fact that thousands may use and have no apparent adverse effects is of no consequence – many pharmaceutical drugs are withdrawn from general use when they harm a few – even though they may help many others. Professor Gabriel Nahas writes very eloquently on this very point:

The protagonists of the free availability of cannabis who are convinced that this drug does not constitute a serious health hazard will claim that those who wish to ban cannabis must produce convincing reasons before we restrict the individual’s right to choose (Schofield. 1971) – This view is a transposition of a legal concept regarding man’s innocence until proven guilty into the field of medicine, where a different viewpoint prevails in respect to drug usage. indeed, physicians have to take a guarded view of all drugs. which are considered guilty until proven innocent. The state which has the mandate to protect the health of the people, must hold a view similar to that of the physician.
Professor G. Nahas ‘Marijuana – Deceptive Weed’ 1975 Published by Raven Press

It is clear therefore that saying ‘millions use cannabis’ or ‘ I use and it never did me any harm’ is the same as saying that millions drink alcohol and they are not all alcoholics. True. But many are – and the younger they are when they begin to use alcohol the more likely they are to become problem drinkers. Cannabis is no different and more and more research is being published which shows that early onset use of cannabis and other illegal drugs leads to more problematic and chaotic drug use in later life.

MILLIONS USE CANNABIS WORLDWIDE

The often quoted figures that millions’ use cannabis world-wide or’ 2 -6 million have used cannabis in the UK – are themselves very misleading. Several years go the figure of 2 million users in the UK was bandied about – now one reads ‘Up to 6 million users’. Firstly, where is the hard evidence? The activity is illegal and therefore difficult to portray accurately. Were they users in their youth and are they now non-users ? Have these users tried the drug once, twice or many times ? Did they use daily, weekly, monthly, three times a year or once every five years? Did they smoke ditchweed, grass, ganja, resin, sinsemilla, skunk or chaw? These questions are important because the very real harms from the use of cannabis will vary from person to person and are dependent upon the age of onset of use, the length of time used, the frequency of use, the type and purity of the drug used, the strength of the drug used. Thus it is not possible to compare a 50 year old intelligent male who has occasionally smoked an 0.5% THC joint at parties – from the age of 18 – perhaps a total of 100 low potency joints in his life, to an unemployed and alienated young man of 18 who started smoking 0.5% THC joints at 13 years of age and was a daily smoker of skunk (15 – 27% THC) by 15 – which could be well over 700 joints in 2 years. The risks to their health, their education, their employment prospects, their family and social life and their relationships with the opposite sex will be very different.

IS CANNABIS ADDICTIVE?

There is plenty of research that shows cannabis to be an addictive substance. The following authors have all written affirmatively on the subject of addiction.

One of the single most important reasons why there has been an upsurge in the use of illegal drugs by Western youth is the mistaken belief that marijuana is a ‘soft’ drug. not physically addictive, and mood-altering rather than mind altering. Studies of the characteristics of drugs and patterns of their use and the observations of patients, doctors, teachers and ex-drug users have made it clear how misleading these assumptions have been.
Elaine Walters Marijuana – An Australian Crisis’ 1993

Cannabis is readily available on the streets. Were it to be legalised the addiction rate would inevitably he greater. The following quotation concerned narcotics but the point is made that greater availability of drugs leads to greater addiction.
‘The addiction rate to narcotics among the medical profession is estimated to be 30-50 times greater than that of the general population. These statistics suggest that easy availability and the inherent addictive properties of narcotics are important factors…….
Nils Bejerot, ‘Addiction. An Artificially Induced Drive’ published by Charles Thomas. USA

Like all addictive substances, cannabis is not easy to give up. Some believe that it is more difficult to stop all use of cannabis than it is to stop the use of most other drugs.
A marked and rapid tolerance to most of the physiological and neuropsvchological effects of THC occurs. Withdrawal symptoms occur after cessation of heavy daily cannabis administration. As is the case for other drug dependencies, there is no pharmacological cure for cannabis dependency. Therefore, as for treatment of other dependencies, that of cannabis should employ methods that aim at abstinence from the drug so as to foster a drug-free life. Long-term cannabis smokers are difficult to treat because of their denial of the progressive and subtle negative effects of their dependency.
Gabriel G. Nahas, MD. Ph.D. D.Sc. ‘A Manual on Drug Dependence’ 1992
published by Essential Medical Information Systems. Durant. USA
In a study including people who used both cocaine and marijuana, many stated that giving up the use of marijuana was in some ways more difficult than giving up cocaine.
Strategies for breaking marijuana dependence. Zweben & O 1992 (2):165-71
Published in Journal Psychoactive Drugs
Clinically there is no doubt that psychological dependence on marijuana can and does occur. It is the drug of choice of many of the adolescents in our clinic. … Symptoms of psychological dependence parallel those seen in classic adult-onset alcoholism, and, in fact, such a model seems to serve very well for marijuana dependence. Symptoms such as increasing use to the point of tolerance, solitary use, surreptitious use, symptomatic use, blackouts, personality change when intoxicated, inability to control the amount used, preoccupation with use, inappropriate use, and use despite adverse consequences are seen regularly in our adolescent patients… irritability, anorexia, insomnia, and intensive drug seeking behaviour upon cessation of marijuana use (with) relief of these by return to marijuana use.
…a major clinical issue (is that) many children are referred to paediatricians, child psychiatrists and other health care workers for problematic behaviours and the child is not recognised as an extensive marijuana user.., because health care personnel often do not inquire about such drug use, or if they do inquire the child will minimize the extent of use.. there is extensive enabling behaviour , of both an active and passive nature, among school officials, parents and some professionals who deal with children. There appears to be a need for research and education regarding this behaviour if we are to increase our effectiveness in identifying those individuals whose drug use is problematic and in intervening as early as possible.

Marijuana and Youth – Clinical Observations on Motivation and Learning. pages 98-99 Robert Niven M.D.
Published by the National Institute on Drug Abuse. 1982
The prevalence and severity of psychiatric problems and addiction associated with cannabis, has resulted in ‘marijuana-related-dysfunctioning’ being one of the most frequent admission diagnoses in drug treatment facilities.
TheCannabis Connection by Elaine Walters Australia. 1989
Surveys indicate that the percentages of excessive consumers of illegal dependence producing drugs are related to the respective addictive properties of the drugs. Experts have concluded that marijuana addiction frequency, though not as high as cocaine or heroin, is far higher than alcohol. Still when someone has become dependent on marijuana the addiction is as severe and difficult to treat.
Ibid
In 1968 the official classification of psychiatric disorders did away with the term addiction, replacing it with dependence… The result of a sudden termination in use of the drug of addiction, the withdrawal reaction, is well known in the cases of heroin and alcohol. That it occurs with the marijuana discontinuation, to a different degree, is not generallv appreciated.
Bitter Grass – The Cruel Truth About Marijuana by Roy Hanu Hart M.D. Published by Psychoneurologia Press
in Cooperation with the American Academy of Psychiatry &Neurology (AAPN). Kansas.

The pharmacological classification of dependence-producing drugs is as follows:

Toxicity to brain cells (neuropsychological toxicity) with impairment of mental functions and changed perception of reality (‘spaced out’)
A primary pleasure reward from chemical effects on the Limbic Area of the brain, (‘the pleasure centre’).
Craving, compulsion and repetitive self-administration.
Tolerance with daily use; a progressively greater dose needed to get a high.
Mental and/or physical damage from acute or chronic use.

There is also a summary of dependence in decreasing order of severity:

Opiates.
Major psychostimulants – cocaine, amphetamines.
Psychodepressants – Alcohol if greater than 30 mls. per day.
barbiturates. benzodiazepines.
Cannabis (is a psychodepressant but also a stimulant and a hallucinogenic – depending on type used, eg grass, resin or chaw). Hallucinogens – LSD, PCP, Magic mushrooms etc.
Volatile solvents (e.g. aerosols, glue, acetone etc.)
Minor psychostimulants (caffeine etc.)

Source: Marijuana. Elaine Walters Assoc.Printers. AustraliaISBN 0 646 15066 9

Using the above definitions, and just a few extracts from scientific and medical writings, it is clear that cannabis is both physically and psychologically addictive – as any worker in a drug rehabilitation centre could confirm. Relativists say it’s not a problem because it’s only psychologically addictive – in fact psychological addiction is a bigger problem than physical. It is immaterial as to whether cannabis is physically or psychologically addictive (some would say both); there is research to show that cannabis is one of the most difficult drugs to give up and relapse following de-tox. is very common. That is addiction.

LINKS WITH LEGALISERS

Provided the assertions can be backed up by references to source materials, it is essential that cannabis details are truthful – even if they are considered by some to be ‘hard-hitting’. It has been suggested that NDPA should ‘play down’ the harmfulness of cannabis, and not to become involved in the ‘debates’ over legalisation issues. This would be a very short-sighted strategy – the legalisers hide behind pseudo-scientific groups and big money organisations (Drug Policy Alliance, Lindesmith Institute etc.) and will themselves be citing ‘technical’ papers written by their own members (Nadelmann, Zimmer, John Morgan etc. etc.) – who clearly have an axe to grind. Without pointing up the connections between the legalisation movement and some of the misinformation being published (and posted on the Internet), young people may well accept at face value the ‘facts’ they are given by such people.

It needs to be made clear that when reading any research about drugs in general and cannabis in particular, the credentials and affiliations of the authors should be checked carefully. Even ‘evaluations’ can be biased. Scientists or academics who are members of legalisation bodies do produce ‘research’ which puts an attractive and acquiescent spin on drug use. Many of these have publicly admitted that they themselves use illegal drugs. Scientists and medics who publicise studies which show the opposite may belong to anti-legalisation groups – and some have joined these groups because they have first hand experience in their professional capacities of the problems caused by drug use. In between these two dichotomous groups are a large body of professionals with no affiliations to anti or pro-legalisation groups, and who, year after year. add to the body of knowledge about drugs, especially cannabis. The University of Mississippi has over 15,000 research papers about cannabis ‘and none of them give it a clean bill of health.

The following are some quotations from the proceedings of the Second International Symposium ‘Cannabis. Physiopathology, Epidemiology, Detection’, organized by the National Academy of Medicine in Paris in April 1992. This congress consisted of 53 renowned scientists from all over the world who presented papers on cannabis.

‘At a time when strong voices are advocating the relegalisation of illicit drugs, and public health is threatened by the progression of illicit drug consumption, the City of Paris is proud to support outstanding scientific studies which should help to promote prevention programmes for your youth. ….(scientists) are now seeking methods to curtail the use and trivialisation of substances which pollute the internal milieu of man’s brain and physical health and especially that of future generations. Such is our hope and our goal’.
Jacques Chirac. Mayor of Paris. Former Prime Minister of France.
‘And today, all the clinical symptomatology of cannabis intoxication described so accurately by Moreau, (in 1845), and which has been confirmed by many other psychopharmacologists, is being reinvestigated and correlated with biochemical and neurophysiological markers of the brain. Such studies will be discussed in this colloquium which should be another landmark in our understanding of the human brain.’
Henri Baruk. Prof. Honoraire de La Faculte de Medecin

The general conclusions of this international conference were as follows:

1. The toxicity of cannabis is today well established, experimentally and clinically. This drug adversely effects the central nervous system, the lung, immunity and reproductive function.
2. Epidemiological studies have reported that the use of ‘hard drugs’ rarely occurs among subjects who have never consumed cannabis.

3. Consequently, the participants to this colloquium rebut the distinction made between soft and hard drugs.

4. The trivialisation (decriminalization) of cannabis use, where it has occurred, has resulted in a considerable increase of its consumption and of its subsequent damaging effects.

5. It is important to foster a campaign of information and prevention bearing both on the legal aspects and the health consequences of cannabis consumption.

Professor Henri Balon. President. French National Academy of Medicine. April 1992.

The continued increase in the use of illegal drugs, by young people in particular, is a cause for great concern. As Elaine Walters (Australia) wrote so cogently in 1993:
Experience shows that one cannot be in favour of legalisation, and hope to discourage drug use by youth. In the USA during the period in which eleven states decriminalised marijuana half of high school seniors were using, or had experimented with marijuana and 11% became intoxicated daily. ….Drug legalisation will result in more people experimenting with drugs, more experimenters becoming regular users and more regular users becoming addicts.
‘Marijuana – An Australian Crisis’ Elaine Walters 1993.

Many young people receive out of date information from leaflets widely distributed by schools, health promotion units, youth clubs, young peoples’ counselling services etc. They read in newspapers, or watch on television, pseudo debates about ‘de-criminalisation of cannabis’, they are told that they should make their own ‘informed choices’ about use or non-use and that they should ensure that they use ‘responsibly’.

‘The dramatic increase in illegal drug use among adolescents and young adults indicates that drug education programmes in schools need to be reviewed …relevant, accurate and up-to-date information is an important part of the whole approach. No choices should be given to young people about illegal drugs, and their use cannot be regarded as a civil right or privilege. ‘Just Say No’ is a clear and concise message. ….Young people should be taught how to evaluate advertisements, and how to recognise promotion of drug use in music videos, records and other commercialised forms of entertainment. Drug use and under-age drinking among adolescents should not be regarded as ‘normal’. Neither should it be regarded as a psychological problem. It is a behavioural problem which requires correction, intervention and common sense from parents, teachers and members of the community.
Ibid.

We must give the public, and especially young people, information about cannabis which is clear, up-to-date and unequivocal. NDPA acknowledges this need and will continue to provide such information.

Filed under: Effects of Drugs (Papers) :


By Mary Brett, Head of Health Education, Dr.Challoners Grammar School, Amersham. Bucks.

Paper presented at the Maxie Richards Foundation Conference Glasgow Oct 2003.
Cannabis or marijuana, is our commonest illegal drug, currently used in Britain by around 3.2 million people. Most of them are totally unaware of its damaging effects, especially on the brain.

There are now in excess of 15,000 scientific papers on cannabis. None of the ones I have read say it is a safe drug, and I am assured it is the same for the rest.

We need to know how this damage is caused, and will start with the cells of the brain. Messages pass along the nerve fibres as minute electrical impulses and cross the gap, the synapse, between nerve cells in the form of chemicals called neurotransmitters. These are the brain’s natural drugs and there are dozens of them Each neurotransmitter molecule has a particular shape that fits into its own receptor site on the next cell, as a key fits into a lock.

The mind-altering drugs that people take operate at these synapses. They either mimic the neurotransmitter by shape, increase the rate at which they are released block them or prevent them from being re-absorbed. They take control point out to my pupils that no person can do that, no parent, no teacher or friend. But drugs can.

The psychoactive ingredient in cannabis is a substance called tetrahydrocannabinol, THC for short. It mimics a neurotransmitter called anandamide, from the Sanskrit word, ananda, which means bliss, Receptor sites for anadamide, and therefore THC, exist in many regions of the brain and in other organs of the body. So the actions of cannabis are many and varied.

In the brain, CBI receptors are in the cerebral cortex. In the sensory areas, sound and colour perception are distorted. Muscle coordination and psychomotor skills like driving are impaired in the motor areas, judgement, reasoning and logical thought are also affected. They are also present in the hippocampus where memory and the appreciation of time and space are situated, There are other areas with receptors, but the lack of them in the brain stem which controls automatic functions like respiration, is thought to explain the absence of overdosing. In the rest of the body the receptors are called CB2 receptors.

But it is in .the limbic region of the brain, a circular area in the centre, which suffers the greatest impact from cannabis. This is the seat of the emotions, and its activity determines our moods, whether we are happy or sad anxious or peaceful. Anxiety, depression, panic attacks and even paranoia can be triggered if it is disturbed. It also houses the ‘pleasure ‘or ‘reward’ system. Many drugs affect this area to give a high e.g. cocaine, ecstasy, amphetamines, alcohol and nicotine. Cannabis is no exception. The reason people give for taking cannabis is to get a high or a feeling of euphoria. All these drugs release the neurotransmitter, dopamine. However, THC acts on the CB1 receptors more strongly and for a longer time than anandamide so the effects are enhanced, THC has to be entirely eliminated from the body whereas anandamide is quickly recycled.

One experience of a high leads to another and another. Tolerance develops, receptors need more stimulation and more are produced. Dependence occurs, both psychological and physical. Withdrawal symptoms have been seen, shaking, insomnia, irritability, anxiety and aggression. Not so dramatic as the ‘cold turkey’ of heroin withdrawal since the fat-soluble cannabis remains so long in the body.
Fifty per cent of the THC from a joint will still be there five to six days later and ten per cent after a month, traces can be detected in the hair and urine for weeks after that. Compare this with water-soluble alcohol which disappears at the rate of one unit an hour, the amount in half a pint of beer a glass of wine etc.

In September, 2002, out of the six million drug addicts in the United States, sixty per cent were dependent on cannabis, and more youngsters were being treated there for marijuana dependence than for alcohol. An Australian researcher, Professor Wayne Hall, estimates that of those who ever try cannabis, ten per cent will become addicted, roughly the same as for alcohol.

There is no foolproof cure for any type of addiction.

The effects on the brain are not limited to addiction. People don’t always get the desired euphoria they are seeking. The most common adverse effect is anxiety or even panic. Symptoms can range from restlessness to loss of control to paranoia and fears of impending death. Although these are usually short-lived, occasionally they persist for several weeks.

An American paper in 2001 using nearly 2,000 participants, reported a four-fold increased risk of major depression. The same risk factor emerged in an Australian study of daily teenage female users. A paper in the British Journal of Psychiatry May 2002, found the increased risk for depression was 26 times in teenagers who use cannabis, alcohol and tobacco.

Acute psychosis can occur. A ten-year experiment with decriminalization in Alaska was terminated in 1991 by a public referendum after over 2,.000 people had to be hospitalized and treated in the previous two years for cannabis psychosis. The four to six week treatments were carried out at the taxpayers expense, fuelling anger and resentment. I personally know of six people in some way connected with my school, who have young relatives or friends who have become psychotic due to cannabis use.

A friend of mine lost a son to drugs 2 years ago. He had started using cannabis at the age of fifteen at his public school. And as so often happens progressed through all the other drugs and spent the last few years of his life in care homes and psychiatric institutions. He died of a particularly pure dose of heroin at the age of 45. Shortly before he died, he told his mother he could handle any drug now except cannabis. It made him paranoid and terrified him.

Swedish studies which followed the progress of over 50,000 conscripts, aged eighteen to twenty-five, over fifteen years, discovered that the risk of developing schizophrenia was increased by a factor of six for those who had used cannabis more than fifty times. This was when the concentration of THC was much lower than it is today. In the sixties, the average THC content was 0.5%, now at 5%, it is ten times stronger. Skunk and nederweed, selectively bred varieties from Holland can have THC contents of anything from 9% to 27%. This is a very different drug from the one that fuelled the ‘hippy’ generation.

Other studies have confirmed these findings of mental illness, and one from New Zealand by Dr Louise Arsenault of the Institute of Psychiatry in London in 2002, found a correlation with cannabis and violence. Young males were five times more likely to be violent than non-users, the increased risk for alcohol was three. So much for the cry of the pro-legalisers that youngsters are better off stoned and peaceful than drunk and violent. Whether cannabis actually causes schizophrenia is still to be discovered, but it certainly triggers and exacerbates the condition in vulnerable people. It is interesting to note that increased dopamine activity is implicated in schizophrenia, and other dopamine releasing drugs like amphetamines and cocaine can cause a schizophrenic psychosis. Could this give us a clue as to how cannabis operates?

In a Swedish investigation into suicides, users of alcohol, amphetamines and heroin were compared with marijuana users. More cases occurred in cannabis users than in any other group and the methods used were more violent, No other group jumped from high buildings or murdered others before taking their own lives. There have been several tragic tales in the press in the last year or so, of young people committing suicide after taking cannabis. Maybe people don’t die of an overdose, a common cry of the pro-legalisers but in 1999, in the United States, out of 664 marijuana related deaths, in 187 of them the only drug involved was marijuana.

There is increasing suggestive evidence, both from animal experiments and scans of the human brain, that some cells may die. Brain cells are never replaced. Permanent brain damage is a distinct possibility. It would be slow, subtle, insidious but cumulative.

High densities of CB1 receptors in the cortex and hippocampus cause concentration and the learning and memory processes to be badly impaired. The persistence of THC in the membranes for a long time, compounds the problems. As a schoolteacher, this is the area that causes me most concern.

Even on one or two joints a month, a cannabis personality develops. Users become inflexible, can’t plan their day properly, their problem-solving skills deteriorate, they can’t take criticism and they feel misunderstood. School grades take a nosedive and they often miss out on their chosen university places. At the same time they are lonely and miserable, Trying to talk sense to them becomes a futile exercise. Few children, using cannabis even occasionally, will achieve their full potential.

A few years ago, a former pupil came to see me. He was in his last year of a degree in pharmacology and wanted to do his dissertation on cannabis. Having been a user of cannabis while at school, he had only just managed to scrape into university with C and D grades Most of his friends didn’t make it. “What stopped you”, I asked. He looked surprised. “You did”, he said, “I could quote every word you ever said about cannabis, and all of it came true.”. He also managed to stop some of his friends. He got a first for his dissertation, spent a year with a friend of mine, a toxicologist as a technician, did an MSc in neurology, and is now researching brain diseases towards a PhD.

Because CB1 receptors are in the motor area of the cortex, psychomotor performance and muscle control are affected. People should not drive. Airline pilots, on flight simulators could not land their planes properly even up to and beyond twenty-four hours after a joint and had no idea that anything was amiss. If you have a joint today, you should not be driving tomorrow. Cannabis has been implicated in more vehicle accidents in some American surveys than alcohol, although ten times as many people drink. One ‘spliff’ is thought by some experts to have the same effect as the amount of alcohol needed to just exceed the drink-drive limit.

THC, by dissolving in the fatty cell membranes, expands them, it is a partial anaesthetic, and so interferes with their structures and alters other receptor sites. The transmission of other neurotransmitters is therefore disrupted. It is a multi-faceted drug.

CB2 receptors are found in the cells of our immune system and THC disrupts the copying of DNA into new cells being made in the body. Fewer white blood cells are produced and some are abnormal. As a result, people are more likely to fall ill, their sickness will be prolonged and more severe. AIDS patients, with an already weakened immune system would be well advised to steer clear of this drug.

The heart also contains CB2 receptors. The heart rate is increased and blood pressure rises. A report from an Athens hospital in 2000, found three young men, heavy cannabis users, average age twenty-five, with heart attacks that could not be explained away except by their use of cannabis. A report in 2002 found that middle-aged people were 5 times more likely to have a heart attack in the hour following the smoking of a joint.

Cannabis smoke contains more of some of the carcinogens found in tobacco smoke and deposits three to four times as much tar in the airways. Even 20 years ago, lung biopsies of young French and American soldiers were finding pre cancerous cells, not usually found till middle age in tobacco users. As well as lung cancers, rare head and neck cancers are now being seen in young cannabis users, not found in tobacco smokers till the average age of sixty-four.

Doctors in Sweden are advised to suspect cannabis use when young people present with bronchitis, the link is so common.

Cannabis smoke burns at a higher temperature, the smoke is inhaled deeper and held longer in the lungs. One joint in cancer terms is thought to be the equivalent of five cigarettes. The British Lung Foundation was planning recently to start warning young pot-smokers of these dangers by text messages. Collapsed lungs, lungs shot through with holes and young people needing transplants are all part of the sorry saga.

Sperm have very high concentrations of CB2 receptors, and the female uterus is rich in anandamides, so it is hardly surprising that cannabis can have significant effects on the reproductive process. THC also interferes with the production of the sex hormones.

Human sperm have consistently been seen to be lower in numbers, and with decreased mobility. Surveys on young male pot-smoking patients, twenty years ago in Kingston Hospital, Jamaica, found 20% complaining of impotence and 35% with a sperm count so low, it would render them sterile. And that was when the strength of cannabis was a tenth of what it is today.

A very recent report from Buffalo in The States, showed sperm of cannabis users were less likely to be able to fertilise eggs. The sperm were swimming too fast too soon and burning themselves out long before they could reach the eggs. It also confirmed the significantly reduced numbers of sperm and seminal fluid in cannabis smokers.

In the late seventies and early eighties, a rash of papers found various abnormalities and even stillbirths in the offspring of mice and rats exposed to cannabis. Some of this older research has been criticized for various reasons but in 1994, the eminent cannabis researcher, Australian Professor Wayne Hall said, ‘It would be unwise to exclude cannabis as a cause of malformations until larger studies incorporating better controls have been carried out’.

One thing that is consistent in the research of today and twenty years ago, is the reduction in weight and length of the baby, the equivalent of smoking ten to fifteen cigarettes a day. Low birth weight relates in later life to diabetes, heart disease and high blood pressure. These babies also had mild symptoms of withdrawal. Three studies in the nineties linked cannabis use to a ten-fold increase in cases of one form of leukaemia, and increases in two other forms of childhood cancer.

In December, 2002, one in every eight babies born in The Princess Royal Maternity Hospital in Glasgow, had been exposed to cannabis before birth. Seventy-five per cent of babies exposed to drugs in the womb have medical problems later in life compared to twenty-seven per cent who are not exposed.

Just as I was preparing this talk about a month ago, I met a woman whose daughter had become schizophrenic from cannabis use. She then became pregnant and had a baby at the age of seventeen. She begged her mother to take in the little boy as she could not look after him herself. Grandparents have very few rights so they had to fight through the courts which took most of their savings. The baby suffered from epilepsy for some time after it was born, her daughter will be on medication for life.

The progress of babies born to cannabis-using mothers is being followed in a long-running investigation in Ottawa by Peter Fried and others:

The parents reported above average problems with behaviour, decreased attention and more impulsiveness. Fried has also warned of the delayed maturing of the visual system.

Deficiences in neurological behaviour are not really apparent till the age of four. This is when children start using their ‘executive functions’ (the ability to plan things and solve problems). By the age of 12 these problems were still apparent. Fried also warns that today’s stronger varieties will almost certainly make things worse.

Other researchers have come up with supporting evidence. In two studies of three year-olds, one found the results of intelligence tests to be below normal, the other, investigating sleep patterns, found more problems, more arousals and low sleep efficiency.

I would like now, to address a few of the controversies surrounding cannabis.

The first is the medical argument.

In 1979, a pot-using American lawyer, Keith Stroup, said, “We will use the medical marijuana argument as a red herring to give pot a good name”. In the early nineties, Richie Cowan his successor at NORML, the National Organization for the Reform of the Marijuana Laws, echoed this by saying, “Medical marijuana is our strongest suit. It is our point of leverage which will move us toward the legalisation of marijuana for personal use. This campaign is still ongoing.

There may well be some ingredients in the cannabis plant that may prove beneficial in medicine. But that is the point — the ingredients. Medicines, by law, have to be pure single chemicals so that their actions are predictable and controllable. Heroin and cocaine fall into this category. THC is already available as Nabilone in Britain and Marinol in the USA. The pro-legalisers don’t tell you this — they want their joints. These prescription drugs however are unpopular with doctors because of their side effects. Currently the BMA is testing some of the other cannabinoids, there are around sixty of them in the plant, and no one should have a problem with this. It is estimated that people suffering from glaucoma would need six joints a day to maintain reduced pressure in the eyeball. Hardly useful members of the community. It’s like saying to someone, “take up smoking to get your weight down”. Nicotine suppresses the appetite. Any GP giving this advice would be severely censured.

In November 1996, Proposition 200 permitted physicians in Arizona to prescribe marijuana with no limitation on the age of the patient or the disorder involved. Two months later, in January, 1997, a poll revealed that 85% of the voters believed it should be changed, 60% wanted it repealed and 70% said it gave kids the impression that it was OK to smoke pot. In 1998, 109 distinguished scientists from all over the world, held a conference in New York on medical marijuana. In 1999 their conclusions, published in Marijuana and Medicine, stated, ‘Marijuana or THC do not qualify as safe or effective medications which aim at restoring or maintaining physiological functions of cells, organs and organisms .They have no place in a modern pharmacopoeia from which cannabis was eliminated in the first part of the century’.

A more recent ‘ploy’ of the pro-legalisers is the promotion of hemp. Hemp is cannabis. They claim its needed for everything from ropes to cloth and newsprint. In reality it’s twice the price of the finest linen, paper from trees is much cheaper and ropes rot, and are not so strong as the synthetic ones we use today. Why? — It is a very simple chemical process to extract the 0.25% THC from hemp, purify and concentrate it to a very powerful 40% which they call CHAW.

There is a strong movement for the legalization of cannabis. So who are these people?

Most are users, or their children are. Some, like Richard Branston, would make a lot of money selling it, Others are libertarians. “We can do what we like with our bodies, it’s no one else’s business”. That’s fine as long as it doesn’t affect or interfere with anyone else. But, stoned drivers can and do kill others. Addicts get treatment at taxpayers’ expense. Stoned workers are inefficient and unproductive, and yes, passive smoking does occur. And where’s the liberty in making yourself a slave to a toxic drug for life?

Another controversy is the gateway theory. “Does cannabis lead onto other drugs’ ? Well it can! Lots of surveys in America by Denise Kandel point to this being the case. Level of usage is closely correlated. She found that, of those using mar between 10 and 100 times in their lifetime, 51% went on to harder drugs. From 100 to 1,000, it rose to 79%, and over 1,000 times it was 90%. Studies more recently from Australia and New Zealand, always controlled for confounding factors, have found that weekly users are sixty times more likely to progress, and the trend is confirmed by research on twins.Of course not everyone will go down this route, but almost one hundred per cent of heroin users started on cannabis.

People often compare the cannabis situation today with prohibition in the 30’s. The comparison is false. An attempt was made then to make a drug that was legal, illegal A drug that was used by most of the population, could be used without damage to health and had been around for centuries.

Cannabis is currently illegal, and even when it was legal, was only used by a minority of individuals. Use over the centuries has always been patchy. Regular use of cannabis today is around 8 to 9%, not the 30 to 40% of people who have tried it. How many children try smoking? — 90%? We’re stuck with tobacco and alcohol, If introduced now, they would almost certainly be controlled drugs. We are desperately campaigning to stop people from smoking and abusing alcohol, do we really need another easily obtainable legal drug to add to the misery caused by the other two? Pulling the genie back in the bottle is not an easy task.

In fact, from a health point of view, prohibition was a spectacular success. Alcohol consumption declined, deaths from cirrhosis of the liver fell by one third, cases of alcohol-induced psychosis plummeted. Child neglect, juvenile delinquency and alcohol-related divorces all dropped by 50%.

Now I want to tell you, at least in my view, why we are in such a mess with drugs.

Parents must naturally assume that drug education in schools strongly discourages children from starting to use drugs. They could not be more wrong.

The vast majority of drug educators teach harm reduction and have done so for the past fifteen years or so, Harm reduction has its legitimate place when dealing with known users to try to limit the damage with the aim of getting them to stop. They can be encouraged to ‘chase the dragon’ inhale the fumes from heroin rather than inject it, and so avoid all the blood-borne diseases like AIDS and hepatitis. It has no place in the classroom where around 90% of pupils have no intention of following that way of life.

One of the favourite phrases of harm reductionists is “informed choice There should be no choice — drugs are illegal. Surely teachers of all people should be seen to be upholding the law. And anyway, they are currently not being informed properly, especially about cannabis, to make a choice, more on this later.

Harm reductionists don’t tackle” drugs, they accommodate them. Adults are opting out and abrogating their responsibilities. The first duty of parents, and indeed all adults, is the protection of vulnerable youngsters from anything that puts them in danger. We don’t let our offspring cross a busy road till they are old enough, or run towards a fire and burn themselves, why abandon them to drugs? Nor do we let them choose to break the law in other ways, e.g. speeding or petty pilfering.

It’s not surprising in this climate of acceptance, that drug use is rising, Preventing children from starting to use drugs is, after all not the aim of harm reduction, Children need rules and regulations. The only way they feel safe and secure is when they have boundaries to kick against. They often use their parents as an excuse when they want to opt out. “Dad would kill me”, is a phrase frequently overheard. They have no time for teachers who can’t control a class or try to be trendy. Often the boys who come back to see me after they have left are the ones I have had to discipline most severely.

I never say, “Don’t do drugs” or “just say no”. I simply point out, in biological terms, what can happen to their brains and bodies. I add to that all the social, family, emotional, educational and employment consequences of that way of life and they begin to appreciate its futility of it. Nor am I above a bit of emotional blackmail. I remind the boys that when they were pregnant, their mothers would have been fanatical about what they put into their bodies in case it harmed their unborn child. How devastating must it be for parents to have to sit back and watch their offspring ruining their brains and bodies with toxic chemicals.

Prevention does work. The most spectacular success of a prevention programme was seen in the United States between 1979 and 1991. This was the famous “Just say no” campaign. Don’t let anyone tell you it didn’t work. Parents got fed up with the trendy excuses for drug taking and collaborated with teachers, the police, social and youth workers, customs and excise and the children themselves, to foster the idea that drug-taking is not normal and was indeed harmful, and it worked ! The number of drug users fell from 23 to 14 million, a reduction of 60%, use of cannabis and cocaine halved, daily cannabis taking fell by 75%.

In surveys at the time, the most common reason for abstaining from, or quitting cannabis use was 70% with concerns over physical and psychological damage. Parental disapproval played a large part with a surprising 60%, as did the law, 40%. In 1991, they thought they had licked the problem and took their eyes off the ball. Inevitably usage once again rose, but now, under a new preventionist drug tsar, John Walters, once again it is on the decline.

The Swedes have always had excellent prevention programmes in place, and their whole culture is anti-drug. Sweden has a very low level of drug use.

Harm reduction literature consistently trivializes cannabis. Schools are bombarded with harm reduction literature, some of it is unbelievable and quite shocking. Here are some examples of the Manchester-based charity, Lifeline’s approach. Their leaflet on cannabis shows how a joint is rolled, The last line reads, “A lot of people who are now both parents and grandparents smoked cannabis during the sixties and seventies The first piece of advice they give to kids when their parents find out they are using drugs is ‘Don’t get caught in the first place”. Other street-wise pamphlets are full of graphic pictures of sex and four-letter words.

When I gave evidence to the Home Affairs Select Committee on cannabis, I showed them some of this stuff. They were, to give them their due, collectively shocked, and initiated an inquiry into their funding, which incidentally comes from central government and health authorities. The Sunday Telegraph at that time, took up the story. The latest catalogue had “self-funded” beside many of the pamphlets, so it would appear that something has been done, it would have been nice to have been told.

Drug scope, currently advising the government on all aspects of drugs, distribute a cannabis leaflet with two young men in a field of marijuana, on the policeman’s helmet of one it says, ‘Have fun, take care. They consistently deny that cannabis is physically addictive in spite of abundant scientific evidence to the contrary, and fail to mention some of its effects, while playing down the significance of others. They demand conclusive proof of the long-term effects. We don’t have conclusive proof that cigarettes cause lung cancer, but because of animal experiments and statistical correlations we accept the fact. Why is it different with cannabis? They don’t want anyone arrested for the possession of small quantities of drugs — any drugs! Needless to say, they are enthusiastically endorsing David Blunkett’s ill-advised proposal to down grade cannabis. On Radio 4 on the 27th May this year, Roger Howard, then Head of DrugScope, called for the reclassification of ecstasy and LSD as well as cannabis.

For a government that banned beef-on-the-bone with its infinitesimal risk of causing CJD, it is incomprehensible that they are contemplating a move that will inevitably result in more people using a substance proved to be harmful ‘We must err on the side of caution’, said a government spokesman at the time, Indeed we must, Have we learned nothing from the lawsuits brought by tobacco users?

Since David Blunkett’s ill-advised announcement to down grade cannabis, taking of the drug by 14 to 15 year olds has shot up 50%, from 19 to 29%.

Connexions, an organization now charged by the government to give advice to schools on such matters as careers, counselling and drugs, recently sent drug leaflets to my school, They were written in trendy ‘street-cred’ language by ‘The Clued-up Posse’ a group of kids from Kirkcaldy, Fife. The one on cannabis contained virtually no information on the dangers of pot, but masses on risk reduction. My sixth form thought it was patronizing, useless and positively encouraging of drug use. They also pointed out that it mimicked a Rizla packet. What sort of message does that send out? I made a fuss and The Sunday Telegraph, The Daily Mail and even The Sun took up the story. The leaflet has now been withdrawn.
Talking of messages, this is a worksheet from a book specially written for PHSE in schools. No comment!

Then we have all the blatant promotion of cannabis with logos on T-shirts, jackets and bags and on the front of magazines like Ministry. We have pop-stars and even MPs openly boasting about using cannabis, and songs that glorify drugs. Pro-legalisation articles vastly outnumber those against in the national press, and information about where to get cannabis seeds and paraphernalia is freely available in magazines and on the web. Propaganda like this makes my job a never-ending uphill struggle.

Drugs are illegal because they are dangerous, not dangerous because they are illegal.

The war on drugs has not failed. It has yet to be fought. And it must start with children. Remove the demand and you remove the problem.

I want to finish with two quotes.

Dr Robert Dupont, founder of the National Institute for Drug Abuse in The United States said, ‘I have been apologizing to the American people for the last ten years for promoting the decriminalization of cannabis, I made a mistake. Marijuana combines the worst effects of alcohol and tobacco and has other ill-effects that neither of these two have”.

He also said, ‘In all of history, no young people have ever taken marijuana regularly on a mass scale. Therefore our youngsters are in effect making themselves guinea pigs in a tragic experiment. Thus far our research clearly suggests we will see horrendous results’.

Filed under: Effects of Drugs (Papers) :
By George Biernson
BS, MS Massachusetts Institute of Technology; January, 2000
In considering the claim that marijuana is useful in treating AIDS patients, a fundamental issue arises. Why have the severe effects of marijuana in weakening the immune system not been recognized in efforts to combat AIDS? As reported in Science News the rate at which a person infected by the AIDS virus progresses from the HIV-positive state to the condition defined as AIDS varies greatly among different individuals, and many HIV-positive individuals may never develop AIDS. Clearly the health of the immune system is an important factor in this process.

Why has there not been a study to investigate the effect that marijuana may have on the rate at which the immune system degrades in patients who are HIV positive?

Brain Damage Produced by Cocaine

This document has concentrated on the harmful effects of marijuana, because this drug is the fundamental cause of the drug epidemic. Nevertheless, it is prudent to review evidence that cocaine also does serious damage to the human brain, so that youngsters will have all the more reason to reject cocaine.

As reported in 1990, brain scans were employed at Brigham and Women’s Hospital in Boston, Massachusetts to measure blood flow in the brains of cocaine users. Radioactive iodine was injected into the blood, and a three-dimensional projection of the emission from the iodine in the brain was obtained from single photon-emission computed tomography (SPECT). The SPECT display was sensitive to the rate of blood flow in different regions of the brain.

The results were displayed in a dramatic video tape, prepared by English and Holman . The brain scans for all of the regular cocaine users, even those who took cocaine lightly, showed voids in the brain where blood flow was very low. The brain scan of one subject, who used cocaine heavily, had so many voids his brain image looked like Swiss cheese. Yet, this heavy cocaine user was still a functioning individual, who held a full-time job, and so might superficially seem to be using cocaine safely.

This study proved that cocaine cannot be used in moderation. Even in light cocaine users, cocaine drastically reduces blood flow in significant regions of the brain, and so must seriously harm the brain. A copy of this video tape ought to be shown in all drug education programs.
Up to a few years ago, both cocaine and marijuana were widely claimed to be ‘safe, non-addictive drugs’ by many so-called drug abuse ‘experts’. Medical evidence proves that it is physically impossible for anyone to use either marijuana or cocaine in moderation because regular use of either drug, even in modest amounts, produces serious brain damage.

Conclusions

Mark Twain once said: “It ain’t what you don know that hurts you. It’s what you do know that ain’t so.” This is an ideal motto to characterize our failure to stop the drug epidemic.

In the late 1960’so many so-called “experts” on drug abuse expounded the Marijuana Myth, claiming that marijuana is a soft drug, very much less dangerous than heroin, and no more harmful than alcohol.

The Marijuana myth is based on a gross misinterpretation of the effects of marijuana which fails to recognize that THC the psychoactive ingredient in marijuana, is strongly fat soluble, and so is extremely slow acting. Although THC is highly potent, it appears to be mild because it acts so slowly.

The facts show that all arguments supporting the Marijuana myth are fallacious. Scientific medical evidence proves that marijuana is a very dangerous drug, at least as harmful as heroin.

Marijuana itself causes serious damage to the brain and to other elements of the body. Besides, it is a deceptive trap that often lures an unsuspecting casual user into escalating drug abuse, which typically includes other illegal psychoactive drugs and heavy alcohol drinking.

The Marijuana myth was broadly accepted by the public, and this led to extensive marijuana use, particularly by the young. Drug education programs were set up to combat the resultant drug epidemic. However, most of these programs have endorsed the Marijuana Myth, and fail because they are faced with an impossible task. ‘They try to teach kids to keep away from drugs, while supporting the claim that marijuana is no more harmful than alcohol.

Drug educators often teach that “All psychoactive drugs, including alcohol, are equally bad”. But the kids know that many people use alcohol without harm, and this often includes the drug educator himself. Since marijuana and alcohol are equally bad’, the kids frequently conclude that marijuana is no worse than alcohol, and like alcohol can be taken safely if used in moderation.

Regardless of how strongly one preaches “Say No to drugs!”, some kids will experiment with pot if they believe it is relatively harmless. They make the classic statement ‘Since my parents (or other adults that I know) are able to drink alcohol without harm, I should be able to smoke a little pot safely’.

The fat-soluble THC gradually builds up in the bodies of the kids experimenting with pot, and drags them into a trap. More and more kids are drawn, into this maelstrom, as the pot smokers induce others to try their harmless drug, often to provide money to support their steadily escalating desire for pot and other drugs.

Eventually, the damage that marijuana is doing to the pot smokers becomes apparent to their associates and so the other kids learn from direct experience to leave marijuana alone. It is my belief that direct experience is what is saving most young people from drug abuse, not drug education. Unfortunately, this direct experience requires that the lives of the pot smokers be sacrificed in order to educate the rest.

The Marijuana myth is widely believed today for many reasons. Regular pot smokers form a strong body of foot soldiers who are quick to support their favourite drug. Behind them is the disguised propaganda, spread by the very sophisticated and rich leaders illegal drug dealing. These efforts of confusion are magnified by a great many others, who, out of ignorance, are very reluctant to think that their concept of marijuana can be so fallacious.

Many people have experimented lightly with marijuana and luckily escaped without serious harm. They do not want to admit that they played around with a very dangerous drug. How can the harmless ‘grass’ they toyed with be as damaging as is charged? Obviously, they feel, anyone who says that marijuana is highly dangerous must be exaggerating.

A fallacious claim often made to support the Marijuana Myth is that many responsible people have been able to smoke marijuana for long periods without apparent harm. The answer to this claim is that it is very difficult to determine in a specific case how much marijuana a person has smoked, and how much harm it has caused. Remember that the primary damage that marijuana does to the brain occurs in the deep limbic region which controls the emotions. Consequently, a person can appear to be intellectually competent, yet be severely damaged emotionally by his use of marijuana.

A few years ago, Abbie Hoffman wrote a book extolling the virtues of marijuana and telling the readers how to deceive a drug test. Superficially it might appear that marijuana had not harmed him. However, a little later he committed suicide.

The potency of available pot has increased enormously since the 1960 from 1% THC (or less) to as high as 25% today. Hence, the destruction from marijuana is now progressing at a much faster rate. School children today are being seriously harmed by marijuana, even at early grades. It is essential that we discard the gross misconceptions of this drug and give an honest picture a drug education classes.

When our young people are taught the scientific truths about marijuana very few will touch it and our drug epidemic will end.

 

 

Filed under: Effects of Drugs (Papers) :

By John-Manuel Andriote 

In Parts of Washington’s Gay Community, Crystal Methamphetamine Is Starting to Take a Toll — and Creating a Demand for Treatment

Chad Upham had been the kind of kid any parent would be proud of — an Eagle Scout, a good child who didn’t cause problems in his fundamentalist Christian family. He didn’t touch a beer until he was 21.

Jump forward to an early Monday morning this past July. Upham, now 27, had been up all night after another weekend of drugs and sexual hookups with strangers he met online.

But instead of pushing his limits for indulgence again, he made a different choice. Around 3 a.m., Upham sent an e-mail to his friends and family with some unexpected news.

“Over the past four months,” he wrote, “I have become a regular user of crystal methamphetamine.” He added, “I acknowledge, without shame, a concern for my mental, physical and emotional health.”

While meth abuse is well-established in the U.S. heartland and increasing in New York and Los Angeles, it has had a low profile in the Washington area, where crack cocaine and marijuana are still the targets of most anti-drug programs run by law enforcement and public health agencies.

But meth use is increasing in portions of the gay community, according to local health officials, area addiction and mental health practitioners, and specialists in gay health issues. The District’s Whitman-Walker Clinic, which provides HIV/AIDS and other health services to a largely gay clientele, reports that 75 percent of its new drug treatment clients list crystal meth as their primary drug of abuse. Five Crystal Meth Anonymous groups meet near Dupont Circle, a neighborhood with many gay residents. Two and a half years ago there were none. Suburban treatment centers report an increase in meth-related referrals, including some in teenagers. The D.C. government has just awarded its first grant for an anti-meth public education campaign, which will target the gay community.

The Post reported in July that police in Southern Maryland had found a small methamphetamine lab in the bathroom of a La Plata townhouse — along with a cache of weapons, including grenades and seven rifles, some with bayonets. But that close-in lab is an exception. Federal drug authorities said in a 2002 report that the few meth labs in this region are located in the rural Shenandoah Valley.

Methamphetamine is a homemade, highly impure version of amphetamine, a stimulant that was widely abused in the 1950s through the 1970s. Its main ingredient is distilled from the pseudoepinephrine found in many over-the-counter cold and allergy medications.

Commonly known as crystal, crystal meth and Tina, meth is a potent, highly addictive drug that some experts say can cause long-term neurological and cardiovascular damage. The drug supercharges the central nervous system, causing the brain to churn out dopamine. This neurotransmitter affects brain processes that control movement, emotional response and the ability to feel pleasure and pain.

“Someone said [meth] is like smoking a cigarette, having an orgasm and eating chocolate all at the same time,” said Amy Bullock-Smith, clinical program manager for the Whitman-Walker Clinic’s addiction services, “and all that lasting about 12 hours.”

Meth induces euphoria almost immediately after the odorless, bitter-tasting powder is smoked, the most common way meth is used. It takes a few minutes to feel the same rush from snorting, swallowing, injecting or, less commonly, dissolving it in water and taking it as an enema. This is followed by six to eight hours, and sometimes as much as 24 hours, of increased energy, suppressed appetite and other stimulating effects.

Meth labs can be set up in homes, motels, apartments, trailers, houseboats, cars — anywhere that heat and basic lab tools can be used to cook down cold and allergy medications to extract their active ingredients. Other chemicals used to make meth — according to news reports and numerous Web sites that offer “recipes” — include iodine crystals, red phosphorous from the strike pad on matchbooks, muriatic acid, acetone, methanol and drain cleaner.

A Local View

Aside from its growing use in gay clubs, meth has made little impact in local jurisdictions, officials say.

In its most recent drug threat assessment report, published in 2002, the Department of Justice’s National Drug Intelligence Center described meth abuse as “limited” in Maryland, “a low but increasing threat to Virginia,” particularly southwestern Virginia, and “not yet a serious problem in the District.”

The department said that most meth available in this area was produced in southwestern states or Mexico. It was distributed to users by teenagers and young adults, mostly at nightclubs and raves, large dance parties usually held in warehouses or open fields.

Over the past five years there has been a surge in the number of gay men in the Washington area seeking treatment for meth abuse. Kevin Shipman, manager for special populations in the District’s Addiction Prevention and Recovery Administration, notes that the number of meth referrals to the Whitman-Walker Clinic’s outpatient drug programs is five times higher this year than in 2000.

Local substance abuse treatment programs for adolescents report seeing small but growing numbers of youthful meth abusers.

At the Inova Kellar Center, senior case manager Mary Ellen Ruff said this mental health center in Fairfax is seeing a lot of adolescents who have experimented with meth, though she does not have specific figures. She blames the drug’s accessibility, pointing out that teens “don’t have to go downtown to get it, but can buy it from their neighbors.” She said some teens who abuse attention-deficit hyperactivity disorder (ADHD) drugs — kids without the disorder who get the drugs illegally and use them as stimulants — move up to crystal meth.

Whitman-Walker’s Bullock-Smith said the men turning to her clinic for help with meth addiction are typical of Washington’s professional caste — Type A personalities in fast-paced jobs that require a lot of mental energy. “It’s not necessarily the folks who want to party all the time,” she said.

She points out that people with untreated ADHD seem especially attracted to meth because, much like legally prescribed stimulants such as Ritalin (methylphenidate), the drug paradoxically calms and focuses them. Researchers have suggested that, like crystal meth, methylphenidate amplifies the brain’s release of dopamine, thereby improving attention and focus in individuals who have weak dopamine signals.

Because the drug’s effects can include a supercharged libido, extended periods of high energy and sleeplessness and a much-reduced ability to make sound judgments, unprotected and promiscuous sex is a high risk. Recent studies from San Francisco and Chicago confirm that gay meth abusers are at significantly heightened risk for becoming infected with HIV and other sexually transmitted infections.

A 2003 study in the American Journal of Drug and Alcohol Abuse found that meth users are likely to experience increased respiration and blood pressure, irregular heartbeat and insomnia.

A report in Psychological Medicine in 2003 said that long-term users may experience paranoia, hallucinations, tremors, mood disturbances, repetitive motor activities, homicidal or suicidal thoughts and irreversible damage to small blood vessels that increase the risk of stroke. Children of meth users frequently are at risk for neglect and abuse, the authors found.

Researchers reported in the American Journal of Psychiatry in 2001 that prolonged exposure to even low doses of meth can damage up to 50 percent of the brain’s dopamine-producing cells.

Those who overdose on meth experience hyperthermia and convulsions that, if not treated, can result in death.

“While some people enjoy the short-term benefits,” said Bullock-Smith, “it’s the long-term effects, like the psychosis, that bring them to me.”

Breaking Tina’s Spell

The National Institute on Drug Abuse says the only treatment known to be effective for methamphetamine addiction is cognitive behavioral therapy to modify thinking and behaviors and to increase skills in coping with stressors. The agency says that meth recovery groups, such as Crystal Meth Anonymous, appear to help sustain drug-free recovery, though relapse rates are high.

As for the brain damage meth causes, researchers Gene-Jack Wang and colleagues at the Brookhaven National Laboratory in Upton, N.Y., have offered evidence that some areas of the brain begin to heal after abstaining for as little as two months. Other damage is longer-lasting.

George Kolodner, a board-certified addiction psychiatrist and medical director of the Kolmac Clinic in Silver Spring, said his clinic saw an increase in crystal meth users beginning about two years ago, but the trend has not accelerated since then. He said meth users are the most difficult patients to treat because there is no medication to prevent craving or treat the protracted post-use symptoms, such as dysphoria, or depressed mood.

“With other substances,” said Kolodner, “we can help people get off and keep off by decreasing their cravings. With meth and cocaine, we don’t have that.”

Randy Pumphrey, executive director of the Washington Psychiatric Institute’s Lambda Center, which provides substance abuse services to gay people, said that in the past four years meth has increased from being “something we saw every once in a while” to the third most commonly abused substance, after alcohol and crack, among new clients.

If someone is dependent, said Pumphrey, “they are going to need a period apart from their environment — and also need hospitalization” to deal with the paranoia, severe depression or even homicidal feelings that can accompany the detox process.

After this acute phase, Pumphrey said, patients usually participate in a daytime treatment program for several weeks before joining an extended support program such as Whitman-Walker’s six-month evening program for recovering addicts.

Kolodner said the relative newness of meth-specific support groups is a challenge to treatment because few have been in recovery long enough to serve as mentors.

Bullock-Smith explains that Whitman-Walker’s three-phase ddiction recovery program requires a substantial commitment. To graduate, clients must attend one to three meetings a week at the clinic, participate in an outside 12-step group, have a sponsor, undergo breathalyzer and urinalysis tests to verify that they are not using, see a therapist, have a psychiatric evaluation and complete “lots of homework.”

Let’s Talk About It

A committee including the police department and other District agencies, substance abuse professionals, youth organizations, nightclub owners and recovering addicts began to meet this summer to plan a response to what they view as a growing meth crisis.

Like community-level anti-meth efforts in other cities, the D.C. Crystal Meth Working Group is planning a campaign aimed at educating the nonusing public, preventing meth abuse among gay men and offering treatment referrals to current users. The District health department has provided a $42,000 grant for the group to work with Whitman-Walker on the campaign.

This is a good start, said group member Bruce Weiss, executive director of the Sexual Minority Youth Assistance League, which serves gay, lesbian, bisexual and transgendered youth. The group will seek $1 million from the D.C. government and try to ensure that fighting meth is included in the five-year plan of the task force advising the mayor on anti-drug priorities.

Community activist Christopher Dyer, who chairs the group’s social marketing campaign subcommittee, said the campaign’s slogans, “Let’s Talk About Crystal Meth” and “Crystal Meth Sucks,” will be launched in nightclubs with posters, pins and T-shirts.

Another group member, Ed Bailey, co-owner of Nation, a Southeast Washington dance club, said major club owners across the country support anti-meth campaigns like this one. The drug has cut into their business because people typically do not drink alcohol when they are using meth, he said. Over time they also become increasingly isolated and don’t go to clubs.

Since deciding to live meth-free after one too many sleepless, drug-driven weekends, Chad Upham said he depends mainly on Crystal Meth Anonymous groups and constructive activities with family and friends to support his recovery. Although he saw a doctor for a standard checkup, he — unlike some of his recovering friends — isn’t taking any medications to treat anxiety or depression.

Upham is discovering that Tina continues to tempt.

“I am thinking desirously about the people, places and things that were associated with my using,” he said. Running into a person he knew from those “hot days and nights” revives thoughts of “all that fun.”

But he pulls himself back to his new reality — denying the drug, listening to his family, co-workers and new friends in the support groups he attends several nights a week.

They have “embraced me in my weakness,” said Upham, “continually saying that I am brave, courageous and strong for taking the steps to get and stay healthy and live independent of drugs for satisfaction.”

Source: The Washington Post Tuesday, November 8, 2005

John-Manuel Andriote, author of “Victory Deferred: How AIDS Changed Gay Life in America,” is a Washington journalist. To comment on this article, send e-mail tohealth@washpost.com.

 © 2005 The Washington Post Company

Filed under: Effects of Drugs (Papers) :

© HNN INTERNATIONAL CENTRE. SWEDEN Oct.2002

Did you know that….

• The Drug Abuse Warning Network (DAWN), a system for monitoring the health impact of drugs, estimated that, in 2001, marijuana was a contributing factor in more than 110,000 emergency department visits in the United States, with about 15 per cent of the patients between the ages of 12 and 17, and almost two-thirds male.

• In 1999, the US National Institute of Justice’s Arrestee Drug Abuse Monitoring Program (ADAM), which collects data from 34 sites on the number of adult arrestees testing positive for various drugs, found that, on average, 39 per cent of adult male arrestees and 26 per cent of adult female arrestees tested positive for marijuana.

• ADAM collected data on juvenile arrestees in nine sites and found that marijuana was the most commonly used drug among these youths. On average, 53 per cent of juvenile male and 38 per cent of juvenile female arrestees tested positive for marijuana.

• Through its effects on the brain and body, marijuana intoxication can cause accidents. Studies show that approximately 6 to 11 per cent of fatal accident victims test positive for THC. In many of these cases, alcohol is detected as well.

• In a study conducted by the US National Highway Traffic Safety Administration, a moderate dose of marijuana alone was shown to impair driving performance; however, the effects of even a low dose of marijuana combined with alcohol were markedly greater than for either drug alone. Driving indices measured included reaction time, visual search frequency (driver checking side streets), and the ability to perceive and/or respond to changes n the relative velocity of other vehicles.

• Marijuana use has been shown to increase users’ difficulty in trying to quit smoking tobacco. This was recently reported in a study comparing smoking cessation in adults who smoked both marijuana and tobacco with those who smoked only tobacco. The relationship between marijuana use and continued smoking was particularly strong in those who smoked marijuana daily at the time of the initial interview, 13 years prior to the follow up interview.

• A study of 450 individuals found that people who smoke marijuana frequently but do not smoke tobacco have more health problems and miss more days of work than non-smokers do. Many of the extra sick days used by the marijuana smokers in the study were for respiratory illnesses.

• A study comparing 173 cancer patients and 176 healthy individuals produced strong evidence that smoking marijuana increases the likelihood of developing cancer of the head or neck, and that the more marijuana smoked, the greater the increase. A statistical analysis of the data suggested that marijuana smoking doubled or tripled the risk of these cancers.

• Marijuana has the potential to promote cancer of the lungs and other parts of the respiratory tract because it contains irritants and carcinogens. IN fact, marijuana smoke contains 50 per cent to 70 per cent more carcinogenic hydrocarbons than does tobacco smoke. It also produces high levels of an enzyme that converts certain hydrocarbons into their carcinogenic form, levels that may accelerate the changes that ultimately produce malignant cells.

• Some adverse health effects caused by marijuana may occur because THC impairs the immune system’s ability to fight off infectious diseases and cancer. IN laboratory experiments that exposed animal and human cells to THC or other marijuana ingredients the normal disease-preventing reactions of many of the key types of of immune cells were inhibited. IN other studies, mice exposed to THC or related substances were more likely than unexposed mice to develop bacterial infections and tumours.

• One study has indicated that a person’s risk of heart attack during the first hour after smoking marijuana is four times his or her usual risk. The researchers suggest that a heart attack might occur, in part, because marijuana raises blood pressure and heart rate and reduces the oxygen-carrying capacity of blood.

• Students who smoke marijuana get lower grades and are less likely to graduate from high school, compared with their non-smoking peers. In one study, researchers compared marijuana smoking and non-smoking 12th-graders’ scores on standardized tests of verbal and mathematical skills. Although all of the students had scored equally well in 4th grade, the smokers’ scores were significantly lower in 12th grade than the non-smokers scores were.

• Several studies have associated workers’ marijuana smoking with increased absences, tardiness, accidents, workers’ compensation claims, and job turnover. A study among municipal workers found that employees who smoked marijuana on or off the job reported more ‘withdrawal behaviors’ – such as leaving work without permission, day-dreaming, spending work time on personal matters, and shirking tasks – that adversely affect productivity and morale.

• Because marijuana compromises the ability to learn and remember information, the more a person uses marijuana the more her or she is likely to fall behind in accumulating intellectual, job, or social skills. Moreover, research has shown that marijuana’s adverse impact on memory and learning can last for days or weeks after the acute effects of the drug wear off. For example, a study of 129 college students found that among heavy users of marijuana, those who smoked the drug at least 27 of the preceding 30 days, critical skills related to attention, memory, and learning were significantly impaired, even after they had not used the drug for at least 24 hours. The heavy marijuana users in the study had more trouble sustaining and shifting their attention and in registering, organising, and using information than did the study participants who had used marijuana no more than 3 of the 30 previous days. As a result, someone who smokes marijuana once daily may be functioning at a reduced intellectual level all of the time.

• More recently, the same researchers showed that a group of long-term heavy marijuana users’ ability to recall words from a list was impaired 1 week following cessation of marijuana use, but returned to normal by 4 weeks. An implication of this finding is that even after long-term heavy marijuana use, if an individual quits marijuana use, some cognitive abilities may be recovered.

• Another study produced additional evidence that marijuana’s effects on the brain can cause cumulative deterioration of critical life skills in the long run. Researchers gave students a battery of tests measuring problem-solving and emotional skills in 8th grade and again in 12th grade. The results showed that the students who were already drinking alcohol plus smoking marijuana in 8th grade started off slightly behind their peers but that the distance separating these two groups grew significantly by their senior year in high school. The analysis linked marijuana use, independently of alcohol use, to reduced capacity for self-reinforcement, a group of psychological skills that enable individuals to maintain confidence and persevere in the pursuit of goals.

• Research has shown that babies born to women who used marijuana during their pregnancies display altered responses to visual stimuli, increased tremulousness, and a high-pitched cry, which may indicate problems with neurological development. During infancy and preschool years, marijuana-exposed children have been observed to have more behavioural problems and to perform tasks of visual perception, language comprehension, sustained attention, and memory more poorly than non-exposed children do. In school, these children are more likely to exhibit deficits in decision-making skills, memory and the ability to remain attentive.

• Long-term marijuana use can lead to addiction for some people; that is, they use the drug compulsively even though it often interferes with family, school, work, and recreational activities.

• According to the 2001 US National Household Survey on Drug Abuse, an estimated 5.6 million Americans age 12 or older reported problems with illicit drug use in the past year. Of these, 3.6 million met diagnostic criteria for dependence on an illicit drug. More than 2 million met diagnostic criteria for dependence on marijuana/hashish. IN 1999, more than 220,000 people entering drug abuse treatment programs reported that marijuana was their primary drug of abuse.

• Along with craving, withdrawal symptoms can make it hard for long-term marijuana smokers to stop using the drug. People trying to quit report irritability, difficulty sleeping, and anxiety. They also display increased aggression on psychological tests, peaking approximately 1 week after they last used the drug.

Filed under: Effects of Drugs (Papers) :

By Mary Brett

There are several problems associated with the investigation of possible links between cannabis use and any carcinogenic effects it may have on human cells.

There are now some 140,000 or so scientific research papers on tobacco, while those on cannabis still amount only to about a tenth of that number. It is a relatively young science and, like tobacco, its side effects are usually not apparent for decades.

Cannabis smoking has only been widespread in Western society since the early 1970s and there would presumably be a 20 to 30 year latency period between the initiation of smoking and the development of cancer as is the case with tobacco.

Cannabis smokers often mix tobacco with their cannabis so they run all the well-documented risks of developing cancer associated with tobacco smoke. Relatively few of them smoke cannabis alone so any consequences and therefore causes are almost impossible to separate out. Marijuana smokers are more likely to under report their smoking, if they report it at all.

Large samples are required for case-control studies to take place. It is very difficult to get reliable information about an illegal substance from a large number of people. Questions about cannabis smoking are rarely asked of lung cancer patients.

On the other hand the similarities between tobacco and cannabis are many, the main difference being the presence of nicotine in tobacco and the 60 or so cannabinoids in cannabis (Hoffman et al 1975, Tashkin et al 1997, BMA 1997). So similar side effects may be expected.


Although the number of cannabis “cigarettes” consumed in a day would generally be much fewer than the daily total of tobacco cigarettes, the technique is different. Cannabis smoke is usually inhaled more deeply, held in the lungs for longer and smoked right down to the butt to get full money value. Cannabis cigarettes generally lack filters. (Wu et al 1988). More tar is inhaled from the cannabis butt than from its tip (Tashkin et al 1999).

Cannabis smoke contains 4 to 5 times as much tar as tobacco smoke so the amount of tar deposited in the lungs daily in a cannabis smoker is comparable to that of a tobacco smoker with a 20 a day habit (Benson et al, 1995).

Also the tar from cannabis contains 50% more of some of the carcinogens found in tobacco, notably benzpyrene, a potent carcinogen and a key factor in the promotion of lung cancer (Hoffman et al 1997, Tashkin et al 1997, Novotny et al 1976, Leuchtenberger et al 1983).

For lung cells to become cancerous, a particular combination of cell-growth regulating genes (oncogenes) must become activated or undergo mutation (suppressor genes of tumours).

Marijuana smoke has been reported to produce chromosome aberrations in bacteria as demonstrated by the Ames test (Busch et al 1979 and Wehner et al 1980).

Biopsies of bronchial mucosa have yielded interesting results. Abnormal proliferation of cells (goblet and reserve), transformation of normal ciliated cells to squamous metaplasia (skin-like cells), accumulation of inflammatory cells and abnormal cell nuclei have all been observed (Gong et al 1987, Fliegel et al 1997, Barsky et al 1998). A much higher proportion of these abnormalities was seen in marijuana smokers compared to non-smokers, the number was similar to that of tobacco smokers. Smokers of both tobacco and marijuana exhibited the highest number of all, suggesting the two have an additive effect. Precursors of the development of lung cancer in tobacco smokers include squamous metaplasia and abnormal nuclei (Auerbachet al 1961). Confirmation of these observations also came in 1980 from FS Tennant when he examined US servicemen who were heavy hashish smokers. The mutagenic properties of cannabis smoke were previously recorded in papers in the seventies (Magus and Harris 1971 and Hoffman et al 1975). Human lung explants, exposed to marijuana smoke resulted in DNA and chromosomal alterations (Van Hoozen et al 1997).

Oncogenes and tumour suppressive genes, when mutated, produce proteins which cause cells to multiply rapidly and uncontrollably, resulting in tumours. Two of these proteins were found to be markedly increased in cannabis smokers compared to tobacco or non-smokers, the effects of tobacco and cannabis being additive (Roth et al 1998). The mutagenic effects of marijuana smoke have also been observed by Chiesara and Rizzi 1983, Gilmore et al 1971, Herha and Obe 1974 and Stenchever et al 1974.

Benzpyrene can cause alteration of a gene, P53, one of the commonest tumour suppressor genes if acted on by a chemical particle, CYP1A1. THC has been shown to increase production of this particle so making possible the development of respiratory cancer. P53 is thought to play a part in 75% of lung cancers and it is expressed in 11% of cannabis and tobacco smokers (Dinissenko et al 1996, Marques-Magallanes et al 1997).

The immune system has a role to play in the development of cancer. Alveolar macrophages protect the lungs from infection, they also kill tumour cells. Marijuana and tobacco smokers produce two or three times as many of these cells as non-smokers. The effects of smoking both being additive (Barbers et al 1987). The macrophages in both tobacco and marijuana smokers were larger and had more inclusions, probably due to the ingestion of smoke particles (Beals et al 1989). A more recent paper by Baldwin et al in 1997 found significant impairment of the macrophage cells of both tobacco and marijuana smokers. These cells have been shown to have cannabis receptors (Bouaboula et al 1993). Anti-tumour immunity depends on antigen-presenting dendritic cells being able to stimulate the proliferation of T lymphocytes that identify and destroy tumour cells. In in-vitro studies in which dendritic cells and T lymphocytes were incubated with or without THC, the THC suppressed the T cell proliferation in a dose-dependent manner (Roth et al 1997). Two earlier papers on this subject were written in 1975, Peterson et al and Nahas et al. DNA alterations have been seen in the lymphocytes of pregnant marijuana smokers and their newborns. This study is particularly important as tobacco smokers were excluded (Ammenheuser et al 1998). Cannabis smoking also depressed pro-inflammatory cytokine production. Cytokines regulate macrophage function so this may account for the impairment of their ability to kill tumour cells (Baldwin et al 1997).


Experiments on animals have yielded confirmatory evidence for many of the previous observations. In 1979 Rosenkranz and Fleischman found changes in the bronchial epithelia of rats after they had inhaled marijuana smoke for several months. These changes were consistent with precancerous alterations in cells. In the same year Fried and Charlebois administered cannabis smoke to rats during pregnancy and discovered impaired development in the F2 generation, so not only was damage caused to the first but also the second generation. In 1997 Zhu and others treated mice for 2 weeks with THC prior to the implantation of Lewis lung cancer cells. Larger faster-growing tumours resulted suggesting that the THC impairs the development of anti-tumour immunity in vivo. Dubinett et al in 2000 also found that mice injected with THC had reduced capability to fight the growth of tumours.

Painting tar from marijuana smoke on the skins of mice produced lesions correlated with malignancies (Cottrell 1973).

There are a significant number of reports of human cancers which may be linked to the smoking of marijuana. FM Taylor in 1988 examined adults with upper respiratory tract cancer over a period of 4 years. Of 6 men and 4 women, average age 33.5 years, nine had carcinomas of the lungs tongue or larynx, five were heavy cannabis smokers, two smoked it regularly, one had possibly used other drugs and two were non cannabis smokers. It was complicated by the fact that six were heavy alcohol users and six were smokers of tobacco. He concluded that regular marijuana use was a potent factor especially in the presence of other risk factors. He conceded that alcohol and tobacco may have played a part, but pointed out that the peak incidence for cancers due to tobacco or alcohol is in the seventh decade of life. All of these victims were much younger.

In 1989 Caplan and Brigham reported two cases of tongue cancer. One was a man of 37 the other a man of 52. Both were heavy cannabis users, neither smoked tobacco or drank alcohol. Endicott and Skipper in 1991 conducted a 2-centre USA retrospective study. Twenty-six patients of age 41 or less were diagnosed with throat or head tumours. The normal average age for tumours of this type is 57. All 26 were current or former marijuana smokers.

PJ Donald in 1993 examined patients with cancer of the head and throat over a 20-year period. He found 22 patients of age 40 or under on diagnosis, with squamous cell cancer. Their average age was 26. Nineteen of them were cannabis smokers, 16 being heavy users. In 13 the tumour was in the tongue or elsewhere in the oral cavity. Only half of them smoked tobacco.

110 private patients with lung cancer were studied. Nineteen (17%) of them were under 45. Thirteen of these had smoked marijuana of whom 12 reported current tobacco use. No tobacco-only smoking patients under 45 were noted (Sridhar et al 1994).

An epidemiological study to examine a possible association between cancer and marijuana was published in 1997 by Sidney and colleagues. 65,000 health plan members aged between 15 and 49 in 1979 to 1985 were followed for the development of new cancers till 1993. 182 tobacco-related cancers were detected, of which 97 were in the lungs. The study revealed no risk factors for cancers for lifetime or current use of marijuana.

The major limitation in this exercise is that those who were heavy or long-term users of cannabis were not followed up for long enough to detect cancers. Another criticism is that there may not have been sufficient of these long-term or heavy users to make the study effective. It must be remembered that most marijuana users quit before the level of exposure is sufficient to initiate the development of cancer and cannabis smoking has only been widespread in the USA since the 70s.


Zhang et al in 1999 studied 173 patients with carcinoma of the head and neck and compared them with 176 cancer-free controls. Age, sex, race, education, alcohol consumption and exposure to cigarette smoke either actively or passively, were all controlled for. Marijuana smoking increased the risk of squamous cell carcinoma of the head or neck, and a further increased risk was suggested with rising doses. Among people who smoked once a day the risk factor was 2.1 times compared with non-smokers, with those using it more than once a day the risk factor rose to 4.9. With patients who smoked cannabis and tobacco the risk was 36 times that for non-smokers.

The most prominent name and authority on cannabis and diseases of the respiratory system is that of Dr Donald Tashkin. He has researched the topic since the early seventies.

In 1993 he listed the factors suggesting that cannabis smoking may be associated with an increased risk of respiratory tract cancers.

1. Cannabis smoke has 50% more of certain carcinogens than tobacco smoke, especially the highly carcinogenic benz-pyrene.

2. Four times as much tar is produced by a cannabis cigarette than a tobacco one.

3. Experiments on animals have shown that cannabis smoke or tar from it is carcinogenic.

4. Heavy cannabis consumers have significantly higher numbers of cellular changes consistent with the preliminary stages of cancer.

5. There have been several reports of young cannabis-using people exhibiting the development of cancer. Tumours have appeared 10 to 30 years earlier than those who smoked tobacco alone.

In a review paper in 2002 he added that examination of the mucous membranes in long-term smokers suggests that THC weakens the immune defences against tumour cells.

In November 2002 the British Lung Foundation produced a paper “A Smoking Gun? The Impact of Cannabis Smoking on Respiratory Health”. One of their recommendations was: “ The British Lung Foundation recommends a public health education campaign aimed at young people to ensure that they are fully aware of the increased risk of pulmonary infections and respiratory cancers associated with cannabis smoking”.

In September 2003 The Thoracic Society of Australia and New Zealand produced a position paper in The Internal Medicine Journal on the respiratory health effects of cannabis (Taylor and Hall). They also called for a campaign. “Public Health Education should dispel the myth that cannabis smoking is relatively safe by highlighting that the adverse respiratory effects of smoking cannabis are similar to those of smoking tobacco…that the respiratory hazards of smoking cannabis are significant…almost all studies indicate that the effects of cannabis and tobacco smoking are additive and independent”.

In June 2005 Roth and Tashkin of UCLA, the two leading authors of many papers linking cannabis and cancer for over 10 years, described an epidemiological study at the meeting of the International Cannabinoid Research Society in Tampa, Florida. This paper has yet to appear on the ICRS website. Tashkin reported that they had failed to substantiate the link. Needless to say the press immediately issued banner headlines like “Marijuana is safer than tobacco”. However it has emerged that the study lacked statistical power. Tashkin and Roth explained that they had very few patients smoking more than 6 joints a day, a very mild level of consumption. Had they had more moderate and heavy smokers, their outcomes would almost certainly have been different. The study was originally designed to have 3 controls for each cancer case, in reality the ratio was around 0.7. Statistics are powerful but not powerful enough to account for gross flaws in sampling errors and study design.

In 1981 the WHO report on cannabis use said, “It is instructive to make comparisons with the study of effects of other drugs, such as tobacco or alcohol. With these drugs, “risk factors” have been freely identified, although full causality has not yet been established. Nevertheless such risk factors deserve and receive serious attention with respect to the latter drugs. It is puzzling that the same reasoning is often not applied to cannabis”… “To provide rigid proof of causality in such investigations is logically and theoretically impossible, and to demand it is unreasonable”.

Mary Brett, biologist and former head of health education, Dr Challoner’s Grammar School (boys) Chesham Road, Amersham, Bucks. HP6 5HA, UK 17th July 2005 References are available for this paper – please send a s.a.e. to NDPA

Filed under: Effects of Drugs (Papers) :

by Jane Wheatley

Our correspondent hears testimony to the link between cannabis and psychosis

Judy Mylne woke with a start and glanced at her bedside clock; it was 3am. She went to the window and looked out over the quiet street of terraced houses: in the middle of the road her son James was Rollerblading, up and down, up and down, between the rows of parked cars. He must have woken her as he went out, she thought, leaning her forehead against the cool glass, watching him, feeling sick and afraid.

At first when James had started behaving oddly, being difficult, she’d put it down to normal teenage moodiness, probably exacerbated by his parents’ divorce when he was 16.  He’d always been very good at art, won prizes; you had to make allowances for artistic souls didn’t you? But now, two years later, it was a lot more worrying. He would rant at his mother obsessively about such things as the power of purple; friends avoided him, tutors on his art foundation course said they couldn’t teach him. “He’s a mess,” they told Judy.

One evening he dropped his Walkman on the floor, stamped on it and screamed: “I’m going to kill myself and take you with me.” He head-butted the wall, put his fist through a door and, with blood pouring from head and hand, ran out on to the street. The next day Judy took him to their GP, who referred him to a psychiatrist, to whom James admitted that he had been smoking cannabis regularly. By now he was hearing voices and thought people were following him. One night Judy came home from dinner to find James packing a few random objects into a bag inside a nest of twisted coat hangers. He said he was going to walk to Nepal in the morning.

“I thought: ‘My God, he’s really, really ill’,” Judy recalls. She closed the door quietly, fetched two sleeping pills, dissolved them in a glass of Coca-Cola and took it to him. Then she packed a bag and went to a friend’s house. In the morning she rang her GP, the psychiatrist, her older stepsons and her ex-husband. “I’m not going back to the house,” she told them, “you must go and get James and take him somewhere safe.”

James’s father, a barrister, was in court and asked leave to speak to the judge in his chambers. There he explained that his son had been taking drugs and was possibly psychotic. The judge looked at him: “My son has the same problem,” he said. “Go, and take as long as you need.” 

There but for fortune, it seems, go any of us with teenage children.

Though most people use cannabis without any obvious harm, most of us know of someone — our own child or a friend’s, a friend of a friend’s — who has got into trouble smoking weed, often skunk, which has higher levels of THC, the compound that gets you stoned.

The most extreme cases, such as James, develop a psychosis (schizophrenia or bipolar disorder) from which they may or may not recover. And it is no respecter of class, education or background. Dr Zerrin Atakan, a psychiatrist, sees severe cases at her clinic at London’s Maudsley Hospital: “Sadly many of these young people had been bright, sensitive, happy children,” she says. “Parents often feel dreadfully guilty for allowing them to smoke weed, because in their day, it was relatively harmless.”

Dr Atakan’s patients have usually been smoking from a young age, while the brain is still developing: “We know now that this is a significant risk factor in the development of psychosis. In an ideal world, no one would smoke before the age of 18.”

So, does cannabis cause psychosis? Almost certainly not by itself.

Cannabis-related psychosis is a relatively new feature in the landscape of mental illness and there is little reliable data on it. One study found that people who use cannabis before the age of 15 are at least four times more likely to develop schizophrenia, but all of them probably had a predisposition for psychosis in the first place — sometimes, though not always, indicated by a family history of mental health problems.

A new Australian review of current evidence found that 42 per cent of patients with psychosis had used cannabis. Yet, despite much greater use of skunk during the Nineties, there has been no significant increase in the incidence of psychosis in the past 30 years. Why not? David Kavanagh, of the University of Queensland, is one of the authors of the review:  

 “While cannabis may not cause psychosis, there is no doubt that it will trigger psychosis much earlier in vulnerable young people. This is very important because the period of late adolescence is critical for the completion of education and the development of social, emotional and sexual competence and a psychotic episode during this period is extremely disrupting.

“We also know that cannabis use tends to worsen subsequent symptoms and triggers further episodes.” British researchers believe that, because cannabis use by children is a recent phenomenon, the effects have yet to show in the figures and that there will be an increase in schizophrenia in this current decade. In one study of 2,500 young people, the effect of cannabis use was much stronger in those with a predisposition for psychosis (23.8 per cent) than in those without (5.6 per cent). But even when there is no known family history of mental illness, some children may be genetically more vulnerable than their peers, or have a personality that does not handle cannabis very well, and the Government has ordered a review of the evidence for this. There are genetic tests, but they are expensive and unlikely to be ordered until the damage is done. So how do you tell?

“Well, it’s not written on the forehead,” says Dr Atakan, wryly. Marjorie Wallace, founder of the mental health charity SANE, agrees that you cannot know who is vulnerable: “It’s like watching children playing Russian roulette; one of them is going to be a victim.”

Wallace has worked with schizophrenic young people for 20 years: is there a classic type? “Well, yes,” she concedes, “usually male, often more inward-looking, artistic and sensitive. Often very promising but then he starts to drop out of college, loses friends and slides quietly into isolation. After one psychotic breakdown, there is treatment and partial recovery but then he’ll go back to cannabis, substituting it for his medication.” The key, says Dr Atakan, is early intervention: “There is a prodromal phase of psychotic illness that parents can look out for: a teenager might be a bit more withdrawn, excitable, suspicious, touchy, anxious; he might develop an extreme interest or obsession with one thing, ignoring everything else and avoiding social contact. untreated psychosis — is critical, yet people are baffled and don’t know how to ask for help.”   Like many parents, Judy Mylne did not relate her son’s behaviour to drugs. “I think I was in denial,” she says now. By the time the family rescue squad was called in, he was in full-blown psychosis. He spent a month in the secure Nightingale Clinic, where he was put on a heavy dose of the antipsychotic drug Risperdal and underwent group therapy. He came home and, under the watchful eye of his mother, gradually reduced his dosage. He came off medication entirely in the summer of 2004. This year he completed his art degree, embarked on an MA and is successfully selling his art work.
 
James was lucky: he had a mother who stuck by him and, when the crisis hit, there was money to pay for instant professional help. After the medical insurance ran out, there was high-quality psychiatric support at his local Hammersmith Hospital. But services across the rest of the country are patchy, to say the least. How can parents and teenagers get the help that they need?   Eddie Greenwood is the clinical services director of the mental health charity Rethink; he says that, because governments have been so slow to recognise the causal link between cannabis and psychosis, there is a dearth of provision for young sufferers: “Primary care diagnostic services are often poor. A GP may refer a young person to a community mental health team, but they are unlikely to have a case worker experienced in dual diagnosis — that is, a combination of psychosis and substance abuse.”
The Government is now urging NHS trusts to develop early intervention teams for young people with first-onset psychosis. “But the demand wildly outstrips supply,” says Greenwood, “and the problem is going to get worse before it gets better. ”

“This is the time to seek help. What we call D.U.P. — duration of

Last Christmas, says Judy, she asked him if he would come and help her to get the tree. “He asked me if I’d had a tree when he was in the clinic and who was at home for Christmas Day. I told him, just me and his sister. ‘Oh, Mum,’ he said, ‘I’m so sorry!’” Judy felt like punching the air. “I thought: ‘Yes! Insight, empathy, at last.’ And humour has returned, too. For four years, I hadn’t heard him laugh.”

At the moment, a young person presenting with psychotic symptoms is likely to be sent by his GP for assessment and then referred to a psychiatrist who may prescribe antipsychotic drugs and send him home. For families in rural and under-resourced areas, this could be disastrous. “If you leave these people with arm’s-length treatment, they will just deteriorate,” cautions Greenwood. “The key is active engagement: getting an intervention programme organised around the young person’s needs.”

Dr Atakan agrees: “Where these specialist services exist, they are resourced to supply psychological support as well as medical. Treatment is a contentious issue; it is not ethical to prescribe antipsychotics to young people who may not be psychotic. It’s a complex area.” And cannabis may be a useful scapegoat for families not wanting to face the stigma of mental illness. David Kavanagh: “When a young person develops a psychotic disorder, family members naturally search for reasons. The young person may be blamed for bringing it on himself by smoking. Not only may this not be true, but such hostile criticsm increases the likelihood of further episodes.” Last month, after pressure from police and some drugs charities, the Advisory Council on the Misuse of Drugs considered reclassifying cannabis as a Class B drug. But they are expected to recommend no change on the grounds that there is not enough new evidence to link it with mental illness. The council was also asked to consider giving a higher classification for skunk — “a more potent form of cannabis” — but this is thought to be unworkable. Dr Atakan would rather see cannabis legalised: “The present system is so bad; at least if it were legalised, some control mechanisms could be applied. At the moment it is in the hands of the dealers and it is in their interest to sell strong skunk. It needs to be regulated, like cigarettes, but most importantly there should be a thorough education campaign starting in primary school.”

Marjorie Wallace is dubious. “Until we know more about these new forms of cannabis, with their high THC levels and their effect on the young brain, we should not be giving out the message that this is a soft drug.”

                                                   *     *     *     *     *

“Sometimes I felt that people were talking about what I was thinking about”.  From the age of 14, I was smoking cannabis at weekends; by 18, I was smoking almost every night and doing some chemicals and pills at the weekends (LSD, ketamine, MDMA and cocaine). But, in comparison to others, I wasn’t doing many Class A drugs; I believe it was the consistent and accelerated use of cannabis that led to my diagnosis of drug-induced psychosis in 2000.   Out of about 25 drug users I knew then, three people, including myself, were creative, sensitive individuals — and not as bright as everyone else. I believe we were particularly vulnerable to the effects of cannabis. One of them, my best friend, jumped off a multistorey car park two years ago. The main difference between him and me was that I stopped taking drugs in 2001 and he didn’t. The thing about having something wrong with your mental state is that you can never escape it. When you can’t help yourself, you get angry, frustrated and sad about yourself. I would fleetingly remember my old self, when everything was fine and I was having so much fun — until it hurt too much. I wanted to be that person again. I believed that people were talking about me in public — and what was worse, what they were saying seemed to feed into the tangled web of delusional beliefs that  I had about my life. Sometimes I felt that people were talking about what I was thinking about. As a result, I thought I was some special character in a world that everyone knew of.

Paranoia is fundamentally egotistic and every conspiracy theory serves in some way to aggrandise the believer. My research into Buddhism has shone light on this and given me hope and help. I have recently been told by a doctor that my case is a great success. Certainly I feel one hundred times better than I did four years ago.

JAMES MYLNE

A search on Cannabis Psychosis produced 444 references. Here are the first 10.

 1:  Ferdinand RF, van der Ende J, Bongers I, Selten JP, Huizink A, Verhulst FC. Related Articles, Links  Cannabis-psychosis pathway independent of other types of psychopathology. Schizophr Res. 2005 Nov 15;79(2-3):289-95. Epub 2005 Aug 25. PMID: 16125368 [PubMed – in process]

2:  Verdoux H, Tournier M, Cougnard A. Related Articles, Links  Impact of substance use on the onset and course of early psychosis. Schizophr Res. 2005 Nov 1;79(1):69-75. Epub 2005 Jan 11. PMID: 16198239 [PubMed – in process]

3:  Broome MR, Woolley JB, Tabraham P, Johns LC, Bramon E, Murray GK, Pariante C, McGuire PK, Murray RM. Related Articles, Links  What causes the onset of psychosis? Schizophr Res. 2005 Nov 1;79(1):23-34. PMID: 16198238 [PubMed – in process]

4:  Green B, Young R, Kavanagh D. Related Articles, Links  Cannabis use and misuse prevalence among people with psychosis. Br J Psychiatry. 2005 Oct;187:306-13.PMID: 16199787 [PubMed – in process]

5:  Viveros MP, Llorente R, Moreno E, Marco EM. Related Articles, Links  Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods.Behav Pharmacol. 2005 Sep;16(5-6):353-62.  PMID: 16148439 [PubMed – in process]

6:  Long LE, Malone DT, Taylor DA. Related Articles, Links  Cannabidiol Reverses MK-801-Induced Disruption of Prepulse Inhibition in Mice.Neuropsychopharmacology. 2005 Jul 27; [Epub ahead of print] PMID: 16052245 [PubMed – as supplied by publisher]

7:  Clough AR, d’Abbs P, Cairney S, Gray D, Maruff P, Parker R, O’Reilly B. Related Articles, Links  Adverse mental health effects of cannabis use in two indigenous communities in Arnhem Land, Northern Territory, Australia: exploratory study.Aust N Z J Psychiatry. 2005 Jul;39(7):612-20.
PMID: 15996143 [PubMed – in process]

8:  Henquet C, Murray R, Linszen D, van Os J. Related Articles, Links  The environment and schizophrenia: the role of cannabis use.  Schizophr Bull. 2005 Jul;31(3):608-12. Epub 2005 Jun 23. PMID: 15976013 [PubMed – in process]

9:  Maki P, Veijola J, Jones PB, Murray GK, Koponen H, Tienari P, Miettunen J, Tanskanen P, Wahlberg KE, Koskinen J, Lauronen E, Isohanni M.

Related Articles,

 Predictors of schizophrenia–a review.

Br Med Bull. 2005 Jun 9;73:1-15. Print 2005.

PMID: 15947217 [PubMed – in process]

10:  van Os J, Henquet C, Stefanis N. Related Articles, Links  Cannabis-related psychosis and the gene-environment interaction: comments on Ferdinand et Al. 2005.  Addiction. 2005 Jun;100(6):874-5. No abstract available. PMID: 15918820 [PubMed – indexed for MEDLINE]

 Links

Where to get help:

         www.ukcia.org

          www.rethink.org
       
        www.knowcannabis.org.uk   www.turning-point.co.uk

       

 

The Maudsley Hospital provides a programme for people wishing to cut down their cannabis intake.

Further reading: Marijuana and Madness, edited by David Castle and Robin Murray. Cambridge University Press.

 Source:  The Times November 14, 2005

Filed under: Effects of Drugs (Papers) :

 

Margret Drewe, Jürgen Drewe, Anita Riecher-Rössler
Psychiatric Outpatient Department and Clinic for Pharmacology und Toxicology,University Hospital Basel, Switzerland

Legalisation of cannabis use in Switzerland has recently been debated by the Swiss Parliament. Although legalisation has not yet been decided upon, it is still the subject of impassioned public discussion. If cannabis use is legalised, an increase in consumption is to be expected. One of the manifold negative consequences for mental health will probably be an increase in the prevalence of psychoses – not only acute, toxic psychosis but also chronic psychoses. Schizophrenic psychoses are expected to be triggered at an earlier age and to be negatively influenced in their course. This eventuality could have deleterious consequences not only for many currently healthy individuals predisposed to psychosis, but also for the disability pension.

 

In Switzerland cannabis is a widely used drug due to its psychotropic effects. It enjoys an almost legally accepted status. The National Health Inquiry (Schweizerische Gesundheitsbefragung 2002) showed that the recreational use of cannabinoids increased significantly during the period 1992–2002. In 2002, 225,000 persons in the 15–64 age group consumed cannabinoids, corresponding to 4.7% of the Swiss population. The proportion of consumers increased in the under-40 age group from 12.2% in 1992 to 21.7% in 2002. In 2002 between 36% and 24.4% of men and women respectively of the 15–24 age group reported that they had consumed cannabis at least once [1]. It may be speculated that the prevalence of cannabis consumption would increase further if consumption were legalised in Switzerland, as the Swiss Parliament has debated. Hence the implications for mental health are of importance. Besides its disturbing effects on psychomotor performance and driving ability [2], development of psychological and physical dependence on cannabis and other drugs [3–5], impairment of cognitive function (memory, attention) [6], changes in personality such as loss of motivation, as described by the term “amotivational syndrome” [7], as well as development of depression and psychosis [5], are reported in the literature. With respect to psychosis, a distinction must be drawn between dose-dependent toxic, so-called drug-induced psychoses and schizophrenic psychoses. The existence of the usually reversible toxic psychoses has been well described [5, 8], but there is still controversy as to whether acute or chronic cannabis consumption can lead to the development of chronic, especially schizophrenic psychoses. In the Mannheim ABC Schizophrenia Study the last author of this paper demonstrated that first-admitted patients with schizophrenia showed a twofold higher prevalence of drug abuse (predominantly cannabis) compared with healthy controls [9, 10]. Experience in our Basel FEPSY – (Früherkennung von Psychosen – Early Detection of Psychosis) project show a similar disproportionate use of cannabis: approximately 75% of our newly diagnosed patients with schizophrenia reported regular use of cannabis (at least several times per month). We shall therefore discuss the evidence in the literature for a causal relationship between the use of cannabis and the development of (chronic) schizophrenic psychoses. We are aware that the kind of relationship between cannabis consumption and development of schizophrenic psychoses is highly controversial [11]: one view is that cannabis use is secondary to psychiatric disorders, or caused by other, concomitantly consumed drugs, or is even due to confounding factors (both cannabis use and psychosis are caused by one or more as yet unknown factors).

A different view is that of a causal or modulating effect (in vulnerable patients) of cannabis use for the development of psychoses. And an integrative view, supported by our own earlier data [9], postulates that both kinds of interaction are possible. In what follows, our criteria for deciding between these views are similar to other authors’ [11, 12]:

Summary

Introduction – Cannabis and risk of psychosis

1) Is there biological evidence of an interaction between the cannabis and the dopaminergic system in cerebral tissue?

2) Is there a statistical association between cannabis use and psychosis and, more specifically,

3) Is there a temporal relationship between antecedent cannabis use and later onset of psychotic symptoms, and, finally

4) Is there a dose-response relationship for cannabis use and development of schizophrenic psychoses?

The importance of dopamine balance in specific brain areas for the development of psychoses has been sufficiently demonstrated, being the basis of the dopamine-antagonistic therapy with neuroleptic drugs. Cannabis may affect this balance by its active psychotropic components, such as tetrahydrocannabinol (THC) and its metabolite 11-OH-THC. It increases dopaminergic activity in relevant areas of the mesolimbic system, possibly by blockade of GABAergic neuronal activity [4, 13]. Cannabis exerts these effects by binding to specific receptors (mainly the CB1-receptor), which interact with local dopamine D2-receptors [14]. Both receptor genes show a significant homology in regulatory parts [15]. Interactions between the two receptors were reported for the striatum of rats and monkeys [16]. The most extensive expression of CB1-receptors is found be important for the development of schizophrenia, namely the mesolimbic and mesocortical dopaminergic system [4]. Further, it has been proposed that genetic mutations of the CB1-receptor gene are accompanied by an increased risk of developing cannabis abuse in schizophrenic patients [17]. The finding of increased blood concentrations of anandamide, an endogenous CB1-receptor agonist, in a group of schizophrenic patients [18] corroborates these findings.

Neurobiological background

Can cannabis consumption lead to short-lasting, “toxic” psychoses?

In the literature there are many case reports on acute psychiatric symptoms after the consumption of sometimes high doses of cannabis, showing the clinical picture of short, reversible toxic psychosis with organic features such as confusion or disorientation. In India, 200 patients were hospitalised after consumption of exceptionally high doses of cannabis because of severe psychiatric symptoms (confusion, emotional lability, disorientation, depersonalisation, paranoid symptoms) [19]. The symptoms lasted for some days, but longer in patients with a history of psychiatric disorders.

Can cannabis consumption also lead to non-toxic psychoses/psychotic symptoms?

In a large-scale enquiry in 1000 persons in New Zealand aged between 18 and 35, 38% reported cannabis consumption. 22% of these subjects reported anxiety and panic attacks and 15% psychotic symptoms following cannabis use. Women reported panic attacks significantly more often than men [20]. In Germany, 36,000 US soldiers were questioned about cannabis consumption. 5120 admitted consuming cannabis at least 3 times weekly. Psychiatric symptoms such as panic attacks or toxic psychoses following consumption of a single high dose of cannabis were reported by 720 soldiers [21]. Van Os and co-workers investigated the effect of cannabis in 4045 healthy subjects and 59 psychotic patients [22]. In a 3-year follow-up investigation the consumers showed a 2.8-fold higher risk (95% CI: 1.2–6.5) of developing psychotic symptoms than non-consuming controls. In the group of patients with pre-existing psychotic symptoms, the risk was 24.2-fold (95% CI: 5.4–107.5) It emerged that the severity of In this study more than 50% of psychotic episodes could be related to consumption of cannabis. The authors concluded that cannabis consumption increases the risk of developing psychotic symptoms in healthy subjects and worsens the prognosis in psychotic patients. The impact of cannabis consumption on the risk of developing psychoses has also been investigated in other studies. Thus, in the National Survey of Mental Health and Well-Being (NSMHWB) [23], a representative poll (N = 10641) showed that cannabis abuse was accompanied by a significant 2.8-fold (95% CI: 1.4–5.9) increased risk of developing psychosis. However, these studies did not further investigate the type of psychosis.

Clinical studies

Can cannabis consumption cause a schizotypal personality?

Cannabis consumption is associated with a schizophrenia-like personality. Several authors show that young consumers and previous consumers have higher scores on schizotypy, and psychoticism scales even when they do not show other psychiatric symptoms. They also show deficits in attentional inhibition and decreased reaction time compared to never-users [24, 25]. The causal relationship of this association is, however, not yet clear: do these personality traits predispose to cannabis abuse or does cannabis abuse induce these changes of personality?

Can cannabis consumption also trigger or even cause schizophrenic psychoses?

A historical cohort study in more than 50,000 Swedish conscripts over an observation period of some 27 years investigated the importance of cannabis consumption for the development of schizophrenia and psychoses [26]: young men who reported previous cannabis consumption on more than 50 occasions at the outset of the observation period showed a 6.7-fold (95% CI: 4.5–10.0) increased risk of later hospitalisation for schizophrenia and other psychoses. The latter author also reported very interesting results in the ABC study (Age, Beginning and Course of Schizophrenia): this study investigated 276 first-time hospitalised schizophrenic patients (232 with first episode) [27, 28]. Twice the number of patients reported a lifetime history of substance abuse than healthy controls – 14.2% versus 7% [9, 29]. Of these patients 88% consumed cannabis, in approx. 60% of whom cannabis consumption preceded even the first still very unspecific symptoms of schizophrenia [29], on average by about 4.5 years [9]. In 35% of cases the first unspecific symptoms were reported to have occurred in the same month as the start of drug consumption. Cannabis-consuming patients were significantly younger than non-consuming patients. The authors therefore concluded that cannabis consumption may have precipitated (triggered) the onset of schizophrenia in predisposed (vulnerable) patients and aggravated the symptoms [29, 30]. However, there may also be a subgroup of patients who have started to use cannabis to attenuate the first [9, 31, 32]. (pre-)psychotic symptoms as a form of self-therapy.

In a recent reanalysis of five large (N = 1011 to 50,053 patients) studies [22, 26, 33–35] Smit et al. pointed out that in these studies there was a clear temporal relationship of antecedent cannabis use before first psychiatric symptoms were observed[11]. Effects of other concomitantly used drugs were excluded and the effects of other confounders were taken into account in four of these studies. In two of them [22, 26] a dose-dependent increase in psychosis risk was observed. As the authors pointed out, this does not imply that psychotic patients “do not use cannabis as a form of ‘self-medication’, but these results do imply that cannabis use increases the risk of later schizophrenia even when self-medication can be ruled out as an explanation” [11]. Verdoux et al. [36] found that young undergraduate students with high vulnerability to development of psychosis reported more unusual perceptions and feelings of thought influence after cannabis consumption than subjects with low vulnerability. Interestingly, they could not find evidence of increased use of cannabis following the occurrence of psychotic experiences. This contradicts the self-medication model in the psychotic stage but not necessarily in the still unspecific prodromal stage. Young age appears to increase the risk of developing psychotic symptoms following cannabis use. In a prospective longitudinal study Arseneault et al. [34] investigated whether adolescent cannabis use is a risk factor for adult schizophreniform disorders. The study was performed in 1037 adolescents from New Zealand and showed that cannabis consumption at age 15 years significantly increased the risk of developing schizophrenia(4.5-fold, 95% CI: 1.1–18.2) up to age 26. However, cannabis consumption at age 18 increased the risk only 1.7-fold (95% CI: 0.7–4.2). These results were corroborated by a birth cohort in 1265 children [35] studied to age 21. The authors showed that subjects fulfilling DSM-IV criteria for cannabis dependence had elevated rates of psychotic symptoms as compared to individuals without cannabis dependence – at age 18 the increase was 3.7-fold (95% CI: 2.8–5.0) and at age 21 2.3- fold (95% CI: 1.7–3.2). This significant increase was still present when data were adjusted for pre-existing symptoms or other background factors. Despite this close association of cannabis use with schizophrenia, the causal relationship between cannabis consumption and schizophrenic psychosis is still controversial. On the one hand, many studies show an increased risk of developing schizophrenia in patients consuming cannabis; on the other hand, in a simulation Degenhardt [37] showed that a causal relationship would have led to a significant increase in the incidence of schizophreniain Australia, which has, however, not been observed [8]. A possible explanation for the lack of evidence of an increase in schizophrenia rates in epidemiological studies may be a reporting bias: in clinical studies, which usually find this association, exposed patients have been systematically studied for psychiatric disturbances in one or more follow-up investigations. This has led to detection of mild psychotic symptoms, which outside clinical studies may not have been detected (underreporting). Also, the proportion of cannabis-induced schizophrenia may be small and, therefore, an increase inschizophrenia rate attributed to cannabis use may not be easily detectable. On the other hand, Boydell et al. [38] recently reported a continuous and statistically significant increase in the incidence of schizophrenia from the London area for the period 1965–1997. Interestingly, this increase was most marked in people under 35 years of age and was not gender-specific. Furthermore, it is conceivable that cannabis is not causal in a narrow sense, but merely triggers the outbreak of schizophrenic psychoses in individuals with a specific (genetic) vulnerability for this disease. Cannabis use would then simply result in earlier manifestation of schizophrenia in these vulnerable patients rather than an increased incidence. Evidence for this has just been published [39]. This alone would also be relevant, since it has important implications for the mental and educational development of these patients. If the onset of first symptoms is earlier, have not usually completed their professional education and have not developed a sufficient social network. Earlier onset due to a “cannabis trigger” may therefore be associated with a worse prognosis of schizophrenia, especially regarding its psychosocial course.

Can cannabis consumption worsen the progression of schizophrenia?

The productive symptoms of psychosis are amplified by concomitant consumption of cannabis. Compliance with antipsychotic treatment and utilisation of rehabilitation programmes are impaired [29]. Schizophrenia patients with cannabis use suffer from more frequent and earlier relapse episodes [40, 41]. Because of the dopaminergic effects of cannabis it can be speculated that cannabis-consuming patients suffering from schizophrenia may need higher doses of antipsychotic (anti-dopaminergic) medication. Psychotic patients with cannabis consumption are usually younger, predominantly male and show more criminal behaviour [42]. On the basis of our criteria, the following conclusions can be drawn:

– Cannabis consumption modulates dopamine concentrations in certain brain areas, and can thus induce or modulate the development of psychotic symptoms and psychosis.

– Cannabis in high doses may induce acute, reversible (toxic) psychoses.

– Cannabis may also induce the manifestation of schizophrenic psychoses in vulnerable patients (“dopaminergic stress”) or at least trigger an earlier onset in this population.

– Young age is an additional risk factor for the development of psychoses.

– Concomitant cannabis consumption may affect the progression of schizophrenic psychoses and worsen the prognosis.

– Cannabis consumption is associated with a schizotypical personality, the causal relationship of which is not yet clear.

– Cannabis consumption can also lead to other psychiatric disorders, including depression and may result in a severe loss of energy and cognitive disturbances.

Conclusions

To obtain more definite answers to the questions of causality, dose-effect relationship, the severity and time course of these effects, the importance of other confounding factors, and, finally, the size of the impending burden for the individual and the society, we urgently need additional prospective longitudinal studies. Nevertheless, at this stage of research we can and should, depending on our view, already sound a note of warning, especially as the potency of the substances used and the prevalence of abuse and dependence are apparently growing [43]. Increased cannabis consumption in our society could have deleterious consequences for many so far healthy individuals, not only because of the negative influences on education and work performance due to impairment of cognitive function and loss of energy, but also due to the “psychotogenic” properties of cannabis. Healthy individuals with a currently “hidden” predisposition to psychosis could develop full blown psychosis. In individuals vulnerable to schizophrenia the outbreak of this disorder could be triggered at an earlier age and negatively influenced in its course. This would not only have severe psychosocial consequences for the individual and his family. As schizophrenia is already one of the most expensive diseases, this could also have negative consequences for the national economy – inter alia due to the high level of disability pensions at a very young age. What conclusions can be drawn? Politicians, health professionals and teachers should more intensively pinpoint the potential health risks of cannabis use, in particular for young adolescents. Information campaigns should be launched in the media. Although complete prohibition of cannabis may be neither enforceable nor successful in our society, legalisation of cannabis could – on the other hand – send the wrong message concerning the potential harm done by its use. It goes without saying that people who are already dependent need our help and should not be criminalised; but methods of controlled use for dependent persons have also been found for other substances and drugs. Our main focus should in any case be on the prevention of new cases of cannabis dependence.

Correspondence:

Prof. Anita Riecher-Rössler, MD Psychiatric Outpatient Department University Hospital / Universitätsspital Basel Petersgraben 4 CH-4031 Basel E-Mail: ariecher@uhbs.ch

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Filed under: Effects of Drugs (Papers) :
By Timothy Wilens, M.D.

The overlap between attention-deficit/ hyperactivity disorder and alcohol or drug abuse or dependence (referred to here as substance use disorders [SUDs]) in adolescents has been an area of increasing clinical, research and public health interest. Appearing in early childhood, ADHD affects from 6% to 9% of children and adolescents worldwide (Anderson et al., 1987) and up to 5% of adults (Kessler, in press). Longitudinal data suggest that childhood ADHD persists into adolescence in 75% of cases and into adulthood in approximately one-half of cases (for review, see Weiss, 1992). Substance use disorders usually appear in adolescence or early adulthood and affect between 10% to 30% of U.S. adults and a less defined, but sizable, number of juveniles (Kessler, 2004). The study of comorbidity between SUDs and ADHD is relevant to both research and clinical practice in developmental pediatrics, psychology and psychiatry with implications for diagnosis, prognosis, treatment and health care delivery.

Overlap Between ADHD and SUD

Structured psychiatric diagnostic interviews assessing ADHD and other disorders in substance-abusing groups have indicated that from one-third to one-half of adolescents with SUDs have ADHD (DeMilio, 1989; Milin et al., 1991). For example, aggregate data from government-funded studies of mainly cannabis-abusing youth indicate that ADHD is the second most common comorbidity with from 40% to 50% of both girls and boys manifesting full criteria for ADHD. Data largely ascertained from adult groups with SUDs also show an earlier onset and more severe course of SUD associated with ADHD (Carroll and Rounsaville, 1993; Levin and Evans, 2001).

ADHD as a Risk Factor or Precursor for SUD

The association of ADHD and SUDs is particularly compelling from a developmental perspective as ADHD appears to manifest itself earlier than the SUD; therefore, the SUD is an unlikely risk factor for ADHD. Thus, it is important to evaluate to what extent ADHD is a precursor of SUDs. Prospective studies of children with ADHD have provided evidence that the group with conduct or bipolar disorders co-occurring with ADHD have the poorest outcome with respect to developing SUDs and major morbidity (Biederman et al., 1997; Mannuzza et al., 1993). As part of an ongoing prospective study of ADHD, it was found that differences in the risk for SUDs in adolescents with ADHD (mean age=15) compared to controls without ADHD were accounted for by comorbid conduct or bipolar disorders (Biederman et al., 1997). However, it also has been shown that the age of risk for SUD onset in adolescents without comorbid ADHD is approximately 17 years in girls and 19 years in boys (Biederman et al., in press-a; Milberger et al., 1997b). These findings were confirmed by Katusic and associates (2005) and Molina and Pelham (2003), who have shown elevated risk of SUDs in adolescents with ADHD.

ADHD treatment and SUD. Clarification of the critical influence of ADHD treatment in youth on later SUDs remains hampered by methodological issues. Since prospective studies in youth with ADHD are naturalistic, and hence not randomized for treatment, attempts to disentangle positive or deleterious effects of treatment from the severity of the underlying condition(s) are hampered by serious confounds. Whereas concerns of the abuse liability and potential kindling of specific types of abuse (e.g., cocaine) secondary to early stimulant exposure in children with ADHD have been raised (Drug Enforcement Administration, 1995; Vitiello, 2001), the preponderance of clinical data do not appear to support such a contention.

To reconcile findings in this important area, my group completed a meta-analysis of the literature (Faraone and Wilens, 2003; Wilens et al., 2003). We included studies examining the later risk of SUDs in children exposed to stimulant pharmacotherapy, identifying two studies into adolescence and five studies into adulthood. We found that stimulant pharmacotherapy did not increase the risk for later SUDs. In fact, we found that stimulant pharmacotherapy protected against later SUDs (odds ratio of 1.9) and that the effect was stronger in adolescents relative to adults (Wilens et al., 2003). It is notable that the magnitude of risk reduction (e.g., 50% reduction in risk) indicated that the ultimate risk of SUDs in treated individuals with ADHD may approximate the level of risk in individuals without ADHD (general population).

SUD Pathways Associated With ADHD

An increasing body of literature shows an intriguing association between ADHD and cigarette smoking. It has been previously reported that ADHD is a significant predictor for early initiation of cigarette smoking (before age 15) and that conduct and mood disorders comorbid with ADHD put youth at particularly high risk for early-onset smoking (Milberger et al., 1997a) data also suggest that one-half of smokers with ADHD go on to later SUDs (Biederman et al., in press-b). This is not surprising given that not only does smoking lead to peer group pressures and availability of illicit substances, but that nicotine exposure may make the brain more susceptible to later behavioral disorders and SUDs (Trauth et al., 2000). Furthermore, nicotinic-modulating agents are increasingly being evaluated for the treatment of ADHD (Wilens et al., in press-b). Of interest, prospective data funded by the National Institute on Drug Abuse suggest that stimulant treatment of ADHD reduces not only the time to onset but also the incidence of cigarette smoking (Monuteaux, 2004).

The precise mechanism(s) mediating the expression of SUDs in ADHD remains to be seen. The self-medication hypothesis is compelling in ADHD considering that the disorder is chronic and often associated with demoralization and failure, factors frequently associated with SUDs in adolescents. Moreover, it has been found that among substance-abusing adolescents with and without ADHD, adolescents with ADHD reported using substances more frequently to attenuate their mood and to help them sleep. No evidence of differences in types of substances has emerged between substance-abusing teen-agers with or without ADHD (Biederman et al., 1997). In addition, the potential importance of self-medication needs to be tempered against more systematic data showing the strongest association between ADHD and SUDs is comorbidity and familial contributions, such as exposure to parental SUDs during vulnerable developmental phases.

Diagnosis and Treatment Guidelines

Evaluation and treatment of comorbid ADHD and SUDs should be part of a plan in which consideration is given to all aspects of the teen-ager’s life. Any intervention in this group should follow a careful evaluation of the adolescent including psychiatric, addiction, social, cognitive, educational and family evaluations. A thorough history of substance use should be obtained that includes past and current usage and treatments. Although no specific guidelines exist for evaluating the patient with an active SUD, in my experience at least one month of abstinence is useful in accurately and reliably assessing for ADHD symptoms. Semi-structured psychiatric interviews or validated rating scales of ADHD are invaluable aids for the systematic diagnostic assessments of this group.

The treatment needs of individuals with SUDs and ADHD need to be considered simultaneously; however, the SUD needs to be addressed initially (Riggs, 1998). If the SUD is active, immediate attention needs to be paid to stabilization of the addiction(s). Depending on the severity and duration of the SUD, adolescents may require inpatient treatment. Self-help groups offer a helpful treatment modality for many with SUDs. In tandem with addiction treatment, adolescents with co-occurring SUDs and ADHD require intervention(s) for the ADHD as well as other co-occurring psychiatric disorders.

Medication serves an important role in reducing the symptoms of ADHD and other concurrent psychiatric disorders. Effective agents for adolescents with ADHD include the stimulants, noradrenergic agents and catecholaminergic antidepressants (Wilens et al., 2002). Findings from a meta-analysis of 10 studies of open and controlled trials suggest that medications used in adolescents and adults with ADHD plus SUDs have only a meager effect on the ADHD, but have little effect on substance use or cravings (Riggs et al., 2004; Schubiner et al., 2002; Wilens et al., 2005). Of interest, no evidence exists that treating ADHD pharmacologically through an active SUD exacerbates the SUD. This is consistent with the work of Grabowski et al. (2004), who used stimulants to block cocaine and amphetamine abuse. Also consistent with these findings, earlier work by Volkow et al. (1998) demonstrated significant differences between binding at the dopamine transporter between methylphenidate and cocaine, suggesting a much smaller abuse risk for methylphenidate in contrast to cocaine.

In ADHD adults with SUDs, the nonstimulant agents (atomoxetine [Strattera]), antidepressants (bupropion [Wellbutrin]), and extended-release or longer-acting stimulants with lower abuse liability and diversion potential are preferable (Riggs, 1998). While of particular interest because of the drug’s broad spectrum of activity in ADHD and lack of abuse liability (Heil et al., 2002), results from ongoing trials of atomoxetine in SUDs are not yet available. In individuals with SUDs and ADHD, frequent monitoring of pharmacotherapy should be undertaken–including evaluation of compliance with treatment, use of questionnaires (Gignac et al., 2005), random toxicology screens as indicated, and coordination of care with addiction counselors and other caregivers.

Issues of diversion. Surprisingly, limited information is available on the inappropriate use of stimulants in terms of the magnitude of the problem and the characteristics of misuse in individuals for whom they are prescribed. Musser et al. (1998) surveyed 161 children with ADHD responding to methylphenidate in order to assess diversion. The authors reported that 16% of children had been approached to sell or give away their prescribed medication; however, the actual rates of diversion were not reported. Marsh et al. (2000), using a retrospective review of the medical charts of 240 adolescents with ADHD, reported that 12% had misused their methylphenidate, although the characteristics of those youth were not reported. Poulin (2001) surveyed 13,549 students in grades 7 through 12 and found that 8.5% had used nonprescribed stimulants in the year prior to the survey. Of those students who were receiving prescribed stimulants, 14.7% had given their medications and 7.3% had sold their medication to other students. Similar to other studies, those to whom the stimulants were diverted misused the stimulants in context with other substances of abuse.

Similarly, we recently found that 11% of adolescents and young adults with ADHD diverted (sold) and 22% had misused their stimulants (e.g., escalated dose, used with other substances, became euphoric) (Wilens et al., in press-a). We also found that ADHD individuals with conduct disorder or SUDs accounted for the misuse and diversion and that there appeared to be more misuse and diversion of immediate-release compared to extended-release stimulants (Wilens et al., in press-a).

Summary

There is a strong literature supporting a relationship between ADHD and SUDs. Both family/genetic and self-medication influences may be operational in the development and continuation of SUDs in ADHD. Adolescents with ADHD and SUDs require multimodal interventions incorporating addiction and mental health treatment. Pharmacotherapy in individuals with ADHD and SUDs needs to take into consideration timing, misuse and diversion liability, potential drug interactions, and compliance concerns.

While the existing literature has provided important information on the relationship of ADHD and SUDs, it also points to a number of areas in need of further study. The mechanism by which untreated ADHD leads to SUDs, as well as the risk reduction of ADHD treatment on cigarette smoking and SUDs, needs to be better understood. Given the prevalence and major morbidity and impairment caused by SUDs and ADHD, prevention and treatment strategies for these adolescents need to be further developed and evaluated.

Acknowledgements

This research was supported by National Institutes of Health grants R01 DA14419 and K24 DA016264 to Dr. Wilens.

Dr. Wilens is director of Substance Abuse Services at Massachusetts General Hospital’s Pediatric Psychopharmacology Clinic and associate professor of psychiatry at Harvard Medical School.

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Source: Psychiatric Times January 2006 Vol. XXV Issue 1
Filed under: Effects of Drugs (Papers) :

By LINDA CARROLL

Thirty years ago, scientists linked prenatal alcohol exposure with a perplexing pattern of birth defects including neurological problems, low birth weight, mental retardation and a set of facial malformations.

Up to that time, many doctors had assumed that alcohol was so harmless that it was sometimes administered intravenously to women who were thought to be at risk of losing their pregnancies.

But in recent decades, scientists have discovered that alcohol can be remarkably toxic — more than any other abused drug — to developing fetuses. New research with imaging techniques is helping experts uncover which parts of the developing brain are damaged by alcohol exposure.

By pinpointing the damaged areas, they are beginning to understand the origins of the problem behaviors and learning disabilities linked to alcohol.

Scientists are also homing in on a protein important to the developing brain that is affected by alcohol. It is possible, they say, that a medication can be created to protect the brains of developing fetuses, even if pregnant women cannot quit drinking.

It is not surprising that it has taken researchers so long to tease out the link between alcohol exposure and birth defects. For one thing, the effects of alcohol exposure seem to vary widely.

Some fetuses seem to escape unscathed, even when their mothers drink heavily, while others are severely damaged. No one knows why.

”It’s not like thalidomide, where anyone who took it had an affected child,” said Dr. Sandra W. Jacobson, a professor at Wayne State School of Medicine in Detroit, referring to the morning-sickness drug linked to birth defects in the late 1950’s and early 1960’s. ”There’s a range with alcohol. You might get the full-blown syndrome in 4 out of 100 heavy drinkers.”

There are also many babies who are affected, but not severely enough for the syndrome to be diagnosed. Some with fetal alcohol effects may appear relatively normal but have behavioral problems and learning deficits like those with the syndrome.

Further complicating matters is the question of how much alcohol it takes to cause harm. In the past few years, successive studies have shown an effect at increasingly lower levels. One study, published last year, found a small but significant effect on average in children born to women who consumed just a drink and a half a week.

”We were surprised by this,” said the lead author, Dr. Nancy Day, a professor of psychiatry at the Western Psychiatric Institute and Clinic in Pittsburgh. The women in the study were recruited from a prenatal clinic between May 1983 and July 1985.

”The children were in the normal range of growth,” Dr. Day said, ”but if you compare them to children whose mothers didn’t drink at all, they weighed less, were shorter and had smaller head circumferences.”

The effect of low levels of alcohol appears to be subtle, said Dr. James R. West, head of the department of anatomy and neurobiology at the Texas A&M medical school.

”Perhaps instead of having an I.Q. of 120, you might end up with 115,” he said. ”You might seem perfectly normal, but not have the motor skills to make the high school football team.”

Another factor making it difficult to tease out the impact of alcohol is its widespread effects on the developing brain and body.

”Alcohol is a dirty drug,” Dr. West added. ”It affects a number of different neurotransmitters, and all cells can take it up.” Compare this with cocaine, Dr. West said, which is taken up by only one neurotransmitter.

It is also difficult to identify the effects of alcohol because a woman’s drinking habits seem to make a big difference. Experts say it matters when a pregnant woman drinks, how often she drinks and what her pattern of drinking is: whether she drinks small amounts daily or periodically binges.

Drinking in the first trimester can lead to facial malformations, while in the second it can interrupt nerve formation in the brain, Dr. West said. During the third, it can kill existing neurons and interfere with nervous system development, he added.

Researchers have also determined that babies are more likely to be affected if mothers drink in a binge pattern, like five drinks one day rather than a single drink daily, Dr. Jacobson of Wayne State said.

Because alcohol affects so many sites in the brain, researchers have come to believe that alcohol is far worse for the developing fetus than any other abused drug.

Dr. Jacobson’s study included cocaine users who also used varying quantities of alcohol. ”We found more serious cognitive impairment in relation to alcohol than cocaine or other drugs, including marijuana and smoking,” Dr. Jacobson said.

The damage done to fetuses often has been wrongly connected to cocaine, many experts say.

”The consensus, I think, at this point is that most of the adverse effects that had been reported due to cocaine and crack use were from alcohol use,” said Dr. Kenneth R. Warren, the director of the office of scientific affairs at the National Institute on Alcohol Abuse and Alcoholism. ”It is the leading cause of birth defects due to an ingested environmental substance in this country.”

In 1973, researchers coined the phrase fetal alcohol syndrome to describe babies born with a certain pattern of neurologic and physiologic defects related to alcohol exposure in utero.

Early on, it was clear that exposed children were wired differently from normal ones and that they exhibited an array of disabilities.

Dr. Ann P. Streissguth, the director of the fetal alcohol and drug unit at the University of Washington and a professor at the medical school there, ticked off a list: ”These included attention problems, hyperactivity, learning problems — particularly in arithmetic — language problems, memory problems, fine and gross motor problems, poor impulse control, poor judgment, intellectual deficits and difficulty integrating past experience to plan and organize future behavior.”

Researchers wondered whether specific areas of the brain were being consistently harmed by alcohol exposure in utero. Poor judgment, for example, might point to damage to the frontal lobes. The lobes, as the control center of the brain, are involved in planning, organizing and inhibiting inappropriate responses, the researchers say.

Thirty years ago, the only way researchers could learn about the effects of alcohol on the brain was to study children who died shortly after birth.

”We knew from brain autopsies that in severe cases the brains were terribly disorganized,” said Dr. Edward P. Riley, the director of the Center for Behavioral Teratology at San Diego State University. Now, researchers use imaging techniques like M.R.I.’s to look at the damage caused by alcohol. Several recent studies using magnetic resonance imaging have shown damage to the corpus callosum, a band of nerve fibers that connects the left and right sides of the brain.

A report published in 2002 compared the brain scans of adults and children who had severe or mild alcohol-related disabilities with the scans of healthy counterparts. The researchers found that the corpus callosa were abnormally shaped in 80 percent of those who had been exposed to alcohol in utero.

Another study found that the corpus callosum was smaller and shifted forward in children and young adults with the syndrome. Using a technique known as diffusion tensor imaging to look closer at the corpus callosum, researchers at Emory University have seen abnormalities in the myelin, the substance that insulates nerve cells.

When the myelin is damaged, signals do not carry as crisply through the cells, said Dr. Claire D. Coles, director of the Fetal Alcohol Center at the Marcus Institute and a professor of psychiatry and behavioral sciences at Emory.

Another study published in 2002 found that frontal lobe structures were smaller in teenagers and young adults who had been exposed to alcohol prenatally.

By pinpointing which sections of the brain are most likely to be damaged by alcohol, scientists may find a way to block its effects.

Researchers recently recognized that some of alcohol’s effects were similar to those experienced by children born with defects in genes that control L1 adhesion cells. Fetal cells that are destined to grow into the brain and nervous system bind to one another with the help of adhesion molecules like L1, said Dr. Michael E. Charness, an associate professor of neurology at Harvard.

In laboratory experiments, Dr. Charness and his colleagues showed that alcohol could interfere with L1’s stickiness, thus hampering crucial cell-to-cell attachments. In an article published in The Proceedings of the National Academy of Sciences in July, they showed that a protein, NAP, could block alcohol’s effect on L1. When NAP was given to mice exposed to alcohol, the protein appeared to stave off neurological effects.

”The idea of giving drugs to pregnant women is controversial,” Dr. Charness said. ”Drugs may have their own risks.”

But, he said, there are areas of the world where fetal alcohol syndrome is a huge problem. In parts of South Africa, the incidence of the syndrome in first graders is around 4.5 percent, he said. ”The rate of drinking is high,” Dr. Charness added. ”And the women won’t stop drinking despite interventions. It might be reasonable to give them a drug that can prevent the more serious effects of alcohol.”

Source: New York Times Nov. 2003

Filed under: Effects of Drugs (Papers) :

Previous studies have demonstrated that the brains of alcoholics are smaller, lighter and “shrunken” when compared to nonalcoholic brains.

Symposium speakers at the October 2004 Congress for the International Society for Biomedical Research on Alcoholism in Mannheim, Germany reviewed what is known about the causes, consequences and clinical implications of alcohol-related brain shrinkage. Proceedings are published in the June issue of Alcoholism: Clinical & Experimental Research.

“The outer layer of brain, also called the cerebral cortex or gray matter, controls most complex mental activities,” explained Clive Harper, symposium organizer and professor of neuropathology at the University of Sydney and Royal Prince Alfred Hospital. “The cortex is filled with nerve cells, also called neurons, that connect by single long fibres to different cortical regions and other neurons deep inside the brain and spinal cord. These nerve fibres make up white matter, which comprises the ‘hard wiring’ of the brain. Most of the fibres are insulated by a material called ‘myelin’ that is similar to the plastic coating around electrical wires. Nerve cells also have shorter and more numerous fibres or processes called dendrites with many fine branching processes – similar to the root system of a tree – that allow them to ‘talk’ with neighbouring neurons, often as many as five to 10,000 at a time.”

Alcohol appears to be particularly damaging to the “white matter” or “hard wiring” of the brain, and can also cause shrinkage or retraction of neuronal dendrites; however, the damage appears to be at least partially reversible with abstinence.

“The aim of this symposium was to bring together scientists from different disciplines to compare results from human and animal studies of the effects of alcohol on the brain,” said Harper. “Our objective was to better understand the mechanisms underlying alcohol’s damage, with the ultimate goal of identifying how to prevent and/or reverse these effects.”

Key presentation highlights were:

A number of toxic, metabolic, and nutritional factors interact in a complex way to cause brain damage in those individuals who abuse or are dependent on alcohol.

“The exact ways in which alcohol damages the brain are uncertain,” said Harper. “It might be that alcohol, or a metabolic byproduct of alcohol such as acetaldehyde, are toxic. Research on malnutrition, a common consequence of poor dietary habits in some alcoholics, indicates that thiamine deficiency can contribute to impaired cognition. Cirrhosis of the liver, also common in alcoholics, is known to cause clinical and structural changes in the brain. In addition, head injury and sleep apnoea are more common in alcoholics and can contribute to brain damage. All of these factors – particularly the alcohol, thiamine deficiency and cirrhosis – are linked and probably contribute in a complex way to cause brain damage.”

Both permanent and transient changes may occur in the alcoholic brain.

“The most important permanent structural change is nerve cell loss,” said Harper. “Some nerve cells cannot be replaced, those in the frontal cortex, cerebellum and several regions deep in the brain.”

However, he added, some changes can be transient, such as the shrinkage of dendrites, those fibers that allow neurons to “talk” with neighbouring neurons. “In experimental animals,” he said, “these have been shown to grow and spread again after periods of abstinence – weeks to months – and have been accompanied by improved brain function. Structural and functional changes seen in cirrhosis of the liver are also potentially reversible if treated. Furthermore, thiamine deficiency can be treated easily with oral or injected thiamine. Patients with acute deficiency respond very quickly but some permanent damage can occur if patients are not treated and particularly if they suffer repeated episodes of the deficiency.”

Combining in vivo brain imaging and animal research allows for an unprecedented examination of underlying mechanisms of damage. “Alcohol dependence follows a longitudinal course,” explained Harper, “from initiation to development of dependence, maintenance, withdrawal, and more often than not, a return to drinking. Throughout this course, the brain undergoes significant biochemical and structural modifications, some for the better and some for the worse, depending on when an individual is studied. Because human alcoholics cannot be forced to drink or not, researchers have no control over when in their course an alcoholic can be studied in the laboratory. By contrast, animal models of alcohol dependence can be exquisitely controlled, in terms of alcohol-exposure amounts, time in development of exposure, withdrawal, nutrition, and the like. When we combine the two approaches, we then have a means of translating knowledge about the change in the condition of the brain from the clinic to the laboratory and back to the clinic.”

Both gene and protein changes can occur in the brains of alcoholics.

“Even after death, tissues can reveal the secrets of diseases,” said Harper. “For this research, brain tissues were obtained, with ethical consent, from autopsies on alcoholic subjects. Scientists used modern molecular techniques to study the control mechanisms (genes) and building blocks (proteins) of the main component of white matter – the myelin. They found that the expression of genes that control the manufacture of structural proteins of the myelin was reduced in the alcoholic cases. In addition, the content of these proteins in the white matter was reduced. These changes likely alter the structure and function of the myelin sheath and ultimately the conduction of nerve impulses.”

It is important for people who abuse alcohol to realize that some of the damage can be reversed.

“Neuropsychological studies have shown that some brain functions improve with abstinence,” said Harper. “Although working memory, postural stability, and visuospatial ability may continue to show impairment for weeks to months with sobriety, with prolonged sobriety these brain functions can show improvement.”

Some alcoholics can achieve long-term abstinence in spite of persistent deficits in decision-making.

“There is accumulating evidence that the generalized inherited vulnerability to alcoholism and other addictions involves abnormalities of the brain systems that process rewards and punishments,” said George Fein, president of and senior scientist at Neurobehavioral Research, Inc., and one of the symposium co-presenters. “People with an inherited vulnerability to addiction, including alcoholism, are much more affected by immediate than delayed rewards. A hallmark of addictive substances is that they provide an immediate reward in the intoxicating experience. When actively drinking, an individual’s inhibition processes become impaired and can further contribute to poor decisions and excessive drinking. With prolonged bouts of drinking, dependence may ensue along with neural systems damage, commonly affecting frontal lobe based systems and their functions, which include decision making, inhibition, problem solving, and judgment. This is part of the dynamic course of alcoholism that likely contributes to its maintenance. In the symposium, [we presented] data showing that alcoholics can surmount these impairments in decision making and evaluation of rewards and punishments to achieve multi-year sobriety.”

Harper praised the symposium’s multi-disciplinary approach to examining alcohol-induced brain damage, calling it critical to solving the puzzle. “The pathologist and neuroradiologist can identify the region of the brain to study, and the molecular biologist can take samples from these regions and look at the genes controlling structure and function and even identify individual proteins that might play a role in cognitive deficits as well as recovery and repair of the brain. Together we can develop strategies for public education and new approaches to therapy in people who use and abuse alcohol. People who abuse alcohol,” he added, “should be informed that some of the brain damage could be reversed.”

Source: news.medical.net June 2005

Filed under: Effects of Drugs (Papers) :

Policy Position Paper #4 Alcohol and Drug Problems Association of North America

Alcohol and other drug dependence is a primary, chronic, progressive and potentially fatal disease. Its effects are systemic, predictable and unique. Without intervention and treatment, the disease runs an inexorable course marked by progressive crippling of mental, physical, and spiritual functioning with a devastating impact on all sectors of life- social, family, financial, vocational, educational, moral/spiritual, and legal.

Drug Addiction is a complex illness. It is characterized by compulsive, at times uncontrollable, drug craving, seeking, and use that persist even in the face of extremely negative consequences. For many people, drug addiction becomes chronic, with relapse possible even after long periods of abstinence.(1)

Alcohol and drug addiction is successfully treatable, and in the domain of public health, subject to prevention measures. Alcohol and drug dependence is not a mental illness or a behavioral health problem. It is a primary disease entity distinct from mental disorders. It should not be trivialized as a behavioral problem arising from personality disorders.

A substantial body of longitudinal studies on the psychological conditions of alcohol and drug dependent people have found that prior to developing alcohol and drug problems the subjects were no more likely to have mental disorders then the general population. (2)

Addictive use of alcohol and other drugs can cause temporary psychological and emotional problems. These problems are the result not the cause of the alcohol and other drug dependence. Mood swings, depression, and other psychological conditions are presented by alcohol and drug dependent people in the throes of their disease, and may become acute in the early withdrawal phase.

These conditions tend to be transitory in nature and are alleviated by a comprehensive abstinence-based regimen of recovery. The scientific literature fails to demonstrate the existence of an “alcoholic” or “addictive” personality in place prior to the onset of alcohol and other drug dependence. (3) A recently reported longitudinal study of 276 individuals entering substance abuse treatment found that, “Subjects recovering from an alcohol use disorder were 16.7 times more likely to recover from their mood/anxiety disorder than subjects who did not recover from their alcohol use disorder. Those recovering from an opioid use disorder were 4.3 times more likely to recover from a mood disorder than subjects who did not recover from an opioid use disorder.” (4) People with pre-existing mental conditions can become alcohol and drug dependent. In these cases, alcohol and other drugs can seriously exacerbate the mental disorders, and conversely, the mental problems can accelerate the progression of the alcohol and drug dependency and impede recovery. This “dually diagnosed” population, those with co-occurring mental disorders and alcohol/drug dependency, is receiving increased attention, and efforts are under way to establish systems offering appropriate treatment for both conditions. (5) Programs for the dually diagnosed require staff trained in both disciplines. Moreover, alcohol and drug dependency in this context is not treated as a symptom of a mental disorder or a secondary psychiatric diagnosis. (6)

The etiology of alcohol and other drug dependence is complex and not yet fully understood. Research increasingly points to biochemical abnormalities in the brain, and other physiological factors, strongly influenced by genetics. (7) Although many mental disorders may have similar origins, alcohol and drug dependency progresses on an independent course to its chronic stages characterized by increasingly destructive use of alcohol and other drugs, which in turn can cause new imbalances in brain chemistry. Unlike mental disorders and most other diseases, the progression stops and remission is achieved by the act of abstention-withdrawing from addicting intoxicating agents. It is the commitment to abstinence that is the unique measure of treatment for alcohol and drug dependence.

Alcohol and other drug dependency is cloaked in a stubborn and perverse stigma that in its worst form rejects even the concept that it is a disease. Rather, it is sometimes portrayed as “willful misconduct,” or the result of defective morals, flawed personalities or weak wills. (8) The stigma attached to illegal drug addiction adds the sinister dimensions of criminality and the entailing social opprobrium. Some aspects of the stigma have been perpetuated by theories and practices that attack the disease concept and maintain that alcoholics can be taught to moderate their drinking. Use of alcohol and other drugs by alcoholics and addicts is portrayed as a matter of personal choice, ignoring the powerful dynamics of addiction. The stigma has the effect of blaming the victims for their disease, and as such works as a barrier to treatment and an impediment to recovery. Additionally, the stigma induced shame interferes with the dependent person and their families ability to engage and succeed in treatment.

The view that alcohol and other drug dependence is a symptom of mental or behavioral disorders contributes to the stigma by promoting the perception that it is not a disease or public health problem in its own right.

Treatment regimens unique to addictions have been developed and refined over the past 50 years. Most models incorporate detoxification, treatment for medical consequences of use, comprehensive assessment, motivational counseling, education about the nature of the disease, family treatment, and group treatment, the core therapeutic vehicle for the recovering addict, Overcoming denial, surrender and readiness to change are treatment goals. Abstinence from alcohol and other addictive drugs is the sine quo non of post treatment success, with after-care focusing on relapse prevention and participation in 12-step and other self-help programs. Recovering alcoholics and addicts participate in the treatment process. As counselors, they are certified on the state and national levels through credentialing mechanisms developed over the past 25 years. The addictions field also pioneered the use of intervention techniques to speed entry into treatment.

The addiction model of treatment differs significantly from the traditional psychiatric model from the defining of the condition to the treatment goal itself. The table  below highlights these differences.

The failure of professionals to recognize the distinctive nature of alcohol and other drug dependence has been a continuing concern of the Alcohol and Drug Problems Association. It leads to the misdiagnosis of patients and treatment in a mental health setting that is not only inappropriate but also potentially harmful. Psychotherapeutic methods that fail to underscore abstinence can delay recovery and potentially result in death.

Professionals in the addictions field believe in the need for clinical separation of their clients from traditional mental health models through the establishment of categorical programs focusing on alcoholism and drug dependence. Before the launching of the Federal alcoholism and drug abuse programs in the early 1970’s, the success of these efforts was limited. Hobbled by sparse public funding and limited third-party reimbursement, a relatively small number of programs offered treatment and rehabilitation to alcoholics and drug dependent people. In the absence of alternatives, alcoholics and drug addicts were admitted to psychiatric wards in state and veterans hospitals for the mentally ill.

The inception of the Federal alcoholism and drug abuse effort, with enactment of legislation by former Sen. Harold Hughes (D-IA), transformed the field with the rich infusion of grant funds for research and for the treatment of alcoholism and drug dependence through categorical programs. The establishment of the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse inaugurated a period of rapid proliferation of publicly funded programs and, with expanding insurance coverage for chemical dependency treatment, a vigorous private sector. A new body of treatment professionals arose, trained in the specifics of alcoholism and other drug abuse and dependence. For the first time in history, treatment became accessible to millions of alcoholics and drug addicts.

The Alcohol and Drug Problems Association believes that at present there is a new urgency for the need to safeguard the separate identity of treatment for alcohol and other drug dependence. Short-sighted economics inflicted by managed care practices have decimated the private treatment sector; many residential programs have had to close their doors; while others have been consolidated with mental health units. And purchasers of chemical dependency treatment services for the public sector, including Medicaid, and state, county and local agencies, are increasingly moving to the managed health environment, (ADPA Position Paper # 1). As result of shifting political priorities, publicly supported treatment systems in many states are under funded and unable to fill the treatment vacuum left by retrenchments in the private sector.

Most ominously, behind the drive to cut back on treatment for alcohol and drug dependence, is the unfounded proposition that treatment is ineffective, and if any is provided, it should be in the least costly setting. Yet study after study concludes there are positive results from treatment. (9)

 

Issue Traditional Psychiatric Model Addiction Model
Definition of addiction Symptoms of underlying psychiatric disorder Primary disorder in its own right
Treatment approach Treatment underlying disorder Treatment addiction directly
Referral once addiction discovered To medical model program To primary non-medical model including self-help groups
Attitude toward alcohol use and other drugs Individualized, permissive Absolutely against use, confrontive, total abstinence
Party primarily responsible for treatment The professional The patient
Role of trust Important from early stages Usually not attainable for months or longer
Admission criteria Usually open Usually selective
Role of psychoactive medication Necessary for some underlying disorders; can be transitional substitute for alcohol Limited to detoxification and deterrence (eg., disulfiram); further use may reinforce substance abuse
Role of family in treatment Variable Usually routine
Role of self-help groups Variable, viewed as Superficial Usually encouraged or required
Third-party involvement (eg., legal, employer) Viewed as intrusive Often arranged to aid treatment
Surveillance for compliance Shunned, violates trust Monitoring of disulfiarm, Breathalyzer checks for drinking, urinalysis checks for other drugs, often arranged
Coercion (eg., legal) Last resort, interpreted as sign of failure Frequently seen as useful
Treatment goals ° Cure (acute disorder), maintenance (Chronic disorder) Rehabilitation, implying long- term work to maintain gains long-term work to maintain gains

 

Another development with threatening implications for the integrity of alcohol and drug dependency treatment has been a debasement of the diagnostic terminology. The term, “disease” has given way to the “disorder” of psychiatric coinage, and drug dependence is being placed under the crowded tent of “behavioral health.”

Behaviorists try to teach “responsible drinking,” with the unmistakable connotation that addictive drinking is “irresponsible.” “Harm reduction” is used as a guise for programs that give up on the need for abstinence. The shifting lexicon serves to blur the very substantial differences between alcohol and other drug dependence, and mental/behavioral problems.

ADPA’s paramount concern is the welfare of the suffering alcoholics and addicts in need of appropriate treatment by trained professionals and in chemical dependency programs geared specifically to address their primary diagnosis. Only these models, with proven track records, can offer hope of recovery and a life free from the consequences of alcoholism and drug dependence.

ADPA believes that public policy advocacy must be redoubled to preserve the integrity of treatment for alcohol and other drug dependence.

Of immediate concern is slippage at the state and local government levels where alcohol and drug dependency is at increasing risk of losing its bureaucratic visibility. When units with responsibility for alcohol and drug treatment programs are subsumed in low echelons under mental health, social services, or other departments, the focal point for advocacy is weakened or lost. The constituency of professionals and volunteers who serve as advocates for the alcohol and drug dependent are in danger of fragmentation.

Agencies charged specifically with programs for alcohol and drug dependency should have their discrete offices for training, communications, budgets, and other public policy functions. Alcohol and drug specialists need to be in a position to influence funding, programmatic, and personnel standards. Because of the pervasive nature of alcohol and other drug dependence, the agency, wherever it is located, must be able to impact policy across a wide range of health and human needs in the domain of departments staffed by personnel not trained to identify the problem. At the local level, where the bureaucratic structure tends to mirror that of the state, there is a critical need to retain control of clinical supervision, case decisions, and treatment protocols.

The Alcohol and Drug Problems Association believes that alcohol and drug dependence is a public health problem of major proportions costing society tens of billions of dollars in economic production, law enforcement, social services, health care and other areas. It exacts a terrible toll in terms of shattered lives of suffering alcoholics and addicts and their families. As such, when government at any level addresses alcohol and drug dependence, responsibility should be assigned to an agency of the highest visibility and independence where aggressive efforts can be mounted commensurate with the enormous dimensions of the problem. This was the inspired purpose of the Hughes Act programs 25-30 years ago, providing access to recovery for millions of alcoholics and addicts. A rededication to the spirit that moved those times may be needed to reestablish the powerful prevention and treatment impact from such organizational arrangements.

FOOTNOTE

1. National Institute on Drug Abuse “Principles of Drug Addiction Treatment, A Research Based C71lide,” NIH pub, No. 99-4181), October 1999.

2, Mark Schuckit. “Educating Yourself About Alcohol and Drugs! A People’s Primer” New York, 1995, “The conclusion from all these studies is basically the same. There is no evidence that people who later develop severe alcohol and drug problems are not more likely than others in the general population to have had severe depression, severe anxiety conditions, or psychotic conditions prior to the development of their alcohol and drug disorder.”

3. T George Verheal, Director of the Study of Adult Development, Harvard Medical School. and author of the 1983 milestone book, “The Natural History of Alcoholism,” is quoted in the March-April, 1999, issue of Harvard Magazine. “The addictive personality probably doesn’t exist…addictions tend to distort personalities. You can’t predict this. Alcoholics look like everyone else until they become alcoholics, much as cigarette smokers do,”

4. Rael Verheal, “Journal of Studies Alcohol,” January 2000, pp 101-1 10.

5. Paper from the “National Dialogue on Co-occurring Mental health and Substance Abuse Disorders,” June 16-17, 1998, Washington, DC, sponsored by the National Association of State Mental Health Program Directors and the National Association of State Alcohol and Drug Abuse Directors, and supported by the Center for Substance Abuse Treatment and the Mental Health Services Administration, Substance Abuse and Mental Health Services Administration. The Executive Summary states the following: “Estimates suggest that up to 10 million people in this country have a combination of at least one co-occurring mental health and substance-related disorder in any given year. There is no single locus of responsibility for people with co-occurring disorders. The mental health and substance abuse treatment systems operate independently of one another, as separate cultures, each with its own treatment philosophies, administrative structures and funding mechanisms. This lack of coordination means that neither consumers nor providers move easily among service settings.”

6. “The Counselor,” The National Association of Alcoholism and Drug Abuse Counselors, January- February 2000. Connecticut on Jan.1 adopted two levels of credentialing alcohol/drug counselors restated to treatment of co-occurring mental disorders a-ad alcohol and drug dependence.

7. “Beyond the Influence – Understanding and Defeating Alcoholism,” by Katherine Ketcham and William F. Asbury with Mel Schulstad and Arthur P. Ciararnicoli, Ed-Ph-D., Bantam Books 2000, summarizes this research and offers the following definition of alcoholism: “Alcoholism is a progressive neurological disease strongly influenced by genetic vulnerability. Inherited or acquired abnormalities in brain chemistry create an altered response to alcohol which in turn causes a wide array of physical, psychological, and behavioral problems. Although environmental and social factors will influence the progression and expression of the disease, they are not in any sense causes of addictive drinking. Alcoholism is caused by biochemical/neuropsychological abnormalities that are passed down from one generation to the next or, in some cases, acquired through heavy or prolonged drinking.”

8. In April 1998, the Supreme Court, in a case brought by two veterans seeking disability benefits for alcoholism from the Department of Veterans Affairs, ruled that alcoholism was the result of “willful misconduct.” The decision cited a “substantial body” of literature contesting the concept that alcoholism is a disease “much less a disease for which the victim bears no responsibility.” The DVA recognizes alcoholism as a disability only when there is a primary psychiatric diagnosis.

9. National Institute on Drug Abuse “Principles of Drug Addiction Treatment, A Research Based Guide,” NIH Pub. No. 99-4 1 80, October 1999.

Filed under: Effects of Drugs (Papers) :

This paper draws on the reservoir of data collected under the National Household Survey of Drug Abuse (NHSDA) over more than 25 years. The author makes a particular study of the use of cannabis and correlates this with self reported behaviours from young people (12- ‘years old general] From within her paper, extracts are given which relate to aggressive behaviour and to criminal behaviour. The romantic view of cannabis is that it mellows people out and is not associated with aggression; assertions are also made that cannabis users are not generally associated with criminal behaviour. These extracts give die lie to both these assertions.

Aggressive behaviour:

Past year cannabis users were more likely than non-users to report all types of aggressive behaviour. For many items, the percentage reporting the behaviour increased as frequency of use of cannabis increased. Weekly users were nearly four times as likely as “on-use’s to report they physically attacked people (26% v 7%) and three times as likely to report they destroy things that belong to others (22% v 7%). they threaten to hurt people (38% v 3%).and the get in many fights (37% v 14%). The weekly users are also twice as likely as non-users to report they disobey at school (59% v 24%) and they destroy their own things (22% v 10%). On average, past year cannabis users, regardless of frequency of use. were twice as likely as non-users to report they destroy things that belong to others, they disobey at school, they get in many fights, and they threaten to hurt people.

Criminal behaviour

In addition to the YSR (Youth Self-Report) Module, the NHSDA included questions about some past-year activities that may have been illegal. In each criminal behaviour compared in this study, adolescents aged 12 to 17 who used cannabis in the past year were three to more times more likely than non-users to report past-year involvement in these activities. Past-year cannabis users were more likely than non-users to reports that in the past year, they were on probation, they had taken something from the store without paying, purposely damaged property that was not theirs, driven under the influence of alcohol or drugs, hurt someone enough to need a bandage, and sold illegal drugs. As before, in most cases, the percentage reporting these behavioural problems increased with the frequency of cannabis use. In particular, weekly users of cannabis were more than five times as likely as those who used only 1-1 I times in the past year to have driven under the influence of drugs (29% v 4%) or to have so illegal drugs in the past year (29% v 6%). Weekly users were also two-to-three times more likely than those who use less often than monthly to be on probation (20% v 7%), to have driven under the influence of alcohol (20% v 9%), or to have purposely damaged property that was not theirs (35% v 18%).
As Greenblatt says in her conclusions, this analysis shows that amongst those aged 12 to 17, cannabis users were more likely than non-users to report problem behaviours. Further, the more frequent the use, the more likely the reporting of problem behaviours. A further worry is that cannabis-using young people were more likely to report behaviours symptomatic of anxiety and depression, including thoughts of suicide. These findings strengthen the argument that cannabis is not a benign substance.

Source: Office of Applied Studies, Substance Abuse and Mental Health Sciences
Administration, USA. Research Paper RP0979
Filed under: Effects of Drugs (Papers) :

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