Effects of Drugs (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

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.


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.


March 2017

‘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 


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.


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.


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).


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

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

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

Robert J. Tait, et al


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


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.


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

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:


* 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.


* 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


* 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


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


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


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

References  1. Accessed on 7/28/16:http://www.fda.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatients andProviders/ucm2008016.htm#rems  2. Accessed on 7/28/16: https://www.revaid.ca  3. Accessed on 7/31/16: http://www.fda.gov/ohrms/dockets/dockets/05n0479/05N-0479-emc0004-04.pdf

4. Accessed on 7/31/16: https://www.cesamet.com/pdf/Cesamet_PI_50_count.pdf

5. Accessed on 7/31/16: http://www.ukcia.org/research/SativexMonograph.pdf

6. Accessed on 7/28/16:https://clinicaltrials.gov/ct2/results?term=CBD+and+ epilepsy&Search=Search

7. National Center for Natural Products Research (NCNPR), Research Institute of Pharmaceutical Sciences. Quarterly Report, Potency Monitoring Project, Report 107, September 16, 2009 thru December 15, 2009. University, MS: NCNPR, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi (January 12, 2010).

8. Orens A, et al. Marijuana Equivalency in Portion and Dosage. An assessment of physical and pharmacokinetic relationships in marijuana production and consumption in Colorado. Prepared for the Colorado Department of Revenue. August 10, 2015.

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

20. College of Family Physicians of Canada. Authorizing Dried Cannabis for Chronic Pain or Anxiety: Preliminary Guidance from the College of Family Physicians of Canada. Mississauga, ON: College of Family Physicians of Canada; 2014.

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

24. Accessed on 2/8/2016. https://www.whitehouse.gov/ondcp/marijuana

25. Accessed on 8/1/2016: https://www.drugabuse.gov/news-events/nida-notes/2010/12/marijuana-linked-testicular-cancer

26. Lacson JCA, et al. Population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Cancer. 2012;118(21):5374-5383.

27. Daling JR, et al. Association of marijuana use and the incidence of testicular germ cell tumors. Cancer. 2009;115(6):1215-1223.

28. Gurney J, et al. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer 2015;15:1-10.  29. Accessed on 7/30/16:http://www.cancer.org/cancer/testicularcancer/ detailedguide/testicular-cancer-diagnosis

30. Takizawa A, et al. Clinical Significance of Low Level Human Chorionic Gonadotropin in the Management of Testicular Germ Cell Tumor. J Urology. 2008;179(3):930-935.

31. Moore TH, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319-328.

32. Large M, et al., Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry. 2011;68(6):555-61.

33. Ashton CH and Moore PB. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand, 2011;124: 250-261.

34. Ranganathan M and D’Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology. 2006;188: 425-444, 2006.

35. Accessed on 8/1/2016:https://www.drugabuse.gov/publications/drug facts/marijuana

36. Sheehan D, et al. Mini International Neuropsychiatric Interview, DSM-IV English Version 5.0.0 2006.

37.  Accessed on 8/1/2016: http://www.who.int/substance_abuse/activities/assist/ en/

38. Accessed on 8/1/16: http://news.gc.ca/web/article-en.do?nid=844329 39. Accessed on 8/3/16: http://www.healthlinkbc.ca/healthtopics/content.asp? hwid=abl2153

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.


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


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


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

 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

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?


PUBLISHED: 00:55, 31 July 2016 | UPDATED: 18:36, 31 July 2016

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

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/

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

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).



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.



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.

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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.


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

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.

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 legalization of marijuana in Colorado

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

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


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.


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

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/

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=

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 body

The body


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

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

Central Nervous System

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

Digestive System

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

Immune System

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.

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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.”


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>.

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

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

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

This article originally appeared on VICE Romania

Ana Iorga is a Romanian neuromarketing pioneer, who specialises in market research using EEG sensorsbiometric measures and implicit-association testsAttending 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

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

A case report of the synthetic amphetamine 2,5-dimethoxy-4-chloroamphetamine. Burish MJ1, Thoren KL2, Madou M1, Toossi S1, Shah M1.


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.

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.


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]

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

Albert Stuart Reece

Medical School, University of Queensland, Highgate Hill, Brisbane, QLD, Australia


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.


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.


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.


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


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


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


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.


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).


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).


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


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.


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