Alcohol and Your Heart

Health benefits of moderate drinking come under fire.

One of those things that “everybody knows” about alcohol is that a drink or two per day is good for your heart. But maybe not as good for your heart as no drinks at all.

Joint first authors Michael V. Holmes of the Department of Epidemiology and Public Health at University College in London, and Caroline E. Dale at the London School of Hygiene & Tropical Medicine in London, recently published a multi-site meta-analysis of epidemiological studies centering on a common gene for alcohol metabolization. The report, published in the UK journal BMJ, brings “the hypothesized cardioprotective effect of alcohol into question,” according to the authors.

People who are born with a particular variant in the gene controlling for the expression of alcohol dehydrogenase, the major enzyme involved in converting alcohol into waste products, will show the familiar flush reaction when they drink. Alcohol, literally, can make many of them sick. This genetic variant, in combination with other enzymes, can be strongly protective against alcohol, and is much more commonly found among Asian populations. Roughly 40% of Japanese, Korean, and Northeastern Chinese populations show the characteristic “Asian glow” to one degree or another if they choose to drink.  (One reason why this effect isn't better known is that the condition is close to nonexistent in Westerners).

 People with this alcohol dehydrogenase deficiency, the researchers found, not only consume less alcohol, for obvious reasons, but “had lower, not higher, odds of developing coronary heart disease regardless of whether they were light, moderate, or heavy drinkers.”  Here are the conclusions in detail: “Carriers of the rs1229984 A-allele had lower levels of alcohol consumption and exhibited lower levels of blood pressure, inflammatory biomarkers, adiposity measures, and non-HDL cholesterol, and reduced odds of developing coronary heart disease, compared with non-carriers of this allele.”

The authors conclude that "reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.”

How does this work? The researchers aren’t completely sure, but note that the “most widely proposed mechanism” is an increase in high-density lipoprotein (HDL) cholesterol. “Although an HDL cholesterol raising effect of alcohol has been reported in experimental studies, the small sample size and short follow-up means existing studies may be prone to bias,” thereby limiting their usefulness. Moreover, the BMJ study itself found “no overall difference between allele carriers and non-carriers in HDL concentration.”

Like most meta-studies, this one has its strengths and weaknesses. The study used a large sample size, used detailed alcohol phenotypic data, and didn't have to deal with the inherent biases of observational-type studies. On the minus side, the lack of a connection between the allele in question and HDL levels is troubling, and stroke data was lacking.

But overall, the authors believe that "social pressure in heavier drinking cultures is unlikely to override the effect of the genetic variant on alcohol consumption."

In retrospect, there have been some trouble spots along the way: A 2008 study in Current Atherosclerosis Reports concluded:

In the absence of large randomized trials of moderate alcohol consumption and heart failure, we cannot exclude residual confounding or unmeasured confounding as possible explanations for the observed relationships. Thus, for patients who do not consume any alcohol, it would be premature to recommend light-to-moderate drinking as a means to lower the risk of heart failure, given the possible risk of abuse and resulting consequences.

At present, the American Heart Association does not recommend drinking any amount of wine or other alcoholic beverages in order to gain potential health benefits.


Holmes M.V.,  L. Zuccolo,  R. J. Silverwood,  Y. Guo,  Z. Ye,  D. Prieto-Merino,  A. Dehghan,  S. Trompet,  A. Wong &  A. Cavadino &  (2014). Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data, BMJ, 349 (jul10 6) g4164-g4164. DOI: http://dx.doi.org/10.1136/bmj.g4164

Photo credit: http://qsystem.gblifesciences.com/

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

Synthetic Cannabis Can Cause Cyclic Vomiting

Another reason to skip "Spice."

Cannabinoid hyperemesis,  as it is known, was not documented in the medical literature until 2004. Case studies of more than 100 patients have been reported since then. The biomedical researcher who blogs as Drugmonkey has 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 who are heavy marijuana smokers, and who experience cyclic nausea and vomiting, “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 recent report in Mayo Clinic Proceedings by Dr. Benjamin L. Bick and colleagues documents the 3rd reported case of the syndrome in a regular user of synthetic Spice-style products, rather than marijuana. It’s now clear that THC isn’t necessary for triggering the rare but highly unpleasant vomiting cycle in a small fraction of users.

“A 29-year-old man presented with a 2-year history of recurrent episodes of severe nausea and vomiting with epigastric pain,” according to the authors. Drug tests were negative, including tests for THC. “For his more recent symptoms, he was evaluated multiple times in the primary care setting and emergency department. At each visit he denied use of any ‘illicit substances or drugs’ since he quit using marijuana.”

“Hot showers for up to an hour provided relief. He reported experiencing similar symptoms more than 5 years previously when he was regularly smoking marijuana, and these symptoms resolved with the cessation of cannabis.”

The patient eventually admitted to regularly smoking products sold as K2 and Kryptonite, containing “unidentified and uncertain synthetic cannabinoid agonists marketed as ‘legal’ herbal incense.”

The Mayo clinicians offer diagnostic criteria for cannabis hyperemesis, which include “long-term cannabis use, cyclic nausea and vomiting, resolution with cessation of cannabis, relief of symptoms with hot showers, abdominal pain, and weekly use of marijuana.” And theirs is the third published report of cannabis hyperemesis in a male patient after synthetic cannabinoid use. “After 6 months abstinence,” they report, “he noted complete resolution of symptoms.”

The researchers conclude that “synthetic cannabinoids can be potent agonists of the cannabinoid CB1 receptors, which are the same receptors by which THC produces its effects.” While only three Spice-related incidents of hyperemesis syndrome have thus far been identified, it may go unrecognized in patients using synthetic cannabinoids:

 A urine drug screen negative for THC may point physicians away from this syndrome, and patients may not report use if they believe they are using herbal products rather than illicit drugs. Therefore, regardless of negative urine drug screen results and patient denial of cannabis use, physicians should have a high index of suspicion for synthetic CH syndrome in patients who present with classic symptoms of cyclic emesis.

Sarah A. Buckley and Nicholas M. Mark at the NYU School of Medicine, after reviewing 16 published papers on the syndrome,  asked the obvious question: "How can marijuana, which is used in cancer clinics as an anti-emetic, cause intractable vomiting? And why would symptoms abate in response to high temperature?"

We don't know the answer, but Buckley and Mark note that "cannabis disrupts autonomic and thermoregulatory functions of the hippocampal-hypothalamic-pituitary system," which is loaded with CB-1 receptors. The researchers conclude, however, that the link between marijuana and thermoregulation "does not provide a causal relationship" for what they refer to as "this bizarre learned behavior.”

Bick B.L. &  Thomas F. Mangan (2014). Synthetic Cannabinoid Leading to Cannabinoid Hyperemesis Syndrome, Mayo Clinic Proceedings, 89 (8) 1168-1169. DOI: http://dx.doi.org/10.1016/j.mayocp.2014.06.013

Photo credit: http://www.aquaticcreationsnc.com/custom.htm

Avoid the ‘Noid: Synthetic Cannabinoids and “Spiceophrenia”

Like PCP all over again.

Synthetic cannabis-like “Spice” drugs were first introduced in early 2004, and quickly created a global marketplace. But the drugs responsible for the psychoactive effects of Spice products weren’t widely characterized until late 2008. And only recently have researchers made significant progress toward understanding why these drugs cause so many problems, compared to organic marijuana.

Synthetic cannabinoids (SC), as a class of drugs, are generally more potent at cannabinoid receptors than marijuana itself.  As full agonists, synthetic cannabinoids show binding affinities between 5 and 10,000 times higher than THC at these receptors.

A recent literature study by Duccio Papanti at the University of Trieste and coworkers sheds additional light on the problematic nature of these drugs. In an article for Advances in Dual Diagnosis titled “’Noids in a nutshell: everything you (don’t) want to know about synthetic cannabimimetics,” the researchers note that “Spice products’ effects have been anecdotally described by users as intense and ‘trippy’ marijuana-like, with hallucinatory experiences being associated with higher levels of intake. In comparison with cannabis, SC compounds may be associated with quicker ‘kick off’ effects; significantly shorter duration of action; larger levels of hangover effects; and more frequent paranoid feelings.”

The study also points out a trouble spot: “Super-concentrations of synthetic cannabinoids (e.g. ‘hot-spots’) in herbal blends, originating from a non-optimal homogenization between synthetic cannabinoids and the vegetal substrate, can result in overdoses/intoxications and ‘bad trips’ in users.” In other words, the chemical powder is often so poorly mixed with the vegetable matter that potencies in the batch can be way too high, depending upon the luck of the draw, and are bound to vary from batch to batch in any event.

Nonetheless, there is a cluster of specific health effects that brings users to the emergency room. The typical set of symptoms—bearing in mind that polydrug use always complicates the picture—include elevated heart rate, elevated blood pressure, visual and auditory hallucinations, agitation, anxiety, nausea, vomiting, and seizures.

The authors note that “nausea and seizures are very uncommon in marijuana use, due to the suggested anticonvulsant/antiemetic properties of cannabis.” In fact, misusers who present doctors with vomiting as a symptom are often assumed to be free of cannabis-type drugs. Not so with synthetic cannabinoids. In an email interview, lead author Duccio Papanti told me that “many users describe the occurrence of vomiting, even with a non-recurrent and low use of these compounds. My idea is that this may be due to the smoking of hot-spotted blends, and that at high concentrations these compounds can work more on 5-HT receptors (in fact, vomit and seizures are signs of a serotonin syndrome).”

Less common, luckily, are other medical issues like heart attack, kidney injuries, and stroke. Of primary concern, the authors warn, are the reported incidents of “transient psychotic episodes,” “relapse of a primary psychosis,” and “‘ex novo’ psychosis in previous psychosis-free subjects.”

As for the mechanism behind the reported hallucinogenic effects: “A number of synthetic cannabinoids contain an indole moiety, either in their basic structure or in their substituents.” Indoles are molecular groups structurally similar to serotonin, and are active in drugs like LSD and DMT.

“According to this finding,” Papanti says, “their use could interfere with serotonin 5-HT neurotransmission more than THC. It is possible that the indole moieties incorporated in the molecules of synthetic cannabinoids can bind 5-HT2 receptors, acting as an hallucinogenic drug (in fact visual hallucinations are not uncommon in SC use).”

 One of the main problems, of course, is that physicians know almost nothing about detecting and treating acute overdoses of synthetic cannabinoid products. And even if an OD victim was lucky enough to wash up at a health facility that had access to instant chromatography detection testing, “[due to] the lack of appropriate reference samples, SC compounds are difficult to identify.”

The risk here is not evenly distributed, obviously. Young people, and anybody subject to marijuana urine testing, are the clear market for these products. This includes students, athletes, members of the Armed Forces, transportation workers, mining workers, and many others. Spice users are overwhelmingly male.

How many people are taking the risk? An estimate of student use comes from the U.S. 2013 “Monitoring the Future” survey, which shows that about 8% of 17-18 year-olds have tried Spice products. For 12th graders, Spice products are second only to marijuana itself in many districts. And yet there is a dearth of longitudinal studies in humans to evaluate the long-term impact of using synthetic cannabinoids.

Papanti and colleagues call for the creation of an international agency dedicated to “toxicovigilance” based on a “non-biased ‘real-time’ database,” including adverse drug effects, as a way of clarifying and promoting appropriate clinical guidelines for Spice drugs. “These substances are dangerous, and they have been associated with a number of deaths,” Papanti says. He would like to see a “network in which users report their adverse effects. Such an online system already exists in the Pharmacovigilance program at the Lareb Centre in the Netherlands. They collect reports of medications’ adverse effects from both patients and doctors and it works very well.”

Tolerance, dependence, and withdrawal have all been documented in several categories of Spice products. Spice withdrawal effects can be severe, the authors say, and may include craving, tremor, profuse sweating, insomnia, anxiety, irritability and depression.

Graphics Credit:  http://www.caregroupnz.org.nz/drug-prevention-education-campaign/

Getting Spiced

Synthetic cannabis is stronger than it used to be.

First published 10/07/2013

I wish I could stop writing blog posts about Spice, as the family of synthetic cannabinoids has become known. I wish young people would stop taking these drugs, and stick to genuine marijuana, which is far safer. I wish that politicians and proponents of the Drug War would lean in a bit and help, by knocking off the testing for marijuana in most circumstances, so the difficulty of detecting Spice products isn’t a significant factor in their favor. I wish synthetic cannabinoids weren’t research chemicals, untested for safety in humans, so that I could avoid having to sound like an alarmist geek on the topic.  I wish I didn’t have to discuss the clinical toxicity of more powerful synthetic cannabinoids like JWH-122 and JWH-210. I wish talented chemists didn’t have to spend precious time and lab resources laboriously characterizing the various metabolic pathways of these drugs, in an effort to understand their clinical consequences. I wish Spice drugs didn’t make regular cannabis look so good by comparison, and serve as an argument in favor of more widespread legalization of organic marijuana.

A German study, published in Addiction, seems to demonstrate that “from 2008 to 2011 a shift to the extremely potent synthetic cannabinoids JWH-122 and JWH-210 occurred…. Symptoms were mostly similar to adverse effects after high-dose cannabis. However, agitation, seizures, hypertension, emesis, and hypokalemia  [low blood potassium] also occurred—symptoms which are usually not seen even after high doses of cannabis.”

The German patients in the study were located through the Poison Information Center, and toxicological analysis was performed in the Institute of Forensic Medicine at the University Medical Center Freiburg. Only two study subjects had appreciable levels of actual THC in their blood. Alcohol and other confounders were factored out. First-time consumers were at elevated risk for unintended overdose consequences, since tolerance to Spice drug side effects does develop, as it does with marijuana.

Clinically, the common symptom was tachycardia, with hearts rates as high as 170 beats per minute. Blurred vision, hallucinations and agitation were also reported, but this cluster of symptoms is also seen in high-dose THC cases that turn up in emergency rooms. The same with nausea, the most common gastrointestinal complaint logged by the researchers.

But in 29 patients in whom the presence of synthetic cannabinoids was verified, some of the symptoms seem unique to the Spice drugs. The synthetic cannabinoids caused, in at least one case, an epileptic seizure. Hypertension and low potassium were also seen more often with the synthetics. After the introduction of the more potent forms, JWH-122 and JWH-210, the symptom set expanded to include “generalized seizures, myocloni [muscle spasms] and muscle pain, elevation of creatine kinase and hypokalemia.” The researchers note that seizures induced by marijuana are almost unheard of. In fact, studies have shown that marijuana has anticonvulsive properties, one of the reason it is popular with cancer patients being treated with radiation therapy.

And there are literally hundreds of other synthetic cannabinoid chemicals waiting in the wings. What is going on? Two things. First, synthetic cannabinoids, unlike THC itself, are full agonists at CB1 receptors. THC is only a partial agonist. What this means is that, because of the greater affinity for cannabinoid receptors, synthetic cannabinoids are, in general, stronger than marijuana—strong enough, in fact, to be toxic, possibly even lethal. Secondly, CB1 receptors are everywhere in the brain and body. The human cannabinoid type-1 receptor is one of the most abundant receptors in the central nervous system and is found in particularly high density in brain areas involving cognition and memory.

The Addiction paper by Maren Hermanns-Clausen and colleagues at the Freiburg University Medical Center in Germany is titled “Acute toxicity due to the confirmed consumption of synthetic cannabinoids,” and is worth quoting at some length:

The central nervous excitation with the symptoms agitation, panic attack, aggressiveness and seizure in our case series is remarkable, and may be typical for these novel synthetic cannabinoids. It is somewhat unlikely that co-consumption of amphetamine-like drugs was responsible for the excitation, because such co-consumption occurred in only two of our cases. The appearance of myocloni and generalized tonic-clonic seizures is worrying. These effects are also unexpected because phytocannabinoids [marijuana] show anticonvulsive actions in humans and in animal models of epilepsy.

The reason for all this may be related to the fact that low potassium was observed “in about one-third of the patients of our case series.” Low potassium levels in the blood can cause muscle spasms, abnormal heart rhythms, and other unpleasant side effects.

One happier possibility that arises from the research is that the fierce affinity of synthetic cannabinoids for CB1 receptors could be used against them. “A selective CB1 receptor antagonist,” Hermanns-Clausen and colleagues write, “for example rimonabant, would immediately reverse the acute toxic effects of the synthetic cannabinoids.”

The total number of cases in the study was low, and we can’t assume that everyone who smokes a Spice joint will suffer from epileptic seizures. But we can say that synthetic cannabinoids in the recreational drug market are becoming stronger, are appearing in ever more baffling combinations, and have made the matter of not taking too much a central issue, unlike marijuana, where taking too much leads to nausea, overeating, and sleep.

(See my post “Spiceophrenia” for a discussion of the less-compelling evidence for synthetic cannabinoids and psychosis).

Hermanns-Clausen M., Kneisel S., Hutter M., Szabo B. & Auwärter V. (2013). Acute intoxication by synthetic cannabinoids - Four case reports, Drug Testing and Analysis,   n/a-n/a. DOI: 10.1002/dta.1483

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

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/

Drugs and Disease: A Look Forward

First published 2/18/2014.

Former National Institute on Drug Abuse (NIDA) director Alan Leshner has been vilified by many for referring to addiction as a chronic, relapsing “brain disease.” What often goes unmentioned is Leshner’s far more interesting characterization of addiction as the “quintessential biobehavioral disorder.”

Multifactorial illnesses present special challenges to our way of thinking about disease. Addiction and other biopsychosocial disorders often show symptoms at odds with disease, as people generally understand it. For patients and medical professionals alike, questions about the disease aspect of addiction tie into larger fears about the medicalization of human behavior.

These confusions are mostly understandable. Everybody knows what cancer is—a disease of the cells. Schizophrenia? Some kind of brain illness. But addiction? Addiction strikes many people as too much a part of the world, impacted too strongly by environment, culture, behavior, psychology, to qualify. But many diseases have these additional components. In the end, the meaning of addiction matters less than the physiological facts of addiction.

One of the attractions of medical models of addiction is that there is such an extensive set of data supporting that alignment. Specifically, as set down in a famous paper by National Institute of Drug Abuse director Nora Volkow and co-author Joanna Fowler: “Understanding the changes in the brain which occur in the transition from normal to addictive behavior has major implications in public health…. We postulate that intermittent dopaminergic activation of reward circuits secondary to drug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit.” This cascade of events is often referred to as the “hijacking” of the brain by addictive drugs, but nothing is really being hijacked. Rather, the abusive use of drugs changes the brain, and that should come as no surprise, since almost everything we do in the world has the potential of changing the brain in some way. “Why are we so surprised that when you take a poison a thousand times, it makes some changes in your head?” said the former director of a chemical dependency treatment program at the University of Minnesota. “It makes sense that [addictive drugs] change things.”

Critics like Fernando Vidal object to a perceived shift from “having a brain” to “being a brain.” He is saying that he cannot see the point of “privileging” the brain as a locus for the study of human behavior. In “Addiction and the Brain-Disease Fallacy,” which appeared in Frontiers in Psychiatry, Sally Satel and Scott Lillienfeld write that “the brain disease model obscures the dimension of choice in addiction, the capacity to respond to incentives, and also the essential fact people use drugs for reasons (as consistent with a self-medication hypothesis).”

An excellent example of the excesses of the anti-brain discussions is an article by Rachel Hammer of Mayo Clinic and colleagues, in the American Journal of Bioethics-Neuroscience. “Many believed that a disease diagnosis diminishes moral judgment while reinforcing the imperative that the sick persons take responsibility for their condition and seek treatment.” But only a few paragraphs later, the authors admit: “Scholars have theorized that addiction-as-disease finds favor among recovering addicts because it provides a narrative that allows the person simultaneously to own and yet disown deviant acts while addicted.” Furthermore: “Addiction reframed as a pathology of the weak-brained (or weak-gened) bears just as must potential for wielding stigma and creating marginalized populations." But again, the risk of this potentially damaging new form of stigma “was not a view held by the majority of our addicted participants…”

And so on. The anti-disease model authors seem not to care that addicted individuals are often immensely helped by, and hugely grateful for, disease conceptions of their disorder, even though Hammer is willing to admit that the disease conception has “benefits for addicts’ internal climates.” In fact, it often helps addicts establish a healthier internal mental climate, in which they can more reasonably contemplate treatment. Historian David Courtwright, writing in BioSocieties, says that the most obvious reason for this conundrum is that “the brain disease model has so far failed to yield much practical therapeutic value.” The disease paradigm has not greatly increased the amount of “actionable etiology” available to medical and public health practitioners. “Clinicians have acquired some drugs, such as Wellbutrin and Chantix for smokers, Campral for alcoholics or buprenorphine for heroin addicts, but no magic bullets.” Physicians and health workers are “stuck in therapeutic limbo,” Courtwright believes.

“If the brain disease model ever yields a pharmacotherapy that curbs craving, or a vaccine that blocks drug euphoria, as some researchers hope,” Courtwright says, “we should expect the rapid medicalization of the field. Under those dramatically cost-effective circumstances, politicians and police would be more willing to surrender authority to physicians.” The drug-abuse field is characterized by, “at best, incomplete and contested medicalization.” That certainly seems to be true. If we are still contesting whether the brain has anything essential to do with addiction, then yes, almost everything about the field remains “incomplete and contested.”

Sociologists Nikolas Rose and Joelle M. Abi-Rached, in their book Neuro, take the field of sociology to task for its “often unarticulated conception of human beings as sense making creatures, shaped by webs of signification that are culturally and historically variable and embedded in social institutions that owe nothing substantial to biology.”

And for those worried about problems with addicts in the legal system, specifically, over issues of free will, genetic determinism, criminal culpability, and the “diseasing” of everything, Rose and Abi-Rached bring good news: “Probabilistic arguments, to the effect that persons of type A, or with condition B, are in general more likely to commit act X, or fail to commit act Y, hold little or no sway in the process of determining guilt.” And this seems unlikely to change in the likely future, despite the growing numbers of books and magazine articles saying that it will.

Opponents of the disease model of addiction and other mental disorders are shocked, absolutely shocked, at the proliferation of “neuro” this and “neuro” that, particularly in the fields of advertising and self-improvement, where neurotrainers and neuroenhancing potions are the talk of the moment. Sociologists claim to see some new and sinister configuration of personhood, where a journalist might just see a pile of cheesy advertising and a bunch of fast-talking science hucksters maneuvering for another shot at the main chance. When has selling snake oil ever been out of fashion?

For harm reductionists, addiction is sometimes viewed as a learning disorder. This semantic construction seems to hold out the possibility of learning to drink or use drugs moderately after using them addictively. The fact that some non-alcoholics drink too much and ought to cut back, just as some recreational drug users need to ease up, is certainly a public health issue—but one that is distinct in almost every way from the issue of biochemical addiction. By concentrating on the fuzziest part of the spectrum, where problem drinking merges into alcoholism, we’ve introduced fuzzy thinking with regard to at least some of the existing addiction research base. And that doesn’t help anybody find common ground.

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