Tuesday, November 18, 2014

Another Look at Acamprosate

The most popular pharmaceutical treatment for alcoholism, explained.

(First published February 17, 2014)

“Occasionally,” reads the opening sentence of a commentary published online earlier this year in Neuropsychopharmacology, “a paper comes along that fundamentally challenges what we thought we knew about a drug mechanism.” The drug in question is acamprosate, and the mechanism of action under scrutiny is the drug’s ability to promote abstinence in alcoholics. The author of the unusual commentary is Markus Heilig, Chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Acamprosate, in use worldwide and currently the most widely prescribed medication for alcohol dependence in the U.S., may work by an entirely different mechanism than scientists have believed on the basis of hundreds of studies over decades. Rainer Spanagel of the Institute of Psychopharmacology at the University of Heidelberg, Germany, led a large research group in revisiting research that he and others had performed on acamprosate ten years earlier. In their article   for Neuropsychopharmacology, Spanagel and coworkers concluded that a sodium salt version of acamprosate was totally ineffective in animal models of alcohol-preferring rats.

“Surprisingly,” they write, “calcium salts produce acamprosate-like effects in three animal models…. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.”

At present, the Food and Drug Administration (FDA] has approved three drugs for alcoholism— Antabuse, naltrexone, plus acamprosate in 2004. In addition, there is considerable clinical evidence behind the use of four other drugs—topiramate, baclofen, ondansetron, and varenicline. Acamprosate as marketed is the calcium salt of N-acetyl-homotaurinate, a close relative of the amino acid taurine. It has also been found effective in European studies.

What did scientists think acamprosate was doing? Various lines of research had linked acamprosate to glutamate transmission. Changes in glutamate transmission have been directly implicated in active alcoholism. A decade ago, the Spanagel group had decided that acamprosate normalized overactive glutamate systems, and hypothesized that acamprosate was modulating GABA transmission. So it became known as a “functional glutamate antagonist.”  But specific mechanisms have remained elusive ever since.

Now, as Heilig comments, “the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries.” As the researcher paper explains it: “N-acetylhomotaurinate by itself is not an active psychotropic molecule…. We have to conclude that the proposed glutamate receptor interactions of acamprosate cannot sufficiently explain the anti-relapse action of this drug.” Further work shows that acamprosate doesn’t interact with glutamate binding sites at all.  In other words, calcium appears to be the major active ingredient in acamprosate. Animal studies using calcium chloride or calcium gluconate reduced alcohol intake in animals at rates similar to those seen in acamprosate, the researchers claim.

Subsequently, the researchers revisited the earlier clinical studies, subjected them to secondary analysis, and concluded that “in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.” In addition, calcium salts delivered via different carrier drugs replicated the suppression of drinking in the earlier animal findings.

Where there cues pointing toward calcium? The researchers conclude that “calcium sensitivity of the synapse is important for alcohol tolerance development, calcium given intraventricularly significantly enhances alcohol intoxication in a dose-dependent manner,” and “activity of calcium-dependent ion channels modulate alcohol drinking.”

Interestingly, in the late 50s and early 60s, there was a brief period of interest in calcium therapy for the treatment of alcoholism. In 1964, the Journal of Psychology ran an article titled “Intensive Calcium Therapy as an Initial Approach to the Psychotherapeutic Relationship in the Rehabilitation of the Compulsive Drinker.” Now it appears possible that a daily dose of acamprosate is effective for some abstinent alcoholics because it raises calcium plasma levels. Calcium supplements may be in for a round of intensive clinical testing if these findings hold up.

The authors now call for “ambitious randomized controlled clinical trials,” to directly compare “other means of the Ca++ delivery as an approach to treat alcohol addiction. Data in support of a therapeutic role of calcium would open fascinating clinical possibilities.”  Indeed it would.

Spanagel R., Vengeliene V., Jandeleit B., Fischer W.N., Grindstaff K., Zhang X., Gallop M.A., Krstew E.V., Lawrence A.J. & Kiefer F.  (2013). Acamprosate Produces Its Anti-Relapse Effects Via Calcium, Neuropsychopharmacology, 39 (4) 783-791. DOI: 10.1038/npp.2013.264

Wednesday, November 12, 2014

Marijuana Statistics vs. Perception

Who smokes cannabis, and how much?

(First published 12/27/2013)

Most statistical surveys of marijuana focus on a single quantitative measurement: How many people are using? But there’s a problem: More marijuana use does not necessarily translate into more marijuana users. And that’s because a clear majority of the consumption, and black market dollars, come from the heaviest smokers.

Drug policy researchers at the RAND corporation decided that frequency of use and amount of consumption were valuable parameters gone missing in most policy discussions. So they put the focus not just on use, but also on “use-days,” and pulled a number of buried tidbits from a very big data pile. If you zero in on consumption, and not just consumers, they insist, you will find a wholly different set of inferences.

For example: “Although daily/near-daily users represented less than one-quarter of past-month cannabis users in 2002 and roughly one-third of past-month users in 2011, they account for the vast majority of use-days and are thus presumably responsible for the majority of consumption,” write Rachel M. Burns and her RAND colleagues in Frontiers of Psychiatry. As with alcohol, the majority of cannabis consumption can be accounted for by a minority of users. The heaviest users, the upper 20 percent, consume 88 percent of the U.S. marijuana supply, say the RAND researchers. “Furthermore, if over time there were no change in the number of cannabis users, but the ratio of light vs. heavy users switched from 80/20 to 20/80, then consumption would increase by 250% even though there was no change whatsoever in the number of users.”

The RAND group used two data sets on cannabis consumption—the National Survey on Drug Use and Health (NSDUH) in the U.S., and the EU Drugs Markets II (EUMII) in Europe. Data included figures for past-year and past-month use, past-month use days, and past-month purchases.

Other intriguing figures come to light when you study cannabis use, as opposed to cannabis users. The researchers declared that “only 14% of past-year cannabis users [primarily males] meet the criteria for cannabis abuse or dependence, but they account for 26% of past-month days of use and 37% of past-month purchases.”

Happen to smoke blunts? That turns out to be very telling, according to the RAND study. “Perhaps the most striking contrast concerns blunts. Only 27% of past-year cannabis users report using a blunt within the last month, but those individuals account for 73% of cannabis purchases.” Casual users, it seems, don’t do blunts.

Clearly, it takes a lot of casual users to smoke as much marijuana as one heavy user. But exactly how many? The RAND researchers ran the numbers and concluded that, in terms of grams consumed per month, it would take more than 40 casual smokers to equal the intake of a single heavy user. The share of the market represented by daily/near-daily users is clearly the motive force in their analysis.

The study in Frontiers in Psychiatry also found patterns of interest on the buy side. General use took an upswing beginning in 2007. While the probability of arrest per marijuana smoking episode hovers somewhere in the neighborhood of 1 in 3,000, everything changes if you are purchasing cannabis. RAND reported that young people collectively make more purchases per day of reported use than do older users. Therefore, “statistics indicating that the burden of arrest falls disproportionately on youth relative to their share of all users may not be prima facie evidence of discrimination if making more purchases per day of use increases the risk of arrests per year of use.” Once again, those aging Baby Boomer potheads get the best deal. They have more money with which to buy bigger amounts less often, thereby greatly lessening their chances of arrest and prosecution.

This also applies to minority arrests for marijuana offenses. “Non-Hispanic blacks represent 13% of past-year cannabis users vs. 23% of drug arrests reported by those users, but they report making 24% of the buys. Thus, some of their higher arrest rate may be a consequence of purchase patterns… African-Americans may not only make more buys but also make riskier buys (e.g., more likely to buy outdoors).”

The researchers were able to draw some conclusions about the growth in marijuana usage from 2002 through 2011, based on the NSDUH data. Their main conclusion, after exploring the demographics of this 10-year record of use, is that “consumption grew primarily because of an increase in the average frequency of use, not just because of an increase in the overall number of users.”  The driver of consumption turns out to be… greater consumption. And that increased consumption is coming from… older adults. Those older adults, it turns out, are smoking more weed.

The shift is dramatic: “In 2002, there were more than three times as many youth as older adults using cannabis on a daily/near-daily basis; in 2011 there were 2.5 times more older adults than youth using on a daily/near-daily basis.” The record of alcohol and cigarette use over the same period showed no such inversion of use patterns.  And the tweeners? “In 2002, 12-17-year-olds represented 13% of daily/near-daily users; in 2011, that had dwindled to 7%.” These trends are not just the obvious result of an increase in the proportion of older adults in the population at large. Increases in the proportion of older heavy cannabis users were much greater than the general population drift.

Among the questions raised by the RAND analysis:

— Are older marijuana smokers primarily recreational, or medicinal?

—Do increased use days among older, college-educated marijuana smokers indicate greater social acceptance, or something else?

—Are younger people replacing traditional cannabis use with other substances?

—Why did Hispanic use increase more over the study period than other ethnic groups?

Burns R.M., Caulkins J.P., Everingham S.S. & Kilmer B. (2013). Statistics on Cannabis Users Skew Perceptions of Cannabis Use, Frontiers in Psychiatry, 4   DOI: 10.3389/fpsyt.2013.00138

Monday, October 20, 2014

The End of Combusted Tobacco?

With E-cigarettes, a mixed bag of possible outcomes.

E-cigarettes represent a controversial and uncertain future for nicotine addiction, and for this reason they have attracted acolytes and naysayers in what feels like equal measure.

It has been almost 8 years since e-cigarette imports first reached our shores, and the FDA’s determination that they are subject to regulation as tobacco products brings the industry to a crucial crossroads.

On the one hand: “Marked interdevice and intermanufacturer variability of e-cigarettes… makes it hard to draw conclusions about the safety or efficacy of the whole device class.”

On the other hand: “Published evaluation of some products suggest that e-cigarettes can be manufactured with levels of both efficacy and safety similar to those of NRT [nicotine replacement therapy] products… they could play the same role as NRT but at a truly national, population scale.”

So which will it be? Is there an outside chance that the decision by the FDA’s Center for Tobacco Products will represent the first step in dealing with nicotine products currently “designed, marketed, and sold” outside the regulatory framework established for NRT?  A stalemate presently prevails. Writing in the New England Journal of Medicine, Drs. David Abrams and Nathan K. Cobb, Johns Hopkins professors affiliated with the American Legacy Foundation, a tobacco research and prevention organization funded with lawsuit money from the major tobacco companies, highlight the irony: In order to market e-cigarettes as smoking cessations devices, manufacturers must seek approval from the FDA to market pharmaceutical products, “an expensive and time-consuming process than no manufacturer has yet attempted.”

Thus, questions about nicotine content, additives of various kinds, and assorted carrier chemicals go unanswered. Yet these are precisely the questions that need answers before e-cigarettes can be viewed as tools in the harm reduction armamentarium. Cobb and Abrams note that current e-cigarettes “represent a single instance of a nicotine product on a shifting spectrum of toxicity, addiction liability, and consumer satisfaction.” But the market dictates that “to compete with and displace combusted tobacco products, e-cigarettes will need to remain relatively convenient, satisfying, and inexpensive,” regulation notwithstanding.

Still, the harm reductionists’ dreams for the product remain seductive, because “surely any world where refined nicotine displaces lethal cigarettes will experience less harm, disease, and deaths? That scenario is one endgame model for tobacco control: smokers flee cigarettes en masse for refined nicotine and ultimately quit all use entirely.”

Critics say fat chance: “As Big Tobacco’s scientists shift from blending leaves and additives to manipulating circuit boards, chemicals, and dosing schedules, they’re unlikely to relinquish their tolerance for risk and toxicity that prematurely kills half their users in their efforts to ensure high levels of customer ‘satisfaction,’ addiction, and retention.”

Once again, it is the dictates of the market that may end up shaping the future of tobacco, and making the plans of harm reductionists look naïve indeed. “Tobacco companies and their investors,” write Cobb and Abrams, “need millions of heavily addicted smokers to remain customers for decades, including a replenishing stream of young people. No publicly traded company could tolerate the downsizing implicit in shifting from long-term addiction to harm reduction and cessation.”

The marketing innovations most likely to stem from tobacco companies entering the market for e-cigarettes are those most likely to “sustain high levels of addiction and synergistic ‘polyuse’ of their existing combusted products,” while simultaneously crimping competition from NRT manufacturers and independent e-cigarette manufacturers. Tobacco companies are past masters at manipulating things like nicotine content, vaporization methodologies, flavorings, and unknown additives. They will surely bring this expertise to bear in seeking a major bite out of the e-cigarette market while maintaining acceptable profit margins on traditional cigarettes.

The authors suggest that the FDA could weight the matter in harm reduction’s favor by using its product-standard authority “to cripple the addictive potential of lethal combusted products by mandating a reduction in nicotine levels to below those of e-cigarettes and NRT products and eliminating flavorings such as menthol that make cigarettes more palatable.” Tax breaks for e-cigarettes would further load the dice.

But not today. The FDA’s proposal calls for warning labels or product safety and quality standards for e-cigarettes—but not for at least two years. Two years is a long time in a fast-emerging market already valued in excess of $2 billion. The authors call the delay disturbing, “given the variability in product quality and a documented spike in cases of accidental nicotine poisoning.”

In conclusion, the authors believe that for smokers hoping to quit, “NRT products still represent safer, more predictable choices, even if they are more expensive and less appealing.”

Photo credit:  http://www.rstreet.org/

Tuesday, October 14, 2014

In Search of the Marijuana Breathalyzer

Pissing in a cup may be on the way out.

The good news: Marijuana breathalyzers are coming. The bad news: Marijuana breathalyzers are coming.

For years now, urinalysis using a mass spectrometer has been, if you’ll excuse the expression, the gold standard for drug testing. But in the case of alcohol, exhaled breath has always been the detection matrix of choice. And now, after the publication of several papers analyzing the detection of various drugs of abuse in exhaled breath, companies are hoping to leap into the market for cannabis breathalyzers.

A 2013 paper in the delightfully named Journal of Breath Research, written by neuroscience researchers at the Karolinska Institute in Stockholm, sought to confirm recent research suggesting that amphetamine, THC, and other drugs can be reliably detected in users who exhale into specially treated breath pads. The researchers collected breath, plasma, and urine samples from 47 patients. They tested for metabolites of methadone, amphetamine, morphine, benzodiazepines, cocaine, buprenorphine, and THC.

The results of the testing “provide further support to the possibility of using exhaled breath as a readily available specimen for drugs of abuse testing…. The detection rate for most investigated substances appears to be high, and higher than previously reported, with the exception of benzodiazepines.” The false positive rate was about 8%, which is very good, and is due, presumably, to improved sampling sensitivity.

In collaboration with Karolinska, NIDA researchers published a paper in Clinical Chemistry showing that cannabinoids blown onto breath pads were stable for up to 8 hours at room temperature—and up to 6 months in cold storage evidence lockers. The researchers tested 13 chronic smokers and 11 occasional smokers. Analysis of breath pad samples nailed all 13 of the serious smokers, and all but one of the casual smokers an hour after smoking. With current technology, the cannabis detection window remains very small, somewhere between 30 minutes and two hours. However, testing positive tells us nothing about when, and how much, marijuana was smoked.

Furthermore: “If a correlation to blood concentration can be shown for exhaled breath levels, it may become a substitute matrix for monitoring impairment.” And that, readers, is the Big If. What, exactly, are we testing FOR? Impairment, or just any and all use? Is there a reliable standard for marijuana, like the 0.08 blood level standard for alcohol? Or is a plethora of spurious positives on the horizon?

Roadside drug breathalyzers are presently under development or are in the prototype stage at several North American companies. One such device is a marijuana breathalyzer with a two-hour test window soon to be on offer from Cannabix Technologies. It was developed by a former member of the Royal Canadian Mounted Police because, says the company, there is no standardized way “to detect whether someone has been using marijuana on the spot like a breathalyzer does for alcohol.” So Cannabix is collaborating with Field Forensics Inc. to develop a testing device for roadside use.

An analysis last month at MarketWatch.com  saw a silver lining in the Cannabix breathalyzer, calling it “possibly the next major step towards normalization of more widespread marijuana use being allowed as such a device would offer a ready means of addressing key sticking points that have kept industry, legislators and law enforcement from agreeing on how best to regulate cannabis.”

North America is viewed as a “target-rich market” that is “ripe for the advent of a pot breathalyzer.” In the end, “roadside blood draws by law enforcement and other invasive methods of screening for THC intoxication, like zero-tolerance urine testing at the workplace, are increasing impractical as medical and even recreational cannabis gain ground throughout North America.”

The coming cannabis breathalyzers will be able to tell us the “when.” And soon they may even be able to tell us how much. But it remains unclear whether marijuana breathalyzers will ever be able to tell us how high—to reliably measure cannabis impairment behind the wheel. Somewhat mysteriously, the level of 5 nanograms of THC per blood milliliter has emerged as the de facto standard. But it’s clear to people who are actually familiar with marijuana’s effects that experienced users don’t react the same way as naïve users, and it’s perfectly logical to presume that some users can drive with complete safety at the 5ng level—users such as daily consumers of medical cannabis, whose tolerance is high even though daily quantities smoked is usually low.

One inspiration behind the cannabis breathalyzer is law enforcement’s love of the alcohol breathalyzer. In 1938, Dr. Rolla Harger of Indiana University introduced his Drunkometer, the first device for testing alcohol on a person’s breath. But it wasn’t portable. And it wasn’t until 1954 that Indiana University’s Robert Borkenstein came up with the portable Breathalyzer. The rest is drunk driving history.

In the bad old days before anybody “blew” a 0.08, prosecuting a DUI required court evidence—dash cam footage, field sobriety tests, officer assessments and testimony, and on and on. At present, that’s the situation for law enforcement when it comes to prosecuting a DUI for marijuana. For years, the prevailing court test has been the Duquenois-Levine test—the dominant method for field-testing marijuana since 1930—and it is considered by many to be wildly inaccurate. It involves inserting a bit of the substance in question into a prepared pipette, then waiting to see if it turns purple. If it does, the suspect can be charged with possession. (One U.S. Superior Court judge referred to the test as “pseudo-scientific”).

According to the official drug policy of the United Nations, a positive marijuana ID requires gas chromatography/mass spectrometry analysis. But even sophisticated tests have angered courts, due to the DEA’s muddled standards for lab protocols. A former FBI agent told the Texas Tech Law Review: “We are arresting vast numbers of citizens for possession of a substance that we cannot identify by utilizing the forensic protocol that is presently in use in most crime labs in the United States.”

Russ Belville, writing at the Huffington Post, concludes in a similar vein: “Until science shows a reliable test that only snares pot-impaired drivers and not unimpaired drivers who happen to be pot smokers, [prosecutors] are just asking for an easier way to discriminate against legal cannabis consumers.”

Thursday, October 2, 2014

Strokes in Young People

Drug use as a risk factor.

(First published 12-09-12)

When a stroke happens to anyone under the age of 55, a major suspect is drugs, specifically the stimulants—methamphetamine and cocaine. In the journal Stroke, researcher Brett Kissela and his associates provided additional evidence to support that unpleasant truth.

“We know that even with vascular risk factors that are prevalent—smoking, high blood pressure—most people still don’t have a stroke until they’re older,” Kissela said in a Reuters article. “When a young person has a stroke, it is probably much more likely that the cause of their stroke is something other than traditional risk factors.”

The modest study involved residents of Cincinnati and Northern Kentucky who had suffered a stroke before turning 55. The researchers found that the rate of substance abuse among the stroke group was higher than in control populations. This doesn’t prove that drug or alcohol addiction lead directly to strokes, since drug users often have additional risk factors for stroke and heart disease, particularly if they are also cigarette smokers.

But the suspected link between strokes and young drug abusers is by no means a new one. In 2007, scientists at the University of Texas Southwestern Medical Center in Dallas published a massive survey of more than 3 million records of Texas hospital patients from 2000 through 2003 in the Archives of General Psychiatry. This gigantic database gave the researchers access to the records of virtually every stroke patient in the state of Texas. The researchers found that strokes associated with amphetamine use among young people 18 to 44 years of age represented a rapidly growing category. In fact, the Texas group found that “the rate of strokes among amphetamine abusers was increasing faster than the rate of strokes among abusers of any other drug.”

Curiously, amphetamine and cocaine are responsible for different kinds of strokes. An ischemic stroke, the classic blood clot, is caused by a blockage of blood vessels to the brain. Hemorrhagic strokes result from bleeding caused by the rupture of a weakened blood vessel. In general, hemorrhagic strokes are more severe and more likely to cause death. And what the researchers found was more bad news for speed freaks: “Amphetamine abuse was strongly associated with hemorrhagic stroke, but not with ischemic stroke.” Cocaine abuse was more robustly linked to ischemic strokes. So, it’s not surprising that when it comes to drug and fatal strokes, the clear winner was amphetamine. It’s not entirely clear what causes the difference, but the investigators pointed out that meth injections in lab animals can cause microhemorrhaging, heart attacks, fragmentation of capillary beds, and something called “poor vascular filling.” For cocaine, the culprits are vasoconstriction and disrupted regulation of blood pressure.

More than 14 percent of strokes in hospitals “were accounted for by abuse of drugs,” the researchers wrote. The data showed that for patients with hemorrhagic strokes, “only amphetamine abuse, coagulation defects, and hypertension were strong independent predictors of in-hospital death.”

So what can we conclude? Either the number of speed users in these communities is increasing, or the existing speed communities are using the drug more intensely. Since the rate of increase of speed use was relatively modest during the study years, the researchers concluded that “increased rate in our hospital population is because of the increased intensity of methamphetamine use.” Meaning higher dosages, stronger meth, and more needles.

Sadly, much of this has been known since it least 1990. In that year, research published in the Annals of Internal Medicine, based on a study of stroke victims at San Francisco General Hospital, concluded that “the possibility of serious and sometimes fatal cerebrovascular accidents in people taking potent stimulants and using the intravenous route of administration is not as widely known as it needs to be.”

About 800,000 people in the U.S. suffer a stroke each year, according to figures from the U.S. Centers for Disease Control and Prevention. Strokes are considered America’s leading cause of serious long-term disability.

de los Rios F., Kleindorfer D.O., Khoury J., Broderick J.P., Moomaw C.J., Adeoye O., Flaherty M.L., Khatri P., Woo D. & Alwell K.;  (2012). Trends in Substance Abuse Preceding Stroke Among Young Adults: A Population-Based Study, Stroke, 43 (12) 3179-3183. DOI: 10.1161/STROKEAHA.112.667808

Monday, September 22, 2014

The Genetics of Smoking

Evidence from a 40-year study. 
(First published March 28, 2013)

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 report  published in JAMA Psychiatry. 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

Graphics Credit: http://neurologicalcorrelates.com/

Wednesday, September 17, 2014

Why Will Power Fails

How to strengthen your self-control.

(First published August 12, 2013)

Reason in man obscured, or not obeyed,
Immediately inordinate desires,
And upstart passions, catch the government
From reason; and to servitude reduce
Man, till then free.

—John Milton, Paradise Lost

What is will power? Is it the same as delayed gratification? Why is will power “far from bulletproof,” as researchers put it in a recent article for Neuron? Why is willpower “less successful during ‘hot’ emotional states”? And why do people “ration their access to ‘vices’ like cigarettes and junk foods by purchasing them in smaller quantities,” despite the fact that it’s cheaper to buy in bulk?

 Everyone, from children to grandparents, can be lured by the pull of immediate gratification, at the expense of large—but delayed—rewards. By means of a process known as temporal discounting, the subjective value of a reward declines as the delay to its receipt increases. Rational Man, Economic Man, shouldn’t behave in a manner clearly contrary to his or her own best interest. However, as Crockett et. al. point out in a recent paper in Neuron “struggles with self-control pervade daily life and characterize an array of dysfunctional behaviors, including addiction, overeating, overspending, and procrastination.”

Previous research has focused primarily on “the effortful inhibition of impulses” known as will power. Crockett and coworkers wanted to investigate another means by which people resist temptations. This alternative self-control strategy is called precommitment, “in which people anticipate self-control failures and prospectively restrict their access to temptations.” Good examples of this approach include avoiding the purchase of unhealthy foods so that they don’t constitute a short-term temptation at home, and putting money in financial accounts featuring steep penalties for early withdrawal. These strategies are commonplace, and that’s because people generally understand that will power is far from foolproof against short-term temptation. People adopt strategies, like precommitment, precisely because they are anticipating the possibility of a failure of self-control. We talk a good game about will power and self-control in addiction treatment, but the truth is, nobody really trusts it—and for good reason.  The person who still trusts will power has not been sufficiently tempted.

The researchers were looking for the neural mechanisms that underlie precommitment, so that they could compare them with brain scans of people exercising simple self-control in the face of short-term temptation.

After behavioral and fMRI testing, the investigators used preselected erotic imagery rated by subjects as either less desirable ( smaller-sooner reward, or SS), or more highly desirable ( larger-later reward, or LL). The protocol is complicated, and the analysis of brain scans is inherently controversial. But previous studies have shown heightened activity in three brain areas when subjects are engaged in “effortful inhibition of impulses.” These are the dorsolateral prefrontal cortex (DLPFC), the inferior frontal gyrus (IFG), and the posterior parietal cortex (PPC). But when presented with opportunities to precommit by making a binding choice that eliminated short-term temptation, activity increased in a brain region known as the lateral frontopolar cortex (LFPC).  Study participants who scored high on impulsivity tests were inclined to precommit to the binding choice.

In that sense, impulsivity can be defined as the abrupt breakdown of will power. Activity in the LFPC has been associated with value-based decision-making and counterfactual thinking. LFPC activity barely rose above zero when subjects actively resisted a short-term temptation using will power.  Subjects who chose the option to precommit, who were sensitive to the opportunity to make binding choices about the picture they most wanted to see, showed significant activity in the LFPC. “Participants were less likely to receive large delayed reward when they had to actively resist smaller-sooner reward, compared to when they could precommit to choosing the larger reward before being exposed to temptation.”

Here is how it looks to Molly Crockett and her fellow authors of the Neuron article:

Precommitment is adaptive when willpower failures are expected…. One computationally plausible neural mechanism is a hierarchical model of self-control in which an anatomically distinct network monitors the integrity of will-power processes and implements precommitment decisions by controlling activity in those same regions. The lateral frontopolar cortex (LFPC) is a strong candidate for serving this role.

None of the three brain regions implicated in the act of will power were active when opportunities to precommit were presented.  Precommitment, the authors conclude, “may involve recognizing, based on past experience, that future self-control failures are likely if temptations are present. Previous studies of the LFPC suggest that this region specifically plays a role in comparing alternative courses of action with potentially different expected values.” Precommitment, then, may arise as an alternative strategy; a byproduct of learning and memory related to experiences “about one’s own self-control abilities.”

There are plenty of caveats for this study: A small number of participants, the use of pictorial temptations, and the short time span for precommitment decisions, compared to real-world scenarios where delays to greater rewards can take weeks or months. But clearly something in us often knows that, in the immortal words of Carrie Fisher, “instant gratification takes too long.” For this unlucky subset, precommitment may be a vitally important cognitive strategy. “Humans may be woefully vulnerable to self-control failures,” the authors conclude, “but thankfully, we are sometimes sufficiently far-sighted to circumvent our inevitable shortcomings.” We learn—some of us—not to put ourselves in the path of temptation so readily.

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