January 2019 • Volume 48, Number 1 • Alex Berenson
Alex Berenson Author, Tell Your Children: The Truth About Marijuana, Mental Illness, and Violence

The following is adapted from a speech delivered on January 15, 2019, at Hillsdale College’s Allan P. Kirby, Jr. Center for Constitutional Studies and Citizenship in Washington, D.C.

Seventy miles northwest of New York City is a hospital that looks like a prison, its drab brick buildings wrapped in layers of fencing and barbed wire. This grim facility is called the Mid-Hudson Forensic Psychiatric Institute. It’s one of three places the state of New York sends the criminally mentally ill—defendants judged not guilty by reason of insanity.
Until recently, my wife Jackie—Dr. Jacqueline Berenson—was a senior psychiatrist there. Many of Mid-Hudson’s 300 patients are killers and arsonists. At least one is a cannibal. Most have been diagnosed with psychotic disorders like schizophrenia that provoked them to violence against family members or strangers.
A couple of years ago, Jackie was telling me about a patient. In passing, she said something like, Of course he’d been smoking pot his whole life.
Of course? I said.
Yes, they all smoke.

So marijuana causes schizophrenia?
I was surprised, to say the least. I tended to be a libertarian on drugs. Years before, I’d covered the pharmaceutical industry for The New York Times. I was aware of the claims about marijuana as medicine, and I’d watched the slow spread of legalized cannabis without much interest.
Jackie would have been within her rights to say, I know what I’m talking about, unlike you. Instead she offered something neutral like, I think that’s what the big studies say. You should read them.
So I did. The big studies, the little ones, and all the rest. I read everything I could find. I talked to every psychiatrist and brain scientist who would talk to me. And I soon realized that in all my years as a journalist I had never seen a story where the gap between insider and outsider knowledge was so great, or the stakes so high.

I began to wonder why—with the stocks of cannabis companies soaring and politicians promoting legalization as a low-risk way to raise tax revenue and reduce crime—I had never heard the truth about marijuana, mental illness, and violence.
***
Over the last 30 years, psychiatrists and epidemiologists have turned speculation about marijuana’s dangers into science. Yet over the same period, a shrewd and expensive lobbying campaign has pushed public attitudes about marijuana the other way. And the effects are now becoming apparent.
Almost everything you think you know about the health effects of cannabis, almost everything advocates and the media have told you for a generation, is wrong.
They’ve told you marijuana has many different medical uses. In reality marijuana and THC, its active ingredient, have been shown to work only in a few narrow conditions. They are most commonly prescribed for pain relief. But they are rarely tested against other pain relief drugs like ibuprofen—and in July, a large four-year study of patients with chronic pain in Australia showed cannabis use was associated with greater pain over time.
They’ve told you cannabis can stem opioid use—“Two new studies show how marijuana can help fight the opioid epidemic,” according to Wonkblog, a Washington Post website, in April 2018— and that marijuana’s effects as a painkiller make it a potential substitute for opiates. In reality, like alcohol, marijuana is too weak as a painkiller to work for most people who truly need opiates, such as terminal cancer patients. Even cannabis advocates, like Rob Kampia, the co-founder of the Marijuana Policy Project, acknowledge that they have always viewed medical marijuana laws primarily as a way to protect recreational users.

As for the marijuana-reduces-opiate-use theory, it is based largely on a single paper comparing overdose deaths by state before 2010 to the spread of medical marijuana laws— and the paper’s finding is probably a result of simple geographic coincidence. The opiate epidemic began in Appalachia, while the first states to legalize medical marijuana were in the West. Since 2010, as both the epidemic and medical marijuana laws have spread nationally, the finding has vanished. And the United States, the Western country with the most cannabis use, also has by far the worst problem with opioids.
Research on individual users—a better way to trace cause and effect than looking at aggregate state-level data—consistently shows that marijuana use leads to other drug use. For example, a January 2018 paper in the American Journal of Psychiatry showed that people who used cannabis in 2001 were almost three times as likely to use opiates three years later, even after adjusting for other potential risks.
Most of all, advocates have told you that marijuana is not just safe for people with psychiatric problems like depression, but that it is a potential treatment for those patients. On its website, the cannabis delivery service Eaze offers the “Best Marijuana Strains and Products for Treating Anxiety.” “How Does Cannabis Help Depression?” is the topic of an article on Leafly, the largest cannabis website. But a mountain of peer-reviewed research in top medical journals shows that marijuana can cause or worsen severe mental illness, especially psychosis, the medical term for a break from reality. Teenagers who smoke marijuana regularly are about three times as likely to develop schizophrenia, the most devastating psychotic disorder.

After an exhaustive review, the National Academy of Medicine found in 2017 that “cannabis use is likely to increase the risk of developing schizophrenia and other psychoses; the higher the use, the greater the risk.” Also that “regular cannabis use is likely to increase the risk for developing social anxiety disorder.”
***
Over the past decade, as legalization has spread, patterns of marijuana use—and the drug itself—have changed in dangerous ways.
Legalization has not led to a huge increase in people using the drug casually. About 15 percent of Americans used cannabis at least once in 2017, up from ten percent in 2006, according to a large federal study called the National Survey on Drug Use and Health. (By contrast, about 65 percent of Americans had a drink in the last year.) But the number of Americans who use cannabis heavily is soaring. In 2006, about three million Americans reported using cannabis at least 300 times a year, the standard for daily use. By 2017, that number had nearly tripled, to eight million, approaching the twelve million Americans who drank alcohol every day. Put another way, one in 15 drinkers consumed alcohol daily; about one in five marijuana users used cannabis that often.
Cannabis users today are also consuming a drug that is far more potent than ever before, as measured by the amount of THC—delta-9-tetrahydrocannabinol, the chemical in cannabis responsible for its psychoactive effects—it contains. In the 1970s, the last time this many Americans used cannabis, most marijuana contained less than two percent THC. Today, marijuana routinely contains 20 to 25 percent THC, thanks to sophisticated farming and cloning techniques—as well as to a demand by users for cannabis that produces a stronger high more quickly. In states where cannabis is legal, many users prefer extracts that are nearly pure THC. Think of the difference between near-beer and a martini, or even grain alcohol, to understand the difference.

These new patterns of use have caused problems with the drug to soar. In 2014, people who had diagnosable cannabis use disorder, the medical term for marijuana abuse or addiction, made up about 1.5 percent of Americans. But they accounted for eleven percent of all the psychosis cases in emergency rooms—90,000 cases, 250 a day, triple the number in 2006. In states like Colorado, emergency room physicians have become experts on dealing with cannabis-induced psychosis.
Cannabis advocates often argue that the drug can’t be as neurotoxic as studies suggest, because otherwise Western countries would have seen population-wide increases in psychosis alongside rising use. In reality, accurately tracking psychosis cases is impossible in the United States. The government carefully tracks diseases like cancer with central registries, but no such registry exists for schizophrenia or other severe mental illnesses.

On the other hand, research from Finland and Denmark, two countries that track mental illness more comprehensively, shows a significant increase in psychosis since 2000, following an increase in cannabis use. And in September of last year, a large federal survey found a rise in serious mental illness in the United States as well, especially among young adults, the heaviest users of cannabis.
According to this latter study, 7.5 percent of adults age 18-25 met the criteria for serious mental illness in 2017, double the rate in 2008. What’s especially striking is that adolescents age 12-17 don’t show these increases in cannabis use and severe mental illness.

A caveat: this federal survey doesn’t count individual cases, and it lumps psychosis with other severe mental illness. So it isn’t as accurate as the Finnish or Danish studies. Nor do any of these studies prove that rising cannabis use has caused population-wide increases in psychosis or other mental illness. The most that can be said is that they offer intriguing evidence of a link.
Advocates for people with mental illness do not like discussing the link between schizophrenia and crime. They fear it will stigmatize people with the disease. “Most people with mental illness are not violent,” the National Alliance on Mental Illness (NAMI) explains on its website. But wishing away the link can’t make it disappear. In truth, psychosis is a shockingly high risk factor for violence. The best analysis came in a 2009 paper in PLOS Medicine by Dr.Seena Fazel, an Oxford University psychiatrist and epidemiologist. Drawing on earlier studies, the paper found that people with schizophrenia are five times as likely to commit violent crimes as healthy people, and almost 20 times as likely to commit homicide.

NAMI’s statement that most people with mental illness are not violent is of course accurate, given that “most” simply means “more than half”; but it is deeply misleading. Schizophrenia is rare. But people with the disorder commit an appreciable fraction of all murders, in the range of six to nine percent.
“The best way to deal with the stigma is to reduce the violence,” says Dr. Sheilagh Hodgins, a professor at the University of Montreal who has studied mental illness and violence for more than 30 years.

The marijuana-psychosis-violence connection is even stronger than those figures suggest. People with schizophrenia are only moderately more likely to become violent than healthy people when they are taking antipsychotic medicine and avoiding recreational drugs. But when they use drugs, their risk of violence skyrockets. “You don’t just have an increased risk of one thing—these things occur in clusters,” Dr. Fazel told me.

Along with alcohol, the drug that psychotic patients use more than any other is cannabis: a 2010 review of earlier studies in Schizophrenia Bulletin found that 27 percent of people with schizophrenia had been diagnosed with cannabis use disorder in their lives. And unfortunately—despite its reputation for making users relaxed and calm—cannabis appears to provoke many of them to violence.
A Swiss study of 265 psychotic patients published in Frontiers of Forensic Psychiatry last June found that over a three-year period, young men with psychosis who used cannabis had a 50 percent chance of becoming violent. That risk was four times higher than for those with psychosis who didn’t use, even after adjusting for factors such as alcohol use. Other researchers have produced similar findings. A 2013 paper in an Italian psychiatric journal examined almost 1,600 psychiatric patients in southern Italy and found that cannabis use was associated with a ten-fold increase in violence.

The most obvious way that cannabis fuels violence in psychotic people is through its tendency to cause paranoia—something even cannabis advocates acknowledge the drug can cause. The risk is so obvious that users joke about it and dispensaries advertise certain strains as less likely to induce paranoia. And for people with psychotic disorders, paranoia can fuel extreme violence. A 2007 paper in the Medical Journal of Australia on 88 defendants who had committed homicide during psychotic episodes found that most believed they were in danger from the victim, and almost two-thirds reported misusing cannabis—more than alcohol and amphetamines combined.

Yet the link between marijuana and violence doesn’t appear limited to people with pre-existing psychosis. Researchers have studied alcohol and violence for generations, proving that alcohol is a risk factor for domestic abuse, assault, and even murder. Far less work has been done on marijuana, in part because advocates have stigmatized anyone who raises the issue. But studies showing that marijuana use is a significant risk factor for violence have quietly piled up. Many of them weren’t even designed to catch the link, but they did. Dozens of such studies exist, covering everything from bullying by high school students to fighting among vacationers in Spain.

In most cases, studies find that the risk is at least as significant as with alcohol. A 2012 paper in the Journal of Interpersonal Violence examined a federal survey of more than 9,000 adolescents and found that marijuana use was associated with a doubling of domestic violence; a 2017 paper in Social Psychiatry and Psychiatric Epidemiology examined drivers of violence among 6,000 British and Chinese men and found that drug use—the drug nearly always being cannabis—translated into a five-fold increase in violence.

Today that risk is translating into real-world impacts. Before states legalized recreational cannabis, advocates said that legalization would let police focus on hardened criminals rather than marijuana smokers and thus reduce violent crime. Some advocates go so far as to claim that legalization has reduced violent crime. In a 2017 speech calling for federal legalization, U.S. Senator Cory Booker said that “states [that have legalized marijuana] are seeing decreases in violent crime.” He was wrong.

The first four states to legalize marijuana for recreational use were Colorado and Washington in 2014 and Alaska and Oregon in 2015. Combined, those four states had about 450 murders and 30,300 aggravated assaults in 2013. Last year, they had almost 620 murders and 38,000 aggravated assaults—an increase of 37 percent for murders and 25 percent for aggravated assaults, far greater than the national increase, even after accounting for differences in population growth.

Knowing exactly how much of the increase is related to cannabis is impossible without researching every crime. But police reports, news stories, and arrest warrants suggest a close link in many cases. For example, last September, police in Longmont, Colorado, arrested Daniel Lopez for stabbing his brother Thomas to death as a neighbour watched. Daniel Lopez had been diagnosed with schizophrenia and was “self-medicating” with marijuana, according to an arrest affidavit.

In every state, not just those where marijuana is legal, cases like Lopez’s are far more common than either cannabis or mental illness advocates acknowledge. Cannabis is also associated with a disturbing number of child deaths from abuse and neglect—many more than alcohol, and more than cocaine, methamphetamines, and opioids combined—according to reports from Texas, one of the few states to provide detailed information on drug use by perpetrators.

These crimes rarely receive more than local attention. Psychosis-induced violence takes particularly ugly forms and is frequently directed at helpless family members. The elite national media prefers to ignore the crimes as tabloid fodder. Even police departments, which see this violence up close, have been slow to recognize the trend, in part because the epidemic of opioid overdose deaths has overwhelmed them.
So the black tide of psychosis and the red tide of violence are rising steadily, almost unnoticed, on a slow green wave.
***
For centuries, people worldwide have understood that cannabis causes mental illness and violence—just as they’ve known that opiates cause addiction and overdose. Hard data on the relationship between marijuana and madness dates back 150 years, to British asylum registers in India. Yet 20 years ago, the United States moved to encourage wider use of cannabis and opiates.
In both cases, we decided we could outsmart these drugs—that we could have their benefits without their costs. And in both cases we were wrong. Opiates are riskier, and the overdose deaths they cause a more imminent crisis, so we have focused on those. But soon enough the mental illness and violence that follow cannabis use will also be too widespread to ignore.

Whether to use cannabis, or any drug, is a personal decision. Whether cannabis should be legal is a political issue. But its precise legal status is far less important than making sure that anyone who uses it is aware of its risks. Most cigarette smokers don’t die of lung cancer. But we have made it widely known that cigarettes cause cancer, full stop. Most people who drink and drive don’t have fatal accidents. But we have highlighted the cases of those who do.
We need equally unambiguous and well-funded advertising campaigns on the risks of cannabis. Instead, we are now in the worst of all worlds. Marijuana is legal in some states, illegal in others, dangerously potent, and sold without warnings everywhere.

But before we can do anything, we—especially cannabis advocates and those in the elite media who have for too long credulously accepted their claims—need to come to terms with the truth about the science on marijuana. That adjustment may be painful. But the alternative is far worse, as the patients at Mid-Hudson Forensic Psychiatric Institute—and their victims—know.

Source: Imprimis January 2019 • Volume 48, Number 1

There are several principal pathways to inheritable genotoxicity, mutagenicity and teratogenes is induced by cannabis which are known and well established at this time including the following.
These three papers discuss different aspects of these effects.

1) Stops Brain Waves and Thinking The brain has both stimulatory and inhibitory pathways.  GABA is the main brain inhibitory pathway. Brain centres talk to each other on gamma (about 40 cycles/sec) and theta frequencies (about 5 cycles/sec), where the theta waves are  used as the carrier waves for the gamma wave which then interacts like harmonics in music.
The degree to which the waves are in and out of phase carries information which can be monitored externally. GABA (γ-aminobutyric acid) inhibition is key to the generation of the synchronized firing which underpins these various brain oscillations. These GABA transmissions are controlled presynaptically by type 1 cannabinoid receptors (CB1R’s) and CB1R stimulation shuts them down. This is why cannabis users forget and fall asleep.

2) Blocks GABA Pathway and Brain Formation GABA is also a key neurotransmitter in  brain formation in that it guides and direct neural stem cell formation and transmission and development and growth of the cerebral cortex and other major brain areas. Gamma and theta  brain waves also direct neural stem cell formation, sculpting and connectivity.

Derangements then of GABA physiology imply that the brain will not form properly. Thin frontal cortical  plate measurements have been shown in humans prenatally exposed to cannabis by fMRI.
This implies that their brains can never be structurally normal which then explains the long lasting and persistent defects identified into adulthood.

3) Epigenetic Damage DNA not only carries the genetic hardware of our genetic code but it also carries the software of the code which works like traffic lights along the sequence of DNA bases to direct when to switch the genes on and off. This is known as the “epigenetic code”.

Fetal alcohol syndrome is believed to be due to damage to the software epigenetic code. The long lasting intellectual, mood regulation, attention and concentration defects which have been described after in utero cannabis exposure in the primary, middle and high schools and as college age young adults are likely due to these defects. Epigenetics “sets in stone” the errors of brain structure made in (2) above.

4) Arterial Damage. Cannabis has a well described effect to damage arteries through (CB1R’s) (American Heart Association 2007) which they carry in high concentration (Nature Reviews Cardiology 2018). In adults this causes heart attack (500% elevation in the first hour after smoking), stroke, severe cardiac arrhythmias including sudden cardiac death; but in developing babies CB1R’s acting on the developing heart tissues can lead to at least six major cardiac defects (Atrial- ventricular- and mixed atrio-ventricular and septal defects, Tetralogy of Fallot, Epstein’s deformity amongst others), whilst constriction of various babies’ arteries can lead to serious side effects such as gastroschisis (bowels hanging out) and possibly absent limbs (in at least one series).

5) Disruption of Mitotic Spindle. When cells divide the separating chromosomes actually slide along “train tracks” which are long chains made of tubulin. The tubulin chains are called “microtubules” and the whole football-shaped structure is called a “mitotic spindle”. Cannabis inhibits tubulin formation, disrupting microtubules and the mitotic spindle causing the separating chromosomes to become cut off in tiny micronuclei, where they eventually become smashed up and pulverized into “genetic junk”, which leads to foetal malformations, cancer and cell death. High rates of Down’s syndrome, chromosomal anomalies and cancers in cannabis exposed babies provide clinical evidence of this.

6) Defective Energy Generation & Downstream DNA Damage DNA is the crown jewel of the cell and its most complex molecule. Maintaining it in good repair is a very energy intensive process. Without energy DNA cannot be properly maintained. Cannabis has been known to reduce cellular energy production by the cell’s power plants, mitochondria, for many decades now. This has now been firmly linked with increased DNA damage, cancer formation and aging of the cells and indeed the whole organism. As it is known to occur in eggs and sperm, this will also damage the quality of the germ cells which go into forming the baby and lead directly to damaged babies and babies lost and wasted through spontaneous miscarriage and therapeutic termination for severe deformities.

7) Cancer induction Cannabis causes 12 cancers and has been identified as a carcinogen by the California Environmental Protection agency (2009). This makes it also a mutagen. 4 of these cancers are inheritable to children; i.e. inheritable carcinogenicity and mutagenicity. All four studies in testicular cancer are strongly positive (elevation by three fold). Carcinogen = mutagen = teratogen.

8) Colorado’s Teratology Profile. From the above described teratological profile we would expect exactly the profile of congenital defects which have been identified in Colorado (higher total defects and heart defects, and chromosomal defects) and Ottawa in Canada (long lasting and persistent brain damage seen on both functional testing and fMRI brain scans in children exposed in utero) where cannabis use has become common.

Gastroschisis was shown to be higher in all seven studies looking at this; and including in Canada, carefully controlled studies. Moreover in Australia, Canada, North Carolina, Colorado, Mexico and New Zealand, gastroschisis and sometimes other major congenital defects cluster where cannabis use is highest. Colorado 2000-2013 has experienced an extra 20,152 severely abnormal births above the rates prior to cannabis liberalization which if applied to the whole USA would equate to more than 83,000 abnormal babies live born annually (and probably about that number again therapeutically aborted); actually much more since both the number of users and concentration of cannabis have risen sharply since 2013, and cannabis has been well proven to be much more severely genotoxic at higher doses.

9) Cannabidiol is also Genotoxic and tests positive in many genotoxicity assays, just as tetrahydrocannabinol does.

10) Births defects registry data needs to be open and transparent and public. At present it is not. This looks too much like a cover up.

Source: Email from Dr Stuart Reece to Drug Watch International members May 2018

 

Source:

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

July 2012

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

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

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

Link to source and full articles:

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

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

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

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

Introduction
Synaptic cell-adhesion molecules and their interactions with other molecular pathways affect both synapse formation and its function (Varoqueaux et al., 2006; Sudhof, 2008; Bemben et al., 2015a). Neurexins are presynaptic cell-adhesion molecules that interact with neuroligins and other postsynaptic partners. Neurexins are encoded by three genes, each of which encodes a long and short isoform, termed α- and β-neurexins, respectively (Sudhof, 2008). Interestingly, despite studies linking neurexins to autism and other neuropsychiatric disorders (Leone et al., 2010; Rabaneda et al., 2014), the precise cellular mechanisms underlying the role of neurexins in cognition remain poorly understood.

Since most biochemical studies of neurexins have focused on β-neurexins, investigating the synaptic actions of β-neurexins is particularly imperative. In their timely Cell article, Anderson et al. reported that β-neurexins selectively modulate synaptic strength at excitatory synapses by regulating postsynaptic endocannabinoid synthesis, describing an unexpected trans-synaptic mechanism for β-neurexins to control neural circuits via endocannabinoid signaling. 

Source: https://www.frontiersin.org/articles/10.3389/fnins.2016.00203/full

See also:

https://drugprevent.org.uk/ppp/2018/08/%CE%B2-neurexins-control-neural-circuits-by-regulating-synaptic-endocannabinoid-signaling/

Abstract
α- and β-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that although β-neurexins are expressed at much lower levels than α-neurexins, conditional knockout of β-neurexins with continued expression of α-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The β-neurexin knockout phenotype was attenuated by CB1-receptor inhibition which blocks presynaptic endocannabinoid signaling or by 2-arachidonoylglycerol synthesis inhibition which impairs postsynaptic endocannabinoid release. In synapses formed by CA1-region pyramidal neurons onto burst-firing subiculum neurons, presynaptic in vivo knockout of β-neurexins aggravated endocannabinoid-mediated inhibition of synaptic transmission and blocked LTP; presynaptic CB1-receptor antagonists or postsynaptic 2-arachidonoylglycerol synthesis inhibition again reversed this block. Moreover, conditional knockout of β-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic β-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for β-neurexins in the endocannabinoid-dependent regulation of neural circuits.

Source:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709013/

See also:

https://drugprevent.org.uk/ppp/2018/08/endocannabinoid-mediates-excitatory-synaptic-function-of-%ce%b2-neurexins-commentary-%ce%b2-neurexins-control-neural-circuits-by-regulating-synaptic-endocannabinoid-signaling/

References

Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover In Brief

Fall 2014 • Volume 8 • Issue 3 An Introduction To Co-Occurring Borderline Personality Disorder And Substance Use Disorders

This In Brief is for health and human services professionals (e.g., social workers, vocational counselors, case managers, healthcare providers, probation officers). It is intended to introduce such professionals to borderline personality disorder (BPD)—a condition with very high rates of suicide and self-harm that often co-occurs with substance use disorders (SUDs).

This In Brief presents the signs and symptoms of BPD, with or without a co-occurring SUD, alerts professionals to the importance of monitoring clients with BPD for self-harm and suicidal behavior, and encourages professionals to refer such clients for appropriate treatment.

This In Brief is not meant to present detailed information about BPD or treatment guidelines for BPD or SUDs. How Common Is BPD?1 Estimates of BPD prevalence in the U.S. population range from 1.6 percent to 5.9 percent. BPD affects approximately 10 percent of all psychiatric outpatients and up to 20 percent of all inpatients.

What Is Borderline Personality Disorder?

BPD is one among several personality disorders (e.g., narcissistic personality disorder, paranoid personality disorder, antisocial personality disorder). According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),¹ personality disorders are generally characterized by:

■ Entrenched patterns of behavior that deviate significantly from the usual expectations of behavior of the individual’s culture.

■ Behavior patterns that are pervasive, inflexible, and resistant to change.

■ Emergence of the disorder’s features no later than early adulthood (unlike depression, for example, which can begin at any age).

■ Lack of awareness that behavior patterns and personality characteristics are problematic or that they differ from those of other individuals.

■ Distress and impairment in one or more areas of a person’s life (often only after other people get upset about his or her behavior).

■ Behavior patterns that are not better accounted for by the effects of substance abuse, medication, or some other mental disorder or medical condition (e.g., head injury).

BPD is a complex and serious mental illness. Individuals with BPD are often misunderstood and misdiagnosed. A history of childhood trauma (e.g., physical or sexual abuse, neglect, early parental loss) is more common for individuals with BPD.^1,2 In fact, many individuals with BPD may have developed BPD symptoms as a way to cope with childhood trauma. However, it is important to note that not all individuals with BPD have a history of childhood trauma. It is also important to note that some of the symptoms of BPD overlap with those of several other DSM-5 diagnoses, such as bipolar disorder and posttraumatic stress disorder (PTSD).

Therefore, a diagnosis of BPD should be made only by a licensed and experienced mental health professional (whose scope of practice includes diagnosing mental disorders) and then only after a thorough assessment over time. Individuals with BPD often require considerable attention from their therapists and are generally considered to be challenging clients to treat.^3,4,5 However, BPD may not be the chronic disorder it was once thought to be.

In Brief BPD often respond to appropriate treatment and may have a good long-term prognosis,^1,5 experiencing a remission of symptoms with a relatively low occurrence of relapse.^6,7 The DSM-5 indicates that BPD is diagnosed more often in women than in men (75 percent and 25 percent, respectively).¹ Other research, however, has suggested that there may be no gender difference in prevalence in the general population,^5,6 but that BPD is associated with a significantly higher level of mental and physical disability for women than it is for men.⁶ In addition, the types of co-occurring conditions tend to be different for women than for men. In women, the most common co-occurring disorders are major depression, anxiety disorders, eating disorders, and PTSD. Men with BPD are more likely to have co-occurring SUDs and antisocial personality disorder, and they are more likely to experience episodes of intense or explosive anger.^8,9

What Are the Symptoms of BPD?

The DSM-5 classifies mental disorders and includes specific diagnostic criteria for all currently recognized mental disorders. It is a tool for diagnosis and treatment, but it is also a tool for communication, providing a common language for clinicians and researchers to discuss symptoms and disorders. According to the DSM-5, the symptoms of BPD include:¹

■ Intense fear of abandonment and efforts to avoid abandonment (real or imagined).

■ Turbulent, erratic, and intense relationships that often involve vacillating perceptions of others (from extremely positive to extremely negative).

■ Lack of a sense of self or an unstable sense of self

■ Impulsive acts that can be hurtful to oneself (e.g., excessive spending, reckless driving, risky sex).

■ Repeated suicidal behavior or gestures or self-mutilating behavior. (See the section below on suicide and nonsuicidal self-injury.)

■ Chronic feelings of emptiness

■ Episodes of intense (and sometimes inappropriate) anger or difficulty controlling anger (e.g., repeated physical fights, inappropriate displays of anger)

■ Temporary feelings of paranoia (often stress-related) or severe dissociative symptoms (e.g., feeling detached from oneself, trancelike).

Anyone with some of these symptoms may need to be referred to a licensed mental health professional for a complete assessment. Exhibit 1 presents some examples of how a person with BPD might behave. Suicide and nonsuicidal self-injury BPD is unique in that it is the only mental disorder diagnosis that includes suicide attempts or self-harming behaviors among its diagnostic criteria^.3 The risk of suicide is high among individuals with BPD, with as many as 79 percent reporting a history of suicide attempts¹⁰ and 8 percent to 10 percent dying by suicide—a rate that may be 50 times greater than the rate among the general population.¹¹ More than 75 percent of individuals with BPD engage in deliberate self-harming behaviors known as nonsuicidal self-injury (NSSI) (e.g., cutting or burning themselves).¹² Unlike suicide attempts, NSSI does not usually involve a desire or intent to die. Sometimes the person with BPD does not consider these behaviors harmful.⁴ One study involving 290 patients with BPD found that 90 percent of patients reported a history of NSSI, and over 70 percent reported the use of multiple methods of NSSI.10 Reasons for NSSI vary from person to person and, for some individuals, there may be more than one reason. The behaviors may be: ^4,13,14

■ A way to express anger or pain

■ A way to relieve pain (i.e., shifting from psychic pain to physical pain)

■ A way to “feel” something.

■ A way to “feel real.”

■ An attempt to regulate emotions.

■ A form of self-punishment.

■ An effort to get attention or care from others. NSSI may include: 4,13,14

■ Cutting.

■ Burning.

■ Skin picking or excoriation.

■ Head banging.

■ Hitting.

■ Hair pulling

Exhibit 1. Examples of Symptomatic Behavior (BPD)

■ Patterns of intense and unstable relationships

John comes in to see his case manager, George, and announces that he plans to marry a woman he met at a speed-dating event the night before. George has heard this same story from John at least once a month for the past 4 months.

■ Emotions that seem to change quickly from one extreme to another

Suzie has been working with a vocational rehabilitation counselor, Tony, for 2 weeks to prepare for job retraining. One day, just after Tony gets everything set up for Suzie to begin her training, Suzie storms out of the office screaming at him, “You’re just trying to get rid of me! You don’t understand me at all! I hate you!” Later, when Tony calls to suggest that maybe Suzie would prefer to work with another counselor, Suzie begins to cry and says, “Please don’t drop me, Tony! I need you!”

■ Evidence of self-harm or self-mutilation

José is a probation officer. During his weekly appointment with his client, Annie, José notices a pattern of recent cuts across her left forearm. José asks her about them, and Annie becomes defensive and says, “Okay, I cut myself sometimes, so what? It’s none of your business. I’m not hurting anybody!”

■ Pattern of suicidal thoughts, gestures,* or attempts

Maria is a nurse. As she looks over the health history of her new patient, Sally, she notices that Sally has been hospitalized three times in the past 4 years after suicide attempts, and that she has seen six different therapists. Sally tells her, “Yeah, I get suicidal sometimes. I just can’t seem to find the right therapist who can help me.”

■ Intense displays of emotion that often seem inappropriate or out of proportion to the situation

Regina is a social worker at a domestic violence shelter. She notices one of her clients, Elena, sitting in the living room with a sketchpad in her lap. Regina asks if she can see what Elena is drawing. Elena turns the sketchpad around to reveal a beautiful, detailed drawing of the shelter house. Regina admires it and says how beautiful it is, then says, “That’s funny, I thought that the house number was on the right side of the door.” Elena, who had been smiling, takes the sketchpad from Regina, looks at the drawing, then rips it from the pad and begins tearing it up, saying, “You’re right, it’s all wrong! I’ll have to start all over again!”

*Regarding the word gestures: It is dangerous to dismiss or label any suicidal behavior as a gesture. Anyone who exhibits suicidal thoughts or behaviors of any kind needs to be assessed by a licensed mental health professional.

What Are the Symptoms of SUDs?

SUDs involve patterns of recurrent substance use that result in significant problems, which fall into the following categories:¹

■ Impaired control—taking more of the substance than intended, trying unsuccessfully to cut down on use, spending an increasing amount of time obtaining and using the substance, craving or having a strong desire for substance use

■ Social impairment—failing to fulfill obligations at work, school, or home; continuing substance use in spite of the problems it causes; giving up or reducing other activities because of substance use

■ Risky use—using the substance(s) in situations in which it may be physically dangerous to do so (e.g., driving) or in spite of physical or psychological problems that may have been caused or may be made worse by substance use (e.g., liver problems, depression)

■ Pharmacological criteria—displaying symptoms of tolerance (need for increased amounts of the substance to achieve the desired effect) or withdrawal (a constellation of physical symptoms that occurs when the use of the substance has ceased)

What Is the Relationship Between BPD and SUDs?

One study¹⁵ found that the prevalence of BPD among individuals seeking buprenorphine treatment for opioid addiction exceeded 40 percent, and another16 found that nearly 50 percent of individuals with BPD were likely to report a history of prescription drug abuse. A large survey⁶ found that 50.7 percent of individuals with a lifetime diagnosis (i.e., meeting the criteria for a diagnosis at some point during the individual’s life) of BPD also had a diagnosis of an SUD over the previous 12 months. This same survey found that for individuals with a lifetime diagnosis of an SUD, 9.5 percent also had a lifetime diagnosis of BPD. This is a significantly higher incidence of BPD than that in the general public, which ranges from 1.6 percent to 5.9 percent.¹

One longitudinal study^₁₇ found that 62 percent of patients with BPD met criteria for an SUD at the beginning of the study. However, over 90 percent of patients with BPD and a co-occurring SUD experienced a remission of the SUD by the time of the study’s 10-year follow-up. (Remission was defined as any 2-year period during which the person did not meet criteria for an SUD.) The authors also looked at whether there were recurrences of SUDs after periods of remission and found that the rate of recurrence was 40 percent for alcohol and 35 percent for drugs. The rate of new onsets of SUDs, while lower than expected, was still 21 percent for drugs and 23 percent for alcohol.

Another study¹⁸ found that individuals with BPD had higher rates of new SUD onsets even when their BPD symptoms improved (compared with new SUD onsets for individuals with other personality disorders). A client with BPD and a co-occurring SUD presents some particular challenges. BPD is difficult to treat, partly because of the pervasive, intractable nature of personality disorders and partly because clients with BPD often do not adhere to treatment and often drop out of treatment. The impulsivity, suicidality, and self-harm risks associated with BPD may all be exacerbated by the use of alcohol or drugs.¹⁹ In addition, the presence of BPD may contribute to the severity of SUD symptoms,²⁰ and the course of SUD treatment may be more complicated for clients who also have BPD.²¹

Who Can Best Provide Treatment for People With BPD and SUDs?

Individuals who display some of the symptoms of BPD (as described above) should be referred to an experienced licensed mental health professional for a thorough mental health assessment and possible referral to treatment. It is important to know whether referral sources have experience treating clients with BPD. If individuals display symptoms of substance misuse, they should also be assessed for a co-occurring SUD. Individuals with BPD sometimes trigger intense feelings of frustration and even anger in their therapists and other providers.¹²

Clients with BPD often have difficulty developing good relationships, including productive working relationships with therapists and other providers (e.g., healthcare workers, case managers, vocational counselors). Some individuals with BPD may move from therapist to therapist (or other professionals) in an effort to find “just the right person.” Individuals who have an SUD may receive treatment from an individual counselor or therapist or from an outpatient treatment program. However, a co-occurring diagnosis of BPD may complicate SUD treatment. It is important for the professionals treating the person for either diagnosis to work in consultation with each other.

Treatment for BPD—especially with a co-occurring SUD— sometimes involves a team approach. Depending on the treatment plan, a person may have an individual therapist, a group therapist, a substance abuse counselor, a psychiatrist, and a primary care provider; treatment may need to be planned and managed through the coordinated efforts of all providers. Regular consultation among all providers can ensure that everyone is working toward the same goals from each of their professional perspectives. For example:

■ In individual therapy sessions, a therapist may help the client learn to tolerate gradually increasing levels of uncomfortable emotions (e.g., stress, anxiety) so that the client may begin to have more control over those emotions.

■ A psychiatrist may consider the use of medication for the client or evaluate currently prescribed medications to determine adherence and their effect on the client’s ability to engage in the emotional work of therapy.

■ A substance abuse counselor may work with the client to achieve abstinence, identify relapse triggers that may come up as the client does emotional work in therapy, and identify coping strategies for remaining abstinent.

■ A vocational counselor may need to work with the client on distress tolerance as it relates to employment issues, such as applying for jobs or beginning a new job. This may mean helping the client understand the importance of being at interviews, vocational training classes, or work on time (even if emotional problems make that difficult) and helping the client develop strategies to achieve a pattern of good work habits. Some people with BPD may consciously or unconsciously attempt to sabotage treatment by providing conflicting information to providers or by trying to turn one provider against another. Consultation among all providers can help deter this.

What Treatments Are Available for Individuals With BPD and SUDs?

Many studies have been done on treatment approaches for BPD or SUDs, but very few have involved participants with co-occurring BPD and SUDs.^22,23,24 However, based on the studies that have been done on co-occurring BPD and SUDs, a few approaches seem to show promise.

Perhaps the most researched approach is Dialectical Behavior Therapy, which has been adapted for treatment of co-occurring BPD and SUDs (Dialectical Behavior Therapy-S [DBT-S]). It is important to note, however, that DBT-S and other promising approaches involve structured, manualized treatments that are quite intensive and require a significant amount of training and resources (e.g., staffing, space, finances) that may not be available in all areas.²⁵ Many therapists work on their own with individuals who have BPD, using the best techniques that their training and experience have to offer—hopefully in regular consultation with an experienced clinical supervisor. Therapists often adapt psychotherapy to better meet the needs of an individual client, sometimes combining different therapeutic approaches or mixing techniques.⁴

However, for clients with both BPD and SUDs, the therapist may need to work with an SUD treatment provider to provide comprehensive care. Pharmacotherapy for BPD and SUDs The Food and Drug Administration (FDA) has not approved any medications for the treatment of BPD. However, individuals with BPD may take medications to alleviate some of their symptoms.^11,22 For example, selective serotonin reuptake inhibitors may be prescribed for depressed mood, irritability, anger, and impulsivity.¹¹ There are several FDA-approved medications for SUD treatment. For alcohol use disorder, these include acamprosate, disulfiram, and naltrexone.²⁶

For opioid use disorder, approved medications include buprenorphine, a combination of buprenorphine and naloxone, methadone, and naltrexone.²⁷ Some of these medications may be prescribed on a short-term basis (e.g., to ease withdrawal symptoms, lessen cravings), and others may be prescribed for long-term use (e.g., to facilitate longer periods of abstinence).^26,27 Individuals may receive their prescriptions and medication management from a psychiatrist, from other types of healthcare providers, or from both (or, in the case of methadone, from an opioid treatment program). Individuals may take medication as one part of a treatment plan that also includes attending individual therapy, group therapy, group skill-building sessions, or a mutual-help group (e.g., 12-step program), or some combination of these.

What Are Some Things To Remember When Working With Someone Who Has Co-Occurring BPD and SUDs?

Some of the same guidelines that have been identified as necessary for mental health professionals who work with clients who have these two diagnoses may also be helpful for all human services professionals. Working with a client who has co-occurring BPD and SUDs requires:

■ Strong (but not rigid) professional boundaries—Be clear with the person about the expectations in the working relationship (e.g., length of appointments, level of support, contact outside regular appointments). Be aware of special requests to make exceptions to the usual rules for working with clients. These requests sometimes escalate over time. If in doubt about making an exception to the rules, discuss the situation with a supervisor who is knowledgeable about working with individuals who have BPD (within applicable confidentiality requirements).¹¹

■ A commitment to self-care—If possible, schedule appointments with someone who has BPD right before lunch or before a break. Avoid scheduling back-to-back appointments with two individuals who have BPD. It is important to have some time between them to see clients with other diagnoses, to work on other tasks, or simply to take a break. Develop the habit of leaving work at work (i.e., don’t “replay” interactions with individuals who have BPD).

■ An awareness of how BPD may affect any kind of work with the individual—For example, fearing abandonment and avoiding abandonment are characteristics of BPD and may manifest in some unexpected ways. For example, if the professional relationship has focused on the person with BPD completing certain goals, that person may thwart his or her own progress to avoid the feelings of abandonment that would result from ending the working relationship.

■ Knowledge about what skills the individual who has BPD is learning in therapy—The person may need assistance applying those new skills to broader life situations. For example, perhaps one skill the person has learned is how to break down a seemingly overwhelming task into a series of small steps. Work with the person to apply that particular skill to the situation at hand.

Conclusions

It is important to remember that:

■ Most human services professionals will encounter clients with BPD in the course of their work.

■ Individuals with BPD often have co-occurring diagnoses (e.g., depression, SUDs). ■ BPD is often characterized by intense emotional displays and impulsive acts (e.g., self-harm, suicide attempts).

■ Working with an individual with BPD (with or without a co-occurring SUD) can be challenging.

■ Individuals with BPD (with or without a co-occurring SUD) deserve to receive appropriate treatment and deserve to be treated with compassion and respect.

■ Individuals with BPD often respond to appropriate treatment and experience a remission of symptoms with a relatively low occurrence of relapse.

■ Individuals with BPD (with or without a co-occurring SUD) may have a team of professionals who provide different aspects of care (e.g., therapist, psychiatrist).

■ It is important for all professionals involved in the care of an individual with BPD to communicate and work together.

Resources

SAMHSA resources

National Registry of Evidence-based Programs and Practices http://nrepp.samhsa.gov

Treatment Improvement Protocols (TIPs) (see back page for electronic access and ordering information)

TIP 36: Substance Abuse Treatment for Persons With Child Abuse and Neglect Issues

TIP 42: Substance Abuse Treatment for Persons With Co-Occurring Disorders

TIP 44: Substance Abuse Treatment for Adults in the Criminal Justice System

TIP 50: Addressing Suicidal Thoughts and Behaviors in Substance Abuse Treatment Web resources

American Psychiatric Association http://www.psych.org

American Psychological Association http://www.apa.org

Borderline Personality Disorder Resource Center http://bpdresourcecenter.org

Behavioral Health Is Essential To Health • Prevention Works • Treatment Is Effective • People Recover 7 An Introduction to Co-Occurring Borderline Personality Disorder and Substance Use Disorders Fall 2014, Volume 8, Issue 3

National Education Alliance for Borderline Personality Disorder http://www.borderlinepersonalitydisorder.com

National Institute of Mental Health http://www.nimh.nih.gov

National Institute on Drug Abuse http://www.drugabuse.gov

Notes

¹ American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

² Battle, C. L., Shea, M. T., Johnson, D. M., Yen, S., Zlotnick, C., Zanarini, M. C., et al. (2004). Childhood maltreatment associated with adult personality disorders: Findings from the Collaborative Longitudinal Personality Disorders Study. Journal of Personality Disorders, 18(2), 193–211.

³ Dimeff, L. A., Comtois, K. A., & Linehan, M. M. (2009). Cooccurring addiction and borderline personality disorder. In R. K. Ries, D. A. Fiellin, S. C. Miller, & R. Saitz (Eds.), Principles of addiction medicine (4th ed., pp. 1227–1237). Philadelphia: Lippincott Williams & Wilkins.

⁴ National Institute of Mental Health. (2011). Borderline personality disorder. NIH Publication No. 11‑4928. Bethesda, MD: Author.

⁵ Substance Abuse and Mental Health Services Administration. (2011). Report to Congress on borderline personality disorder. HHS Publication No. (SMA) 11‑4644. Rockville, MD: Substance Abuse and Mental Health Services Administration.

⁶ Grant, B. F., Chou, S. P., Goldstein, R. B., Huang, B., Stinson, F. S., Saha, T. D., et al. (2008). Prevalence, correlates, disability, and comorbidity of DSM-IV borderline personality disorder: Results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. Journal of Clinical Psychiatry, 69, 533–545.

⁷ Zanarini, M. C., Frankenburg, F. R., Hennen, J., Reich, D. B., & Silk, K. R. (2005). The McLean Study of Adult Development (MSAD): Overview and implications of the first six years of prospective follow-up. Journal of Personality Disorders, 19(5), 505–523.

⁸ Sansone, R. A., & Sansone, L. A. (2011). Gender patterns in borderline personality disorder. Innovations in Clinical Neuroscience, 8(5), 16–20.

⁹ Tadíc, A., Wagner, S., Hoch, J., Başkaya, Ö., von Cube, R., Skaletz, C., et al. (2009). Gender differences in axis I and axis II comorbidity in patients with borderline personality disorder. Psychopathology, 42, 257–263.

¹⁰ Zanarini, M. C., Frankenburg, F. R., Reich, D. B., Fitzmaurice, G., Weinberg, I., & Gunderson, J. G. (2008). The 10-year course of physically self-destructive acts reported by borderline patients and axis II comparison subjects. Acta Psychiatrica Scandinavica, 117, 177–184.

¹¹ American Psychiatric Association. (2001). Practice guideline for the treatment of patients with borderline personality disorder. American Journal of Psychiatry, 158, 1–52.

¹² Black, D. W., & Andreasen, N. C. (2011). Introductory textbook of psychiatry (5th ed.). Washington, DC: American Psychiatric Publishing.

¹³ Brown, M. Z., Comtois, K. A., & Linehan, M. M. (2002). Reasons for suicide attempts and nonsuicidal self-injury in women with borderline personality disorder. Journal of Abnormal Psychology, 111(1), 198–202.

¹⁴ Kleindienst, N., Bohus, M., Ludäscher, P., Limberger, M. F., Kuenkele, K., Ebner-Priemer, U. W., et al. (2008). Motives for nonsuicidal self-injury among women with borderline personality disorder. Journal of Nervous and Mental Disease, 196(3), 230–236.

¹⁵ Sansone, R. A., Whitecar, P., & Wiederman, M. W. (2008). The prevalence of borderline personality among buprenorphine patients. International Journal of Psychiatry in Medicine, 38(2), 217–226.

¹⁶ Sansone, R. A., & Wiederman, M. W. (2009). The abuse of prescription medications: Borderline personality patients in psychiatric versus non-psychiatric settings. International Journal of Psychiatry in Medicine, 39(2), 147–154.

¹⁷ Zanarini, M. C., Frankenburg, F. R., Weingeroff, J. L., Reich, D. B., Fitzmaurice, G. M., & Weiss, R. D. (2011). The course of substance use disorders in patients with borderline personality disorder and axis II comparison subjects: A 10-year follow-up study. Addiction, 106(2), 342–348.

¹⁸ Walter, M., Gunderson, J. G., Zanarini, M. C., Sanislow, C. A., Grilo, C. M., McGlashan, T. H., et al. (2009). New onsets of substance use disorders in borderline personality disorder over 7 years of follow-ups: Findings from the Collaborative Longitudinal Personality Disorders Study. Addiction, 104, 97–103.

¹⁹ van den Bosch, L. M. C., Verheul, R., & van den Brink, W. (2001). Substance abuse in borderline personality disorder: Clinical and etiological correlates. Journal of Personality Disorders, 15, 416–424.

²⁰ Morgenstern, J., Langenbucher, J., Labouvie, E., & Miller, K. J. (1997). The comorbidity of alcoholism and personality disorders in a clinical population: Prevalence rates and relation to alcohol typology variables. Journal of Abnormal Psychology, 106(1), 74–84.

²¹ Center for Substance Abuse Treatment. (2005). Substance abuse treatment for persons with co-occurring disorders. Treatment Improvement Protocol (TIP) Series 42. HHS Publication No. (SMA) 13‑3992. Rockville, MD: Substance Abuse and Mental Health Services Administration.

²² Gianoli, M. O., Jane, J. S., O’Brien, E., & Ralevski, E. (2012). Treatment for comorbid borderline personality disorder and alcohol use disorders: A review of the evidence and future recommendations. Experimental and Clinical Psychopharmacology, 20(4), 333–344.In Brief In Brief, An Introduction to Co-Occurring Borderline Personality Disorder and Substance Use Disorders

²³ Kienast, T., & Foerster, J. (2008). Psychotherapy of personality disorders and concomitant substance dependence. Current Opinion in Psychiatry, 21, 619–624.

²⁴ Pennay, A., Cameron, J., Reichert, T., Strickland, H., Lee, N. K., Hall, K., et al. (2011). A systematic review of interventions for co-occurring substance use disorder and borderline personality disorder. Journal of Substance Abuse Treatment, 41(4), 363–373.

²⁵ Zanarini, M. C. (2009). Psychotherapy of borderline personality disorder. Acta Psychiatrica Scandinavica, 120, 373–377.

²⁶ Center for Substance Abuse Treatment. (2009). Incorporating alcohol pharmacotherapies into medical practice. Treatment Improvement Protocol (TIP) Series 49. HHS Publication No. (SMA) 13‑4380. Rockville, MD: Substance Abuse and Mental Health Services Administration.

²⁷ Center for Substance Abuse Treatment. (2005). Medication-assisted treatment for opioid addiction in opioid treatment programs.

Treatment Improvement Protocol (TIP) Series 43. HHS Publication No. (SMA) 12‑4214. Rockville, MD: Substance Abuse and Mental Health Services Administration.

In Brief

This In Brief was written and produced under contract numbers 270-09-0307 and 270-14-0445 by the Knowledge Application Program, a Joint Venture of JBS International, Inc., and The CDM Group, Inc., for the Substance Abuse and Mental Health Services Administration (SAMHSA), U.S. Department of Health and Human Services (HHS). Christina Currier served as the Contracting Officer’s Representative.

Disclaimer: The views, opinions, and content of this publication are those of the authors and do not necessarily reflect the views, opinions, or policies of SAMHSA or HHS.

Public Domain Notice: All materials appearing in this document except those taken from copyrighted sources are in the public domain and may be reproduced or copied without permission from SAMHSA or the authors. Citation of the source is appreciated. However, this publication may not be reproduced or distributed for a fee without the specific, written authorization of the Office of Communications, SAMHSA, HHS. Electronic Access and Copies of Publication: This publication may be ordered or downloaded from SAMHSA’s Publications Ordering Web page at http://store.samhsa.gov. Or, please call SAMHSA at 1-877-SAMHSA-7 (1-877-726-4727) (English and Español).

Recommended Citation: Substance Abuse and Mental Health Services Administration. (2014). An Introduction to Co-Occurring Borderline Personality Disorder and Substance Use Disorders. In Brief, Volume 8, Issue 3. Originating Office: Quality Improvement and Workforce Development Branch, Division of Services Improvement, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, 1 Choke Cherry Road, Rockville, MD 20857. HHS Publication No. (SMA) 14-4879 Printed 2014

Source:

https://store.samhsa.gov/product/An-Introduction-to-Co-Occurring-Borderline-Personality-Disorder-and-Substance-Use-Disorders/SMA14-4879

[As illustrated in the Obituary of pioneering FDA scientist, Frances Oldham Kelsey in The Washington Post 8/8/15.]

THIS POST OBITUARY WAS A GODSEND, COMING JUST AS MANY POLITICAL LEADERS ARE BEGINNING A HEADLONG RUSH TO USURP FDA’S AUTHORITY TO APPROVE MARIJUANA-BASED MEDICINES IN FAVOR Of MONEY-CORRUPTED POLITICAL APPROVAL. THE ENDANGERED CITIZENRY, THEIR HEALTH PROFESSIONALS,POLITICAL LEADERS AND OBJECTIVE NEWS MEDIA JOURNALISTS , MUST STRONGLY RESIST THIS MISGUIDED ACTION BY POLTICIANS WHO ARE BLINDLY IGNORING THE HORRIFIC THALIDOMIDE PRECEDENT.

Edited excerpts with commentary follow: The full article is available at the following link:

http://www.washingtonpost.com/national/health-science/frances-oldham-kelsey-heroine-of-thalidomide-tragedy-dies-at-101/2015/08/07/ae57335e-c5da-11df-94e1-c5afa35a9e59_story.html

Frances Oldham Kelsey, FDA scientist who kept thalidomide off U.S. market, dies at 101

In the annals of modern medicine, it was a horror story of international scope: thousands of babies dead in the womb and at least 10,000 others in 46 countries born with severe deformities… The cause, scientists discovered by late 1961, was thalidomide, a drug that, during four years of commercial sales… was marketed to pregnant women as a miracle cure for morning sickness and insomnia.

The tragedy was largely averted in the United States, with much credit due to Frances Oldham Kelsey, a medical officer at the Food and Drug Administration in Washington, who raised concerns about thalidomide before its effects were conclusively known. For a critical 19-month period, she fastidiously blocked its approval while drug company officials maligned her as a bureaucratic nitpicker…

The global thalidomide calamity precipitated legislation…in October 1962 that substantially strengthened the FDA’s authority over drug testing. The new regulations, still in force, required pharmaceutical companies to conduct phased clinical trials, obtain informed consent from participants in drug testing, and warn the FDA of adverse effects, and granted the FDA with important controls over prescription-drug advertising…

In Washington, (Kelsey) joined a corps of reform-minded scientists who, although not yet empowered by the 1962 law that required affirmative FDA approval of any new drug, demanded strong evidence of effectiveness before giving their imprimatur.

At the time, a drug could go on the market 60 days after the manufacturer filed an application with the FDA… Meanwhile, pharmaceutical drug companies commonly supplied doctors with new drugs and encouraged them to test the product on patients, an uncontrolled and dangerous practice that relied almost entirely on anecdotal evidence. NICAP note: Much like today’s treatment of “medical marijuana.”

Thalidomide, which was widely marketed as a sedative as well as a treatment for pregnancy-related nausea during the first trimester of pregnancy, had proven wildly popular in Europe and a boon for its German manufacturer. NICAP note: Much like pro-pot propaganda today has created “wildly popular” support among a fact-deprived public, and boom-times for the Big Marijuana industry.

By the fall of 1960, a Cincinnati-based drug company, William S. Merrell, had licensed the drug and began to distribute it under the trade name Kevadon to 1,200 U.S. doctors in advance of what executives anticipated would be its quick approval by the FDA. NICAP note: Today, illegal drug companies produce and market hundreds of uncontrolled marijuana products and distribute them to corrupt doctors willing to “recommend” such unapproved marijuana “medicines.”

The Merrell application landed on Dr. Kelsey’s desk within weeks of her arrival at the agency…Immediately the application alarmed her. Despite what she called the company’s “quite fulsome” claims, the absorption and toxicity studies were so incomplete as to be almost meaningless. NICAP note: Much like the “quite fulsome claims” for pot medicines are legion today, as is the dearth of valid

studies verifying those claims. For the true documented scientific case against smoking weed as “medicine” see “The DEA Position on Marijuana” at link:

www.justice.gov/dea/docs/marijuana_position_2011.pdf

Dr. Kelsey rejected the application numerous times and requested more data. Merrell representatives, who had large potential profits riding on the application, began to complain to her bosses and show up at her office, with respected clinical investigators in tow, to protest the hold-up. NICAP note: Much as the Pot Legalization Lobbyists and ACLU show up at any attempts to limit sales and use of marijuana—and for the same reason: “large potential profits.”

Another reason for her concern was that the company had apparently done no studies on pregnant animals. At the time, a prevailing view among doctors held that the placental barrier protected the fetus from (harms from) what Dr. Kelsey once called “the indiscretions of the mother,” such as abuse of alcohol, tobacco or illegal drugs. Earlier in her career, however, she had investigated the ways in which drugs did in fact pass through the placenta from mother to baby… NICAP note: Today there are numerous valid studies showing that both mental and physical defects in children can be caused by a pregnant mother’s use of marijuana and other illegal drugs.

While Dr. Kelsey stood her ground on Kevadon, infant deaths and deformities were occurring at an alarming rate in places where thalidomide had been sold… NICAP note: Today, drug addiction, drug-related permanent disabilities and overdose deaths are “occurring at an alarming rate,” nearly all of which began with a shared joint of marijuana from a schoolmate or friend.

Dr. Kelsey might have remained an anonymous bureaucrat if not for a (previous) front-page story in The Post. The newspaper had received a tip about her from staffers working for Sen. Estes Kefauver, a Tennessee Democrat who had been stalled in his years-long battle with the pharmaceutical industry to bolster the country’s drug laws.

The coverage of Dr. Kelsey gave her — and Kefauver — a lift. As thousands of grateful letters flowed in to Dr. Kelsey from the public, the proposed legislation became hard to ignore or to water down. The new law was widely known as the Kefauver-Harris Amendments.

“She had a huge effect on the regulations adopted in the 1960s to help create the modern clinical trial system,” said Daniel Carpenter, a professor of government at Harvard University and the author of “Reputation and Power,” a definitive history of the FDA. “She may have had a bigger effect after thalidomide than before.”…

For decades, Dr. Kelsey played a critical role at the agency in enforcing federal regulations for drug development — protocols that were credited with forcing more rigorous standards around the world…

In Chicago, she helped Geiling investigate the 107 deaths that occurred nationwide in 1937 from the newly marketed liquid form of sulfanilamide, a synthetic antibacterial drug used to treat streptococcal infections. In tablet form, it had been heralded as a wonder-drug of the age, but it tasted unpleasant.

Because the drug was not soluble in water or alcohol, the chief chemist of its manufacturer, S.E. Massengill Co. of Bristol, Tenn., dissolved the sulfanilamide with an industrial substance that was a chemical relative of antifreeze. He then added cherry flavoring and pink coloring to remedy the taste and appearance.

Massengill rushed the new elixir to market without adequately testing its safety. Many who took the medicine — including a high number of children — suffered an agonizing death.

At the time, the FDA’s chief mandate, stemming from an obsolete 1906 law, was food safety. At the agency’s request, Geiling joined the Elixir Sulfanilamide investigation and put Dr. Kelsey to work on animal testing of the drug. She recalled observing rats as they “shriveled up and died.”

Amid national outrage over Elixir Sulfanilamide, Congress passed the Federal Food, Drug and Cosmetic Act of 1938, legislation that vastly expanded federal regulatory oversight over drugs and set a new benchmark for drug safety before marketing… NICAP note: Today, pro-pot politicians are rushing headlong into a massive campaign to block that objective FDA approval process for drugs and instead substitute a money-driven political process that will create a new “Thalidomide” out of marijuana and destroy many more American lives and futures.

Babies who suffered from the effects of thalidomide and survived grew up with a range of impairments. Some required lifelong home care… NICAP note: Is this to be the legacy of current politicians whose corrupt abandonment of the nation’s premier drug approval system will create generations of children “who suffered from the effects of POLITICAL APPROVED “medical” marijuana and survived with a range of impairments, some requiring lifelong home care?”

—————————————————————————————————————

Source: National Institute of Citizen Anti-drug Policy (NICAP)

NICAP COMMENTARY BY: DeForest Rathbone, Chairman.NICAP 8/9/15, Rev. 8/26/15

There is current research into the probable genotoxicity of marijuana and this has been likened to the harm to the foetus in the womb from the drug Thalidomide in the 1960’s.

In the annals of modern medicine, it was a horror story of international scope: thousands of babies dead in the womb and at least 10,000 others in 46 countries born with severe deformities. Some of the children were missing limbs. Others had arms and legs that resembled a seal’s flippers. In many cases, eyes, ears and other organs and tissues failed to develop properly. The cause, scientists discovered by late 1961, was thalidomide, a drug that, during four years of commercial sales in countries from Germany to Australia, was marketed to pregnant women as a miracle cure for morning sickness and insomnia.

The tragedy was largely averted in the United States, with much credit due to Frances Oldham Kelsey, a medical officer at the Food and Drug Administration in Washington, who raised concerns about thalidomide before its effects were conclusively known. For a critical 19-month period, she fastidiously blocked its approval while drug company officials maligned her as a bureaucratic nitpicker. Dr. Kelsey, a physician and pharmacologist later lauded as a heroine of the federal workforce, died Aug. 7 at her daughter’s home in London, Ontario. She was 101. Her daughter, Christine Kelsey, confirmed her death but did not cite a specific cause.

Dr. Kelsey did not single-handedly uncover thalidomide’s hazards. Clinical investigators and health authorities around the world played an important role, as did several of her FDA peers. But because of her tenacity and clinical training, she became the central figure in the thalidomide episode.

In July 1962, The Washington Post directed national attention on the matter — and on Dr. Kelsey — with a front-page article reporting that her “scepticism and stubbornness … prevented what could have been an appalling American tragedy.” [From 1962: ‘Heroine’ of FDA keeps bad drug off the market].

 

The global thalidomide calamity precipitated legislation signed by President John F. Kennedy in October 1962 that substantially strengthened the FDA’s authority over drug testing. The new regulations, still in force, required pharmaceutical companies to conduct phased clinical trials, obtain informed consent from participants in drug testing, and warn the FDA of adverse effects, and granted the FDA with important controls over prescription-drug advertising.

As the new federal law was being hammered out, Kennedy rushed to include Dr. Kelsey in a previously scheduled White House award ceremony honouring influential civil servants, including an architect of NASA’s manned spaceflight program.“In a way, they tied her to the moonshot in showing what government scientists were capable of,” said Stephen Fried, a journalist who investigated the drug industry in the book “Bitter Pills.” “It was an act of incredible daring and bravery to say we need to wait longer before we expose the American people to this drug.”

Dr. Kelsey became, Fried said, “the most famous government regulator in American history.”

‘I was the newest person there and pretty green’

Dr. Kelsey had landed at the FDA in August 1960, one of seven full-time medical officers hired to review about 300 human drug applications per year.The number of women pursuing careers in science was minuscule, but Dr. Kelsey had long been comfortable in male-dominated environments. Growing up in Canada, she spent part of her childhood in an otherwise all-boys private school. She had two daughters while shouldering the demands of medical school in the late 1940s.

In Washington, she joined a corps of reform-minded scientists who, although not yet empowered by the 1962 law that required affirmative FDA approval of any new drug, demanded strong evidence of effectiveness before giving their imprimatur.At the time, a drug could go on the market 60 days after the manufacturer filed an application with the FDA. If the medical officer determined that the submission was incomplete, the drug company could provide additional information, and the clock would start anew.

Meanwhile, pharmaceutical drug companies commonly supplied doctors with new drugs and encouraged them to test the product on patients, an uncontrolled and dangerous practice that relied almost entirely on anecdotal evidence. Thalidomide, which was widely marketed as a sedative as well as a treatment for pregnancy-related nausea during the first trimester of pregnancy, had proven wildly popular in Europe and a boon for its German manufacturer, Chemie Grünenthal.

By the fall of 1960, a Cincinnati-based drug company, William S. Merrell, had licensed the drug and began to distribute it under the trade name Kevadon to 1,200 U.S. doctors in advance of what executives anticipated would be its quick approval by the FDA.The government later estimated that more than 2.5 million tablets were given to about 20,000 patients, several hundred of whom were pregnant.

The Merrell application landed on Dr. Kelsey’s desk within weeks of her arrival at the agency. “I was the newest person there and pretty green,” she later said in an FDA oral history, “so my supervisors decided, ‘Well, this is a very easy one. There will be no problems with sleeping pills.’ ” Immediately the application alarmed her. Despite what she called the company’s “quite fulsome” claims, the absorption and toxicity studies were so incomplete as to be almost meaningless.

Dr. Kelsey rejected the application numerous times and requested more data. Merrell representatives, who had large potential profits riding on the application, began to complain to her bosses and show up at her office, with respected clinical investigators in tow, to protest the hold-up. Dr. Kelsey’s FDA superiors backed her as she conducted her research. By February 1961, she had found more evidence to support her suspicions, including a letter in the British Medical Journal by an English doctor who reported that his patients on thalidomide experienced a painful “tingling” in the arms and feet.

 

Dr. Kelsey also discovered that, despite warnings of side effects printed on British and German drug labels, Merrell had not notified the FDA of any adverse reactions.  Another reason for her concern was that the company had apparently done no studies on pregnant animals. At the time, a prevailing view among doctors held that the placental barrier protected the foetus from what Dr. Kelsey once called “the indiscretions of the mother,” such as abuse of alcohol, tobacco or illegal drugs. Earlier in her career, however, she had investigated the ways in which drugs did in fact pass through the placenta from mother to baby.

While Dr. Kelsey stood her ground on Kevadon, infant deaths and deformities were occurring at an alarming rate in places where thalidomide had been sold. The development of seal-like flippers, a condition known as phocomelia that previously affected an estimated 1 in 4 million infants, began to crop up by the dozens in many countries.

Clinical investigators, because of a variety of complications including spotty tracking systems, only belatedly made the link to thalidomide.  Grünenthal began pulling the drug from the market in Germany in late 1961. Health authorities in other countries issued warnings. Merrell waited until March 1962 to withdraw its U.S. application. By then, at least 17 babies were born in the United States with thalidomide-related defects, according to the FDA

Influence beyond thalidomide

Dr. Kelsey might have remained an anonymous bureaucrat if not for the front-page story in The Post. The newspaper had received a tip about her from staffers working for Sen. Estes Kefauver, a Tennessee Democrat who had been stalled in his years-long battle with the pharmaceutical industry to bolster the country’s drug laws. The coverage of Dr. Kelsey gave her — and Kefauver — a lift. As thousands of grateful letters flowed in to Dr. Kelsey from the public, the proposed legislation became hard to ignore or to water down. The new law was widely known as the Kefauver-Harris Amendments.

“She had a huge effect on the regulations adopted in the 1960s to help create the modern clinical trial system,” said Daniel Carpenter, a professor of government at Harvard University and the author of “Reputation and Power,” a definitive history of the FDA. “She may have had a bigger effect after thalidomide than before.”

In 1963, Dr. Kelsey was named chief of the FDA’s investigational drug branch. Four years later, she was named director of the new Office of Scientific Investigations, a position she held until 1995.  She spent another decade, until her retirement at 90, working at the FDA’s Center for Drug Evaluation and Research. In that role, she advised the director of its compliance office on scientific and medical issues and analyzed historical drug review issues.

According to historians of the FDA, she was instrumental in establishing the institutional review boards — a cornerstone of modern clinical drug development — that were created after abusive drug testing trials were exposed in prisons, hospitals and nursing homes. For decades, Dr. Kelsey played a critical role at the agency in enforcing federal regulations for drug development — protocols that were credited with forcing more rigorous standards around the world.

Name mistaken for a man’s

Frances Kathleen Oldham was born near Cobble Hill, on Vancouver Island, British Columbia, on July 24, 1914. Her father was a retired British army officer, and her mother came from a prosperous Scottish family.  The young “Frankie,” as she was called, grew up exploring the woods and shorelines, sometimes bringing home frogs for dissection. At McGill University in Montreal, she studied pharmacology — the effects of drugs on people — and received a bachelor’s degree in 1934 and a master’s degree in 1935.

A McGill professor urged her to apply for a research assistant job at the University of Chicago, where pharmacology professor Eugene Geiling accepted her without an interview. Geiling, who had mistaken the names Frances for the masculine Francis, addressed her by mail as “Mr. Oldham.”

“When a woman took a job in those days, she was made to feel as if she was depriving a man of the ability to support his wife and child,” Dr. Kelsey told the New York Times in 2010. “But my professor said: ‘Don’t be stupid. Accept the job, sign your name and put “Miss” in brackets afterward.’ ”

In Chicago, she helped Geiling investigate the 107 deaths that occurred nationwide in 1937 from the newly marketed liquid form of sulfanilamide, a synthetic antibacterial drug used to treat streptococcal infections. In tablet form, it had been heralded as a wonder-drug of the age, but it tasted unpleasant.Because the drug was not soluble in water or alcohol, the chief chemist of its manufacturer, S.E. Massengill Co. of Bristol, Tenn., dissolved the sulfanilamide with an industrial substance that was a chemical relative of antifreeze. He then added cherry flavouring and pink colouring to remedy the taste and appearance.

Massengill rushed the new elixir to market without adequately testing its safety. Many who took the medicine — including a high number of children — suffered an agonizing death.  At the time, the FDA’s chief mandate, stemming from an obsolete 1906 law, was food safety. At the agency’s request, Geiling joined the Elixir Sulfanilamide investigation and put Dr. Kelsey to work on animal testing of the drug. She recalled observing rats as they “shrivelled up and died.”

Amid national outrage over Elixir Sulfanilamide, Congress passed the Federal Food, Drug and Cosmetic Act of 1938, legislation that vastly expanded federal regulatory oversight over drugs and set a new benchmark for drug safety before marketing. Massengill’s owner ultimately was fined a maximum penalty of $26,000 for mislabelling and misbranding; by technical definition, an elixir contains alcohol.

‘We need to take precautions’

Dr. Kelsey received a doctorate from Chicago in 1938, then joined the faculty. In 1943, she wed a pharmacology colleague, Fremont Ellis Kelsey.  After graduating from Chicago’s medical school in 1950, Frances Kelsey taught pharmacology at the University of South Dakota medical school and was a fill-in doctor at practices throughout the state. She also became a U.S. citizen before arriving in Washington in 1960 when her husband was hired by the National Institutes of Health. He died in 1966 after a heart attack.

Survivors include their daughters, Susan Duffield of Shelton, Wash., and Christine Kelsey of London, Ontario; a sister; and two grandchildren. Dr. Kelsey moved to Ontario from suburban Maryland in 2014.

Babies who suffered from the effects of thalidomide and survived grew up with a range of impairment. Some required lifelong home care. Others held jobs and were not severely hindered by their disabilities. Many legal settlements were reached between drug companies and the victims of thalidomide, and new claims continue to surface. Grünenthal formally apologized to victims of thalidomide in 2012.

The drug, however, never disappeared entirely. Researchers have investigated thalidomide’s effects on H.I.V. and Crohn’s disease and have conducted clinical trials for on its use for rheumatoid arthritis and macular degeneration, a leading cause of blindness.

In 1998, the FDA approved the drug for the treatment of lesions from leprosy. In 2006, thalidomide was cleared for use with the medicine dexamethasone for certain cases of multiple myeloma, a cancer of the bone marrow.

The agency enforced strict safeguards, including pregnancy testing, for such new uses. “We need to take precautions,” Dr. Kelsey told an interviewer in in 2001, “because people forget very soon.”

Source:https://www.washingtonpost.com/national/health-science/frances-            oldham-kelsey-heroine-of-thalidomide-tragedy-dies-at-101/2015/08/07

Mathias B. Forrester and Ruth D. Merz

Hawaii Birth Defects Program, Honolulu, Hawaii, USA

Extracts from Study 

The literature on the association between prenatal illicit drug use and birth defects is inconsistent. The objective of this study was to determine the risk of a variety of birth defects with prenatal illicit drug use.

Data were derived from an active, population based adverse pregnancy outcome registry. Cases were all infants and foetuses with any of 54 selected birth defects delivered during 1986–2002.

The prenatal methamphetamine, cocaine, or marijuana use rates were calculated for each birth defect and compared to the prenatal use rates among all deliveries.

Among all deliveries, the prenatal use rate was 0.52% for methamphetamine,0.18% for cocaine, and 0.26% for marijuana.

Methamphetamine rates were significantly higher than expected for 14 (26%) of the birth defects.

Cocaine rates were significantly higher than expected for 13 (24%) of the birth defects.

Marijuana rates were significantly higher than expected for 21 (39%) of the birth defects. Increased risk for the three drugs occurred predominantly among birth defects associated with the central nervous system, cardiovascular system, oral clefts, and limbs. There was also increased risk of marijuana use among a variety of birth defects associated with the gastrointestinal system. Prenatal uses of methamphetamine, cocaine, and marijuana are all associated with increased risk of a variety of birth defects.

The affected birth defects are primarily associated with particular organ systems.

DISCUSSION

Using data from a Statewide, population-based registry that covered over 300,000 births and a 17-yr period, this investigation examined the association between over 50 selected birth defects and maternal use of methamphetamine, cocaine, or marijuana during pregnancy. Much of the literature on prenatal illicit drug use and birth defects involved case reports, involved a small number of cases, were not population-based, or focused on only one or a few particular birth defects.

There are various limitations to this investigation. The number of cases for many of the birth defects categories was relatively small, limiting the ability to identify statistically significant differences and resulting in large confidence intervals.

In spite of this, a number of statistically significant analyses were identified. Some statistically significant results might be expected to occur by chance. If 1 in every 20 analyses is expected to result in statistically significant differences solely by chance, then among the 162 analyses performed in this study, 8 would be expected to be statistically significant by chance. However, 48 statistically significant differences were identified. Thus, not all of the statistically significant results are likely to be due to chance.

This study included all pregnancies where methamphetamine, cocaine, or marijuana use was identified through either report in the medical record or positive toxicology test. This was done because neither self-report nor toxicology testing is likely to identify all instances of prenatal illicit drug use (Christmas et al., 1992).

In spite of using both methods for determining prenatal illicit drug use, all pregnancies involving methamphetamine, cocaine, or marijuana were not likely to have been identified. The degree of under ascertainment is unknown. A previous study examined the maternal drug use rate around the time of delivery in Hawaii during 1999 (Derauf et al., 2003). This study found 1.4% of the pregnancies involved methamphetamine use and 0.2% involved marijuana use. Among 1999 deliveries, the HBDP identified a prenatal methamphetamine use rate of 0.7% and a marijuana use rate of 0.4%. However, comparisons between the 2 studies should be made with caution because the previous study collected data from a single hospital during only a 2-mo period.

Another limitation is that the present study did not control for potential confounding factors such as maternal demographic characteristics, health behaviors, and prenatal care. Increased risk of birth defects has been associated with inadequate prenatal care (Carmichael et al., 2002), maternal smoking (Honein et al., 2001), and maternal alcohol use (Martinez-Frias et al., 2004).

These factors are also found with maternal illicit drug use (Cosden et al., 1997; Hutchins, 1997; Norton-Hawk, 1997). Thus the increased risk of selected birth defects with illicit drug use in this study might actually be due to one of these other underlying factors. Unfortunately, informationon some of the potential confounding factors such as socioeconomic status are not collected by the HBDP. Information collected on some other factors such as smoking and alcohol use is suspect because of negative attitudes toward their use during pregnancy. Moreover, the small number of cases among many of the birth defects groups would make controlling for these factors difficult.

Finally, this investigation included use of the illicit drugs at any time during the pregnancy. Most birth defects are believed to occur at 3–8 wk after conception (Makri et al., 2004; Sadler, 2000). In a portion of the cases, the drug use might have occurred at a time when it could not have caused the birth defect. Furthermore, this study does not include information on dose; however, teratogenicity of a substance may depend on its dose (Werler et al., 1990). In spite of the various potential concerns of the present study, data may suggest future areas of investigation where the limitations inherent in the present one are excluded.

This investigation found significantly higher than expected rates for prenatal use of methamphetamine, cocaine, and marijuana among a number of specific birth defects. Although not identical, there were general similarities between the three illicit drugs and the birth defects with which they were associated. Increased rates for methamphetamine, cocaine, and marijuana occurred predominantly among birth defects affecting the central nervous system, cardiovascular system, oral clefts, and limbs. There were also increased rates of marijuana use with a variety of birth defects associated with the gastrointestinal  system. With the exception of marijuana and encephalocele, none of illicit drugs were associated with neural-tube defects (anencephaly, spina bifida, encephalocele). The rates of use for the three illicit drugs were not significantly elevated with eye defects other than anophthalmia/microphthalmia, genitourinary defects, and musculoskeletal defects aside from limb defects.

In the majority of instances, the associations between particular illicit drugs and birth defects were found whether or not those cases involving use of multiple types of drugs were included.

Of the 14 significant associations between methamphetamine and specific birth defects, 10 (71.4%) remained once multiple drug cases were excluded. Corresponding rates were 61.5% (8 of 13) for cocaine and 81.0% (17 of 21) for marijuana.

The similarities in the patterns of birth defects with which methamphetamine, cocaine, and marijuana are associated might suggest that the three drugs exert similar effects on embryonic and foetal development. This might not be expected, considering that the three illicit drugs differ in their mechanisms of action and clinical effects (Leiken & Paloucek, 1998).

Some of the associations between methamphetamine, cocaine, and marijuana observed in the present investigation were previously reported. Other studies observed similar associations, or lack thereof, of methamphetamine or amphetamine with neural-tube defects (Shaw et al., 1996) and cardiovascular and musculoskeletal defects (McElhatton et al., 2000); cocaine with neural-tube defects (Shaw et al., 1996), cardiovascular defects (Lipshultz et al., 1991), ventricular septal defect and atrial septal defect (Ferencz et al., 1997c; Martin & Edmonds, 1991), tricuspid atresia (Ferencz et al., 1997d), craniosynostosis (Gardner et al., 1998), and situs inversus (Kuehl & Loffredo, 2002); and marijuana with neural-tube defects (Shaw et al., 1996), single ventricle (Steinberger et al., 2002), ventricular septal defect (Williams et al., 2004), tricuspid atresia (Ferencz et al., 1997d), and gastroschisis (Torfs et al., 1994).

In contrast, this study differed from other research with respect to their findings regarding methamphetamine or amphetamine and gastroschisis (Torfs et al., 1994); cocaine and microcephaly (Martin & Edmonds, 1991), conotruncal defects (Adams et al., 1989), endocardial cushion defect (Ferencz et al., 1997b), situs inversus (Ferencz et al., 1997a), oral clefts (Beatyet al., 2001), and genitourinary defects (Abe et al., 2003; Battin et al., 1995; Martin & Edmonds, 1991); and marijuana and conotruncal defects (Adams et al., 1989), Ebstein anomaly (Ferencz et al., 1997e; Correa-Villasenor et al., 1994), and oral clefts (Beaty et al., 2001).

The inconsistent findings between this and the other studies could be due to differences in study methodology, case classification, or number of cases. The mechanisms by which methamphetamine, cocaine, and marijuana might contribute to the rates for birth defects is currently unknown. Any potential explanation would have to take into account the observation that each of the illicit drugs was associated with a variety of specific birth defects affecting different organ systems. This might suggest that these three drugs would need to influence a basic, common factor involved in embryonic development.

Folic acid is involved in nucleic acid synthesis and cellular division (Scholl & Johnson, 2000) and thus would play an important role in the early growth and cellular proliferation of the embryo. Folic acid has been found to prevent a variety of birth defects (Forrester & Merz, 2005). Thus, anything that interferes with the activity of folic acid might be expected to increase the risk for these birth defects. Many of these birth defects were associated with methamphetamine, cocaine, and/or marijuana in the present study.

However, two of the birth defects most closely affected by folic acid—anencephaly and spina bifida—were not associated with any of the three illicit drugs. Vascular disruption has been suggested as a potential cause for a variety of different birth defects such as intestinal atresia/stenosis, limb reduction defects, and gastroschisis.

Since cocaine is a vasoconstrictor, it has been hypothesized that cocaine use could increase the risk of these vascular disruption defects (Hume et al., 1997; Martin et al., 1992; Hoyme et al., 1983; de Vries, 1980). Although this investigation found an association between cocaine and limb reduction deformities, no association was found with intestinal atresia/stenosis or gastroschisis.

In conclusion, this study found that prenatal use of methamphetamine, cocaine, or marijuana were associated with increased risk of a variety of birth defects. The affected birth defects were primarily associated with particular organ systems. Because of various limitations of the study, further research is recommended.

Source:  Journal of Toxicology and Environmental Health, Part A, 70: 7–18, 2007

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

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

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

CASE VIGNETTE

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

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

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

Epidemiology of CIP

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

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

Neurobiology of CIP

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

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

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

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

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

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

Assessment of CIP

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

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

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

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

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

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

Treatment of CIP

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

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

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

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

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

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

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

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

Conclusions

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

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

It is vital that physicians—particularly psychiatrists who are on the frontlines with patients who struggle with cannabis use—are able to identify and characterize cannabis use disorders; provide education; and offer effective, evidence-based treatments. This article provides a brief overview of each of these topics by walking through clinical decision-making with a case vignette that touches on common experiences in treating a patient with cannabis use disorder.

A separate and important issue is screening for emerging drugs of abuse, including synthetic “marijuana” products such as K2 and spice. Although these products are chemically distinct from the psychoactive compounds in the traditional cannabis plant, some cannabis users have tried synthetic “marijuana” products because of their gross physical similarity to cannabis plant matter.

CASE VIGNETTE

Mr. M is a 43-year-old legal clerk who has been working in the same office for 20 years. He presents as a referral from his primary care physician to your outpatient psychiatry office for an initial evaluation regarding “managing some mid-life issues.” He states that while he likes his job, it is the only job he has had since graduating college and he finds the work boring, noting that most of his co-workers have gone on to law school or more senior positions in the firm. When asked what factors have prevented him from seeking different career opportunities, he states that he would “fail a drug test.” Upon further inquiry, Mr. M says he has been smoking 2 or 3 “joints” or taking a few hits off of his “vaping pen” of cannabis daily for many years, for which he spends approximately $70 to $100 a week.

He first used cannabis in college and initially only smoked “a couple hits” in social settings. Over time, he has needed more cannabis to “take the edge off” and has strong cravings to use daily. He reports liking how cannabis decreases his anxiety and helps him fall asleep, although he thinks the cannabis sometimes makes him “paranoid,” which results in his avoidance of family and friends.

More recently, he identifies conflict and regular arguments with his wife over his cannabis use—she feels it prevents him from being present with his family and is a financial burden. He admits missing an important awards ceremony for her work and sporting events for his children, for which he had to “come up with excuses,” but the truth is that he ended up smoking more than he had intended and lost track of the time.

Mr. M reports multiple previous unsuccessful attempts to reduce his use and 2 days when he stopped completely, which resulted in “terrible dreams,” poor sleep, sweating, no appetite, anxiety, irritability, and strong cravings for cannabis. Resumption of his cannabis use relieved these symptoms. He denies tobacco or other drug use, including use of synthetic marijuana products such as K2 or spice, and reports having a glass of wine or champagne once or twice a year for special occasions.

The diagnosis

In the transition from DSM IV-TR to DSM-5, cannabis use disorders, along with all substance use disorders, have been redefined in line with characterizing a spectrum of

pathology and impairment. The criteria to qualify for a cannabis use disorder remain the same except for the following:

1. The criterion for recurrent legal problems has been removed.

2. A new criterion for craving or a strong desire or urge to use cannabis has been added, and the terms abuse and dependence were eliminated.

To qualify as having a cannabis use disorder, a threshold of 2 criteria must be met. Severity of the disorder is characterized as “mild” if 2 or 3 criteria are met, “moderate” if 4 or 5 criteria are met, and “severe” if 6 or more criteria are met. Mr. M demonstrates 3 symptoms of impaired control: using longer than intended, unsuccessful efforts to cut back, and craving; 3 symptoms of social impairment: failure to fulfil home obligations, persistent problems with his wife, and reduced pursuit of occupational opportunities; 1 symptom of risky use: continued use despite paranoia; and 2 symptoms of pharmacological properties: tolerance and withdrawal. As such, he meets 9 criteria, which qualify him for a diagnosis of severe cannabis use disorder.

You summarize Mr. M’s 9 symptoms and counsel him about severe cannabis use disorder. He becomes upset and states that he was not aware one could develop an “addiction” to cannabis. He expresses an interest in treatment and asks what options are available.

Treatment options

Psychotherapeutic treatments, including motivational enhancement treatment (MET), cognitive behavioral therapy (CBT), and contingency management (CM), have demonstrated effectiveness in reducing frequency and quantity of cannabis use, but abstinence rates remain modest and decline after treatment. Generally, MET is effective at engaging individuals who are ambivalent about treatment; CM can lead to longer periods of abstinence during treatment by incentivizing abstinence; and CBT can work to enhance abstinence following treatment (preventing relapse). Longer duration of psychotherapy is associated with better outcomes. However, access to evidence-based psychotherapy is frequently limited, and poor adherence to evidence-based psychotherapy is common.

In conjunction with psychotherapy, medication strategies should be considered. Because there are no FDA-approved pharmacological agents for cannabis use disorder, patients should understand during the informed consent process that all pharmacotherapies used to treat this disorder are off-label. A number of clinical trials provide evidence for the off-label use of medications in the treatment of cannabis use disorder. The current strategies for the off-label treatment of cannabis use disorder target withdrawal symptoms, aim to initiate abstinence and prevent relapse or reduce use depending on the patient’s goals, and treat psychiatric comorbidity and symptoms that may be driving cannabis use. Here we focus on the evidence supporting these key strategies.

Targeting withdrawal and craving

Cannabis withdrawal is defined by DSM-5 as having 3 or more of the following signs and symptoms that develop after the cessation of prolonged cannabis use:

• Irritability, anger, or aggression

• Nervousness or anxiety

• Sleep difficulty

• Decreased appetite or weight loss

• Restlessness

• Depressed mood

• At least one of the following physical symptoms that causes discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache

Withdrawal symptoms may be present within the first 24 hours. Overall, they peak within the first week and persist up to 1 month following the last use of cannabis. In the case of Mr. M, insomnia, poor appetite, and irritability as well as sweating are identified, which meet DSM-5 criteria for cannabis withdrawal during the 2 days he abstained from use. He also identifies strong craving and vivid dreams, which are additional withdrawal symptoms included on marijuana withdrawal checklists in research studies, although not included in DSM-5 criteria. These and other symptoms should be considered in clinical treatment.

Medication treatment studies for cannabis withdrawal have hypothesized that if withdrawal symptoms can be reduced or alleviated during cessation from regular cannabis use, people will be less likely to resume cannabis use and will have better treatment outcomes. Studies have shown that dronabinol and nabilone improved multiple withdrawal symptoms, including craving; and quetiapine, zolpidem, and mirtazapine help with withdrawal-induced sleep disturbances.1-5

Combining dronabinol and lofexidine (an alpha-2 agonist) was superior to placebo in reducing craving, withdrawal, and self-administration during abstinence in a laboratory model. However, in a subsequent treatment trial, the combined medication treatment was not superior to placebo in reducing cannabis use or promoting abstinence.6

Six double-blind placebo-controlled pharmacotherapy trials in adults with cannabis use disorder have looked at withdrawal as an outcome.7 Of these studies, only dronabinol, bupropion, and gabapentin reduced withdrawal symptoms.8-10 In addition to reducing withdrawal symptoms, nabiximols/Sativex (a combination tetrahydrocannabinol [THC] and cannabidiol nasal spray not available in the US) increased retention (while actively on the medication in an inpatient setting) but did not reduce outpatient cannabis use at follow-up.11

All of the medications available for prescription in the US can be monitored reliably with urine drug screening to assess for illicit cannabis use except dronabinol, which will result in a positive screen for cannabis. When using urine drug screening, remember that for heavy cannabis users the qualitative urine drug screen can be positive for cannabis up to a month following cessation. When selecting a medication, take into account the cost of the medication, particularly since insurance will likely not cover THC agonists such as dronabinol for this indication, and possible misuse or diversion of scheduled substances (eg, dronabinol, nabilone). In addition, monitoring for reductions in substance use and withdrawal symptoms is key.

Abstinence initiation and relapse prevention

Other clinical trials have looked at medications to promote abstinence by reducing stress-induced relapse, craving (not as a component of withdrawal), and the reinforcing aspects of cannabis. Of these trials, the following results show potential promise with positive findings: gabapentin reduced quantitative THC urine levels and improved cognitive functioning (in addition to decreasing withdrawal), and buspirone led to more negative urine drug screens for cannabis (although the difference was not significant compared with placebo).10,12 However, in a follow-up larger study, no differences were seen compared with placebo and women had worse cannabis use outcomes on buspirone.13

N-acetylcysteine resulted in twice the odds of a negative urine drug screen in young adults and adolescents (although there was no difference between adolescent groups in self-report of cannabis use).14 Gray and colleagues15 reported that no differences were seen between N-acetylcysteine and placebo (results of the trial are soon to be published). Topiramate resulted in significantly decreased grams of cannabis used but no difference in percent days used or proportion of positive urine drug screens.16 In a recent small clinical trial, reductions in cannabis use were seen with oxytocin in combination with MET.17 Studies with nabilone and long-term naltrexone administration reduced relapse and cannabis self-administration and subjective effects, respectively, which suggests promising avenues yet to be explored by clinical trials.2,18

Treatment of psychiatric comorbidity

Other studies have looked at the effects of treating common comorbid psychiatric disorders in adults with cannabis use disorder, postulating that if the psychiatric disorder is treated, the individual may be more likely to abstain or reduce his or her cannabis use. For example, if a person is less depressed, he may better engage in CBT for relapse prevention.

Fluoxetine for depression and cannabis use disorder in adolescents decreased cannabis use and depression, although there was no difference compared with placebo.19 A trial of venlafaxine for adults with depression and cannabis use disorder demonstrated less abstinence with greater withdrawal-like symptoms compared with placebo.20,21 These findings suggest that this antidepressant might not be beneficial for treatment-seeking individuals with cannabis use disorder and may actually negatively affect outcomes.

CASE VIGNETTE CONT’D

After discussing and presenting the different psychotherapy and medication treatment options to Mr. M, you and he decide to start CBT to help with abstinence initiation. In addition, you prescribe 20 mg of dronabinol up to 2 times daily in combination with 50 mg of naltrexone daily, to help globally target Mr. M’s withdrawal symptoms and prevent relapse once abstinence is achieved. However, a few days later, Mr. M calls to say that his insurance will not cover the prescription for dronabinol and he cannot afford the high cost. Given his main concerns of cannabis withdrawal symptoms, you select gabapentin up to 400 mg 3 times daily and continue weekly individual CBT.

Mr. M calls back several days later and reports that he has made some improvements in reducing the frequency of his cannabis use, which he attributes to the medication, but he thinks he needs additional assistance. After reviewing the treatment options again, he gives informed consent to start 1200 mg of N-acetylcysteine twice daily. After 10 weeks of this medication, his urine screens are negative.

You continue to provide relapse prevention CBT. He reports to you that his anxiety and insomnia are almost resolved, and you suspect that withdrawal was the cause of these symptoms. He reports significant improvement in his relationship with his family and recently received a promotion at work for “going above and beyond” on a project he was given the lead.

Over the next 6 months, he has 2 relapses that in functional analysis with you are determined to be triggered by unsolicited contact from his former drug dealer. Together, you develop a plan to block any further contact from the drug dealer. After several months, both the gabapentin and N-acetylcysteine are tapered and discontinued. Mr. M continues to see you for biweekly therapy sessions with random drug screens every 4 to 6 weeks.

Conclusion

Based on the available evidence, gabapentin, THC agonists, naltrexone, and possibly N-acetylcysteine show the greatest promise in the off-label treatment of cannabis use disorders. System considerations, such as medication cost, need to be factored into the decision-making as well as combination medication and psychotherapy approaches, which—as demonstrated in the case of Mr. M—may ultimately work best. Until further research elucidates the standard of medication practices for cannabis use disorder, the best off-label medication strategy should target any co-occurring disorders as well as any identified problematic symptoms related to cannabis use and cessation of use. When available, referral for evidence-based psychotherapy should be made.

Source:  (http://www.psychiatrictimes.com)  30th June 201

Findings From A UK Birth Cohort

ABSTRACT

Background

Evidence on the role of cannabis as a gateway drug is inconsistent. We characterise patterns of cannabis use among UK teenagers aged 13–18 years, and assess their influence on problematic substance use at age 21 years.

Methods

We used longitudinal latent class analysis to derive trajectories of cannabis use from self-report measures in a UK birth cohort. We investigated (1) factors associated with latent class membership and (2) whether latent class membership predicted subsequent nicotine dependence, harmful alcohol use and recent use of other illicit drugs at age 21 years.

Results

5315 adolescents had three or more measures of cannabis use from age 13 to 18 years. Cannabis use patterns were captured as four latent classes corresponding to ‘non-users’ (80.1%), ‘late-onset occasional’ (14.2%), ‘early-onset occasional’ (2.3%) and ‘regular’ users (3.4%).

Sex, mother’s substance use, and child’s tobacco use, alcohol consumption and conduct problems were strongly associated with cannabis use.

At age 21 years, compared with the non-user class, late-onset occasional, early-onset occasional and regular cannabis user classes had higher odds of nicotine dependence (OR=3.5, 95% CI 0.7 to 17.9; OR=12.1, 95% CI 1.0 to 150.3; and OR=37.2, 95% CI 9.5 to 144.8, respectively); harmful alcohol consumption (OR=2.6, 95% CI 1.5 to 4.3; OR=5.0, 95% CI 2.1 to 12.1; and OR=2.6, 95% CI 1.0 to 7.1, respectively); and other illicit drug use (OR=22.7, 95% CI 11.3 to 45.7; OR=15.9, 95% CI 3.9 to 64.4; and OR=47.9, 95% CI 47.9 to 337.0, respectively).

Conclusions

One-fifth of the adolescents in our sample followed a pattern of occasional or regular cannabis use, and these young people were more likely to progress to harmful substance use behaviours in early adulthood.

Source:  http://dx.doi.org/10.1136/jech-2016-208503

ABSTRACT

PURPOSE:

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

METHOD:

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

RESULTS:

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

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

CONCLUSION:

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

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

Ketamine Continues to Impress and Confound Researchers

A novel glutamatergic hypothesis of depression, using a 50-year-old anaesthesia medicine, has had a remarkable run as of late. First an anaesthetic, then a popular club drug in the 90s known as “Special K” (and currently still popular in Hong Kong as a “Rave Drug”), and now a novel, fast acting antidepressant, ketamine is a N-Methyl D-Aspartame (NMDA) receptor antagonist. Ketamine was FDA-approved in the U.S. as an anaesthetic nearly 50 years ago. It is used primarily by anaesthesiologists in both hospital and surgical settings. As an N-Methyl D-Aspartame (NMDA) receptor antagonist with dissociative properties, NMDA receptors possess high calcium permeability, which allows ketamine to reach its target quickly. Increasing clinical evidence has shown that a single sub-anaesthetic dose (0.5 mg/kg) of IV-infused ketamine exerts impressive antidepressant effects within hours of administration. These effects have stabilized suicidality in severely depressed, treatment-resistant individuals. The effects of low-dose ketamine infusion therapy can last up to seven days, although the dosing and patient characteristics regarding its optimal effectiveness have not been established.

In my book, “The Good News About Depression: Cures And Treatments In The New Age of Psychiatry”–Revised (1996), I said there was never a better time to be depressed, due in part to recent breakthroughs in understanding of the underlying biology of depression, plus the discovery of novel therapeutics e.g., the SSRIs. Today that book might be called the “Better News About Depression” as a result of the effectiveness of novel treatments such as Transcranial Magnetic Stimulation (TMS) and now ketamine, which has illuminated and broadened our understanding and view of treating depression.

Why Is This Better News?

New clinical and preclinical studies suggest that dysfunction of the glutamatergic system is perhaps more relevant and important than the current catecholamine hypothesis and therapy that targets serotonin, norepinephrine and sometimes dopamine. These medications often take four to six weeks to exert any therapeutic benefit, whereas rapid reductions in depressive symptoms have been observed in response to a single dose of ketamine. This is a vast departure from the SSRIs and SSNRIs that have occupied the mainstream of pharmacological therapy for depression and anxiety disorders for more than 30 years.

Lastly, the mechanism of action of NDMA antagonists are comparatively underexplored but vitally important to our understanding of depression, reversal of suicidality, as well as the debilitating, depressive symptoms induced by abuse of alcohol and other drugs. This review highlights the current evidence supporting the antidepressant effects of ketamine as well as other glutamatergic modulators, such as D-cycloserine, riluzole, CP-101,606, CERC-301 (previously known as MK-0657), basimglurant, JNJ-40411813, dextromethorphan, nitrous oxide, GLYX-13, and esketamine. This all adds up to some very good news for depressed persons and especially those who do not respond to previous SSRI or SSNRI treatments.

Source: http://www.rivermendhealth.com/resources/ketamine-fast-acting-antidepressant/  June2017

 

A recognized deficiency: Inadequate protective protocols

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

Current Government-approved Cannabinoid Products

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

The longest approved agents, dronabinol and nabilone are indicated for short term use in nausea and vomiting due to chemotherapy and appetite stimulation.3,4  Nabiximols is used as a buccal spray for multiple sclerosis and as an adjunct for cancer pain.5  The maximum delta-9-THC strengths available are 10 mg for dronabinol and 2.7 mg/spray of nabiximols.3,5  Cannabidiol (CBD), a non-psychoactive compound, is one of many cannabinoids found in marijuana.   CBD is currently available for free from the U.S. National Institute of Health in government-sponsored clinical trials as potential treatment of resistant seizures (Dravet’s Syndrome and Lennox-Gastaut Syndrome).6

‘Medical’ Marijuana products

All marijuana products, including marijuana for medical purposes, fit the prerequisites for a REMS program. The average potency of marijuana more than doubled between 1998 and 2009.7 In 2015 common leaf marijuana averaged 17.1% THC in Colorado.8  Examples of oral marijuana products contain 80 mg of THC in chocolates, cookies and drinks and even 420 mg of THC in a “Dank Grasshopper” bar.9  Butane hash oil (BHO) is a concentrated THC product used in water bongs and/or e- cigarettes and contains upwards of 50 – 90% THC with a Colorado average of 71.7 % THC.8   One “dab” (280 mg) of 62.1% BHO is equal to 1 gram of 17% THC in marijuana leaf form.8  These extremely elevated levels of THC make true scientific research with these products incapable of passing Patient Safety Committee standards.10

The Thalidomide Parallel

The risks are so severe for thalidomide, in terms of use in pregnancy that a special protocol that educates, evaluates, mitigates and monitors has been made obligatory.11

Thalidomide (Contergan®) was developed by a German company, Chemie Gruenenthal, in 1954 and approved for the consumer market in 1957.12 It was available as an over-the-counter drug for the relief of “anxiety, insomnia, gastritis, and tension” and later it was used to alleviate nausea and to help with morning sickness by pregnant women. Thalidomide was present in at least 46 countries under a variety of brand names and was available in “sample tablet form” in Canada by 1959 and licensed for prescription on December 2, 1961. Although thalidomide was withdrawn from the market in West Germany and the UK by December 2, 1961, it remained legally available in Canada until March of 1962. It was still available in some Canadian pharmacies until mid-May of 1962.12

Canada had permitted the drug onto the Canadian market when many warnings were already available

An association was being made in 1958 of phocomelia (limb malformation) in babies of mother’s using thalidomide.  A trial conducted in Germany against Gruenenthal, for causing intentional and negligent bodily injury and death, began in 1968 ending in 1970 with a claim of insufficient evidence.  Later, the victims and Gruenenthal settled the case for 100 million dollars.11

In 1962 the American pharmaceutical laws were increased by the Kefauver-Harris Drug Amendment of 1962 and proof for the therapeutic efficiency through suitable and controlled studies would be required for any government approved medication.13 According to paragraph 25 of the Contergan foundation law, every 2 years a new report is required to determine if further development of these regulations are necessary.13

In 1987 the War Amputations of Canada established The Thalidomide Task Force, to seek compensation for Canadian-born thalidomide victims from the government of Canada.12

In 1991, the Ministry of National Health and Welfare (the current Health Canada) awarded Canadian-born thalidomide survivors a small lump-sum payment.12

In 2015 the Canadian government agreed on a settlement of $180 million dollars to 100 survivors of thalidomide drug exposure and damage.14 Through Rona Ambrose, in her capacity as the Health Minister for the government of Canada at the time of the negotiations, an attempt was made to involve the drug companies related to the thalidomide issue in the survivor’s settlement agreement. Negotiations with the drug companies failed.  The Canadian taxpayer alone paid to amend the survivors by way of monetary award.

Thalidomide continues to be sold under the brand name of Immunoprin®, among others in a REMS program. It is an immunomodulatory drug and today, it is used mainly as a treatment of certain cancers (multiple myeloma) and leprosy.11

Question: If the drug thalidomide included psychotropic properties and offered the “high” of marijuana would it be prudent or responsible to allow it to be legally sold and marketed for non-medical purposes – acknowledging thalidomide’s record for toxicity in pregnancy?

Marijuana Risk Assessment and Government Acknowledgement

Risks demonstrated in the scientific literature include genetic and chromosomal damage.15, 16

When exposure occurs in utero, there is an association with many congenital abnormalities including cardiac septal defects, anotia, anophthalmos, and gastroschisis. Marijuana use can disrupt foetal growth and the development of organs and limbs and may result in mutagenic alterations in DNA. Cannabis has also been associated with foetal abnormalities in many studies including low birth weight, foetal growth restriction, preterm birth spontaneous miscarriage, spina bifida and others.15

Phocomelia has been shown in testing in a similar preclinical model (hamster) to that which revealed the teratogenicity of thalidomide.15

THC has the ability to interfere with the first stages in the formation of the brain of the fetus; this event occurs two weeks after conception.  Exposure to today’s high potency marijuana in early pregnancy is associated with anencephaly, a devastating birth defect in which infants are born with large parts of the brain or skull missing.15

The existence of specific health risks associated with marijuana products are acknowledged by national and various local governments and a plethora of elected officials in both Canada and the United States.16, 17, 18

Warnings and the contraindications for use by specific populations and in association with identified conditions, have been publicized by the Federal Government of Canada and the Federal Government of the United States of America through their respective health agencies.16, 17, 18

A government of Canada leaflet produced by Health Canada and updated in December 2015: Consumer Information – Cannabis (Marihuana, marijuana) reads19:

“The use of this product involves risks to health, some of which may not be known or fully understood. Studies supporting the safety and efficacy of cannabis for therapeutic purposes are limited and do not meet the standard required by the Food and Drug Regulations for marketed drugs in Canada.”19

“Using cannabis or any cannabis product can impair your concentration, your ability to think and make decisions, and your reaction time and coordination. This can affect your motor skills, including your ability to drive. It can also increase anxiety and cause panic attacks, and in some cases cause paranoia and hallucinations.”19

“When the product should not be used: under the age of 25, are allergic to any cannabinoid or to smoke, have serious liver, kidney, heart or lung disease, have a personal or family history of serious mental disorders such as schizophrenia, psychosis, depression, or bipolar disorder, are pregnant, are planning to get pregnant, or are breast-feeding, are a man who wishes to start a family, have a history of alcohol or drug abuse or substance dependence.”19

“A list of health outcomes related to long term use includes the following:

Increased risk of triggering or aggravating psychiatric and/or mood disorders (schizophrenia, psychosis, anxiety, depression, bipolar disorder), decrease sperm count, concentration and motility, and increase abnormal sperm morphology. Negatively impact the behavioural and cognitive development of children born to mothers who used cannabis during pregnancy.”19

In Canada, the College of Family Physicians has issued guidelines for issuing marijuana prescriptions.20

“Dried cannabis is not appropriate for patients who: a) Are under the age of 25 (Level II) b) Have a personal history or strong family history of psychosis (Level II) c) Have a current or past cannabis use disorder (Level III) d) Have an active substance use disorder (Level III) e) Have cardiovascular disease (angina, peripheral vascular disease, cerebrovascular disease, arrhythmias) (Level III) f) Have respiratory disease (Level III) or g) Are pregnant, planning to become pregnant, or breastfeeding (Level II)”20

“Dried cannabis should be authorized with caution in those patients who: a) Have a concurrent active mood or anxiety disorder (Level II) b) Smoke tobacco (Level II) c) Have risk factors for cardiovascular disease (Level III) or d) Are heavy users of alcohol or taking high doses of opioids or benzodiazepines or other sedating medications prescribed or available over the counter (Level III)”20

In February 2013 The College of Family Physicians of Canada issued a statement advancing the position that physicians should sign a declaration rather than write a prescription as the potential liability, as well as the ethical obligations, for health professionals prescribing marijuana for medical purposes appears not to have been adequately addressed by Health Canada. 21

“In our view, Health Canada places physicians in an unfair, untenable and to a certain extent unethical position by requiring them to prescribe cannabis in order for patients to obtain it legally. If the patient suffers a cannabis-related harm, physicians can be held liable, just as they are with other prescribed medications. Physicians cannot be expected to prescribe a drug without the safeguards in place as for other medications – solid evidence supporting the effectiveness and safety of the medication, and a clear set of indications, dosing guidelines and precautions.”21

Representatives of the government of the United States held a press conference at the Office of National Drug Policy (ONDCP) in 2005. Mental health experts and scientists joined high-ranking government officials to discuss an emerging body of research that identified clear links between marijuana use and mental health disorders, including depression, suicidal thoughts and schizophrenia.22

The US Substance Abuse and Mental Health Service Administration (SAMHSA) report about the correlation between age of first marijuana use and serious mental illness; and an open letter to parents on “Marijuana and Your Teen’s Mental Health,” signed by twelve of the Nation’s leading mental health organizations, ran in major newspapers and newsweeklies across the country.23

Included were the following announcements:

“Regular use of the drug has appeared to double the risk of developing a psychotic episode or long-term schizophrenia.”23

“Research has strongly suggested that there is a clear link between early cannabis use and later mental health problems in those with a genetic vulnerability – and that there is a particular issue with the use of cannabis by adolescents.” 23

“Adolescents who used cannabis daily were five times more likely to develop depression and anxiety in later life.” 23

In 2016 the Obama Administration steadfastly opposes legalization of marijuana and other drugs because legalization would increase the availability and use of illicit drugs, and pose significant health and safety risks to all Americans, particularly young people.24 The US government still maintains marijuana is classified as a Schedule I drug, meaning it has a high potential for abuse and no currently accepted medical use in treatment in the United States.17, 18

Risk Evaluation and Mitigation Strategy for Marijuana Products

The dispensing of marijuana for medical purposes must follow a strict dispensing and monitoring protocol; no less arduous than that used for the delivery of drugs such as thalidomide.

Recommendation – The implementation of a REMS for marijuana products (REMSMP).

1. The first order for a government is to protect the public. As such, it befits a government approving marijuana for medical purposes to implement a REMS program.

2. Medical cannabis/marijuana dispensaries/stores/delivery systems will be       required to comply with all necessary components of a rigorous REMS program prior to selling and dispensing marijuana products.

3. Governmental regulatory organizations must be responsible for the cannabis/marijuana for medical purposes programs and obtain the required evaluations [(i.e. laboratory tests (pregnancy, HCG, etc.), physical and mental health examination documentation], signed patient consent, provider contract and education forms – performed in the required time frames both before initiation, during and after continued usage of marijuana products for medical purposes.

4. Quarterly audits will be performed, by the government regulatory organization, on each medical marijuana/cannabis dispensary for compliance.  Failure to comply with the REMSMP program will result in fines and other appropriate penalties to the marijuana dispensaries.

A REMS for Marijuana Product Potential Framework:

EMBRYO-FETAL TOXICITY & BREASTFEEDING

* Marijuana causes DNA damage in male and female patients.15  If marijuana is used during conception or during pregnancy, it may cause birth defects, cancer formation in the offspring, Downs Syndrome or embryo-fetal death.15, 16, 18

* Pregnancy must be ruled out before the start of marijuana treatment.  Pregnancy must be prevented by both the male and female patients during marijuana treatment by the use of two reliable methods of contraception.

* When there is no satisfactory alternative treatment, females of reproductive potential may be treated with marijuana provided adequate precautions are taken to avoid pregnancy.

* Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning marijuana therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.  Females must commit to either abstain continuously from heterosexual intercourse or use two methods or reliable birth control as mentioned.  They must have two negative pregnancy tests prior to initiating marijuana therapy and monthly pregnancy test with normal menses or two months with abnormal menses and for at least 1 month after stopping marijuana therapy.

* Males (all ages): DNA damage from marijuana is present in the semen of patients receiving marijuana.15 Therefore, males must always use a latex or synthetic condom during any sexual contacts with females of reproductive potential while using marijuana and for up to at least 28 days after discontinuing marijuana therapy, even if they have undergone a successful vasectomy.  Male patients using marijuana may not donate sperm.

* Blood Donation: Patients must not donate blood during treatment with marijuana and for at least 1 month following discontinuation of marijuana because the blood might be given to a pregnant female patient whose fetus should not be exposed to marijuana.

* Marijuana taken by any route of administration may result in drug-associated DNA damage resulting in embryo-fetal toxicity. Females of reproductive potential should avoid contact with marijuana through cutaneous absorption, smoke inhalation or orally.

* If there is contact with marijuana products topically, the exposed area should be washed with soap and water.

* If healthcare providers or other care givers are exposed to body fluids of a person on marijuana, the exposed area should be washed with soap and water.  Appropriate universal precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to marijuana.

* Several psychoactive cannabinoids in marijuana are fat soluble and are found to concentrate in breast milk.  Nursing mothers must not be receiving marijuana.16 Consult the primary care provider about how long to be off of marijuana before considering breast feeding.

NON-SEMINOMA TESTICULAR GERM CELL CARCINOMA

* Marijuana use is a known risk factor in the development of non-seminoma testicular germ cell carcinoma in males.25 – 28

* The presence of non-seminoma testicular germ cell carcinoma must be excluded before the start of marijuana treatment.  The patient’s primary care provider must perform a testicular examination and review the patient’s human chorionic gonadotropin (HCG) blood test before starting marijuana.  Male patients must perform weekly testicular self-evaluations while receiving marijuana.  They are also required to have their primary care provider perform a testicular evaluation and a HCG blood test performed every 4 months while receiving marijuana.29, 30

MENTAL HEALTH:

* Short term high dose and chronic marijuana usage is a known risk factor for the development of multiple mental health disorders.16, 18, 20, 31 – 34  Depression, paranoia, mental confusion, anxiety, addiction and suicide potential are all associated with acute and chronic exposure to marijuana.16, 18   Decline in intelligence is a potential risk of adolescent-onset marijuana exposure. 16, 18, 35

The presence of these mental health disorders must be evaluated by a licensed psychiatrist or psychologist by use of the Mini International Neuropsychiatric Interview or equivalent validated diagnostic instrument before marijuana is started.  The diagnostic mental health evaluation tool will be completed every 1month by an independent licensed psychiatrist or psychologist for a minimum of 6 months until unchanging and then every 4 months thereafter while receiving marijuana ending 4 months after the last exposure to marijuana.36

PSYCHIATRIC EVALUATIONS:

History of Substance Abuse Disorder: As the prevalence of substance use disorders amongst those patients requesting medical authorization of marijuana products is known to be extremely high the patient population must be screened prior to dispensing marijuana products for risk of a substance use disorder.  Substance use must be monitored prior to onset of marijuana with the World Health Organization, Smoking and Substance Involvement Screening Test (WHO-ASSIST, V3.0), and repeated at monthly intervals until unchanging and every 3 months thereafter while receiving marijuana, ending 6 months after the last exposure to marijuana.37

Conclusion

The evidence that thalidomide and tobacco products were harmful was known to the manufacturers/distributors before government and the populous acknowledged these dangers.

To date, there continue to be legal repercussions to said manufacturers/distributors/government for knowingly placing the public at risk.  We believe that the same will happen for marijuana products and that it is our responsibility to assist the Canadian government to protect the public from a similar outcome.

Since the government is fully aware of the marijuana harms, the  government must not be complicit in risking Canadian health/lives, but rather must mitigate any and all such risk to current and future generations.38, 39

The REMSMP program described assists in providing patient education, provider education and required patient monitoring before any marijuana products are allowed to be dispensed.  The program also requires on-going data collection and analysis, to determine the actual hazards from marijuana use and whether the program should even continue.  As the stewards of the country’s human and financial resources, it is critical that government protect the public from potential irreversible harm and itself from litigation risk by harmed individuals knowing that, in the context of marijuana use, harm is not only possible but probable.

Source:  Pamela McColl,  National Director,  Smart Approaches to Marijuana Canada and The Marijuana Victims’ Association,    Vancouver BC Canada    August  2016

Endorsements

Philip Seeman, M.D. Ph.D., O.C. Departments of Pharmacology and Psychiatry University of Toronto,   Nobel Prize nominee (Science)

Elizabeth Osuch, M.D. Associate Professor Rea Chair of Affective Disorders, University of Western Ontario Schulich School of Medicine and Denistry,  London, Ontario

Ray Baker, M.D., FCFP, FASAM, Associate Clinical Professor, University of British Columbia Faculty of Medicine,  Vancouver, British Columbia

Pamela McColl, Smart Approaches to Marijuana – Canada.  Board Member Campaign for Justice Against Tobacco Fraud

Robert L. DuPont, MD,  President, Institute for Behavior and Health, Inc. Clinical Professor of Psychiatry, Georgetown University School of Medicine,  First Director, National Institute on Drug Abuse,  Second US White House Drug Chief

Bertha K Madras, PhD Professor of Psychobiology, Department of Psychiatry,Harvard Medical School

Phillip A. Drum Pharm. D., FCSHP.    Smart Approaches to Marijuana – USA

Professor Gary Hulse, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Australia

Grainne Kenny, Dublin, Ireland Co-founder and Hon. President of EURAD ,Brussels, Belgium

Peter Stoker Director, National Drug Prevention Alliance, United Kingdom

Mary Brett, BSc (Hons), Chair of Charity Cannabis Skunk Sense (CanSS) www.cannabisskunksense.co.uk ,United Kingdom

Deidre Boyd, CEO: DB Recovery Resources, Editor: Recovery Plus UK

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

Dramatic acceleration of reproductive aging, contraction of biochemical fecundity and healthspan-lifespan implications of opioid-induced endocrinopathy—FSH/LH ratio and other interrelationships

Highlights

· The classically described opioid related female reproductive endocrinopathy including central dysregulation and peripheral ovarian resistance is confirmed.

· Advance of the age of the inversion of the ratio of FSH/LH by 18.06 years from 46.26+4.76 to 28.06+9.36 is demonstrated by statistical modelling

· This important finding is likely related to the sexual differential in opioid pathophysiology in which females are significantly disadvantaged.

· Statistical modelling showed that many elements of the reproductive endocrinopathy had a non-linear relationship to chronological age, including squared, cubed and quartic functions of age suggesting a feed-forward bidirectional relationship with age and the ageing process.

· These findings have major implications for the incidence of morbidity and mortality events, and for frequently recommended treatments such as indefinite opioid agonist replacement therapies for opioid dependence.

Abstract

Whilst disturbances of female reproductive hormones and function are commonplace in opioid dependence, their pathophysiological interrelationships are not well understood. Hormonal levels in females were compared in 77 opioid dependent patients (ODP) and 148 medical controls (MC) including 205 and 364 repeat studies. Significant changes in FSH, LH, oestradiol, testosterone and SBG were noted including power functions with age.

The FSH/LH was lower in ODP (P=0.0150) and the ratio inversion point occurred at 28.06+9.36 v. 46.26+4.76 years, implying a 58% reduction in fertility duration. FSH has been shown to induce ovarian failure and GnRH (controlling LH and FSH) has been shown to regulate longevity systemically. This implies that, far from being benign, these findings explicate the adverse experience of female compared to male ODP, exacerbate opioid-dependent aging amongst females, and informs the care of opioid dependent women, particularly relating to the choice, dose and duration of agonist or antagonist therapy.

Introduction

Rates of morbidity and mortality from medical and illicit opioid dependence are rising in manyparts of the world, with the proportion of female consumers increasing [1-3].

Accordingly, increasing attention is not only being paid to the effects of chronic opiate exposure on traditional areas of women’s health such as pregnancy, lactation and contraception, but also domestic violence, child abuse, manner of initiation into opiate use, time to from first use to dependence and physical and mental health morbidity [4-9].

Reports from this centre [10] and elsewhere [11, 12] indicate that the health of opioid dependent women is significantly worse than that of non-opiate using women or their male counterparts.

It has been shown that the hypothalamopituitary-gonadal (HPG) axis is coordinated and integrated particularly by the triple positive Kisspeptin-Neurokinin B-Dynorphin (KNDy) cells of the lateral hypothalamus [13, 14]; that cytokines have a powerful impact on brain structure and function [15, 16]; and HPG and hypothalamic function [17]; that the hypothalamus integrates and controls mammalian lifespan via gonadotrophin releasing hormone (GnRH) [18]; and that sexual reproductive and fecundity factors are powerful predictors of longevity [19, 20].

This suggests that disruption of these integrated systems through opiate use would have a profound pathophysiological impact that extends beyond gynaecological, endocrine or addiction medicine. While different gender associated health outcomes are, in part, attributed to different sex hormones or ratios, more recent data of profound genetic [21], immunological [21-25] and epigenetic [26] gender differences imply that the total aetiological “palette” of factors with which the hormonal milieu bi-directionally interacts may be significantly richer and more complex than has previously been appreciated.

Reduced fertility, impaired lactation, and aberrant, late and scanty menses are all well described in the literature relating to female opioid dependent patients [27-29]. Premature ovarian failure may also be part of the picture. Osteoporosis and osteopaenia are also known to be common in male and female opioid dependent patients (30,31), and impaired bone homeostasis is known to be related to both hypogonadal and hypothalamic failure and immune stimulation (24,29).

Of particular interest hypothalamic GnRH [18] and FSH [30] have recently been causally implicated in reduced mammalian lifespan, and oocyte depletion and ovarian failure respectively. The hypothalamic GnRH pulse generator in the arcuate nucleus is known to be the master regulator of both commencement of menstrual cycles at menarche and the cyclicity of the cycles once established [31, 32]. Age at menarche is linked with lifespan, cardiovascular disorders, type 2 diabetes and breast cancer [31]. Its activity is governed by nuclear hormone (estrogen, progesterone, thyroid hormone and vitamin D) signalling, by many genes of the δ- aminobutyric acid B receptor (GABABR) 2 system, by nutritional signals including the leptin receptor, histone and polycomb silencing complex demethylation patterns and steroidal biogenesis pathways amongst others [31]. Opioids have been shown to be directly suppressive of GnRH release both directly [33] and via their effects in elevating prolactin [27, 28].

Indeed the proopiomelanocortin cells of the arcuate nucleus are physiological negative regulators of the GnRH pacemaker cells [33]. Moreover a direct effect of oestradiol on telomerase expression in human stem cells has been demonstrated [34]. Hence multiple interacting mechanistic pathways exist by which opioids can interact with nutritional and metabolicfunction and reproductive hormonal status.

Thus while it has long been recognized that systemic health factors impact upon a woman’s reproductive fitness, these considerations imply that HPG physiology may itself be a sensitive – if complex – readout of the female hypothalamic function. Female HPG factors may integrate and provide an output of systemic health, and thereby formulate a prospective predictor of longevity and thus health-based morbidity and mortality [18, 35, 36].

For these reasons this study reviewed and compared female reproductive hormones of opioid dependent and general medical controls with particular attention to FSH, LH and their relationship. Other key ratios of physiological significance are also described.

Methods

Patient Selection As hepatitis C serology is only performed in this clinic on drug dependent patients this test is a surrogate marker for the drug dependent state. Patients were therefore assigned to either the medical control group or the drug dependent group based upon whether or not they had had hepatitis C serology performed.

The analysis included results from all patients for whom pathology was requested. Two patients who were pregnant were excluded from the analysis. The age range was restricted to 15-50 years in view of the dramatic changes in the hormonal milieu in females in the reproductive age group compared to other periods ofa woman’s life. This is also the period in which the majority of addiction occurs.  Blood tests were taken in the period 1995-2015 as clinically indicated for patient care in the course of their routine medical care.

Pathology Analysis.

All pathology was performed by Queensland Medical Laboratory (QML) according to National Association of Testing Authorities Australia (NATA) accredited methods to the Australian Laboratory standard AS-15189. QML is accredited both with NATA and to the international clinical laboratory standard ISO 9001. The Free Androgen Index (FAI) was obtained from the laboratory and is defined as 100x Total Testosterone / Sex Hormone Binding Globulin (SBG). The Free Estradiol Index (FEI) was defined similarly as 100x Total Estradiol / Sex Hormone Binding Globulin [37]. Other ratios which were specifically defined and studied include the FSH/LH, LH/Testosterone, LH/Estradiol and FSH/ Progesterone indices.

Statistics.

Pathology data was downloaded as an Excel comma separated file (csv file) from QML and re-formatted as a Microsoft Excel worksheet. Categorical data were compared in EpiInfo 7.1.4.0 from Centres for Disease control in Atlanta Georgia, USA. Bivariate statistics were compared by categories in Statistica 7.1 from Statsoft, Oklahoma, USA. All t-tests were two tailed. “R” version 3.0.1 was downloaded from the University of Melbourne Central “R” Archive Network (CRAN) mirror. Continuous data was compared in “R”. Continuous data was log transformed to satisfy normality assumptions, as indicated by the Shapiro test. Linear regression was performed in “R”. Graphs were drawn using ggplot2 in “R”. Loess curves of best fit were drawn as localized polynomials. Linear regression was performed by the classicalmethod with deletion of the least significant term until only significant terms remained.

In view of the fluctuating levels of sex hormones across the lifespan, polynomial models in age were fitted as suggested by the form of the graphical loess curves. Final models for analysis were chosen based on an Analysis of Variance (Anova) comparison of final polynomial models for each dependent variable, as indicated in the text. Special interest centred on the log (FSH/LH) ratio. As explained in the text the points at which it crossed zero in each group were of particular interest. These points were estimated based on Fieller’s theorem, as were the associated confidence intervals. P<0.05 was considered significant.

Ethics. Ethical approval for this study was given by the Human Research Ethics Committee (HREC) of the Southcity Medical Centre (SMC). The SMC HREC has been accredited by the National Health and Medical Research Centre (NHMRC). The conduct of this study complied with the Declaration of Helsinki.

Results

753 opioid dependent patients (ODP’s) and 1867 medical control (MC) patients were  compared. All patients were in the age range 15-50 years. The mean ages in the two groups were 31.42+0.27 (mean+SEM) and 30.34+0.22 years respectively (Student’s t = 2.96,df =1727, P = 0.0020). Their clinical pathology was sampled on 1360 and 4310 occasions. All patients were female. In seven cases their group assignment changed based on their drug use dependency status which changed over the course of the study.

Since this data is derived from our clinical pathology no other demographic or drug use data is available. Drug use and demographic data for this cohort has previously been presented [38- 41]. Similarly no menstrual or contraceptive data is available. Table 1 shows a bivariate comparison of the two groups. The data presented relates only to the first occasion on which each patient was studied. The data are presented by category.

Significant differences are noted between the two groups on metabolic, hepatic, immune and infectious parameters, and on the two hormonal parameters oestradiol and the sex hormone binding globulin SBG. SBG is produced from the liver and is not usually classified as a hormone, but many aspects of its function resemble hormonal activity since its level and binding characteristics and subtypes determine the hormonal availability particularly of oestradiol and testosterone to the tissues. It’s level is known to rise in hepatic dysfunction [42,43]. It is therefore considered as a hormone for the purposes of this analysis. This table also

presents the sample sizes of the different groups on the first occasion they were analyzed and

in the cross-sectional dataset. As opioids are known to impact metabolic, immune and hepatic

function [44, 45] these various parameters are reported and show many significant differences.

The sample size in the longitudinal dataset is shown in Supplementary Table 1.

Figure 1 presents the hormonal levels by age. The rise of the gonadotrophins LH and FSH, the decline of the sex hormones oestradiol, progesterone and testosterone with age, is well known. SBG is also noted to fall with age. It is noted that all the figures show the changes up to age 60 years, whilst the statistical analysis is limited to changes occurring less than age 50 years.

This allows the changes in the data trend lines to be shown graphically, but allows the analysis to be conducted without the confounding effect of the dramatic hormonal changes which occur in females as they enter their sixth decade of life. Supplementary Figure 1 shows the same hormones over time. Figure 2 shows various selected hormone ratios as a function of chronologic age. Interestingly the FAI and FEI both appear lower throughout life, apparently due to the higher SBG noted in Figure 1.

The relationship of LH/estradiol, FSH/Progesterone and LH/testosterone, which are all

physiologically meaningful, is shown. Supplementary Figure 2 shows these ratio relationships over time.

Figure 3 displays the mean log ratios between the hormones and ratios in the opioid dependent group to that in the opioid naive group. The figure shows that SBG is elevated the most, and LH is depressed the most severely in ODP. Similarly the FSH/LH ratio is most elevated whilst the LH/Estradiol ratio is most depressed. The presentation in this manner allows the direct and rapid comparison of the various changes across the spectrum of parameters examined.

Table 2 summarizes the results from mixed effects repeated measures linear regressions in which terms for the addictive status were significant. The first column lists the biological parameter of interest. The second column gives the form of the model. The third column gives the statistical parameter measured. The remainder of the table lists the parameter and model values respectively. One notes that progesterone, LH/estradiol and LH/Testosterone are missing from the table, as the optimal model for these contained no significant term in addictive status. One will note that the higher order design of the optimal model chosen in this table closely parallels the form of the curves in Figures 1and 2. This Table emphasizes the polynomial relationship of these hormonal parameters with age.

Table 3 is a statistical technical table which formally presents a concise extract from Anova analyses of model comparisons which lead to the choice of model design in Table 2. Naturally it would have been too cumbersome to present all the model comparisons, so typically the linear model is compared with the best or next best model determined by Anova. This Table emphasizes that models polynomial in age account for the variance in the data very significantly better than simple linear models.

The serum prolactin levels were not different between the two groups considered either by chronological age or by time (data not shown). Interestingly the FSH and LH appear to have a very different relationship, even when plotted as logarithms in Figure 1. This is of particular interest, as the FSH is normally lower than the LH in the reproductive years, but the relationship reverses premenopausally and in the postmenopause. This crossover point is therefore of particular biochemical and endocrinologic interest. We then returned to the fascinating subject of the point at which the log(FSH/LH) ratio became equal to zero in Figure 1. Clearly a log(FSH/LH) = 0 has a similar physiological meaning to FSH/LH = 1. It was possible to estimate this point using Fieller’s theorem.

The estimates given for the ODP was 28.06+9.36 years, and for the medical controls 46.26+4.76 years. Clearly this is a truncation of this measure of the perimenopause by 18.20 years. If one assumes a menarche occurring at 15 years [46], this represents a compression of this measure of hormonal fertility from 31.26 years in MC patients to 13.06 years in ODP, a 58.2% reduction.

Since liver disease is known to elevate both estrogen and SBG it may be considered that the high rates of liver disease in this population were significant confounding effects for the primary comparison described in this study. Importantly hepatitic inflammation is known to elevate both estradiol and SBG [27, 32] so that these hepatofugal effects on their relative relationship, and thus their effect on the free circulating estrogen is uncertain. These confounding factors were therefore evaluated formally. By comparing controls with opioid dependent patients who were both infected and uninfected with hepatotrophic viridae the effect of drug dependency alone can be isolated from a concomitant effect of hepatic inflammation.

Supplementary Figures 3-5 show the effect of seropositivity for HbsAg (Hepatitis B surface antigen) , HBcAb (Hepatitis B core antibody) and HCV (Hepatitis C virus) on the estradiol, SBG, Free Estrogen Index (FEI) FSH, LH and FSH/LH ratio respectively. Patients were considered to be hepatitis C positive if the HCV PCR (Polymerase chain reaction) was positive or the HCV antibody was positive in the absence of a negative HCV PCR result. These results are shown in the Supplementary Figures. Three groups were considered – non hepatitic control patients, patients tested and found to be negative, and patients tested and found to be positive.

Formal statistical analysis of these data by selected hormonal parameters in mixed effects repeated measures models are shown in Supplementary Tables 2-4. In each case the medical control patients were used as statistical comparator controls for linear regression modeling which was undertaken in R. Only statistically significant results are listed in the Tables.

Figure 4 illustrates the effect of Hepatitis B or C seropositivity considered together on these hormones and their ratios, and Table 4 provides the applicable statistical analysis for log (FSH/LH) compared to the medical control group. These studies show that in uninfected opioid dependent patients estradiol is mildly elevated at trend level significance (P=0.08-0.09) except in the case of HBcAb where this elevation reaches significance (P=0.0135, Supplementary Table 2). Estradiol is further elevated by chronic viral hepatitis (all P<0.02). Our analysis shows that opioid dependency alone without chronic viral hepatitis (CVH) significantly elevates SBG (most P≤0.01), an elevation which is furthered by CVH (P≤0.001, Supplementary Table 3). However when these two indices are considered together as the (log) Free Estrogen Index these effects are mostly abrogated

(Supplementary Table 4).

Opioid dependency elevates the FSH and reduces LH so that the net effect of opioid dependency on the (log) FSH/LH ratio is to raise it in both CVH -infected and -uninfected opioid dependent patients. As shown graphically in the Figures and quantitated in Table 4, theeffect is actually more marked in uninfected ODP (most P≤0.002) in the case of Hepatitis B,and is highly statistically significant in both HCV -infected and -uninfected ODP patients.

Another way in which to compare the relationship between hepavirus infection and drug dependency status directly from our data is to include both factors as independent variables in models of our main parameter of interest. In such models the classical regression process of model reduction from initial to final model should either completely remove extraneous variables, or indicate their relative weights. Unsurprisingly this was not possible when addictive status and Hepatitis C status was considered concurrently, or when all hepaviridae were considered together with addictive status, as all such models both linear and quadratic for age failed to converge due to collinearity. However it was possible to compare HBsAg and addictive status together with age directly in mixed effects models of Estradiol, SBG, FEI and log (FSH/LH). Whilst models linear in age were functional in this analysis higher order models as suggested by Table 3 in general failed to converge (other than as shown in Supplementary Table 5). Detailed results for linear mixed effects models are presented in Supplementary Table 5 which shows that opioid dependency features in five terms in this table and HBsAg status is included in four terms with effect sizes broadly comparable. This result indicates that both addictive status and Hepatitis B virus infection together are statistically significant determinants of these parameters.

When models accounting for the variance of the log (FSH/LH) ratio were formally directly compared by Anova comparisons of mixed effects maximum likelihood models the addictive status was more highly predictive than the HbsAg serostatus. The addition of addictive status to age as dependent variables was more significant than the addition of HBsAg to age (AIC’s 1257.84 v 1274.49. Log Ratio = 14.65, P = 0.0001) and the addition of a term for HbsAg status did not significantly improve an additive model between age and addictive status (AIC’s 1259.22 v 1257.84, Log Ratio = 2.61, P=0.2703).

Overall these data show that whilst both HBV and HCV CVH elevate both estradiol and SBG,their rise is proportional so that when considered as the Free Estrogen Index there is little change seen in opioid dependence. This result implies that the biologically available level of oestradiol is unchanged by hepaviridae infection. However when one considers the gonadotrophins both CVH -infected and -uninfected opioid dependent patients display elevated FSH, depressed LH and therefore a markedly and highly significantly elevated FSH/LH ratio which is therefore independent of the CVH status. These data indicate therefore that particularly in the case of the gonadotrophins, the observed changes relate more to the opioid dependency than the chronic viral hepatitis infection as confirmed in the analysis of log(FSH/LH) when both addictive and infective independent variables are included as factors concurrently.

Discussion

These data confirm and extend previous data showing perturbation of reproductive hormonal axes in opioid dependence amongst females. Data indicate that opioid dependence is characterized by marked fluctuation from normal in the mean levels of several sex hormones and their key physiological ratios from 50% elevated to 50% reduced. A key factor in this is the increased SBG level which rises presumably due to hepatic stimulation which is known to occur in ODP related to cytokine stimulation and often infection with hepatotrophic viridae including Hepatitis B and C [42, 43]. Significant alterations in FSH, LH, estradiol, testosterone and SBG, and in the FAI, FEI, FSH/LH, LH/estradiol, and FSH/Progesterone ratio were demonstrated in sensitive models, mostly polynomial in chronological age.

Particularly interesting findings relate to the altered FSH/LH ratio.

Early in a young woman’s life the FSH is low and the LH generally higher. After the menopause the reverse situation applies, so that the crossover or equality point becomes a sensitive biochemical and endocrinologic marker of the premenopause. Because FSH has been shown to have an aetiological role in ovarian failure and therefore the decline in systemic health [30], this is a very important biochemical harbinger of systemic health and likely foreshadows healthspan.

Study data indicate the FSH/LH equality point for opioid dependent women is reached at 28.06+9.36 years as opposed to 46.26+4.76 in controls. This likely represents a severe reduction in this measure of the reproductive lifespan and optimal reproductive fitness from 31.26 years to 13.06 years (58.2% ). This in turn implies an increased incidence of premature ovarian failure in opioid dependence. None of these findings were simply explainable on the basis of co-existing hepatitic liver disease alone.

Earlier studies showing that altered gonadotrophin levels have a systemic effects contributing to longevity [18] and in particular the role of FSH in contributing causally to ovarian compromise [30], together with the well described impact of fertility and fecundity on lifespan and longevity [19, 20] implies in turn that the clearly demonstrated failure of physical health across all body systems [11] may in fact be related to systemically impaired health and indeed reduced healthspan. Healthspan is a term which refers to the period of life for which individuals maintain optimal health [47, 48].

Hence this dramatic alteration of reproductive fitness is likely to impact both the healthspan of women, and their lifespan or longevity as the rate of aging is known to accelerate dramatically after both the menopause and in the fifth decade (after the age of forty) when the FSH/LH ratio normally inverts. This is turn carries major implications for the type and duration of treatment for the illicit opiate user. For example whilst internationally most opioid dependent patients are maintained on methadone, an opioid agonist or buprenorphine, a partial agonist, however it may be that maintenance on an opioid antagonists such as naltrexone or nalmefene may re-awaken and reignite the HPG axis following extended chronic illicit opiate use [27, 28, 32, 49] and thereby repair and renovate the healthspan. Similarly most opiate agonist or partial agonist treatment regimes are usually recommended to be of indefinite duration. The principal aim of such treatment appears to be to minimize reduce crime and illicit opiate use, overdose related death, and spread of blood borne viral infection (i.e. HCV; HIV). However it would appear from exhaustive analyses [11] that such treatment comes at an inexorable cost of pan-systemic disease, potentially relating to allostasis in multiple systems [50, 51] and generalized derangement of health including dysmetabolism [52] and immune stimulation [35, 53] and ultimately immune exhaustion [54, 55].

It is of some interest that the OPD in this study have been shown elsewhere to be maintained upon a relatively low dose of buprenorphine with a mean of 6.98mg [10]. It is likely therefore that in cohorts managed more traditionally with high dose full agonists, these effects may be more profound. This heightens the concerns expressed at other points herein. The hormonal ratios chosen in this study were of physiological import, as LH controls estradiol and testosterone secretion, and FSH is a prime determinant of progesterone secretion. The importance of the FAI and the FEI relate to the free availability of physiologically active levels of androgen and estrogen respectively. The importance of the FSH/LH ratio as a sensitive endocrinological measure of the premenopause has been mentioned above.

Of particular concern is the repeated demonstration that the effects of opioid dependence may be more severe in female patients [10-12]. The present clear demonstration of the altered female hormonal milieu of opioid dependence implies that endocrine factors may be an important, if likely not the only factor in this heightened disease severity. Whilst this finding is clearly suggestive it cannot be regarded as demonstrating a necessarily causal relationship between hormonal dysregulation and heightened female sensitivity to opioid induced pathophysiology. Although this study did not show any differences in either the time- or age- dependent changes in serum prolactin levels by group, it is well established that long term opioid administration is associated with hyperprolactinaemia [27, 28, 32, 49]. Greying of the temporal hair is well known to be the sine qua non of human aging [56] and this key metric has previously been shown to be greatly advanced in opioid dependency [39].

It is fascinating therefore that both the cellular stress system mediated in all addictions by Activator Protein-1 (AP-1) and c-Jun terminal kinase (JNK) activity [57], together with the prolactin receptor (prlr) were recently demonstrated to be the most salient signalling transduction pathways of extrinsic pro-ageing signals to the stem cells of the hair bulge where they were integrated with cell-intrinsic epigenetic processes particularly Foxc1 status to regulate hair follicle stem cell aging and thus hair physiological status [58], which are clearly therefore important and powerful metrics of ageing in accelerated aging syndromes such as opioid dependency. Of particular interest is the clear demonstration in Tables 2 and 3 that many of these hormones and ratios are best modelled by non-linear functions polynomial in chronological age. This is a very important finding as it suggests not only that opioids effect hormonal function in a deleterious manner, but that a feed forward relationship is in operation. That is that opioids effect the hormonal status negatively, but this advance in biological-hormonal age then further exacerbates the reproductive ageing effects themselves. This is consistent with the effects of sexuality and fecundity on the ageing process itself as has been previously documented [19, 56].

The present study has a number of strengths and limitations. It is of significant size, and has both cross-sectional and longitudinal components. It uses advanced statistical polynomial repeated measures mixed effects modelling in conjunction with graphical and Anova model comparison analyses. Whilst the study is descriptive only and not mechanistically oriented, this observational framework is placed within a relatively sophisticated pathophysiological conceptual framework as a stimulus and springboard to future work. The shortcomings of this study include that it does not have drug use data included in it, and that hormonal and contraceptive details are not available. All of these features may be improved in future iterations or replications of this work. It is also noted that the mean ages of the two groups is significantly different.  Extensive use of linear regression techniques has been made in the analysis of this dataset to account for this.

In conclusion this observational study replicates and confirms previously noted reproductive endocrinopathies. However while earlier authors frequently discount the clinical significance of these findings it is likely that they contribute meaningfully both to the experience of females in opioid dependence, and also the heightened morbidity and organ specific mortality frequently experienced by OPD women. The dramatic reduction of the modelled FSH – LH age of equality from 46.26 to 28.06 years is of particular concern in signalling system-wide metabolic and reproductive dysfunction. The far reaching impact of these findings on immune [21], genetic [21] and epigenetic [26] and longevity factors implies that treatment type and agonist administration and duration are key concerns deserving of further close attention. The present findings emphasize concerns derived from other studies of the particular and remarkable sensitivity of females to long term opioid agonist therapies [10-12] and introduce further endocrinologic concerns in relation to the common practice of indefinite opioid agonist treatment [59, 60] as have been previously expressed [10, 35, 38, 61-64]. Overall these findings powerfully and meaningfully inform our appreciation of, and insights into, the experience of females entrapped by the perils of opioid dependence.

Source:  Reece Albert Stuart, Thomas Mervyn Rees, Norman Amanda, Hulse GaryKenneth.Dramatic acceleration of reproductive aging, contraction of biochemical fecundity and healthspan-lifespan implications of opioid-induced endocrinopathy—FSH/LH ratio and other interrelationships

Reproductive Toxicology    http://dx.doi.org/10.1016/j.reprotox.2016.09.006

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There are many reports of drug use leading to mental health problems, and we all know of someone having a few too many drinks to cope with a bad day. Many people who are diagnosed with a mental health disorder indulge in drugs, and vice versa. As severity of both increase, problems arise and they become more difficult to treat. But why substance involvement and psychiatric disorders often co-occur is not well understood.

In addition to environmental factors, such as stress and social relationships, a person’s genetic make-up can also contribute to their vulnerability to drug use and misuse as well as mental health problems. So could genetic risk for mental illness be linked to a person’s liability to use drugs?

This question has been addressed in a new study, published in the open-access journal Frontiers in Genetics.

“Our research shows that if someone is genetically predisposed towards having mental illness, they are also prone to use licit and illicit substances and develop problematic usage patterns,” says Caitlin E. Carey, a PhD student in the BRAINLab at Washington University in St. Louis and lead author of this new study. “This is important because if a mental illness, like depression, runs in your family, you are presumed at risk of that disorder. But we find that having a genetic predisposition to mental illness also places that person at risk for substance use and addiction.”

This is the first study to compare genetic risk for mental illness with levels of substance involvement across a large sample of unrelated individuals. Rather than analysing family history, Carey and her co-authors used information across each person’s genetic code to calculate their genetic risk for psychiatric disorders.

“Previous research on the genetic overlap of mental illness and drug use has been limited to family studies. This has made it difficult to examine some of the less common disorders,” says Carey. “For example, it’s hard to find families where some members have schizophrenia and others abuse cocaine. With this method we were able to compare people with various levels of substance involvement to determine whether they were also at relatively higher genetic risk for psychiatric disorders.” As well as finding an overall genetic relationship between mental health and substance involvement, the study revealed links between specific mental illnesses and drugs. Dr. Ryan Bogdan, senior author of the study and Director of the BRAINLab, notes, “We were fortunate to work with data from individuals recruited for various forms of substance dependence. In addition to evaluating the full spectrum of substance use and misuse, from never-using and non-problem use to severe dependence, this also allowed us to evaluate specific psychiatric disorder-substance relationships”. He continues, “For example, we found that genetic risk for both schizophrenia and depression are associated with cannabis and cocaine involvement.”

The study opens up new avenues for research evaluating the predictive power of genetic risk. For example, could genetic risk of schizophrenia predict its onset, severity and prognosis in youth that experiment with cannabis and other drugs?

Dr. Bogdan concludes, “It will now be important to incorporate the influence of environmental factors, such as peer groups, neighborhood, and stress, into this research. This will help us better understand how interplay between the environment and genetic risk may increase or reduce the risk of co-occurring psychiatric disorders and substance involvement. Further, it will be important to isolate specific genetic pathways shared with both substance involvement and psychiatric illness. Ultimately, such knowledge may help guide the development of more effective prevention and treatment efforts decades in the future.”

Source:  Caitlin E. Carey et al, Associations between Polygenic Risk for Psychiatric Disorders and Substance Involvement, Frontiers in Genetics (2016). DOI: 10.3389/fgene.2016.00149 

People with light-colored eyes may have a higher risk of alcoholism than people with dark-brown eyes, new research suggests.

In the study, researchers looked at 1,263 Americans of European ancestry, including 992 people who were diagnosed with alcohol dependence and 271 people who were not diagnosed with alcohol dependence. They found that the rate of alcohol dependence was 54 percent higher among people with light-colored eyes — including blue, green, gray and light-brown eyes — than among those with dark-brown eyes.

“This suggests an intriguing possibility — that eye color can be useful in the clinic for alcohol dependence diagnosis,” study co-author Arvis Sulovari, a graduate student in cellular, molecular and biological science at the University of Vermont, said in a statement. The prevalence of alcoholism was the highest in people with blue eyes — their rate was about 80 percent higher than that of people with other eye colors, according to the study.

Moreover, the connection between eye color and an increased risk of alcoholism was confirmed by the results of a genetic analysis, which showed a significant link between the genetic components responsible for eye color and those that studies have linked with a person’s risk of alcohol dependence, the researchers said. [7 Ways Alcohol Affects Your Health]

However, the researchers still don’t know the exact reasons that could underlie the link, and more research is needed to examine it, study co-author Dawei Li, an assistant professor of microbiology and molecular genetics at the University of Vermont, said in a statement. Previous research on people of European ancestry has shown that those with light-colored eyes may consume more alcohol on average than dark-eyed individuals, the researchers said. Other studies also have demonstrated a link between eye color and people’s risk of psychiatric illness, addiction and behavioral problems, according to the study. For example, studies have established a link between light eye color and an increased risk of seasonal affective disorder (SAD), which often co-occurs with alcohol dependence, the researchers said. A possible explanation for the link between light eye color and SAD is that light-eyed people may be more sensitive to variations in light levels, which has been associated with abnormal changes in the production of the sleep-regulating hormone melatonin and, consequently, with SAD, the researchers said.

However, the new study has shortcomings, said Gil Atzmon, an associate professor of medicine and genetics at Albert Einstein College of Medicine in New York, who was not involved in the study.

For example, although the researchers took into account participants’ gender and age, to see whether those factors may have played a role in people’s risk of alcohol dependence, they did not examine other factors that also may have affected the participants’ risk of alcoholism, such as their income level or their mental health status, Atzmon said.  The researchers did not look at whether any of the people in the study had depression, a condition that may be associated with excessive drinking, he said.

The new study was published in the July issue of the American Journal of Medical Genetics: Neuropsychiatric Genetics Part B.

Source: http://www.livescience.com/51495-eye-color-alcoholism.html  15th July 2015

On-the-job exposure to low doses of powerful medications commonly administered to patients intravenously in the operating room may be a factor leading some anesthesiologists to abuse drugs, a theory University of Florida researchers will present Saturday at the 34th annual Society for Neuroscience meeting in San Diego.

Dr. Mark Gold, a distinguished professor with UF’s McKnight Brain Institute, said anesthesiologists who sit near a patient’s head during surgery are exposed secondhand to anesthetic drugs as they are exhaled by the patient.

Blood sampling and further studies are necessary to determine if anesthesiologists truly suffer ill effects from inhaling trace amounts of the drugs just as nonsmokers are adversely affected by secondhand smoke, Gold said.

“Most people thought that in the evolution of anesthetic practice from inhaled gases * nitrous and ether, and so forth * to drugs that are administered intravenously, there wouldn’t be secondhand exposure,” Gold said. “[Now we see] that those narcotics, which may be 1,000 times more potent than heroin, get into the air, may reach their brain, may change their brain and make it more likely that they’ll crave and want drugs, [become] depressed, and may be more likely that they’ll have a host of behavioral problems.”

Gold said the unintentional exposure may one day be determined to be an “occupational hazard” for anesthesiologists.

Anesthesiologists — who as a group are up to four times more likely to be treated for drug addiction than other physicians — may become sensitized to the intravenous drugs fentanyl and propofol after repeated exposure during long surgical procedures, said Gold, chief of the Division of Addiction Medicine and a professor in the departments of psychiatry and neuroscience.

In 2003, anesthesiologists represented only 5.6% of physicians in Florida but accounted for almost 25% of physicians monitored for substance abuse, according to Gold’s research. National statistics show a similar overrepresentation for anesthesiologists among drug-abusing physicians.

Gold theorized reasons other than access to drugs caused anesthesiologists to be overrepresented among addicted physicians, and that the presence of analgesic and anesthetic agents in the air in operating rooms might be one of them.

To test the theory, UF researchers initially used sensors developed for the military for detection of nerve gas and explosives. They also used standard analytical equipment called gas chromatography-mass spectroscopy to identify minute quantities of propofol in the exhaled breath of subjects in a clinical trial.

Next, using an analytical device called liquid chromatography-mass spectroscopy-mass spectroscopy, Gold worked with UF anesthesiologists Drs.

Donn Dennis, Timothy Morey and Richard Melker to measure and analyze multiple operating room air samples for fentanyl and propofol molecules.

They found the drugs present throughout the operating room, with the largest concentrations over the patient’s mouth. The amounts are so low they can only be detected with recently developed, ultra-sensitive instruments.

“We don’t know what doses they are exposed to at this time,” Gold said. “We will do blood sampling of anesthesiologists to learn that. But fentanyl and related analgesics are very powerful opiates, given in very large doses during cardiac surgery. Anesthesiologists may become sensitized.

“It has been shown that children of smokers are more likely to smoke,” Gold added. “It is currently understood that they have been smoking their whole lives secondhand. So their brain is changing and they are de facto smokers.

I believe the same thing happens with anesthesiologists. They had no intention to become addicts, their brains changed, they don’t feel right and they do come to associate the drug with relief.”

Until now, reasons such as family history and access to drugs were considered the main factors leading some anesthesiologists to drug use and addiction, Gold said, but the new findings may change that perception, as well as how recovering anesthesiologists are perceived. It may also lead to changes in air-handling systems, masks and length of shifts in the operating room.

Dr. Mark Aronson, a professor of medicine at Harvard Medical School, said the current theory of easy access to drugs provides a simple explanation for higher levels of addiction among anesthesiologists. However, hospitals monitor drug usage more rigorously now, making access more difficult and the access theory less plausible.

“Gold’s study offers an interesting and certainly plausible alternative explanation and makes the operating room a potentially dangerous occupational hazard for anesthesiologists,” Aronson said. “Obviously this needs further research, but I found this work quite intriguing.”
Source:Mark S. Gold, M.D. Distinguished Professor & Chief;McKnight Brain Institute. October 2004