The Chemistry of Modern Marijuana

Is low-grade pot better for you than sinsemilla?

First published September 3, 2013.

Australia has one of the highest rates of marijuana use in the world, but until recently, nobody could say for certain what, exactly, Australians were smoking. Researchers at the University of Sydney and the University of New South Wales  analyzed hundreds of cannabis samples seized by Australian police, and put together comprehensive data on street-level marijuana potency across the country. They sampled police seizures and plants from crop eradication operations. The mean THC content of the samples was 14.88%, while absolute levels varied from less than 1% THC to almost 40%.  Writing in PLoS ONE, Wendy Swift and colleagues found that roughly ¾ of the samples contained at least 10% total THC. Half the samples contained levels of 15% or higher—“the level recommended by the Garretsen Commission as warranting classification of cannabis as a ‘hard’ drug in the Netherlands.”

In the U.S., recent studies have shown that THC levels in cannabis from 1993 averaged 3.4%, and then soared to THC levels in 2008 of almost 9%. THC loads more than doubled in 15 years, but that is still a far cry from news reports erroneously referring to organic THC increases of 10 times or more.

CBD, or cannabidiol, another constituent of cannabis, has garnered considerable attention in the research community as well as the medical marijuana constituency due to its anti-emetic properties. Like many other cannabinoids, CBD is non-psychoactive, and acts as a muscle relaxant as well. CBD levels in the U.S. have remained consistently low over the past 20 years, at 0.3-0.4%. In the Australian study, about 90% of cannabis samples contained less than 0.1% total CBD, based on chromatographic analysis, although some of the samples had levels as high as 6%.

The Australian samples also showed relatively high amounts of CBG, another common cannabinoid. CBG, known as cannabigerol, has been investigated for its pharmacological properties by biotech labs. It is non-psychoactive but useful for inducing sleep and lowering intra-ocular pressure in cases of glaucoma.

CBC, yet another cannabinoid, also acts as a sedative, and is reported to relieve pain, while also moderating the effects of THC. The Australian investigators believe that, as with CBD, “the trend for maximizing THC production may have led to marginalization of CBC as historically, CBC has sometimes been reported to be the second or third most abundant cannabinoid.”

Is today’s potent, very high-THC marijuana a different drug entirely, compared to the marijuana consumed up until the 21st Century? And does super-grass have an adverse effect on the mental health of users? The most obvious answer is, probably not. Recent attempts to link strong pot to the emergence of psychosis have not been definitive, or even terribly convincing. (However, the evidence for adverse cognitive effects in smokers who start young is more convincing).

It’s not terribly difficult to track how ordinary marijuana evolved into sinsemilla. Think Luther Burbank and global chemistry geeks. It is the historical result of several trends: 1) Selective breeding of cannabis strains with high THC/low CBD profiles, 2) near-universal preference for female plants (sinsemilla), 3) the rise of controlled-environment indoor cultivation, and 4) global availability of high-end hybrid seeds for commercial growing operations. And in the Australian sample, much of the marijuana came from areas like Byron Bay, Lismore, and Tweed Heads, where the concentration of specialist cultivators is similar to that of Humboldt County, California.

The investigators admit that “there is little research systematically addressing the public health impacts of use of different strengths and types of cannabis,” such as increases in cannabis addiction and mental health problems. The strongest evidence consistent with lab research is that “CBD may prevent or inhibit the psychotogenic and memory-impairing effects of THC. While the evidence for the ameliorating effects of CBD is not universal, it is thought that consumption of high THC/low CBD cannabis may predispose users towards adverse psychiatric effects….”

The THC rates in Australia are in line with or slightly higher than average values in several other countries. Can an increase in THC potency and corresponding reduction in other key cannabinoids be the reason for a concomitant increase in users seeking treatment for marijuana dependency? Not necessarily, say the investigators. Drug courts, coupled with greater treatment opportunities, might account for the rise. And schizophrenia? “Modelling research does not indicate increases in levels of schizophrenia commensurate with increases in cannabis use.”

One significant problem with surveys of this nature is the matter of determining marijuana’s effective potency—the amount of THC actually ingested by smokers. This may vary considerably, depending upon such factors as “natural variations in the cannabinoid content of plants, the part of the plant consumed, route of administration, and user titration of dose to compensate for differing levels of THC in different smoked material.”

Wendy Swift and her coworkers call for more research on cannabis users’ preferences, “which might shed light on whether cannabis containing a more balanced mix of THC and CBD would have value in the market, as well as potentially conferring reduced risks to mental wellbeing.”

Graphics Credit: http://www.ironlabsllc.co/view/learn.php

Swift W., Wong A., Li K.M., Arnold J.C. & McGregor I.S. (2013). Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile., PloS one, PMID: 23894589

Hunting For the Marijuana-Dopamine Connection

Why do heavy pot smokers show a blunted reaction to stimulants?

Most drugs of abuse increase dopamine transmission in the brain, and indeed, this is thought to be the basic neural mechanism underlying the rewarding effects of addictive drugs. But in the case of marijuana, the dopamine connection is not so clear-cut. Evidence has been found both for and against the notion of increases in dopamine signaling during marijuana intoxication.

Marijuana has always been the odd duck in the pond, research-wise. Partly this is due to longstanding federal intransigence toward cannabis research, and partly it is because cannabis, chemically speaking, is damnably complicated. The question of marijuana’s effect on dopamine transmission came under strong scrutiny a few years ago, when UK researchers began beating the drums for a theory that chronic consumption of strong cannabis can not only trigger episodes of psychosis, but can be viewed as the actual cause of schizophrenia in some cases.

It sounded like a new version of the old reefer madness, but this time around, the researchers raising their eyebrows had a new fact at hand: Modern marijuana is several times stronger than marijuana in use decades ago. Selective breeding for high THC content has produced some truly formidable strains of pot, even if cooler heads have slowly prevailed on the schizophrenia issue.

One of the reports helping to bank the fires on this notion appeared recently in the Proceedings of the National Academy of Sciences (PNAS). Joanna S. Fowler of the Biosciences Department at Brookhaven National Laboratory, Director Nora Volkow of the National Institute on Drug Abuse (NIDA), and other researchers compared brain dopamine reactivity in healthy controls and heavy marijuana users, using PET scans. For measuring dopamine reactivity, the researchers chose methylphenidate, better known as Ritalin, the psychostimulant frequently prescribed for attention-deficit hyperactivity disorder (ADHD). Ritalin basically functions as a dopamine reuptake inhibitor, meaning that the use of Ritalin leads to increased concentrations of synaptic dopamine.

In the study, heavy marijuana users showed a blunted reaction to the stimulant Ritalin due to reductions in brain dopamine release, according to the research. “The potency of methylphenidate (MP) was also reported to be stronger by the controls than by the marijuana abusers." And in marijuana abusers, Ritalin caused an increase in craving for marijuana and cigarettes.

 “We found that marijuana abusers display attenuated dopamine responses to MP including reduced decreases in striatal distribution volumes,” according to the study’s conclusion. “The significantly attenuated behavioral and striatal distribution volumes response to MP in marijuana abusers compared to controls, indicates reduced brain reactivity to dopamine stimulation that in the ventral striatum might contribute to negative emotionality and drug craving.”

Down-regulation from extended abuse is another complicated aspect of this: “Although, to our knowledge, this is the first clinical report of an attenuation of the effects of MP in marijuana abusers, a preclinical study had reported that rats treated chronically with THC exhibited attenuated locomotor responses to amphetamine. Such blunted responses to MP could reflect neuroadaptations from repeated marijuana abuse, such as downregulation of DA transporters.”

 Animal studies have suggested that these dopamine alterations are reversible over time.

Another recent study came to essentially the same conclusions. Writing in Biological Psychiatry, a group of British researchers led by Michael A.P. Bloomfield and Oliver D. Howes analyzed dope smokers who experienced psychotic symptoms when they were intoxicated. They looked for evidence of a link between cannabis use and psychosis and concluded: “These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.” And again, the higher the level of current cannabis use, the lower the level of striatal dopamine synthesis capacity.  As for mechanisms, the investigators ran up against similar causation problems: “One explanation for our findings is that chronic cannabis use is associated with dopaminergic down-regulation. This might underlie amotivation and reduced reward sensitivity in chronic cannabis users. Alternatively, preclinical evidence suggests that low dopamine neurotransmission may predispose an individual to substance use.”

The findings of diminished responses to Ritalin in heavy marijuana users may have clinical implications, suggesting that marijuana abusers with ADHD may experience reduced benefits from stimulant medications.

Photo Credit: http://www.biologicalpsychiatryjournal.com/

NIDA’s Dark View of Teen Marijuana Use

Federal study also discusses medical marijuana.

Considering the impasse on marijuana policy between state and federal governments in the U.S., the primary government agency in charge of drug research—NIDA, the National Institute on Drug Abuse—would seem to be caught between a rock and a hard place. Neuroscientists and other marijuana investigators who do research under NIDA grants have a fine line to walk in their efforts to disseminate research findings on cannabis.

From a public health point of view, NIDA is expected to keep up the pressure against drug legalization, or at least keep out of the fight, while also researching the medical pros and cons of cannabis. So it was with some interest that drug policy officials took in a recent article in the New England Journal of Medicine by NIDA director Nora Volkow titled “Adverse Health Effects of Marijuana Use.”

While the press has understandably centered on the risk of marijuana use among teens, which is the focus of the study, the report also contains some surprising admissions about marijuana’s health benefits as well as its addictive potential.

The teen risk emphasis comes from recent studies on two fronts—impaired driving and impaired brain function. The first is seriously confounded by dual use with alcohol, and the second is based, at least in part, on a controversial long-term study showing that marijuana use in the early years demonstrably lowers adult IQs.

No one would suggest that heavy marijuana smoking is good for developing teen brains, and there is sufficient evidence to worry about impairment to memory and to certain so-called “executive” cognitive functions. It is not clear how lasting these effects can be, but lead author Volkow is confident enough to say in a prepared statement that “Physicians in particular can play a role in conveying to families that early marijuana use can interfere with crucial social and developmental milestones and can impair cognitive development.” 

That these negative effects can be the outcome of heavy pot smoking in the teen years seems established beyond reasonable doubt. The extent and duration of these negative outcomes remain the topic of vociferous debate—although it is increasingly clear that the body’s endogenous cannabinoid system plays a key role in synapse formation during early brain development.

Meanwhile, the report re-emphasized the fact that marijuana is an addictive drug for some users—a fact that should not need re-emphasizing, but, lamentably, does. As Volkow and her co-authors write: “The evidence clearly indicates that long-term marijuana use can lead to addiction. Indeed, approximately 9% of those who experiment with marijuana will become addicted.”

Moreover, as regular readers of Addiction Inbox already know, “there is also recognition of a bona fide cannabis withdrawal syndrome (with symptoms that include irritability, sleeping difficulties, dysphoria, craving, and anxiety), which makes cessation difficult and contributes to relapse.” And, in line with the report’s overall theme, “those who begin in adolescence are approximately 2 to 4 times as likely to have symptoms of cannabis dependence within 2 years after first use.”

To their credit, the investigators decline to endorse the claim that marijuana use exacerbates or initiates episodes of illness in patients with schizophrenia and other psychoses, noting that “it is inherently difficult to establish causality in these types of studies because factors other than marijuana use may be directly associated with the risk of mental illness.” Furthermore, while early marijuana use is associated with an increased risk of dropping out of school, “reports of shared environmental factors that influence the risks of using cannabis at a young age and dropping out of school suggest that the relationship may be more complex…. The relationship between cannabis use by young people and psychosocial harm is likely to be multifaceted, which may explain the inconsistencies among studies.”

Indeed. The report also declares that the effects of long-term pot smoking on the risk of lung cancer are “unclear,” and that “the smoking of cigarettes containing both marijuana and tobacco products is a potential confounding factor with a prevalence that varies dramatically among countries.”

In conclusion, the strict demands of causality mean that the long-term effect of chronic marijuana exposure is not known with any certainty. It is possible, even likely, that these effects can vary dramatically from one smoker to another. But the equally persuasive demands of common sense dictate that inhaling dried, super-heated vegetable matter on a regular basis is likely to degrade your health, the more so if you are young and healthy to begin with.

As for other health issues: “The authoritative report by the Institute of Medicine, Marijuana and Medicine, acknowledges the potential benefits of smoking marijuana in stimulating appetite, particularly in patients with the acquired immunodeficiency syndrome (AIDS) and the related wasting syndrome, and in combating chemotherapy-induced nausea and vomiting, severe pain, and some forms of spasticity. The report also indicates that there is some evidence for the benefit of using marijuana to decrease intraocular pressure in the treatment of glaucoma.”

A detailed section titled “Clinical Conditions with Symptoms That May Be Relieved by Treatment with Marijuana or other Cannabinoids” brought additional research to light:

—Glaucoma: “More research is needed to establish whether molecules that modulate the endocannabinoid system may not only reduce intraocular pressure but also provide a neuroprotective benefit in patients with glaucoma.”

—Nausea: “THC is an effective antiemetic agent in patients undergoing chemotherapy, but patients often state that marijuana is more effective in suppressing nausea…. Paradoxically, increased vomiting (hyperemesis) has been reported with repeated marijuana use. [See various blog posts by Drugmonkey and me, starting with this and this.]

—AIDS-associated conditions: “Smoked or ingested cannabis improves appetite and leads to weight gain and improved mood and quality of life among patients with AIDS.”

—Chronic pain: “Studies have shown that cannabinoids acting through central CB1 receptors, and possibly peripheral CB1 and CB2 receptors, play important roles in… various models of pain. These findings are consistent with reports that marijuana may be effective in ameliorating neuropathic pain, even at very low levels of THC.”

—Inflammation: “Cannabinoids (e.g., THC and cannabidiol) have substantial anti-inflammatory effects…. Animal models have shown that cannabidiol is a promising candidate for the treatment of rheumatoid arthritis and for inflammatory diseases of the gastrointestinal tract (e.g., ulcerative colitis and Crohn’s disease).”

—Multiple sclerosis: “Nabiximols (Sativex, GW Pharmaceuticals), an oromucosal spray that delivers a mix of THC and cannabidiol, appears to be an effective treatment for neuropathic pain, disturbed sleep, and spasticity in patients with multiple sclerosis. Sativex… is currently being reviewed in phase 3 trials in the United States in order to gain approval from the Food and Drug Administration.”

—Epilepsy: In a recent small survey of parents who use marijuana with a high cannabidiol content to treat epileptic seizures in their children, 11% reported completed freedom from seizures…. Although such reports are promising, insufficient safety and efficacy data are available on the use of cannabis botanical for the treatment of epilepsy. However, there is increasing evidence of the role of cannabidiol as an antiepileptic agent in animal models.”

Volkow N.D., Baler R.D., Compton W.M. & Weiss S.R.B.  Adverse health effects of marijuana use., The New England journal of medicine,    PMID: 24897085

Does Strong Marijuana Cause Addiction?

Strong pot matters, but maybe not the way we think.

Colorado, Washington, and some 20 additional states have now made various provisions for legal transactions involving marijuana. And since time immemorial, there has been an illegal market for marijuana. But try getting your hands on some marijuana straightforwardly, through appropriate channels, for purposes of medical research, and, well, most researchers have just said forget it.

Because in the U.S., a bizarre system of drug classification has led to the ludicrous situation of a virtual government monopoly on cannabis for experimental purposes. Can’t researchers just walk around this roadblock and procure pot in some manner that is legal in their state? No, they cannot—not if they want any serious research grants, or publication in refereed journals. Without the federal government imprimatur, marijuana research isn’t kosher, and could put researchers at legal risk. Researchers who go through channels report frequent and unpredictable delays, and this has been true for decades. Yet millions of recreational marijuana users can secure a supply of the drug, often accompanied by specific genetic information, often with relatively little effort.

The Drug Enforcement Administration (DEA) has refused to budge on its opposition to petitions for reclassification of cannabis. A recent Washington Post article  attributed the problem to “stigma associated with the drug, lack of funding and legal issues…. Scientists say they are frustrated that the federal government has not made any efforts to speed the process of research.”

However, as almost everyone knows, things are different in The Netherlands. It isn’t a big problem for researchers at the University of Amsterdam and elsewhere in that country to engage in behavioral studies of actual marijuana smokers. Participants in a recent study, the results of which appear in Addiction, were even allowed to use their own weed. (Thanks to Ivan Oransky for bringing this study to my attention.) The thesis being tested by Peggy van der Pol and colleagues is a familiar one: Do marijuana smokers “titrate” very strong pot—that is, do they modify their smoking/dosing behavior accordingly, in order to reduce overall THC exposure? If so, just because a cannabis user is ingesting high-THC plant material doesn’t mean that his or her THC blood levels are that much higher than smokers of less potent weed. But if this is NOT true—if smokers of strong pot are boosting their THC exposure significantly, the results could conceivably include impaired driving and greater rates of marijuana addiction.

Most studies that attempt to estimate the risk of cannabis dependence in pot smokers rely on a familiar yardstick—the number of days a smoker smokes per month. Dosing behavior, and other behavioral aspects of marijuana smoking that affect THC exposure, are usually ignored. The Dutch researchers found that, in a group of 600 frequent cannabis users, some smokers did in fact show “shorter puff duration and inhaled lower smoke volumes when joints with a higher THC concentration were used.” So, yes, users did engage in partial titration when they smoked stronger marijuana. However, this did not translate into the expected results. In a final sample of 98 participants, the scientists discovered that “users of stronger cannabis generally used larger amounts of cannabis to prepare their regular joint.” (The study participants smoked marijuana European-style, mixing their marijuana with tobacco.) And even though subjects smoking joints with higher THC levels did inhale at slightly lower volumes and at a slower pace, the average user of pot with THC levels of 12% or higher definitely inhaled more liters of smoked THC per month than users of less potent pot. But just to confound matters, total THC exposure over a month’s time turned out to be “a weak predictor of dependence severity, and did not remain significant after adjustment for baseline dependence severity.”

Nonetheless, even with some degree of titration, “a positive association between total puff volume and withdrawal/craving was found, indicating that a larger inhaled volume may increase the THC exposure sufficiently to result in significant effects on clinical outcomes.” (Here is the UK National Health Service take on the research.) 

It is always difficult to say for certain in a prospective, cross-sectional study of behavior whether participants are acting the way they would act in “real life,” although efforts were made to allow smoking at home, or in Dutch coffee shops, as well as the laboratory. Interestingly, the one behavior that seemed to predict dependence in post-hoc analyses was a simple one. Smokers were allowed to mix a joint however they wished, and smoke however much of it they wanted to. Smokers who finished their joints, rather than leaving a portion of it for later, were the smokers more likely to be associated with dependence in the follow-up studies. In fact, “percentage of the joint smoked may be a simple proxy for risky smoking behavior.”

In addition, certain withdrawal symptoms correlated with dependence: “Increased somatic withdrawal symptoms are predictive of relapse, and…. increased physical tension is a significant predictor of relapse.”

As with alcohol, it seems that it is not necessarily how much you smoke or drink. It is how you smoke or drink. Strong marijuana doesn't cause addiction. The way certain people use strong pot can result in addiction, however.

Earlier research has shown that higher levels of cannabis dependence are associated with greater functional impairment, and that "the average level of impairment caused by cannabis, while mild for most users, can rise to the level of tobacco withdrawal which is of well established clinical significance.”

 Physical distress, a “somatic” variable, often matters more, in terms of relapse, than the amount of marijuana smoked, or any other symptom on the roster of functional impairments—including mood and other negative affect variables.  In an earlier study published in PLOS ONE,  investigators found that “cannabis withdrawal is clinically significant because it is associated with elevated functional impairment to normal daily activities, and the more severe the withdrawal is, the more severe the functional impairment is. Elevated functional impairment from a cluster of cannabis withdrawal symptoms is associated with relapse in more severely dependent users.”

van der Pol P., Liebregts N., Brunt T., van Amsterdam J., de Graaf R., Korf D.J., van den Brink W. & van Laar M. (2014). Cross-sectional and prospective relation of cannabis potency, dosing and smoking behaviour with cannabis dependence: an ecological study, Addiction,   n/a-n/a. DOI: 10.1111/add.12508

State Marijuana Legalization: The Opposing Voices

Repeating Our Alcohol Mistakes?

A recent article in the always insightful Alcoholism and Drug Abuse Weekly, edited by Alison Knopf, concerns itself with the voices speaking out against Attorney General Holder’s announcement that federal authorities would not interfere with state efforts to legalize marijuana. It’s no secret that we here at Addiction Inbox have been longtime advocates for decriminalization along Dutch lines. So it’s high time we heard from some prominent dissenters on this issue.

Kevin A. Sabet, Ph.D., director of Project SAM (Smart Approaches to Marijuana) and former White House advisor on marijuana policy: “It’s the same thing with alcohol:  The marijuana industry is giving lip service, saying that they don’t want kids to use.”

Sue Thau, public policy consultant for Community Anti-Drug Coalitions of America (CADCA): “This is the start of Big Marijuana the way we have Big Alcohol and Big Tobacco…. Anyone who cares about addiction has to care about this.”

Rafael Lemaitre, spokesman for the Office of National Drug Control Policy: “We know that marijuana use, particularly long-term, chronic use that began at a young age, can lead to dependence and addiction. Marijuana is not a benign drug, and we continue to oppose marijuana legalization because it runs counter to a public health approach to drug policy.”

Gen. Arthur T. Dean, CEO of Community Anti-Drug Coalitions of America (CADCA): "This decision sends a message to our citizens, youth, communities, states, and the international community at large that the enforcement of federal law related to marijuana is not a priority."

The article is entitled “Advocates dismayed as legalization moves forward.”

Here are a few I have come across recently from other sources:

Citizens Against Legalizing Marijuana (CALM): "After decades of study the FDA continues to reaffirm that there is no medical benefit provided by the use of smoked marijuana and that, in fact, considerable harm can be caused by such use. We affirm the 2006 FDA finding and vast scientific evidence that marijuana causes harm. The normalization, expanded use, and increased availability of marijuana in our communities are detrimental to our youth, to public health, and to the safety of our society."

Office of National Drug Control Policy: "The Office of National Drug Control Policy is working to reduce the use of marijuana and other illicit drugs through development of strategies that fully integrate the principles of prevention, treatment, recovery, and effective supply reduction efforts. Proposals such as legalization that would promote marijuana use are inconsistent with this public health and safety approach.... Marijuana use is associated with dependence, respiratory and mental illness, poor motor performance, and impaired cognitive and immune system functioning, among other negative effects."

CNBC: "Contrary to the beliefs of those who advocate the legalization of marijuana, the current balanced, restrictive, and bipartisan drug policies of the United States are working reasonably well and they have contributed to reductions in the rate of marijuana use in our nation.... The rate of current, past 30-day use of marijuana by Americans aged 12 and older in 1979 was 13.2 percent. In 2008 that figure stood at 6.1 percent. This 54-percent reduction in marijuana use over that 29-year period is a major public health triumph, not a failure."


Photo Credit: LARRY MAYER/Billings Gazette Staff

A Chemical Peek at Modern Marijuana

Researchers ponder whether ditch weed is better for you than sinsemilla.

Australia has one of the highest rates of marijuana use in the world, but until recently, nobody could say for certain what, exactly, Australians were smoking. Researchers at the University of Sydney and the University of New South Wales recently analyzed hundreds of cannabis samples seized by Australian police, and put together comprehensive data on street-level marijuana potency across the country. They sampled police seizures and plants from crop eradication operations. The mean THC content of the samples was 14.88%, while absolute levels varied from less than 1% THC to almost 40%.  Writing in PLoS one, Wendy Swift and colleagues found that roughly ¾ of the samples contained at least 10% total THC. Half the samples contained levels of 15% or higher—“the level recommended by the Garretsen Commission as warranting classification of cannabis as a ‘hard’ drug in the Netherlands.”

In the U.S., recent studies have shown that THC levels in cannabis from 1993 averaged 3.4%, and then soared to THC levels in 2008 of almost 9%. THC loads more than doubled in 15 years, but that is still a far cry from news reports erroneously referring to organic THC increases of 10 times or more.

CBD, or cannabidiol, another constituent of cannabis, has garnered considerable attention in the research community as well as the medical marijuana constituency due to its anti-emetic properties. Like many other cannabinoids, CBD is non-psychoactive, and acts as a muscle relaxant as well. CBD levels in the U.S. have remained consistently low over the past 20 years, at 0.3-0.4%. In the Australian study, about 90% of cannabis samples contained less than 0.1% total CBD, based on chromatographic analysis, although some of the samples had levels as high as 6%.

The Australian samples also showed relatively high amounts of CBG, another common cannabinoid. CBG, known as cannabigerol, has been investigated for its pharmacological properties by biotech labs. It is non-psychoactive but useful for inducing sleep and lowering intra-ocular pressure in cases of glaucoma.

CBC, yet another cannabinoid, also acts as a sedative, and is reported to relieve pain, while also moderating the effects of THC. The Australian investigators believe that, as with CBD, “the trend for maximizing THC production may have led to marginalization of CBC as historically, CBC has sometimes been reported to be the second or third most abundant cannabinoid.”

Is today’s potent, very high-THC marijuana a different drug entirely, compared to the marijuana consumed up until the 21st Century? And does super-grass have an adverse effect on the mental health of users? The most obvious answer is, probably not. Recent attempts to link strong pot to the emergence of psychosis have not been definitive, or even terribly convincing. (However, the evidence for adverse cognitive effects in smokers who start young is more convincing).

It’s not terribly difficult to track how ditch weed evolved into sinsemilla. It is the historical result of several trends: 1) Selective breeding of cannabis strains with high THC/low CBD profiles, 2) near-universal preference for female plants (sinsemilla), 3) the rise of controlled-environment indoor cultivation, and 4) global availability of high-end hybrid seeds for commercial growing operations. And in the Australian sample, much of the marijuana came from areas like Byron Bay, Lismore, and Tweed Heads, where the concentration of specialist cultivators is similar to that of Humboldt County, California.

The investigators admit that “there is little research systematically addressing the public health impacts of use of different strengths and types of cannabis,” such as increases in cannabis addiction and mental health problems. The strongest evidence consistent with lab research is that “CBD may prevent or inhibit the psychotogenic and memory-impairing effects of THC. While the evidence for the ameliorating effects of CBD is not universal, it is thought that consumption of high THC/low CBD cannabis may predispose users towards adverse psychiatric effects….”

The THC rates in Australia are in line with or slightly higher than average values in several other countries. Can an increase in THC potency and corresponding reduction in other key cannabinoids be the reason for a concomitant increase in users seeking treatment for marijuana dependency? Not necessarily, say the investigators. Drug courts, coupled with greater treatment opportunities, might account for the rise. And schizophrenia? “Modelling research does not indicate increases in levels of schizophrenia commensurate with increases in cannabis use.”

One significant problem with surveys of this nature is the matter of determining marijuana’s effective potency—the amount of THC actually ingested by smokers. This may vary considerably, depending upon such factors as “natural variations in the cannabinoid content of plants, the part of the plant consumed, route of administration, and user titration of dose to compensate for differing levels of THC in different smoked material.”

Wendy Swift and her coworkers call for more research on cannabis users’ preferences, “which might shed light on whether cannabis containing a more balanced mix of THC and CBD would have value in the market, as well as potentially conferring reduced risks to mental wellbeing.”

Swift W., Wong A., Li K.M., Arnold J.C. & McGregor I.S. (2013). Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile., PloS one, PMID: 23894589

Graphics Credit: http://420tribune.com

“Spiceophrenia”

Synthetic cannabimimetics and psychosis.

Not long ago, public health officials were obsessing over the possibility that “skunk” marijuana—loosely defined as marijuana exhibiting THC concentrations above 12%, and little or no cannabidiol (CBD), the second crucial ingredient in marijuana—caused psychosis. In some cases, strong pot was blamed for the onset of schizophrenia.

The evidence was never very solid for that contention, but now the same questions have arisen with respect to synthetic cannabimimetics—drugs that have THC-like effects, but no THC. They are sold as spice, incense, K2, Aroma, Krypton, Bonzai, and dozens of other product monikers, and have been called “probationer’s weed” for their ability to elude standard marijuana drug testing. Now a group of researchers drawn primarily from the University of Trieste Medical School in Italy analyzed a total of 223 relevant studies, and boiled them down to the 41 best investigations for systematic review,  to see what evidence exists for connecting spice drugs with clinical psychoses.

Average age of users was 23, and the most common compounds identified using biological specimen analysis were the now-familiar Huffman compounds, based on work at Clemson University by John W. Huffman, professor emeritus of organic chemistry: JWH-018, JWH-073, JWH-122, JWH-250. (The investigators also found CP-47,497, a cannabinoid receptor agonist developed in the 80s by Pfizer and used in scientific research.) The JWH family consists of very powerful drugs that are full agonists at CB-1 and CB-2 receptors, where, according to the study, “they are more powerful than THC itself.” What prompted the investigation was the continued arrival of users in hospitals and emergency rooms, presenting with symptoms of agitation, anxiety, panic, confusion, combativeness, paranoia, and suicidal ideation. Physical effects can includes elevated blood pressure and heart rate, nausea, hallucinations, and seizures.

One of the many problems for researchers and health officials is the lack of a widely available set of reference samples for precise identification of the welter of cannabis-like drugs now available. In addition, the synthetic cannabimimetics (SCs) are frequently mixed together, or mixed with other psychoactive compounds, making identification even more difficult. Add in the presence of masking agents, along with various herbal substances, and it becomes very difficult to find out which of the new drugs—none of which were intended for human use—are bad bets.

Availing themselves of toxicology tests, lab studies, and various surveys, the researchers, writing in Human Psychopharmacology’s Special Issue on Novel Psychoactive Substances, crunched the data related to a range of psychopathological issues reported with SCs—and the results were less than definitive. They found that many of the psychotic symptoms occurred in people who had been previously diagnosed with an existing form of mental disturbance, such as depression, ADHD, or PTSD. But they were able to determine that psychopathological syndromes were far less common with marijuana than with SCs. And those who experienced psychotic episodes on Spice-type drugs presented with “higher/more frequent levels of agitation and behavioral dyscontrol in comparison with those psychotic episodes described in marijuana misusers.”

In the end, the researchers can do no better than to conclude that “the exact risk of developing a psychosis following SC misuse cannot be calculated.” What would the researchers need to demonstrate solid causality between designer cannabis products and psychosis? More product consistency, for one thing, because “the polysubstance intake pattern typically described in SC misusers may act as a significant confounder” when it comes to developing toxicological screening tools. Perhaps most disheartening is “the large structural heterogeneity between the different SC compounds,” which limited the researchers’ ability to interpret the data.

This stuff matters, because the use of Spice-type drugs is reported to be increasing in the U.S. and Europe. Online suppliers are proliferating as well. And the drugs are particularly popular with teens and young adults. Young people are more likely to be drug-naïve or have limited exposure to strong drugs, and there is some evidence that children and adolescents are adversely affected by major exposure to drugs that interact with cannabinoid receptors in the brain. 

Graphics credit: http://scientopia.org/blogs/drugmonkey/

Marijuana and Diabetes: Does Pot Make You Thin?

Teasing out the insulin effect.

On the face of it, the study seems to come out of left field: A group of researchers claimed that marijuana smokers showed 16 per cent lower fasting insulin levels than non-smokers. The study, called “The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults,”  is in press for The American Journal of Medicine. The authors are a diverse group of medical researchers from Harvard, Beth Israel Deaconess Medical Center, and the University of Nebraska College of Medicine. The study concluded: “We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR [a measure of insulin resistance], and smaller waist circumference.”

Of course, it was that last tidbit about waist circumference that was picked up by the media. “Why Pot Smokers Are Skinnier,” headlined the Atlantic. However, the important implications are not so much for weight control, or the discovery of some built-in offsetting mechanism for the marijuana munchies, but rather for insulin control and the treatment of diabetes.

But in a clinical study, remarkable observations require remarkable documentation. What does the research actually say?

There are problems with the study worth noting. While researchers took blood samples after a 9-hour fast to determine insulin and glucose levels, they relied on self-reporting for marijuana use data. And self-reporting for alcohol and drug use has its limitations as an investigative tool. Namely, lack of honesty. But let’s get beyond that for a moment: From a database of 4,657 men and women who participated in the National Health and Nutrition Examination Survey, the researchers determined that 579 were current marijuana users, while 1,975 were pot smokers in the past.

The marijuana-smoking cohort tended to be young males who also smoked cigarettes. After running everything through a series of complicated multivariable-adjusted models, marijuana came out associated with lower insulin levels, and “lower waist circumference” than those who reported never using marijuana. And the results didn’t change much after adjusting for BMI numbers and excluding participants who actually had diabetes. Furthermore, the association was strongest in current smokers, “suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use.” (It should also be noted that other health habits can affect glucose and insulin activity, including cigarettes, alcohol, and lack of physical activity.)

The investigators don’t offer a solution to the increased appetite/decreased waistline conundrum they claim to have identified. “We did not find any significant associations between marijuana use, and triglyceride levels, systolic blood pressure, or diastolic blood pressure,” they concluded.

We know marijuana has a complicated relationship with appetite mechanisms, as evidenced by its use with chemotherapy patients who need to eat. The theory is that the metabolic effects are mediated by a complex mix of cannabinoid type 1 and type 2 receptor interactions, since type 1 receptor antagonists like rimonabant improve insulin resistance in humans, and type 1 knockout mice also show resistance to diet-induced obesity.

Does marijuana smoking protect against diabetes? Wisely, the researchers don’t go that far, on the basis of this one uncontrolled study.  The researchers’ conclusions neatly hedge the bets, suggesting that with recent trends in the direction of marijuana legalization, “physicians will increasingly encounter patients who use marijuana and should therefore be aware of the effects it can have on common disease processes, such as diabetes mellitus.”

As it happens, the findings aren’t entirely new. Anecdotal reports abound. Back in 2010, on the Diabetes Daily support board, there was a long discussion of marijuana’s effect on blood glucose levels in diabetics. And there are several mouse models showing the same effects. In a prepared statement, lead investigator Murray A. Mittleman of Beth Israel Deaconess Medical Center in Boston conceded that previous epidemiological studies have found “lower prevalence rates of obesity and diabetes mellitus in marijuana users compared to people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes.” However, he believes that “ours is the first study to investigate the relationship between marijuana use and fasting insulin, glucose, and insulin resistance.”

Perhaps so. A 2011 study in the American Journal of Epidemiology concluded that “the prevalence of obesity is lower in cannabis users than in nonusers.” And the British Medical Journal featured a finding in 2012 by Los Angeles researchers that marijuana use was “independently associated with a lower prevalence of diabetes mellitus.” But the online patient guide for marijuana offered by Mayo Clinic  says without equivocation that “cannabis may lower blood sugar. Caution is advised in patients with diabetes or hypoglycemia, and in those taking drugs, herbs, or supplements that affect blood sugar.” In fact, Mayo Clinic advises that patients may want to monitor their blood glucose levels if they smoke medical marijuana.

Regarding the current study, the editor-in-chief of the American Journal of Medicine said in a statement that there is a need for “a great deal more basic and clinical research into the short- and long-term effects of marijuana in a variety of clinical settings such as cancer, diabetes, and frailty of the elderly.” Editor Joseph S. Alpert also called on the National Institutes of Health (NIH) and the Drug Enforcement Administration (DEA) to collaborate in “developing policies to implement solid scientific investigations that would lead to information assisting physicians in the proper use and prescription of THC in its synthetic or herbal form.”

Penner E.A., Buettner H. & Mittleman M.A. (2013). The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults, The American Journal of Medicine,    DOI: 10.1016/j.amjmed.2013.03.002

Photo Credit: http://www.herbalmission.org/

Marijuana and Strokes: Medical Reality or Scare Story?

Heavy tokers may be at higher risk, but alcohol is the hidden confounder.

Young people don’t suffer from strokes, as a rule. And when they do, at least half the time there is no obvious cardiovascular explanation. So it’s not surprising that drugs are often invoked as the culprit.

A New Zealand study earlier this year once again raised the specter of a possible link between stroke and marijuana smoking. As reported by Maia Szalavitz at Time Healthland, the confounding issue, as is typical of such studies, is the coexisting use of other drugs, like alcohol and cigarettes. As Szalavitz writes:

The stroke study, which incorporated preliminary data, is the first trial of its kind to study a possible connection between marijuana use and stroke. It included 160 patients aged 18 to 55 who had suffered a stroke connected to a blood clot in the brain, and who agreed to have their urine tested for marijuana within 72 hours of the stroke.  These results were compared to those from 160 controls who had not had a stroke but came to the hospital for other reasons. They were matched on age, gender and ethnic background, all of which can also affect the risk for this type of stroke. About 16% of the stroke patients showed traces of marijuana in their urine, compared to 8% of those in the control group, suggesting a doubling of the risk of stroke.

However, because of nicotine and other confounding variables, that study was considered inconclusive. In an earlier study published in Stroke, the journal of the American Heart Association, Valerie Wolff and colleagues from the University of Strasbourg in France searched the medical literature and found 59 cases of stroke in which cannabis could be considered a cardiovascular risk factor. The investigators used only cases that had been confirmed by neuroimaging. The researchers focused on cases where a stroke had occurred while smoking marijuana, or within a half hour after the last joint or bong hit.

But proving a cause and effect relationship is tricky. Assuming, for now, that all of the strokes in question were not caused or compounded by alcohol or drugs other than marijuana, the French scientists postulated several mechanisms that could conceivably account for a cannabis-related ischemic stroke (a stroke caused by obstruction of a blood vessel). These include orthostatic hypotension, altered cerebral vasomotor function, major swings in blood pressure, and cardiac arrhythmias. However, the only solid commonality in cannabis-related strokes was that the users were more likely to be heavy smokers.

In the 50 strokes the researchers were able to confirm by cerebral imaging, the patterns in some patients were similar to those observed in a syndrome called reversible cerebral vasoconstriction syndrome (RCVS). RCVS  is marked by severe headaches, strokes, and brain edema, but symptoms typically resolve in a few months.  “Reversibility of the vasoconstriction within 12 weeks is a key point of this syndrome,” the authors write. “The long duration of stenosis [blockage] argues in favor of a drug-induced immunoallergic vasculitis rather than vasospasm. Our point of view is that this disorder may be considered as a variant of RCVS,” rather than as a garden-variety ischemic stroke triggered by excessive use of cannabis.

According to the French study, “The most frequently presented characteristics of cannabis users who experienced a stroke are young male chronic tobacco and cannabis abusers who have had an unusual high consumption of cannabis and alcohol before stroke.” The most convincing mechanism to explain ischemic strokes in young people, the researchers say, is “reversible cerebral angiopathy involving several arteries, associated with cannabis consumption in association with tobacco and alcohol use.”

And there you have it. Smoke weed, and you appear to have a slight risk of suffering stroke, which, under age 50, is an extremely uncommon medical event.  Add tobacco, and the stroke risk goes up. Add alcohol, and the stroke risk ratchets even higher. By itself, marijuana appears to be a minor factor in strokes—but it appears likely that pot is indeed the culprit at least some of the time.

“Cannabis-related stroke is not a myth,” the scientists conclude, “and a likely mechanism of stroke in most cannabis users is the presence of reversible multifocal intracranial stenosis (MIS) induced by this drug. The reality of the relationship between cannabis and stroke is, however, complex, because other confounding factors have to be considered (ie, lifestyle and genetic factors).”

Wolff V., Armspach J.P., Lauer V., Rouyer O., Bataillard M., Marescaux C. & Geny B. (2013). Cannabis-related Stroke: Myth or Reality?, Stroke, 44 (2) 558-563. DOI: 10.1161/STROKEAHA.112.671347

Graphics Credit: http://www.strokegenomics.org/

A Look at the Recent Study of Cannabis and Multiple Sclerosis

Smoked marijuana reduced spasticity in a small trial of MS patients.

The leading wedge of the medical marijuana movement has traditionally been centered on pot as medicine for the effects of chemotherapy, for the treatment of glaucoma, and for certain kinds of neuropathic pain. From there, the evidence for conditions treatable with marijuana quickly becomes either anecdotal or based on limited studies. But pharmacologists have always been intrigued by the notion of treating certain neurologic conditions with cannabis. Sativex, which is sprayed under the tongue as a cannabis mist, has been approved for use against multiple sclerosis, or MS, in Canada, the UK, and some European countries. (In the U.S., parent company GW Pharma is seeking FDA approval for the use of Sativex to treat cancer pain).

There is accumulating evidence that cannabinoid receptors may be involved in controlling spasticity, and that anandamide, the brain’s endogenous form of cannabis, is a specific antispasticity agent.

Additional evidence that researchers may be on to something appeared recently in the Canadian Medical Association Journal. Dr. Jody Corey-Bloom and coworkers at the University of California in San Diego conducted a small, placebo-controlled trial with adult patients suffering from poorly controlled spasticity. Thirty participants were randomly divided into two groups. Those in the first group were given a daily joint, and those in the second group received “identical placebo cigarettes.” After three days, the investigators found that smoked marijuana resulted in a reduction in treatment-resistant spasticity, compared to placebo.

Clearly, it’s hard for a study of this sort to be truly blind: Participants, one presumes, had little trouble distinguishing the medicine from the placebo. And in fact, an appendix to the study shows this to be true: “Seventeen participants correctly guessed their treatment phase for all six visits… For the remaining participants, cannabis was correctly guessed on 33/35 visits.” This raises the question of various kinds of self-selection bias and expectancy effects, and the study authors themselves write that the results “might not be generalizable to patients who are cannabis-naïve.” On the other hand, cannabis-naïve patients were in the minority. The average age of the participants was 50, and fully 80% of them admitted to previous “recreational experience” with cannabis. (I don’t have a good Baby Boomer joke for the occasion, but if I did, this is where it would go).

I asked Dr. Corey-Bloom about this potential problem in an email exchange: “The primary outcome measure was the Ashworth Spasticity Scale, which is an objective measure, carried out by an independent rater,” she wrote. “Their job was just to come in and feel the tone around each joint (elbow, hip, knee), rate it, and leave.  That's why we think it was so important to have an objective measure, rather than just self-report.”

With all this in mind, the study found that “smoking cannabis reduced patient scores on the modified Ashworth scale by an average of 2.74 points.” The authors conclude: “We saw a beneficial effect of smoked cannabis on treatment-resistant spasticity and pain associated with multiple sclerosis among our participants.”

Other studies have found similar declines in spasticity from cannabinoids, but have tended not to use marijuana in smokable form.

Corey-Bloom, J., Wolfson, T., Gamst, A., Jin, S., Marcotte, T., Bentley, H., & Gouaux, B. (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial Canadian Medical Association Journal DOI: 10.1503/cmaj.110837

Photo Credit: http://blog.amsvans.com/

Marijuana Can Make You Vomit, and Other Stories

Short subjects, various.

First, a recap of an earlier story, and a very strange story at that. Cannabinoid hyperemesis, as it's known, was not documented in the medical literature until 2004, and was first brought to wider attention earlier this year by the biomedical researcher who blogs as Drugmonkey. Episodes of serial vomiting appear to be a very rare side effect of regular marijuana use. Posting on his eponymous blog, Drugmonkey documented cases of hyperemesis that had been reported in Australia and New Zealand, as well as Omaha and Boston in the U.S.

As Drugmonkey reported, “patients had discovered on their own that taking a hot bath or shower alleviated their symptoms. So afflicted individuals were taking multiple hot showers or baths per day to obtain symptom relief.”

A year ago, I published a post on this topic, titled "Marijuana, Vomiting, and Hot Baths." Sure enough, a number of people left comments about their own experiences with this unusual and unpleasant effect. Recently, one of my commenters caught drugmonkey’s eye, and he noted it in his new blog post on the phenomenon:

“Dirk Hanson's post on cannabis hyperemesis garnered another pertinent user:

Anonymous said...
My son suffers from this cannabinoid hyperemesis. At this moment he is here at my home on the couch suffering. I have been up with him for 3 days with the vomiting and hot baths. He says this time its over for good. This is our third bout. The first two time we went to ER, they put him on a drip to hydrate him, and gave him some pain medicine and nausea medicine. After a few hours he went home and recovered. This time we went to Urgent Care, put him on a drip, pain med, Benadryl, and Zofran….

Drugmonkey writes: “I reviewed several case reports back in 2010.... and there was considerable skepticism that the case report data was convincing. So I thought I'd do a PubMed search for cannabis hyperemesis and see if any additional case reports have been published…. One in particular struck my eye. Simonetto and colleagues (2012) performed a records review at the Mayo Clinic. They found 98 cases of unexplained, cyclic vomiting which appeared to match the cannabis hyperemesis profile out of 1571 patients with unexplained vomiting and at least some record of prior cannabis use… this is typical of relatively rare and inexplicable health phenomena. The Case Reports originally trickle out... this makes the medical establishment more aware and so they may reconsider their prior stance vis a vis so-called "psychogenic" causes. A few more doctors may obtain a much better cannabis use history then they otherwise would have done. More cases turn up. More Case Reports are published. etc. It's a recursive process. “
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In a story I think of as vaguely related, in the sense that it is a rare drug phenomenon unrecognized by the public, I recently wrote an article  for The Dana Foundation on the subject of “Smoking’s Ties to Schizophrenia.” In addition, check out a story about plans by the Air Force to make their hospitals and clinics smoke-free HERE. In brief: Smoke-free clinics pose major problems for heavy smokers with mental health disorders.
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Speaking of hospitals, Michelle Andrews reports in Kaiser Health News that about half of the patients undergoing treatment in hospital emergency rooms are under the influence of booze. Alcohol screening and counseling can be effective in this context—but there’s a catch. “Regardless of state law, self-insured companies that pay their employee’s health care costs directly can refuse to cover employees for alcohol-related claims.”

Even though the National association of Insurance Commissioners does not recommend it, dozens of states have passed laws allowing health insurers to deny payment for a patient’s injuries if they were incurred while he or she was under the influence of alcohol. About as many states have passed laws prohibiting such exclusions due to alcohol. The result is one big mess, and confusion reigns. As a professor of health law put it: “There’s no reason to think that insurers, eager to hold down costs, wouldn’t continue” to deny payment for alcohol-related injuries.
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And finally, some news about Chantix (varenicline), the drug both patients and doctors love to hate. It often works very well as an anti-craving medication for smoking cessation. But it can also, in some cases, present patients with a bewildering array of psychological side effects, including rare cases of suicidal ideation. A new study  by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco, suggests that Chantix may have application in the treatment of alcoholism as well. Participants in the study reduced the average number of drinker per week on Chantix, compared to placebo. The study was funded by the National Institutes of Health and the State of California. Pfizer, the company that markets Chantix, did not fund or participate in the study.

Graphics Credit: http://teesdiary.files.wordpress.com/

A Drug For Marijuana Withdrawal?

Researchers get good results with gabapentin.

Marijuana, as researchers and pundits never tire of pointing out, is the most widely used illegal drug in the world, by a serious margin. And while the argument still rages, for some years now drug researchers have been migrating to the camp that sees marijuana as an addictive drug for a minority of people who exhibit a propensity for addiction. The scientific literature supporting the contention of marijuana as addictive for some users is robust and growing, as is the body of anecdotal evidence.  It’s also clear that in many countries, cultures, and subcultures, combining cannabis with tobacco is a common practice that increases health risks all around.

Ongoing work at the Scripps Research Institute’s Pearson Center for Alcoholism and Addiction Research in La Jolla, California, has focused in part on the lack of FDA-approved medical therapies for treating marijuana addiction. Barbara J. Mason and coworkers at Scripps have reported preliminary success in a 12-week, double-blind, placebo-controlled pilot study with 50 treatment-seeking volunteers, using the anti-seizure drug gabapentin. Gabapentin, sold as Neurontin, pops up as a possible treatment for various forms of pain and anxiety, and sharp-eyed readers will recall that gabapentin was one of the ingredients in the now-defunct addiction drug Prometa.

Marijuana addiction numbers are hard to come by, and often inflated, since many small-time pot offenders end up in mandatory treatment programs, where they tend to be classified as marijuana addicts, whether or not that is objectively the case. Nonetheless, there are plenty of people seeking treatment on their own for cannabis dependence. For people strongly addicted to pot, the problems are very real, and withdrawal and abstinence pose serious challenges. People for whom marijuana poses no addictive threat should bear this in mind, the way casual drinkers bear in mind the existence of alcoholism in others.

The study, published recently in Neuropsychopharmacology, says that “activation of brain stress circuitry caused by chronic heavy marijuana use” can lead to withdrawal symptoms that persist “for weeks or even months, as in the case of marijuana craving and sleep disturbances.” A variety of existing medications have been tested in recent years, including buspirone, an anti-anxiety medication; Serzone, an antidepressant; and Wellbutrin, an antidepressant commonly used for smoking cessation. None of these treatments has shown any effect on cannabis use or withdrawal, according to Mason.

Gabapentin, as the name suggests, was modeled after the neurotransmitter GABA, and works via a transporter protein to raise GABA levels. Effective only for partial-onset seizures, common side effects include drowsiness, dizziness, and possible weight gain. It is a popular anti-epileptic drug, because it is relatively safe, with a low side-effect profile, compared to many of the medications in its class. For the same reasons, it is a common treatment for neuropathic pain. In addition to neuralgia, it has found some use as a migraine preventative.

Gabapentin normalizes GABA activation caused by corticotrophin-releasing factor, or CRF. CRF is a major player in the brain’s stress responses. As it turns out, withdrawal from both cannabis and alcohol ramp up anxiety levels by increasing CRF release in the amygdala, animal studies have shown. “Gabapentin had a significant effect in decreasing marijuana use over the course of treatment, relative to placebo,” the authors report. In addition, gabapentin produced “significant reductions in both the acute symptoms of withdrawal as well as in the more commonly persistent symptoms involving mood, craving, and sleep.”

As a bonus, the researchers discovered that “overall improvement in performance across cognitive measures was significantly greater for gabapentin-treated subjects compared with those receiving placebo.” Gabapentin was associated with improvement in “tasks related to neurocognitive executive functioning”—things like attention, concentration, visual-motor functioning, and inhibition. Counseling alone, represented by the placebo group, “resulted in less effective treatment of cannabis use and withdrawal, and no improvement in executive function.”

As in the case of Chantix for cigarette cessation, a treatment, which now requires additional caveats about possible suicidal ideation, researchers looking for a treatment for drug withdrawal, must weigh the benefits of pharmacological treatment against the possible side effects of the treatment itself. Does gabapentin for marijuana withdrawal pass the “Do No Harm” test? According to Mason, it does. “Gabapentin was well tolerated and without significant side effects” in the admittedly small trial study. The two groups did not differ in the number of adverse medical events reported in the first two weeks, when dropout rates due to side effects are highest in these kinds of studies. The investigators were not relying solely on self-reporting, either. They used urine drug screens, and verified that only 3% of the study sample tested positive for other drugs.

In short, the authors report that gabapentin reduced cannabis use and eased withdrawal with an acceptable safety profile and no signs of dependence. Gabapentin, the authors conclude, “may offer the most promising treatment for cannabis withdrawal and dependence studied to date.” Further clinical research is needed, of course, but the positive results of this proof-of-concept study should make funding a bit easier.

Mason, B., Crean, R., Goodell, V., Light, J., Quello, S., Shadan, F., Buffkins, K., Kyle, M., Adusumalli, M., Begovic, A., & Rao, S. (2012). A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults Neuropsychopharmacology DOI: 10.1038/npp.2012.14

Photo Credit: http://pep3799.hubpages.com/

From Their Mouth to Your Ear: Researchers Talk Drugs

A collection of five-question interviews.

I’ll be away from the Addiction Inbox office this week, attending the big TEDMED health and medicine powwow in Washington, D.C.

In the meantime, here’s a summation (with links) of the interviews I’ve been doing recently in the “five-question interview” series. I’ve been very lucky to nab some state-of-the-art thinkers, working at the top of their fields, from psychiatry to pharmacology to neuroscience.

See below for the story thus far:



David Kroll, former Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, is now Science Communications Director for the Nature Research Center at the North Carolina Museum of Natural Sciences.

“The attraction to users was, until recently, that Huffman cannabis compounds (prefixed with "JWH-" for his initials) could not be detected in urine by routine drug testing. Hence, incense products containing these compounds have been called ‘probationer's weed.’" MORE

Vaughan Bell is a Senior Research Fellow at the Institute of Psychiatry, King’s College, London. He is also honorary professor at the Universidad de Antioquia in Medellín, Colombia.

"I was very struck by the appearance of classic Kluver form constants [after taking ayahuasca], geometric patterns that are probably caused by the drug affecting the visual neurons that deal with basic perceptual process (e.g. line detection)." MORE

Jon Simons, a cognitive neuroscientist, is a lecturer in the Department of Experimental Psychology at the University of Cambridge, UK, and principal investigator at the University’s Memory Laboratory.

“If you’re at a party and happen to drunkenly strike up conversation with Angelina Jolie (or Brad Pitt, if you prefer) and, bowled over by your charm and witty repartee, she tells you her phone number, you may well not remember it when you wake up sober the next morning. However, the evidence suggests that you would have a better chance of recalling the number if you got drunk again." MORE

Bankole Johnson is professor and chairman of the University of Virginia’s Department of Psychiatry and Neurobehavioral Sciences.

“With growing and clear acceptance of the neurobiological underpinnings of addiction, our work on pharmacogenetics promises to provide effective medications—such as ondansetron—that we can deliver to an individual likely to be a high responder, based on his or her genetic make up." MORE

Michael Farrell is the director of the National Drug and Alcohol Research Centre (NDARC) at the University of New South Wales in Sydney, Australia. Before that, he was Professor of Addiction Psychiatry at the Institute of Psychiatry at Kings College, London.

“The near complete absence of methadone or buprenorphine treatment in American prisons is hard to understand, when you see what a great contribution US research and treatment with methadone and buprenorphine has had globally. Now there are over 300,000 people on methadone in China as part of HIV and AIDS prevention." MORE

Deni Carise is a clinical psychologist who serves as senior vice president and chief clinical officer at Phoenix House, a leading U.S. non-profit drug treatment organization with more than 100 programs in 10 states.

“Those in recovery see the disease of alcoholism or addiction as a moral obligation to get well. If you know you have this disease and the only way to keep it under control is not to use alcohol or drugs, then that’s what you have to do." MORE


Keith Laws is professor of cognitive neuropsychology and head of research in the School of Psychology at the University of Hertfordshire, UK.

"Some may tolerate 100s or even 1000s of E tablets, but for others far fewer may lead to memory problems. We can predict that 3 in 4 users will develop memory problems, but not which 3 or after how many tablets." MORE

photo credit: http://www.startawritingbusiness.co.uk