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

From Failure to Enthusiasm

Guest Post

By Andy

"Success is walking from failure to failure with no loss of enthusiasm." —Winston Churchill

One of the reasons I love this quote, is because for many of us, being able to keep our enthusiasm up in the midst of trying times can be very difficult to achieve. But once you figure out how to never lose it, no matter how hard life can get, it will mark the difference between giving up and succeeding. I love this quote and remind myself every time that sobriety success is shaped by my attitude. In this post I’m going to take you through my personal sobriety journey.

The Addict/Alcoholic

When I was 4 years old my parents made the life changing decision of moving from Colombia to California. It was 1986 and the situation in my country was scary and very violent. Upon arrival in California my parents took on many jobs to be able to provide for me and my siblings; they worked really hard to make sure we would have a life full of opportunities.

The great thing about latinos is that culturally not only are we very hard working people, but we are also very happy people who love to party. And of course, no Colombian party is ever complete without that anise-flavored drink called Aguardiente. Not that all Colombian’s are drunks, it’s just simply something they enjoy once in awhile, when there’s a good excuse to celebrate.
The first time I got drunk was at a family friend’s house party when I was nine years old. I was always a pretty mischievous kid, therefore at the party my cousin and I played a game to see who could steal more shots of aguardiente without getting caught.

After a few shots I was feeling very different inside. I felt comfortable, more secure, I danced salsa with my sister and all my cousins, I felt great. From that night on I drank every time I had the chance.
At 15 a friend introduced me to marijuana. Although today teen drug use is declining, back when I was a teenager the statistic was increasing and at 19 I attended a party and some guys introduced me to meth and so began the downward spiral. At 23 I found myself incarcerated in Idaho on drug related charges for two years.

You might be wondering why I left so many parts of the story untold. Well, I’m not writing this to reminisce on war stories, being eight years sober now I believe myself to be a bit wiser and truth be told, a little tired of recounting my crazy times. Jail in Idaho was the starting point of my recovery, and that is the part of THIS story I really want share.

AA and NA

When you are in prison, any activity that can take you out of your cell is welcomed with open arms. So when I was told that I could attend the Alcoholics Anonymous meetings I did not hesitate. At the time I was not interested in recovery, in fact, I thought I didn't have a drinking problem or substance abuse problem. I just needed to do something else than read in bed. So I attended meetings without participating. It took three months of going to these meetings to realize that I might have a slight drinking and drug problem.

One day, a fellow inmate told the story of how he hit rock bottom. He was a high level accountant abusing drugs in order to deal with the insane amount of work and stress at his job, until one day, having suicidal thoughts, he got drunk and drove his car into a local store. He lost his job, his wife filed for divorce, his family had lost hope (this wasn’t his first run in with the law). He shared that apart from coming to terms with his drug and alcohol problems he had also realized that he also had an anger management problem, he concluded that “rage spawns from anger, anger spawns from hurt, hurt spawns from getting your feelings hurt.”

Like I said before, I thought I didn't have a problem. I was convinced that I was fine, that I wasn’t hurting anyone. But thanks to that inmate sharing his story and his realization my eyes were opened: I had hurt the only person I had to live with for the rest of my life and the damage I had done to myself needed to be repaired. I had a drinking problem, a drug problem, a personality problem...a life problem.

The Workaholic

Prison was everything but easy, but attending the AA and NA meetings and the friendships I built helped me get through it. Once I was released I had a new sense of responsibility, I knew I needed to find a job, and be able to provide for myself. But it wasn't easy. Having a criminal record made it a challenge to find a good job, so I struggled for months. And when I finally found one, I was unmotivated and feeling trapped in a routine. Despite attending my AA and NA meetings on a regular basis, I relapsed. I lost my job and life seemed unbearable, hence my voluntary check in to a rehab center in Idaho.

After 3 months in rehab I moved back to California where I landed a job selling knock-off cologne. Being closer to my family helped me immensely, therefore my motivation was higher than ever. I would wake up at 5:00 am to pick-up my co-workers and go to gas stations, shopping center parking lots, flea markets, etc. to sell perfume out of the trunk of my car. After a few months I had become very good at selling. I had learned how to approach strangers, how to pitch my product, make people feel comfortable and how to overcome rejection. The job was purely commission based, thus if I didn’t sell, I didn’t make money. There is a great feeling about making cash on a sale that I cannot really describe. It is a feeling of accomplishment, it is a feeling that I wanted to replicate time and time again. I was determined to keep working harder and harder.

Months went by and next thing I knew I was training more than 10 people to sell perfumes and other beauty products on the street. I had my own office, had ads running in the paper, had a secretary taking calls, etc. In that year I had lost ten pounds, I had zero friends, and I barely saw my family.

After a long conversation with a friend he presented me with a book by Jeffery Combs called Psychologically Unemployable (Jeffery is also a recovering addict). One of the most important things said is that you should never confuse obsession with passion. After reading it and studying it for a few weeks, I understood that I had simply traded drugs and alcohol for work. It was an addiction and it wasn't any better. I was getting physically sick and emotionally unstable from the pressure I was putting on myself.

The Entrepreneur

I sold my perfume business and moved into my parents house. It was really important in my road to recovery to have their support. After a month I got a job at Target, so I could help my parents pay the bills and have some sort of income. I had no passion for that job whatsoever, and I was completely unmotivated in that point of my life. I couldn't find balance between success and a healthy, happy life. Being afraid of relapsing I started attending weekly AA/NA meetings. I acquired a really good sponsor that I am very grateful for. He gave me the task of taking a class at the local community college.

At the time I was not very happy to do the task. I felt old and I thought there was no point in taking a measly course. I just wanted to go to work, do my job and pay my bills, that was it. Nevertheless, I forced myself to take a class. The class I took was called Introduction to Website Development (HTML). I liked computers and websites, so I thought, why not give it a shot?

You should have seen my bedroom after three months in the class. I had stacks of books and papers about HTML and website design. I found myself at the computer for hours, coding, creating, learning. Finally, one day I thought to myself that it would be great if I could make a business out of my new acquired skill.

Nine years later I co-own a successful digital marketing agency. I have a great team that I feel are like my family, in fact, my brother is part of it. We are based in Medellin, Colombia, which means my life has taken a 180 degree turn. 30 years ago my parents left Colombia to give my siblings and I a better life, now I am back with that better life.

I still go to meeting and try to keep in touch with some of the good friends I made on my way to recovery. We always give each other support during rough times. Being sober has become a part of my life now. My attitude defines me and I do not let anything take control of my emotions, it only gets easier with time. I have learned to attend dinner parties and skip the wine; to dance with my colombian friends and kindly decline those beers and still enjoy myself. In regards to my business, I didn't let myself get lost while pursuing success. I have learned that balance is what makes you successful. Being able to work hard for months enjoying what you do, but also taking a weekend off to recharge has proven to be a critical part of my work-life balance. I feel very fortunate because I went out and found something I was passionate about, put my skills and knowledge to work and built a business. Sobriety, just like building a business, does not happen overnight, one has to commit to it and work hard.

It’s Not All About You

When you are in the process of recovering, every single thing you do to maintain your sobriety seems to be about you. Every one of the 12 steps you complete, every single task or piece of homework your sponsor gives you, every book or article you read is all about you and your recovery. But after a while you realize, there's a bigger picture. And going back to that Winston Churchill quote, "Success is walking from failure to failure with no loss of enthusiasm," learning that failing is just a part of the process. Behind the most successful people are years of failure, even if it's on their way to sobriety or on their way to being a successful entrepreneur. The issue is not failing, since we all will go through it, it's to never lose enthusiasm. Good luck and thank you for reading my story.

Graphics: https://pocketperspectives.com

Revised Drug Wheel

Know your chemicals.

Know Your Mushrooms

Spring has sprung, and the toxic 'shrooms are out.

Know Your Powders

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.

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.