Tuesday, February 16, 2016

Addressing Criticisms of the Disease Model

Volkow, Koob, and McLellan on the neurobiology of addiction.

The New England Journal of Medicine recently published a review article, “Neurobiologic Advances from the Brain Disease Model of Addiction,” authored by three prominent figures in the field of addiction research: Nora Volkow, the director of the National Institute of Drug Abuse (NIDA); George Koob, the director of the National Institute of Alcohol Abuse and Alcoholism (NIAAA); and Thomas McLellan, founder and chairman of the Treatment Research Institute in Philadelphia.  The article summarizes the research that has “increasingly supported the view that addiction is a disease of the brain,” and concludes that “neuroscience continues to support the brain disease model of addiction.”

The implications of this, say the authors, are straightforward: “As is the case in other medical conditions in which voluntary, unhealthful behaviors contribute to disease progression (e.g., heart disease, diabetes, chronic pain, and lung cancer), evidence-based interventions aimed at prevention, along with appropriate health policies, are the most effective ways of changing outcomes.”

And some of the implications are immediate: “A more comprehensive understanding of the brain disease model of addiction many help to moderate some of the moral judgement attached to addictive behaviors and foster more scientific and public health-oriented approaches to prevention and treatment.”

In a supplementary appendix, the authors address some of the common criticisms of the disease model of addiction, and offer counter-arguments. The quotes below are excerpted directly from the appendix.

Most people with addiction recover without treatment, which is hard to reconcile with the concept of addiction as a chronic disease.

This reflects the fact that the severity of addiction varies, which is clinically significant for it will determine the type and intensity of the intervention. Individuals with a mild to moderate substance use disorder, which corresponds to the majority of cases, might benefit from a brief intervention or recover without treatment whereas most individuals with a severe disorder will require specialized treatment

—Addicted individuals respond to small financial rewards or incentives (contingency management), which is hard to reconcile with the notion that there is loss of control in addiction.

The demonstrated effectiveness of contingency management shows that financial cues and incentives can compete with drug cues and incentives – especially when those financial incentives are significant and relatively immediate; and when control has been simply eroded rather than lost. Contingency management is increasingly being utilized in the management of other medical disorders to incentivize behavioral changes (i.e., compliance with medications, diets, physical activity).

—Gene alleles associated with addiction only weakly predict risk for addiction, which is hard to reconcile with the importance of genetic vulnerabilities in the Brain Disease Model of Addiction.

This phenomenon is typical of complex medical diseases with high heritability rates for which risk alleles predict only a very small percentage of variance in contrast to a much greater influence of environmental factors (i.e., cirrhosis, diabetes, asthma, cardiovascular disease). This reflects, among other things, that the risk alleles mediate the response to the environment; in the case of addiction, the exposures to drugs and stressful environments.

Overlaps in brain abnormalities between people with addiction and control groups raises questions on the role that brain abnormalities have on addiction.

The overlap is likely to reflect the limitation of currently available brain imaging techniques (spatial and temporal resolutions, chemical sensitivity), our limited understanding of how the human brain works, the complexity of the neurobiological changes triggered by drugs and the heterogeneity of substance use disorders.

Treatment benefits associated with the Brain Disease Model of Addiction have not materialized.

Medications are among the most effective interventions for substance use disorders for which they are available (nicotine, alcohol and opiates). Moreover, progress in the approval of new medications for substance use disorders has been slowed by the reluctance of pharmaceutical companies to invest in drug development for addiction.

Benefits to policy have been minimal.

The Brain Disease Model of Addiction provided the basis for patients to be able to receive treatment for their addiction and for insurances to cover for it. This is a monumental advance in health policy. The Brain Disease Model of Addiction also provides key evidence-based science for retaining the drinking age at 21 years.

Friday, February 5, 2016

Cannabis sativa vs. Cannabis indica: Science or Folklore?

Golden Goat or  Sour Diesel?

The bland assurances from medical marijuana dispensaries about the physical and psychological effects of the bewildering array of hybrid plant strains on offer is mostly bunk, claim a growing number of cannabis scientists.

Ethan Russo, a neurologist and pharmacology researcher, as well as the medical director of a biotechnology company, author of numerous books about herbal medicine, and a former faculty member at the University of Washington and the University of Montana, has something to say to marijuana connoisseurs: “There are biochemically distinct strains of Cannabis, but the sativa/indica distinction as commonly applied in the lay literature is total nonsense and an exercise in futility.”

How’s that again? The much-vaunted divide between the cerebral sativa strains, and the sedating, body-oriented effects of indica, are an integral part of marijuana lore and legend. Cannabis growers and biologists endlessly debate the hybridization of new strains. Extolling the virtues of a sativa plant crossed with a plant redolent of indica is a common sales pitch.

In an interview with Dr. Daniele Piomelli for the January 2016 issue of the journal Cannabis and Cannabinoid Research, Russo detailed his disagreement with the assumption that hard evidence exists for this distinction. Dr. Piomelli notes that “sativa is often described as being uplifting and energetic, whereas indica as being relaxing and calming.” Folklore, says Russo. Of course different strains have different effects. But in recent years, says Russo, almost all marijuana has been coming from high-THC strains, with a slight increase in CBD-predominant strains:

"The differences in observed effects in Cannabis are due to their terpenoid content, which is rarely assayed, let alone reported to potential consumers. The sedation of the so-called indica strains is falsely attributed to CBD content when, in fact, CBD is stimulating in low and moderate doses. Rather, sedation in most common Cannabis strains is attributable to their myrcene content, a monoterpene with a strongly sedative couch-lock effect that resembles a narcotic."

And, as for sativa strains: “A high limonene content (common to citrus peels) will be uplifting on mood, while the presence of the relatively rare terpene in Cannabis, alpha-pinene, can effectively reduce or eliminate the short-term memory impairment classically induced by THC.”

Well. I for one do not wish to be caught in the firing line between Dr. Russo and the legions of growers who will beg to differ with his conclusions. For years, it has been accepted wisdom that cannabis comes in two different forms, essentially considered two different species even though they readily interbreed. Even Jean-Baptiste Lamarck, the legendary naturalist of the 18th Century, agreed with the indica and sativa concepts.

But Russo will have none of it: “To paraphrase and expropriate an old Yiddish expression: 12 botanical taxonomists, 25 different opinions…. One cannot in any way currently guess the biochemical content of a given Cannabis plant based on its height, branching, or leaf morphology. The degree of interbreeding/hybridization is such that only a biochemical assay tells a potential consumer or scientist what is really in the plant.”

And finally: “I would strongly encourage the scientific community, the press, and the public to abandon the sativa/indica nomenclature and rather insist that accurate biochemical assays on cannabinoid and terpenoid profiles be available for cannabis in both the medical and recreational markets. Scientific accuracy and the public health demand no less than this.”

Russo’s interview is strong evidence of a viewpoint brought to public attention a few years ago by several others, including the controversial cannabis chemist Jeffrey Raber.

Raber told the L.A. Weekly in 2013 that there was no compelling scientific evidence for the claims routinely made by cannabis dispensaries about the effects of a given colorfully named strain of marijuana. “We took a popular [strain] name, Jack Herer, and found that most didn’t even look like each other. OG whatever, Kush whatever, and the marketing that goes along with it—it’s not really medically designed.”

And the difference between sativa and indica? The cerebral, bracing “mental” high vs. the sleepy, couch-lock “body” high? Forget it, said Raber. The two sub-species are distinguished by morphology only—different structures and appearance, but no hard and fast rules about the quality of the smoking experience. They look different, but that’s no guide to the distribution of THC, CBD, and numerous terpenes that determine the actual quality of the marijuana experience. Moreover, extensive crossbreeding by growers and dealers has helped to obliterate any consistent, meaningful distinctions between sativa and indica highs. (The so-called “skunk” varieties are simply high quality female plants that are prevented from going to seed, which dramatically pushes up the THC content. Almost all of the high-quality weed sold in the U.S., Canada, and the U.K. is skunkweed, so the definition is virtually useless.)

Sativa plants are characteristically tall and rangy, with long branches and long, thin leaves. They evolved, scientists believe, in humid jungle climates. Indica plants are shorter, more compact, and stubbier-looking, with shorter branches and fatter leaves designed for a hot, desert-like climate. It has been assumed that sativas originally came from India, and indicas from Afghanistan. However, indica is the term meant to indicate a plant from India, so right away we find that the situation is all muddled up: the plant from Afghanistan is known by the name of the plant from India. Blame this one on esteemed plant drug investigator Richard Evans Schultes, who apparently mislabeled the plants grown in Afghanistan as C. indica when he drew up the first cannabis taxonomy in the 1970s.

It gets worse. In 2014, at a meeting of the International Cannabis Research Society, research John McPartland with GW Pharmaceuticals announced  the results of his study of genetic markers on the three subspecies of cannabis: C. sativa, C. indica, and a third wild variety, known as C. ruderalis, with very little THC. Any of the three subspecies can be bred as hemp or marijuana, said McPartland. Cannabis sativa should really be known as Cannabis indica, being the Indian variety, while the formerly misnamed indica subspecies should now be called Cannabis afghanica. The name of C. sativa, the high-end connoisseur favorite, would now go to the lowly C. ruderalis, otherwise known as ditch weed, under his new classification scheme.

Quite a lot of changes to a decades-old nomenclature, but it means we are finally getting some serious genetic information about one of the most popular drugs in the world. As Jeremy Daw of The Leaf Online writes: “Starbucks, for example, sources coffee beans from farmers spread across four continents…. In an astonishing feat of global supply chain logistics, Starbucks can now claim to have the ability to trace 94% of its coffee beans all the way back to the exact farm where they were produced.” The cannabis industry, he concludes, still has “a lot of growing up to do.”

Krymon deCesare, chief research director at Steep Hill Halent Lab in Oakland, California, a company developing more sophisticated tests for identifying the various compounds found in marijuana, told AlterNet  that “sativa and indica are only really valid for describing the physical characteristics of the cannabis strain in a given environment. They are not nearly as reliable as terms for making assumptions about energy versus couch lock.” To the extent that there is a grain of truth in the basic division between the mind high of sativa and the body high of indica, as traditionally classified, deCesare believes the culprit is myrcene. Based on the analysis of more than 100,000 samples, deCesare says that his team found “consistently elevated levels of the terpenoid myrcene in C. indica as compared to C. sativa. Myrcene is the major ingredient responsible for ‘flipping’ the normal energetic effect of THC….”

Ethan Russo invokes his notion of the “entourage effect,” in which the distinctive highs normally associated with indica and sativa are in fact the result of a complex combination of many different cannabinoids and terpenes working in harmony. Teasing that apart in the lab is not a cheap or easy affair. If you don’t know your terpene levels, says Russo, than you can’t compute your relative chances of full couch-lock. And even if terpene levels are known, the same pot plant, when smoked, can still cause one person to become energized and talkative, while another person may just fall asleep. Same chemicals, different metabolisms. One person’s happy, giggly high is another person’s paranoid bad trip.

The result of this recent research is to bolster the general suspicion about medical marijuana dispensaries: The names of various marijuana varieties are not only stupid and immature, but also completely misleading and unhelpful. Coherent labeling will require much more than listing relative THC percentages. We’ve only just begun.

Monday, February 1, 2016

A Roundtable Discussion on Cannabis Use Disorder

Addressing the habit-forming aspects of marijuana.

A trio of leading marijuana scientists participated in a panel discussion moderated by Dr. Daniele Piomelli from the School of Medicine at the University of California-Irvine, and published in a recent issue of the journal Cannabis and Cannabinoid Research.

Dr. Margaret Haney is with the New York State Psychiatric Institute at Columbia University Medical Center; Dr. Alan J. Budney is affiliated with the Geisel School of Medicine at Dartmouth College; and Dr. Pier Vincenzo Piazza works at the Magendie Neurocenter in Bordeaux, France.

Excerpts from the long discussion appear below:

It seems that most specialists in the field agree that Cannabis is addictive. If you had to choose one piece of evidence, either clinical evidence or animal experiment evidence, in support of this conclusion, which one would you pick?

Dr. Margaret Haney: “One of the key features for me is demonstrating that there is a pharmacologically specific withdrawal from Cannabis use…. We can demonstrate that daily smokers go through a time-dependent and pharmacologically specific withdrawal when they abstain from Cannabis…. I think another really important feature is the clinical data showing how high relapse rates are with Cannabis. Although Cannabis may have a lower abuse liability than other drugs like cocaine or nicotine, once somebody has developed a dependence on the drug, then quitting becomes extremely difficult.

Dr. Alan J. Budney: “If I had to pick out the ‘smoking gun’ to convince the public and the scientific world that Cannabis Use Disorder (CUD) is real, then it would be the data from clinical epidemiological research…. the data on CUDs are remarkably similar to the other substance use disorders…. for a substantial number of people, Cannabis use causes similar and substantial problems that are comparable to other types of drugs that we all agree have addictive potential.”

Dr. Pier Vincenzo Piazza: “[In] Australia, Canada, the United States, and the European Union, over the last two years Cannabis represents the highest new entries for treatment in specialized centers…. Since these four countries have very different rates of referral of patients by the judicial system, these figures really mean that patients experience a discomfort high enough to spontaneously seek treatment…. In France, for example, as well as in many other European countries, referral from the judicial system is very low. Nevertheless, the demand for treatment for CUD is now the highest of all drugs, legal and illegal.”

What is curious is that we now accept the concept that Cannabis is addictive, but for many years we have been told that it was not. Why is it that, for so long, the scientific community failed to recognize the addictive properties of Cannabis?

Dr. Margaret Haney: “I have been speaking about Cannabis addiction for 20 years and was met by full-on boredom for the first 15 years because I felt that scientists, like the public at large, just viewed Cannabis as a benign compound not too different from caffeine in a way…. THC is lipophilic, and so long-lasting, withdrawal takes quite a while to manifest…. if an individual is dependent on nicotine, he or she cannot go a couple of hours without experiencing withdrawal. A heavy Cannabis user, by contrast, has to go quite a while before experiencing withdrawal, and so it was not quite as obvious to people that withdrawal existed.”

Dr. Alan J. Budney: “Moreover, many of those that have experience with using Cannabis, do not get addicted, develop problems, or experience withdrawal. Although the same is true for those who have used alcohol or even opiates, for reasons that are not completely clear, the personal experience of those who used Cannabis and did not develop problems or experience withdrawal, seems to lead to the perception that Cannabis is not a substance that others can become addicted to.”

Dr. Pier Vincenzo Piazza: “What we know now is that, since cannabidiol is an antagonist of THC, the greater the ratio between THC and cannabidiol the greater the risk for Cannabis to be addictive…. Now, we are up to a 5- to 10-fold difference in favor of THC, making Cannabis more addictive.”

How addictive is Cannabis? Is it more addictive than, say, tobacco or alcohol? Is it less addictive? Is this question even correctly asked? Is there a better way to ask it?

Dr. Alan J. Budney: [I] would like to emphasize a point so that our audience does not think we are going way overboard and engaging in reefer madness related to the severity of Cannabis addiction. All factors held constant, the pharmacology of opiates would probably produce a more severe addiction…. Access, dose, route of administration, societal acceptance, perceived risk, cost, societal consequences for use or intoxication, and multiple other factors contribute to the real-world question of how addictive a drug is compared to another.”

Dr. Margaret Haney: “My opinion is that Cannabis has a lower abuse liability than something like cocaine [but] even if Cannabis has a lower abuse liability, the sheer number of people using it will result in a large number of people with a use disorder….”

Dr. Pier Vincenzo Piazza: “If we try to express abuse liability in numbers, the abuse liability for Cannabis… is between 10% and 15%, depending on the survey you look at. However, I believe that abuse liability should also be measured by a second factor; that is, how easy it is to quit if you have developed a substance use disorder. My understanding… is that stopping Cannabis use, if you have developed CUD, is not easier than other drugs.”

The major point, all three experts agree, is that marijuana cannot be considered a completely benign drug. “Cannabis is not the worst drug,” says Dr. Haney, “but it is not a drug without consequences. Again, societal attitudes often seem to skew one way or the other; it is all good or it is all bad, when it is clearly both.”

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