Friday, September 2, 2016

Synthetic Dialectic


Banning New Drugs: What is the Path Forward?

Eighteen months ago, in a post on novel synthetic drugs in the cannabinoid and cathinone families, I wrote that the new fake marijuana and fake Ecstasy were “very nearly the perfect overdose drugs.”  An MDMA-like stimulant called PMMA was implicated in a number of deaths in Florida, Chicago, and Ireland back then. PMMA, like many synthetic highs, is toxic at low doses, and takes a fair amount of time to take effect, thereby encouraging double dosing.

A year and a half later, what has changed? Today’s synthetic pharmaceuticals are not coming from secret underground laboratories, but rather from legitimate, existing Chinese pharmaceutical and chemical companies. In a commentary published in Addiction, Michael Evans-Brown and Roumen Sedefov of the European Monitoring Centre for Drugs and Drug Addiction in Lisbon present an unusually dystopian picture of new psychoactive substances fueling ever-increasing complexities in the world drug market. The authors refer to the situation as a textbook example “of what can happen when entrepreneurs exploit globalization and technology.” They write:

The market continues to grow. Consumers are no longer limited to psychonauts and clubbers, but include the vulnerable and marginalized, such as problem drug users and prisoners… manufacturers have replacement substances ready for sale even before a substance is controlled; the recipes for many thousands more are in the scientific and patent literature ripe for the picking.

The authors provide a grisly list of recent synthetic cannabinoid incidents: In Russia, products containing MDMB-FUBINACA were implicated in more than 600 poisonings and 15 deaths in two weeks in 2014. The same drug was linked to as many as 700 suspected adverse events in a single month in Mississippi in 2015, and in Europe, more than 200 people were hospitalized in Poland last year after smoking something called Mocarz. The causes of these mass poisonings, according to the authors include “high potency of synthetic cannabinoids, producers guess[ing] how much substance to use, and poor manufacturing processes leading to uneven distribution of the substance in the product—manufacturing flaws that are a recipe for disaster.” When users have no idea—not even a reasonable guess—at what chemical they are actually using, regulation and public health initiatives become exceedingly difficult.

In a bold and, according to some drug policy analysts, deeply misguided move, UK officials, tired of the drugs “arms race,” and the cat-and-mouse game of enforcement, made an attempt to do away with synthetic drugs in one monumental swipe, passing the Psychoactive Substances Act. In its earlier incarnations, the measure banned just about everything, including foods with caffeine and alcohol. Having straightened that out somewhat, the United Kingdom now faces a synthetic highs crackdown that drug charity DrugWise said will only push the market underground, “from the shops to the street.” If you think that’s a major improvement, raise your hand.

Another drug policy group, Transform, believes that the ban was aimed rather cynically at “visible sales,” in an effort to demonstrate some political PR success stories. Jane Slater, head of operations for Transform, told Huffington Post UK : “Far from making our communities safer the ban has resulted in increased health harms and criminality.”

“Laws just push forward the list of compounds,” according to Dr. Duccio Papanti, a psychiatrist at the University of Trieste who studies the new drugs. “The market is very chaotic, bulk purchasing of pure compounds are cheaply available from China, India, Hong-Kong, but small labs are rising in Western Countries, too.”

A spokesman for the UK Home Secretary pushed back, saying that “These drugs are not legal, they are not safe and we will not allow them to be sold in this country.”

Still, this negative spiral is not steady or inevitable. “Given how fashions and societies change," the authors note, "it is true that we do not know what the fate will be for many substances [remember that Quaaludes, not MDMA were the original disco biscuits]: but it is also fair to say that suppliers are not looking for the next cannabis, MDMA, heroin or diazepam; they simply make substances that can mimic their effects and that can be produced, transported and sold freely.”

It continues. On September 1, the Irish Examiner  reported that a related cannabis drug, MDMB-CHMICA, often peddled as Black Mamba, has been linked to more than two dozen death in Europe. The European Monitoring Centre for Drugs and Drug Addiction confirmed 25 cases, involving comas, heart problems or seizures. “The high potency of MDMB-CHMICA and the highly variable amounts of the substances in ‘legal high’ products constitute a high risk of acute toxicity.”

In 1975, underground chemist Alexander Shulgin wrote that the variety of drugs capable of causing abuse problems was expanding rapidly. He did not envision an adroit way out of that spiral: “As these materials become better defined and their use better controlled, they will be replaced with substitute compounds, which will provide society with new, unknown, and unmanageable substances.” Managing these new risks effectively will require new and almost unimaginably sophisticated early warning systems to protect the public from new toxic offerings.


Monday, June 20, 2016

Monday, June 13, 2016

Nicotine Genes: Evidence From a 40-Year Study

 How adolescent risk becomes grownup addiction.


 Pediatricians have often remarked upon it: Give one adolescent his first cigarette, and he will cough and choke and swear never to try another one. Give a cigarette to a different young person, and she is off to the races, becoming a heavily dependent smoker, often for the rest of her life. We have strong evidence that this difference in reaction to nicotine is, at least in part, a genetic phenomenon.

But so what? Is there any practical use to which such knowledge can be put? As it turns out, the answer may be yes. People with the appropriate gene variations on chromosomes 15 and 19 move very quickly from the first cigarette to heavy use of 20 or more cigarettes per day, and have more difficulty quitting, according to a new report published in JAMA Psychiatry in 2013. From a public health point of view, these findings add a strong genetic rationale to early smoking prevention efforts— especially programs that attempt to “disrupt the developmental progression of smoking behavior” by means of higher prices and aggressive enforcement of age restrictions on smoking.

What the researchers found were small but identifiable differences that separated people with these genetic variations from other smokers. The gene clusters in question “provide information about smoking risks that cannot be ascertained from a family history, including information about risk for cessation failure,” according to authors Daniel W. Belsky, Avshalom Caspi, and colleagues at the University of North Carolina and Duke University.

The group looked at three prominent genome-wide association studies of adult smoking to see if the results could be applied to “the developmental progression of smoking behavior.” They used the data from the genome work to analyze the results of a 38-year prospective study of 1,037 New Zealanders, known as the Dunedin Study. A total of 405 cohort members in this study ended up as daily smokers, and only 20% of the daily smokers ever achieved cessation, defined as a year or more of continual abstinence.

The researchers came up with a multilocus genetic risk score (GRS) based on single-nucleotide polymorphisms associated with smoking behaviors. Previous meta-analyses had identified several suspects, specifically a region of chromosome 15 containing the CHRNA5-CHRNA3-CHRNB4 gene cluster, and a region of chromosome 19 containing the gene CYP2A6. These two clusters were already strong candidate genes for the development of smoking behaviors. For purpose of the study, the GRS was calculated by adding up the alleles associated with higher smoking quantity. The genetic risk score did not pertain to smoking initiation, but rather to the number of cigarette smoked per day.

When the researchers applied these genetic findings to the Dunedin population cohort, representing ages 11 to 38, they found that an unfortunate combination of gene types seemed to be pushing some smokers toward heavy smoking at an early age. Individuals with a high GRS score “progressed more rapidly to heavy smoking and nicotine dependence, were more likely to become persistent heavy smokers and persistently nicotine dependent, and had more difficulty quitting,” according to the study. However, these effects took hold only when young smokers “progressed rapidly from smoking initiation to heavy smoking during adolescence.” The variations found on chromosomes 15 and 19 influence adult smoking “through a pathway mediated by adolescent progression from smoking initiation to heavy smoking.”

Curiously, the group of people who had the lowest Genetic Risk Scores were not people who had never smoked, but rather people who smoked casually and occasionally—the legendary “chippers,” who can take or leave cigarettes, sometimes have one late at night, or a couple at parties, without ever falling victim to nicotine addiction. These “light but persistent smokers” were accounted for “with the theory that the genetic risks captured in our score influence response to nicotine, not the propensity to initiate smoking.”

Naturally, the study has limitations. Everyone in the Dunedin Study was of European descent, and the life histories ended at age 38. Nor did the study take smoking bans or different ages into account. The study cries out for replication, and hopefully that won’t be long in coming.

Could information of this sort be used to identify high-risk young people for targeted prevention programs? That is the implied promise of such research, but no, probably not. The gene associations are not so dramatic as to cause youngsters with the “bad” alleles to inevitably become chain smokers, nor do the right set of genes confer protection against smoking. It’s not that simple. However, the study is definitely one more reason to push aggressive smoking prevention efforts aimed at adolescents.


Belsky D.W.  Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine DependenceEvidence From a 4-Decade Longitudinal StudyDevelopmental Progression of Smoking Behavior, JAMA Psychiatry,   1. DOI: 10.1001/jamapsychiatry.2013.736


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