The genetics of quitting smoking- Bupropion and nicotine metabolism

If you’ve been reading A3 for a while, you know that we’re big supporters of scientific progress in addiction treatment. While it may be true that addicts need to want recovery in order to truly turn their lives around, the choice is hardly ever that simple and if we can tip the balance in the favor of treatment, or a better way of life, I say let’s go for it. When it comes to genetics and addiction, I’ve normally talked only about the fact that a person’s genetic code may predispose them to addiction or to other related conditions (like depression, anxiety, and so on). Aside from a single mention of pharmacogenomics, I don’t think I’ve spoke much about the way genetics can help us tailor addiction treatment to individual needs. We’re about to fix that.

Replacement therapies and quitting smoking

You’ve heard of nicotine patches and gums, right? In the research community, those are all known as Nicotine Replacement (NR) therapy and they’ve proven to be some of the most helpful tools for those who are quitting smoking. By allowing smokers to still get the nicotine their body craves (even though there are thousands of other chemicals in cigarettes that likely make them even more satisfying) without having to light up, these NR methods let cigarette addicts get their NIC fix while slowly lowering their dose and getting away from the habit of putting a cigarette in their mouth. Like methadone, buprenorphine, and other replacement therapies, the idea is to move addicts one step away from the actual addictive behavior and allowing them to begin adopting a healthier way of living. Replacement therapies are very successful, even if some people hate the idea of giving drugs to drug addicts, and nicotine replacement works well by itself for some people (though only about 20%).

But when it comes to nicotine, like with many other drugs, different people metabolize the stuff at different rates. The individual variability in the internal processing of nicotine greatly affects how many cigarettes individuals smoke and also the probability that they will become addicted to tobacco (people who metabolize nicotine more quickly smoke more and are more likely to become addicted to smoking). Fast metabolizers are also half as likely to be able to use nicotine replacement alone to quit smoking (1). However, when you put all of the addiction research together, it becomes pretty obvious that the same variability in nicotine metabolism can also help us determine the best course of treatment for tobacco addiction.

Metabolism, treatment, and the best way to quit smoking

Bupropion helps fast metabolizers increase their quitting chancesFortunately for smokers, the only research finding in this area hasn’t been that slow metabolizes have a much better chance of quitting smoking with nicotine replacement therapy. The same group of addiction researchers (led by Caryn Lerman of University of Pennsylvania), also found that buporopion, the smoking cessation medication everyone knows as Zyban (and the antidepressant called Wellbutrin), could help those fast metabolizers catch up with the slow metabolizers when it came to quitting (see the figure on the left taken from the actual study – you see that the dark bars, who are the bupropion patients, do as well as the white bars regardless of their metabolism rate, which is on the bottom). The researchers found that while slow matabolizers of nicotine did much better with simple smoking cessation therapy and fast metabolizers did very poorly (30% versus 10% quit respectively in each of the groups), adding bupropion made all groups look essentially the same (2). The moral? While those slow metabolizers don’t really get much of a benefit from using bupropion since they do pretty well with talk therapy or nicotine replacement alone, the fast metabolizers really need it to even their chances of quitting – and once they get bupropion, they do pretty well!

Genetics and addiction treatment – is this just the beginning?

Hopefully you’re now convinced that genetics can really help us determine what treatment course will best suit a specific person over another. There’s little question that this sort of approach is in its infancy, and you certainly can’t go to a doctor right now and get your metabolism rate for a drug analyzed (unless you’re part of a research study), but this sort of work shows great promise in improving the outcomes of addiction treatment. When you look back at that original paragraph, and the quite common thinking that addicts need to WANT to be better – I would argue that those fast metabolizers probably wanted to quit smoking as much as anyone else in the study, and their physical makeup just made it that much more difficult for them. I think that if you look at the science of addiction closely, you’ll find that this supposed lack-of-motivation is sometimes more of a myth than a reality. Many addicts want to get better, they want to stop behaving in ways that specifically mess up their lives but they just find it incredibly difficult. My hope is that this is where science can truly make a difference, by making it just a little bit easier…

Hopefully one day we’ll be able to specifically adjust addiction treatment programs according to individual patients’ needs, including the use of medications, specific behavioral treatments, and more.

Citations:

1) Robert A. Schnoll, Freda Patterson, E. Paul Wileyto, Rachel F. Tyndale, Neal Benowitz, & Caryn Lerman. Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study (2009).

2) F Patterson, RA Schnoll, EP Wileyto, A Pinto, LH Epstein, PG Shields, LW Hawk, RF Tyndale, N Benowitz & C Lerman1. Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo-controlled Trial of Bupropion (2008).

About Addiction: Smoking, Alcohol, Painkillers, Prescriptions

This are new, interesting articles about addiction. Check out the links to the articles, and give us your feedback.

Smoking and related issues

Health Day: Smoking increases the risk of age-related macular degeneration, a disease that robs people of their sight.

Reuters: When cigarette smokers quit smoking, chronic stress levels may go down. This should give smokers reassurance that quitting will not deprive them of a valuable stress reliever.

Reuters: A nicotine mouth spray may help prevent cigarette cravings three times faster than nicotine lozenges or chewing gum. This might help smokers who are trying to quit smoking.

Cesar Fax: The percentage of national tobacco retailers selling to minors appears to have leveled off. The average national retailer violation rate decreased from 40.1% to 10.8%, and stabilized at 10.8%.

wcstv: Under a proposed deal reached by Governor David Paterson and Albany legislators, cigarette taxes would increase by $1.60 per pack. In New York City, the price of one pack of cigarettes would cost over $10 in many stores. The hope is that this huge price increase will help smokers quit smoking and reduce overall levels of smoking in New York.

About addiction to alcohol, painkillers, and prescription medication

Hazelden: Abuse of alcohol, painkillers, and prescription medication is rising dramatically among older people. Signs of alcohol abuse and drug addiction are different in older adults than in younger people.

Science Daily: Religiosity can moderate genetic effects on alcohol abuse during adolescence but not during early adulthood. The heritability of an alcohol abuse phenotype depends upon the social environment within which it is measured.

Medical News TODAY: Sleep problems can predict the onset of alcohol abuse in healthy adults and relapse in abstinent alcoholics. Puberty is related to sleep problems and later bedtimes, which are associated with alcohol abuse.

Health Day: Exercise may be an effective treatment option for alcoholism. In addition, alcoholism disrupts normal daily circadian rhythms, which can lead to disrupted sleep patterns.

About addiction and mental illness

KansasCity.com:  To study drug addiction and mental illness researchers, at the University of Missouri-Kansas City, have received a $1.8 million federal grant. One of the leading researchers states that conditions such as drug addiction and depression are major problems across the globe.

NIDA and ONDCP – American policy on addiction research

At this year’s College on Problems of Drug Dependence (CPDD) Annual Meeting, I got to hear, and talk to, some of the most influential players in the American addiction research field. Here are a few highlights from their talks and our discussion:

Dr. Nora Volkow of NIDA talked about a shift from Genome Wide Association Studies (GWAS), which have been the most recent popular advance in genetics addiction research and into more Deep Sequencing work. The hope is that this will allow us to begin untangling some of the GWAS findings that have seemed counter-intutitive or puzzling. Deep sequencing should let us see what genes really are associated with addiction specifically, not just as markers.

Dr. Volkow also brought up the numerous issues of medications for addictions including the Nabi Nicotine Vaccine, Vivitrol (a Nalexone depot that helps opiate users who wouldn’t take it otherwise), and a host of new medications that are being developed or considered. An interesting idea here was the use of drug combinations which are showing great promise in providing enhanced treatment results (similar to HIV treatment that benefited greatly from drug cocktails). These include combining vernicline and bupropion for smoking and naltrexone and buprenorphine for cocaine (that’s not a type even though both have been typically thought of for opiate addicts).

Dr. Tom McLellan, who I personally believe is one of the most informed and thoughtful people we have when it comes to addiction research in this country, talked about our need to expand the reach of treatment to the drug abuse earlier in the problem cycle. While about 25 million people are considered drug addicts in this country, more than 65 million are drug abusers. By finding ways to reach those people in primary care (as in doctor offices) settings before they develop the full blown addiction we’re used to talking about we can do better. He also mentioned the idea of anonymity in recovery playing a role in the continued stigmatization of addiction, a topic I’ve written about recently.

Stay on the lookout for more amazing new addiction research knowledge!

More to cigarettes than nicotine

A recent talk I gave (click here), highlighted the fact that other aspects of smoking are very important for addiction to cigarettes. For some people, this isn’t news, especially if you’ve been reading our coverage about the importance of cues for smoking addiction. But that’s not all that makes cigarettes so hard to quit.

Cigarettes, chemicals, and addiction

Smoking addictions are very difficult  to quit

Thousands of chemicals are released when cigarettes are smoked, including the nicotine we’ve been hearing so much about as well as formaldehyde, benzene, and other nasty things. Some of the chemicals that are released have psychoactive effects, and a few, like acetaldehyde (the chemical that causes hangovers), and a group of monoamine oxidase inhibitors (yes, like old school MAOI antidepressants), apparently increase the effects of nicotine itself greatly, making it far more rewarding, and therefore theoretically addictive, than it would be without them.

The recent paper by a group at Duke University, suggests that there may be aspects of the smoke in cigarettes, even without nicotine, that are themselves rewarding. In the study, researchers gave people the option of taking nicotine by IV or smoking a de-nicotinzed cigarette – Overwhelmingly, participants chose to smoke the nicotine-free cigarettes.

Limitations and conclusions

Now granted, these were regular smokers, which meant that regardless of the effect, the act of smoking was so pre-programmmed for them as a rewarding one that overcoming it just for an experiment is a far-fetched notion. Still, given the hard time I’m having using nicotine as a reward, it seems likely that the other chemicals, as well as the experience of the smoke itself, play a very important role in addiction to cigarettes. Indeed, researchers years ago were very interested in discussing the role off the insula, a brain region important for bodily sensations (possibly involved in cravings and urges).

Another important limitation of this study was the fact that the “de-nicotinized” cigarettes actually had very  small amounts of nicotine in them. This little tidbit of  information is important because even small, “priming,” doses of a drug can cause very strong effects in terms of drug-seeking and drug-wanting. Maybe in the future there’d be some way of repeating this sort of study with cigarettes that actually contain no nicotine whatsoever.

Citation:

Rose, J.E., Salley, A., Behm, F.M., Bates, J.E.,  and Westman, E.C. (2010). Reinforcing effects of nicotine and non-nicotine components of cigarette smoke. Psychopharmacology, 210, 1-12.

Quitting smoking: Quitlines success

In the world of extremely difficult smoking-cessation (quitting smoking), telephone-based programs are apparently having some real success.

Quitting smoking with quitlines

According to a recent summary-analysis (we call these meta-analyses) of research done on Smoking Cessation Quitlines (CSQs), smokers who call and participate are 1.5 times more likely to quit! These are roughly the same numbers we see for people who use nicotine replacement therapies (NRTs, like the nicotine patch, gum, or lozenge), which are the most successful therapies we’ve got. Not bad when you consider that most quitlines are free to users.

What do quitlines do?

Once a user interested in quitting contacts a CSQ, they are taken through an assessment procedure. The California one is apparently pretty long, lasting 30-40 minutes. Don’t worry, the first call is the longest. Past this point, the lines’ activities vary greatly depending on the specific provider. Some offer phone-based counseling only, others also mail materials, and some offer recorded messages, on-demand counseling, counselor callback, and even access to medication (like patches, gum, or bupropion). Since state-based ones are free, it’s a good idea to make the call and see what your state offers. If you’re an addiction professional, or a psychologist with clients that want to quit smoking but can’t seem to shake it, this might be a great suggestion for them.

Can quitlines be used for other addictions?

Phone-based interventions have already been used for some addiction problems (mostly problem drinking), but usually as a supplement to face-to-face treatment. Still, given the relatively low cost associated, it seems that establishing such a tool for problem drinkers that doesn’t include a face-to-face interaction could be a viable option. Since it was state-based public health officials that made CSQs happen through lobbying, it seems that any addiction, or mental health, problem that is prevalent enough to warrant such attention (and such expenditures) may benefit from a little quitline love.

Citation:

Lichtenstein, E., Zhu, S.H., Tedeschi, G.J. (2010). Smoking cessation Quitlines: An underrecognized intervention success story. American Psychologist, 65, 252-261.

About Addiction: Alcohol, breast cancer & war veterans

Check out our weekly links about addiction!

Health Day: A new study shows that breast cancer survivors who smoke are at increased risk for a second cancer. The time frame to develop second cancer is fifteen years.

Cesar Fax: Drug positives increase consistently with age amongst DC juvenile arrestees. 53% of the juvenile arrestees tested positive for drugs.

Psychology Today: An article from Psychology Today (which Adi has been writing for so check them out!) and discusses the issue of war veterans and drug use as well as PTSD. It relates the discussion to soldiers in Iraq and Afghanistan.

Science Daily: There are some new insights into how alcohol affects brain function. Drinking alcohol over a long period of time does profoundly affect the brain.

Science Daily: More about alcohol! According to Science Daily, genetic differences that make you sleepy when you drink can protect against alcohol dependence.

Time to get high- Circadian rhythms and drug use

Contributing Co-Author: Andrew Chen

Like most living creatures, humans have internal biological clocks known as circadian rhythms. These internal cycles synchronize our bodies with the Earth’s 24-hour day/night cycle and prepare us for predictable daily events (1). Circadian rhythms regulate a number of bodily functions including temperature, hormone secretion, bowel movements, and sleep (2). Recent research suggests that drug use may disturb our circadian rhythms, possibly influencing our decisions to take drugs.

Moon

Environmental drivers of drug use

Our biological clocks are set by external cues from the environment, called zeitgebers (3). The most familiar to us are light and food. However, research on rats has shown that opiates, nicotine, stimulants, and alcohol also have the ability to alter the phase of circadian rhythms independent of light or food (1). Drug use has long been associated with major disruptions in the human sleep cycle. Cocaine, crystal meth, and MDMA users often go without sleep for days, and these sleep disruptions can continue long after people stop using drugs. In fact, sleep disturbance outlasts most withdrawal symptoms and places recovering addicts at greater risk for relapse (3).

The rhythm of drug use

Circadian rhythms could also be the reason why people show 24-hour patterns of drug use. A study of urban hospitals found that overdose victims are admitted to hospitals more around 6:30PM than any other time of the day (2). Fluctuations in drug sensitivity, effect, and reward value are believed to be regulated by genes that control circadian rhythms. In other words, our biological clocks are telling us when to get high.

Researchers are just beginning to explore the relationship between circadian rhythms and drug use. Future understanding of this relationship will help us explain how drug addiction develops and develop better ways to treat it. It’s possible that offering specific aspects of treatment as certain point in the circadian rhythm can improve the probability of success.

Citations:

1. Kosobud, A. E. K., Gillman, A. G., Leffel, J. K., Pecoraro, N.C., Rebec, G.V., Timberlake, W. (2007) Drugs of abuse can entrain circadian rhythms, The Scientific World Journal, 7(S2), 203-212

2. McClung, C.A. (2007) Circadian rhythms, the mesolimbic dopaminergic circuit, and drug addiction, The Scientific World Journal, 7(S2), 194-202

3. Gordon, H.W. (2007) Sleep, circadian rhythm, and drug abuse, The Scientific World Journal, 7(S2), 191-193