Showing posts with label nicotine. Show all posts
Showing posts with label nicotine. Show all posts

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


Wednesday, January 28, 2015

Smoking and Sadness


The chemistry of sorrow during nicotine withdrawal.

When you smoke a cigarette, nicotine pops into acetylcholine receptors in the brain, the adrenal glands, and the skeletal muscles, and you get a nicotine rush. Just like alcohol, a cigarette alters the transmission of several important chemical messengers in the brain. “These are not trivial responses,” said Professor Ovide Pomerleau of the University of Michigan Medical School. “It’s like lighting a match in a gasoline factory.”

Experiments at NIDA’s Addiction Research Center in Baltimore have confirmed that nicotine withdrawal not only makes people irritable, but also impairs intellectual performance. Logical reasoning and rapid decision-making both suffer during nicotine withdrawal. Acetylcholine appears to enhance memory, which may help explain a common lament voiced by many smokers during early withdrawal. As summarized by one ex-smoker, “I cannot think, cannot remember, cannot concentrate.”

But there is another, less widely discussed aspect of nicotine withdrawal: profound sadness. Profound enough, in many cases, to be diagnosed as clinical unipolar depression.

 Of course, people detoxing from addictive drugs like nicotine are rarely known to be happy campers. But quitting smoking, for all its other withdrawal effects, reliably evokes a sense of acute nostalgia, like saying goodbye to a lifelong friend. The very act of abstinence produces sadness, joylessness, dysphoria, melancholia—all emotional states associated with unipolar depression.

Work undertaken by Dr. Alexander Glassman and his associates at the New York State Psychiatric Institute has nailed down an unexpectedly strong relationship between prior depression and cigarette smoking, and the findings have been confirmed in other work. This sheds important light on the question of why some smokers repeatedly fail to stop smoking, regardless of the method or the motivation.  The problem, as Glassman sees it, is “an associated vulnerability between affective [mood] disorders and nicotine.”

A group of Canadian researchers, working out of the Centre of Addiction and Mental Health (CAMH), and the Department of Psychiatry at the University of Toronto, believe they have isolated the specific neuronal mechanisms responsible for the profound sadness of the abstinent smoker.

Writing in the Archives of General Psychiatry, the investigators, who had access to what the CAMH proudly calls the only PET scanner in the world dedicated to mental health and addiction research, gave PET scans to 24 healthy smokers and 24 healthy non-smokers. Non-smokers were scanned once, while heavy and moderate cigarette smokers were scanned after smoking a cigarette, and also after a period of acute withdrawal. Earlier research of this kind had focused on nicotine’s effect on dopamine release. But Ingrid Bacher and her coworkers in Toronto were measuring MAO-A levels in the prefrontal and anterior cingulate regions, two areas known to be involved in “affect,” or emotional responses. When patients suffering from major depressive disorders get scanned, they tend to show elevated levels of MAO-A. The so-called MAO-A inhibitors Marplan, Nardil, Emsam, and Parnate are still in use as antidepressant medications. In general, the higher the levels of MAO-A, the lower the levels of various neurotransmitters crucial to pleasure and reward. A high level of MAO-A would suggest that the enzyme was significantly altering the activity of serotonin, dopamine, and norepinephrine in brain regions involved in mood.

The researchers found that smokers in withdrawal had 25-35% more MAO-A binding activity than non-smoking controls. “This finding may explain why heavy smokers are at high risk for clinical depression," says Dr. Anthony Phillips, Scientific Director of the Canadian Institutes of Health Research's (CIHR's) Institute of Neurosciences, Mental Health and Addiction, which funded this study.

Although researchers involved in these kinds of drug studies almost always claim that the work is likely to lead to new pharmacological therapies, the plain truth is that such immediate spinouts are rare. But in this case, it does seem like the study provides a clear incentive to investigate the clinical standing of MAO-A inhibitors as an adjunct therapy in stop-smoking programs. “Understanding sadness during cigarette withdrawal is important because this sad mood makes it hard for people to quit, especially in the first few days,” said Dr. Jeffrey Meyer, one of the study authors.

As one addiction researcher noted, an associated vulnerability to depression “isn’t going to cover everybody’s problem, and it doesn’t mean that if you give up smoking, you’re automatically going to plunge into a suicidal depression. However, for people who have some problems along those lines, giving up smoking definitely complicates their lives.”


Bacher, I., Houle, S., Xu, X., Zawertailo, L., Soliman, A., Wilson, A., Selby, P., George, T., Sacher, J., Miler, L., Kish, S., Rusjan, P., & Meyer, J. (2011). Monoamine Oxidase A Binding in the Prefrontal and Anterior Cingulate Cortices During Acute Withdrawal From Heavy Cigarette Smoking Archives of General Psychiatry, 68 (8), 817-826 DOI: 10.1001/archgenpsychiatry.2011.82

(First published 8-4-11).


Wednesday, December 3, 2014

Cigarettes and Genetic Risk


Evidence From a 4-Decade Study.

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 last year 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.

(First published March 28, 2013)

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


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/


Thursday, May 8, 2014

Why the CDC Director Hates E-Cigarettes


The pros and cons of getting your vape on.

Last month, the Food and Drug Administration (FDA) began a new era—regulating e-cigarettes. With a non-controversial first step, the FDA banned the sale of e-cigarettes to minors, required health warnings, prohibited health claims, and outlined a plan to register and license all electronic nicotine products at some future date. The FDA’s proposed rules would also give the agency the power to regulate the currently unregulated mixture of chemicals and flavorings that are heated during e-cigarette use.  Whatever regulations the FDA promulgates for electronic cigarettes will also apply to nicotine gels, water pipe tobacco, and hookahs.

Perhaps what rankles e-cigarette activists the most is the FDA’s insistence that companies will have to provide scientific evidence before making any implied claims about risk reduction for their product, compared with cigarettes. The FDA did not restrict advertising or prohibit flavorings (bubble gum, apple-blueberry, gummi bear, and cappuccino are popular).

Within a few days after the FDA’s announcement, Chicago, New York City, and other major cities placed e-cigarettes under the same municipal smoking bans as cigarettes. 

The battle over e-cigarettes is both a public health issue and a private enterprise war for market share. Corporate giants Altria and Lorillard, which dominate the corporate tobacco landscape in the U.S., are fighting for a piece of what has become nearly a $2 billion market in a few short years. (Altria recently boosted  its growth forecast to 6-9% growth for 2014). Lorillard has been making heavy acquisitions of its own, and commands more than half the present market with its Blu brand. Altria has made its own vapor acquisitions, and is launching its own brand, MarkTen.

So far, the moves being contemplated by the FDA do not have these companies shaking in their boots. They anticipated the ban on sales to minors, a system of formal FDA approval, a disclosure of ingredients, and health warnings about the addictive nature of nicotine. And Congress gave the FDA legal authority to draft a set of rules for e-cigarettes five years ago, so the FDA’s reluctance to step in on liquid nicotine delivery systems has been evident.

In an interview with the Los Angeles Times, Tom Frieden, director of the Center for Disease Control and Prevention (CDC), listed the reasons for his opposition to electronic cigarettes:

—E-cigarettes are an additional means of hooking another generation of kids on nicotine, making them more likely to become adult smokers.

—Smokers who might have quit smoking will maintain their nicotine addiction, remaining highly vulnerable to tobacco craving.

—Ex-smokers might make themselves more vulnerable to relapse if they take up vaping.

—Smokers might forego medications that could help them quit, in favor of the unproven promise of tobacco abstention via e-cigarette.

—E-cigarettes might have the cultural effect of “re-glamorizing” smoking.

—E-cigarette users might be exposing children and pregnant women to nicotine via secondhand smoke mechanisms.

—E-cigarette users can refill cartridges with liquid cannabis products and other drugs.

Dr. Michael Siegel, a tobacco expert at the Boston University School of Public Health, worries that smaller players will be squeezed out due to costs associated with the FDA approval process, driving sales toward the traditional cigarette industry leaders. Go-go analysts have predicted market penetration of as much as 50% for e-cigarettes, but Siegel is more pessimistic, and believes the e-cigarette share could top out at 10% if FDA regulations set back efforts by vaping proponents to position their product as a safer and healthier alternative to tobacco cigarettes. And that, says Siegel, would be a shame. He told the Boston Globe: “There simply is no product on the market that’s more dangerous than tobacco cigarettes, and nobody in their right mind would argue that cigarette smoking is less hazardous or even equally hazardous to vaping.”

Frieden at the CDC is sympathetic to the fact that many smokers have indeed quit smoking tobacco with the aid of e-cigarettes. “Stick to stick, they’re almost certainly less toxic than cigarettes.” But like many tobacco experts, he sees the possibility of a new generation of nicotine addicts. Almost two million high school kids have tried e-cigarettes, Frieden told the LA Times, “and a lot of them are using them regularly…. That’s like watching someone harm hundreds of thousands of children.”  The CDC reported that the percentage of high school students who have used an e-cigarette jumped from 4.7% in 2011 to 10% in 2012. Calls to poison control centers involving children and e-cigarettes have increased sharply as well.

Frieden views the Food and Drug Administration as David under siege by Goliath. The FDA, he said, “tried to regulate e-cigarettes earlier, and they lost to the tobacco industry…. So the FDA has to balance moving quickly with moving in a way that’s going to be able to survive the tobacco industry’s highly paid legal challenge.” If E-cigarette makers really want to market to people trying to quit smoking, Frieden told the LA Times, “then do the clinical trials and apply to the FDA. But they don’t want to do that.” (See my post on Big Tobacco’s move into the e-cigarette market).

“It’s really the wild, wild West out there,” a beleaguered FDA commissioner Margaret Hamburg told the press.   “They’re coming in different sizes, shapes and flavors in terms of the nicotine in them.”

On May 4, the New York Times published a report by Matt Richtel, based on an upcoming paper in the journal Nicotine and Tobacco Research. Nicotine researchers discovered that high-end electronic cigarette systems with refillable tanks produce formaldehyde, a known carcinogen, as a component of the exhaled nicotine vapor. Moreover, unlike disposable e-cigarettes, tank systems require users to refill them with liquid nicotine, itself a potent toxin. “Nicotine is a pesticide, fundamentally,” Michael Eriksen, dean of the School of Public Health at Georgia Statue University, told CNN. “We take so many precautions about pesticides for our lawns and how to wear gloves. But what precautions do consumers take when they put the nicotine vials in?”

This was not good news for harm reductionists, who view the advantages of e-cigarettes as self-evident. The New York Times report says that the toxin is formed “when liquid nicotine and other e-cigarette ingredients are subjected to high temperatures,” according to the research. “A second study that is being prepared for submission to the same journal points to similar findings.” In addition, a new study by researchers RTI International documents the release of tiny metal particles, including tin, chromium and nickel, which may worsen asthma and bronchitis.

Eric Moskowitz at the Boston Globe  reported that “thousands of gas stations and convenience stores statewide carry e-cigarettes, usually stocking disposable or cartridge-based versions that resemble traditional cigarettes.”

In U.S. News, Gregory Conley, president of the trade group American Vaping Association, predicted “a huge influx of anti-e-cigarette legislation in the last half of 2014 and especially in 2015 when the legislative sessions get going again.” 

According to Carl Tobias, a law professor at the University of Richmond, “it may be years before  regulations are imposed. The lobbying at FDA and Congress will be intense.”

Effectively regulated, e-cigarettes have the potential to drastically reduce deaths from tobacco-related diseases among cigarette smokers. In an editorial for the journal Addiction, Sara Hitchman, Ann McNeill, and Leonie Brose of King’s College, London, wrote: “E-cigarettes may offer a way out of the smoking epidemic or a way of perpetuating it; robustly designed, implemented and accurately reported scientific evidence will be the best tool we have to help us predict and shape which of these realities transpires.”

Photo credit: http://ecigarettereviewed.com

Sunday, June 16, 2013

A Weak Smoker’s Vaccine Might Be Worse Than None


New PET scans show wide responses to antibodies.

One of the brightest hopes of addiction science has been the idea of a vaccine—an antibody that would scavenge for drug molecules, bind to them, and make it impossible for them to cross the blood-brain barrier and go to work. But there are dozens of good reasons why this seemingly straightforward approach to medical treatment of addiction is devilishly difficult to perform in practice.

Last January, health care company Novartis threw in the towel on NicVax, a nicotine vaccine that failed to beat placebos in Phase III clinical trials for the FDA. And back in 2010, a report in the Archives of General Psychiatry demonstrated that a vaccine intended for cocaine addicts only generated sufficient antibodies to dull the effects of the cocaine in 38 percent of the test subjects. Moreover, it proved possible to overcome immunization by upping the cocaine dose, which sounded like an invitation to overdose.

And now, neuroscientists at the Society of Nuclear Medicine and Molecular Imaging annual meeting have presented a new study, the conclusions of which might help researchers understand why the vaccine results have been so mixed. The research “represents one of the first human studies of its kind using molecular imaging to test an investigational anti-nicotine immunization,” lead author Alexey Mukhin, professor of psychiatry and behavioral science at Duke University Medical Center, said in a prepared statement.


Subjects underwent two PET brain scan as they smoked nicotine labeled with radioactive C-11, one before the vaccine was administered, and one after. Ten subjects who developed “high-affinity antibodies” after vaccination showed a slight decrease in nicotine accumulation in the brain, as judged by the scans. However, another group of ten subjects, who showed “intermediate serum nicotine binding capacity and low affinity of antibodies” actually showed an increase in brain nicotine levels. What the PET scans showed was that “strong nicotine-antibody binding, which means high affinity, was associated with a decrease in brain nicotine accumulation. When binding was not strong, an increase in brain accumulation was observed.”

If the bond that holds the antibodies to the nicotine molecules is weak, the bond can break during passage through the blood-brain barrier, potentially allowing excess nicotine to flood in. This result, said Mukhin, tell us “we should care about not only the amount of antibody, but the quality of the antibody. We don’t want to have low-affinity antibodies because that can negate the anti-nicotine effects of the vaccination.”

Back to the drawing board? Not entirely. Another of the study authors, Yantao Zuo of Duke University Medical Center, said that “with reports of new generations of the vaccines showing potentially much higher potencies in animal studies, we are hopeful that our current findings and methodology in human research will facilitate understanding of how these work in smokers.”

Photo Credit:http://www.medgadget.com

Tuesday, January 22, 2013

Big Tobacco Makes a Move Into E-Cigarettes


“A battery-operated, addiction-based market.”

While the FDA dithered, and health advocates argued, Big Tobacco began placing its bets on the e-cigarette market last year. Tobacco firm Lorillard Inc., the third largest tobacco company in America, bought privately held Blue Ecigs of Charlotte, N.C., for $135 million, driven by what the company says is a market that’s been doubling ever year since e-cigs first arrived from China in 2008.

According to the Wall Street Journal, Blue Ecigs had $30 million in revenues last year, selling through retail outlets like Walgreens, where it competes with e-brands such as NJOY and 21s Century. The FDA has announced vague plans to regulate, and state lawmakers have threatened to ban them outright, or at least place them under the same public smoking bans as cigarettes—bans that some e-smokers love to flout. (E-cigarette manufacturers, based primarily in Asia, quickly changed the electric orange glow at the end of the e-cigarette to a cool shade of blue, to help make clear to bartenders and bouncers that the thing wasn’t a lit cigarette.)

Meanwhile, Reynolds, an industry leader in smokeless products, is developing its own line of e-cigs, and is test-marketing its Vuse and Zonnic brands. “We will be in this category in 2013,” an RJ Reynolds representative said in a CNBC article by Jane Wells. “We have very big plans.”

Altria, the industry giant, is now generating $1.6 billion from smokeless tobacco products, and is expected to make a move into what is viewed as a billion-dollar industry with unlimited growth potential. Last year, the company began testing a new “nicotine-extract product” called Verve, a lozenge that can be sucked or chewed and contains about 1.5 milligrams of nicotine. Late last year, the company reportedly engaged in acquisition talks with e-cig maker Eonsmoke.

Meanwhile, the company that invented the electronic cigarette, Dragonite/Ruyan, is suing practically everybody. And the Argentinean and Venezuelan governments have attempted to ban the use and marketing of electronic cigarettes altogether.

In December, astute American TV viewers may have noticed what looked for all the world like a television commercial for cigarettes—the first since 1971, when Congress banned cigarette ads on TV. It was a commercial for NJOY Kings electronic cigarettes, a brand that currently owns about one-third of the U.S. e-cig market. Patent lawyer Mark Weiss, who founded NJOY, told Time that the company was only competing for the 45 million Americans who are current smokers, not attempting to make new recruits. In the article, Weiss noted three advantages for e-cigarettes: They’re odor free, they don’t burn tobacco, and, at about $8 per e-cigarette, Weiss claims, they’ll last you as long as two regular packs of cigarettes.

When major tobacco companies make moves like this, people notice. “I think they see this as an opportunity to get a seat at the table with opportunities to talk to the FDA about regulation over this growing category,” according to Bonnie Herzog, senior analyst and managing director of tobacco, beverage and consumer research for Wells Fargo Securities. “Lorillard wants to help steer that conversation in the right direction.”

While still a relatively modest market—no more than $500 million, compared to the $100 billion tobacco market in the U.S.—electronic cigarettes have the potential of becoming the most contentious entry in the market for nicotine delivery systems since the advent of the machine-rolled cigarette. “We think e-cigs are to tobacco what energy drinks are to beverages,” Herzog told the media.

Lorillard chairman and CEO Murray Kessler said in an earnings conference call late last year that with e-cigarettes, “you get all of the benefits of not having combustion, but on the other hand you are maintaining the behavior that cigarette smokers enjoyed.” That’s one way of putting it. And according to critics, that’s part of the problem. Anti-smoking activists often view e-cigarettes as gateway products for young adults.

They are cheaper, primarily because of heavy taxes on traditional cigarettes, and produce no second-hand smoke, only steam-like vapor that quickly dissipates. But they have had a rocky start in the U.S. An article in the Winston-Salem Journal in prime tobacco country stated that consumers have “shied away out of safety concerns since most e-cigs are made in China.” Even North Carolina health officials have expressed concerns about “limited regulatory oversight of their contents.” But according to Wells Fargo’s Herzog, Lorillard’s purchase of Blu Ecigs had the effect of “lending credibility and legitimacy to the entire category.”

Brad Rodu, professor of medicine at the University of Louisville, insisted that “tobacco manufacturers have an obligation to smokers to develop, manufacture and sell these vastly safer cigarette substitutes.” In this view, smokers smoke for the nicotine, but it’s the tar that kills them. 

In the same Winston-Salem Journal article, a professor of family and community medicine at Wake Forest School of Medicine said that “many of the carcinogens in tobacco are volatile and would vaporize, and thus be inhaled when heated. I would not recommend that product.”

It seems safe to predict that this “battery-operated, addiction-based market,” as Forbes dubbed it, will be one to watch.

Wednesday, May 23, 2012

The Hidden Story of How Big Tobacco Invented Freebasing



Review of The Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition.

Part I

It’s easy to think of cigarettes, and the machinations of the tobacco industry, as “old news.” But in his revealing 737-page book, The Golden Holocaust, based on 70 million pages of documents from the tobacco industry, Stanford professor Robert N. Proctor demonstrates otherwise. He demonstrates how Big Tobacco invented freebasing. He shows how they colluded in misleading the public about “safe” alternatives like filters, “low-tar,” and “ultra-lights.” We discover in Lorillard’s archives an explanation of menthol’s appeal to African Americans: It is all part of a desire by “negroes” to mask a “genetic body odor.” Radioactive isotopes were isolated in cigarette smoke, and evidence of the find was published, as early as 1953. He reveals that the secret ingredient in Kent’s “micronite filter” was asbestos. And he charges that the “corruption of science” lies behind the industry’s drive to continue its deadly trade. “Collaboration with the tobacco industry,” writes Proctor, “is one of the most deadly abuses of scholarly integrity in modern history.”

Half of all cigarette smokers will die from smoking—about a billion people this century, if present trends continue. In the U.S., this translates into roughly two jumbo jets crashing, killing everyone onboard, once daily. Cigarettes kill more people than bullets. The world smokes 6 trillion of them each year. (The Chinese alone account for about 2 trillion). Some people believe that tobacco represents a problem (more or less) solved, at least in the developed West.

All of this represents a continuing triumph for the tobacco industry. The aiders and abettors of tobacco love to portray the tobacco story as “old news.” But as Stanford Professor Robert M. Proctor writes in The Golden Holocaust, his exhaustive history of tobacco science and industry: “Global warming denialists cut their teeth on tobacco tactics, fighting science with science, creating doubt, fostering ignorance.”

Checking in at 737 pages, The Golden Holocaust is nobody’s idea of a light read, and at times its organization seems clear only to the author. But what a treasure trove of buried facts and misleading science Proctor has uncovered, thanks to more than 70 million pages of industry documents now online (http://legacy.library.ucsf.edu) as part of the Master Settlement Agreement of 1998. Once the material was finally digitized and available online, scholars like Proctor could employ full-text optical character recognition for detailed searchability. Ironically, this surreal blizzard of documentation was meant to obscure meaningful facts, not make them readily available, but tobacco executives seem not to have factored in digital technology when they turned over the material.

The single most important technological breakthrough in the history of the modern cigarette was flue-curing, which lowers the pH of tobacco smoke enough to make it inhalable. The reason few people inhale cigars, and very few used to inhale cigarettes, is that without some help, burning tobacco has a pH too high for comfortable inhalation. It makes you cough. But flue-curing lowered pH levels, allowing for a “milder,” less alkaline smoke that even women and children could tolerate.

World War I legitimized cigarettes in a major way. Per capita consumption in the U.S. almost tripled from 1914 to 1919, which Proctor considers “one of the most rapid increases in smoking ever recorded.” After World War II, the Marshall Plan shipped a staggering $1 billion worth of tobacco and other “food-related items.” (The U.S. Senator who blustered the loudest for big postwar tobacco shipments to Europe was A. Willis Robertson of Virginia, the father of televangelist Pat Robertson.)

The military, as we know, has historically been gung-ho on cigarettes. And Proctor claims that “the front shirt pocket that now adorns the dress of virtually every American male, for example, was born from an effort to make a place to park your cigarette pack.” In addition, cigarette makers spent a great deal of time and effort convincing automakers and airline manufacturers to put ashtrays into the cars and planes they sold. Ashtrays were built into seats in movie theaters, barbershops, and lecture halls. There was even an ashtray built into the U.S. military’s anti-Soviet SAGE computer in the 50s.

In the early 50s, research by Ernest Wynder in the U.S. and Angel Roffo in Argentina produced the first strong evidence that tobacco tars caused cancer in mice. Roffo in particular seemed convinced that tobacco caused lung cancer, that it was the tar rather than the nicotine, and that the main culprits were the aromatic hydrocarbons such as benzpyrene. Curiously enough, it was influential members of Germany’s Third Reich in the 40s who first took the possibility of a link seriously. Hans Reiter, a powerful figure in public health in Germany, said in a 1941 speech that smoking had been linked to human lung cancers through “painstaking observations of individual cases.”

In the December 1953 issue of Cancer Research, Wynder, et al. published a paper demonstrating that “tars extracted from tobacco smoke could induce cancers when painted on the skins of mice.” As it turns out, the tobacco industry already knew it. Executives had funded their own research, while keeping a close eye on outside academic studies, and had been doing so since at least the 30s. In fact, French doctors had been referring to cancers des fumeurs, or smokers’ cancers, since the mid-1800s. All of which knocks the first leg out from under the tobacco industry’s classic position: We didn’t know any stuff about cancer hazards until well into the 1950s.

Only weeks after the Wynder paper was published, tobacco execs went into full conspiracy mode during a series of meetings at the Plaza Hotel in New York, “where the denialist campaign was set in motion.” American Tobacco Company President Paul Hahn issued a press release that came to be known as the “Frank Statement” of 1954. Proctor calls it the “magna carta of the American’s industry’s conspiracy to deny any evidence of tobacco harms.” How, Proctor asks, did science get shackled to the odious enterprise of exonerating cigarettes? The secret was not so much in outright suppression of science, though there was plenty of that: In one memorable action known as the “Mouse House Massacre,” R.J. Reynolds abruptly shut down their internal animal research lab and laid off 26 scientists overnight, after the researchers began obtaining unwelcome results about tobacco smoke. But the true genius of the industry “was rather in using even ‘good’ science, narrowly defined, as a distraction, something to hold up to say, in effect: See how responsible we are?”

Entities like the Council for Tobacco Research engaged in decoy research of this kind. As one tobacco company admitted, “Research must go on and on.”

A good deal of the industry’s research in the 50s and 60s was in fact geared toward reverse engineering competitors’ successes. Consider Marlboro. Every cigarette manufacturer want to know: How did they do it? What was the secret to Marlboro’s success?

As it turns out, they did it by increasing nicotine’s kick. And they accomplished that, in essence, by means of freebasing, a process invented by the cigarette industry. Adding ammonia or some other alkaline compound transforms a molecule of nicotine from its bound salt version to its “free” base, which volatilizes much more easily, providing low-pH smoke easily absorbed by body tissue. And there you have the secret: “The freebasing of cocaine hydrochloride into ‘crack’ is based on a similar chemistry: the cocaine alkaloid is far more potent in its free base form than as a salt, so bicarbonate is used to transform cocaine hydrochloride into chemically pure crack cocaine.” Once other cigarette makers figured out the formula, they too began experimenting with the advantages of an “enhanced alkaline environment.”
  
(End of Part I)

Photo Credit: http://theloungeisback.wordpress.com/

Monday, November 14, 2011

Researchers Eye a Cheap, Organic Alternative to Chantix for Smokers


Meet cytisine, available in Bulgaria for 25 cents a pill.

A clear majority of American smokers say they want to quit. But each year, only a small percentage of them manage to do it. For individual smokers, the will is there, but what’s sometimes missing is the money.

For many smokers, cessation aids like nicotine patches and anti-craving medication are effective. But they are relatively costly, and insurance coverage for such products varies widely. Chantix, the top-of-the-line smoking cessation aid introduced by Pfizer five years ago as a very expensive prescription drug, was discovered by modifying the chemical attributes of an existing plant substance called cytisine.

But what if cytisine itself, found in various plants, including the golden rain tree, a small shrub native to the Alps—worked almost as well as Chantix, but for only pennies a day? Cytisine, packaged as Tabex and marketed by a Bulgarian firm, has already been on the market in Central Europe and Russia for more than 40 years. In Russia, a four-week course of Tabex costs $6.  Chantix will cost smokers about $250 for a 12-week run, or about $3-$4 per pill. In Poland, Tabex sells for about 25 cents per pill.

Moreover, as David Biello pointed out in Scientific American, when Chantix (known as Champix in the U.K.) was first approved for use against cigarettes, “the leaves of Cytisus laburnum, or the golden rain acacia tree, were used as a tobacco substitute by soldiers in World War II.” Later, clinicians in the U.S. paid scant attention to reports of a cheap Bulgarian plant-based supplement that smokers in Russia and Central Europe were using to help break their nicotine addiction. Instead, researchers structurally modified cytisine to produce varenicline, or Chantix. It makes for a more effective drug, but there are always tradeoffs: It is expensive and time-consuming to produce drugs through a process of total syntheses, and they will always come at a considerable cost premium relative to their organic originals. That is partly how pharmacology works, and it’s a good thing, providing you have the money or the health insurance to be able to afford the finished product.

Recently, a group of researchers at a smoking cessation clinic in Poland studied the effect of cytisine, a “partial nicotine agonist,” in a clinical trial published
 ResearchBlogging.orgin the New England Journal of Medicine. The double-blind trial showed that cytisine was not as effective as Chantix, but significantly more effective than a placebo. Dr. Robert West of University College, London, and lead author of the study, said the “net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4.”

“It wasn't compared head-to-head against the Rx drugs, but its reasonable efficacy makes it sound like a cheaper alternative,” said Dr. David Kroll, Professor and Chair of Pharmaceutical Science at North Carolina Central University. “Like nicotine, it can cause side effects like headaches and nausea,” he added.

So is cytisine an eventual possibility in the U.S., where it is not currently licensed and available? Is it something that the National Institute on Drug Abuse is interested in? When I asked NIDA director Nora Volkow that question in an interview last week, the answer was yes. “The data look very interesting,” Volkow said, referring to the New England Journal of Medicine Study.  “The beauty of cytisine is that it’s not just inexpensive, you can also get a response in three weeks.” She added that “we don’t know yet whether we can improve it,” by, for example, combining it with other cessation aids. “The main side effect of cytisine is nausea, but not suicidal ideation,” she said.

An earlier survey in the Archives of Internal Medicine of the admittedly sparse research showed similar results in several placebo-controlled double-blind studies. Cytisine, the Marxist-Socialist answer to cigarette addiction, works about as well as standard nicotine replacement therapy, like patches and gums.

“I hope this drug will be available throughout the world at a cost that every smoker can afford,” said West. And that might be a problem. Cytisine is not currently legal in the U.S. or Canada. Tabex itself was withdrawn from some of the European countries in which it was formerly available, after several Central and Eastern European countries joined the European Union and began adhering to stricter licensing rules.

Meanwhile, a third of the world is still out there smoking tobacco. It seems sensible to have some modest help available for smokers in poverty who want to quit and financially need to quit. “I have long been concerned that effective treatments to help smokers to stop are not affordable by the majority of smokers in the world,” West said. “There are still regulatory hoops to go through, but I hope that before long this drug will be available throughout the world at a cost that every smoker can afford. It should be cheaper to take this drug than to smoke, wherever you are in the world. It is not a magic cure by any means; stopping is still extremely difficult for many people. But it could save many hundreds of thousands of lives, if not millions, which is quite a thought.”

As Dr. Volkow put it: “We urgently need medications for smoking. Five million people die per year” from smoking-related causes in the U.S.

West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, & Stapleton J (2011). Placebo-controlled trial of cytisine for smoking cessation. The New England journal of medicine, 365 (13), 1193-200 PMID: 21991893

Thursday, August 4, 2011

Cigarette Sadness


The chemistry of sorrow during nicotine withdrawal.

When you smoke a cigarette, nicotine pops into acetylcholine receptors in the brain, the adrenal glands, and the skeletal muscles, and you get a nicotine rush. Just like alcohol, a cigarette alters the transmission of several important chemical messengers in the brain. “These are not trivial responses,” said Professor Ovide Pomerleau of the University of Michigan Medical School. “It’s like lighting a match in a gasoline factory.”

Experiments at NIDA’s Addiction Research Center in Baltimore have confirmed that nicotine withdrawal not only makes people irritable, but also impairs intellectual This post was chosen as an Editor's Selection for ResearchBlogging.orgperformance. Logical reasoning and rapid decision-making both suffer during nicotine withdrawal. Acetylcholine appears to enhance memory, which may help explain a common lament voiced by many smokers during early withdrawal. As summarized by one ex-smoker, “I cannot think, cannot remember, cannot concentrate.”

But there is another, less widely discussed aspect of nicotine withdrawal: profound sadness. Profound enough, in many cases, to be diagnosed as clinical unipolar depression.

 Of course, people detoxing from addictive drugs like nicotine are rarely known to be happy campers. But quitting smoking, for all its other withdrawal effects, reliably evokes a sense of acute nostalgia, like saying goodbye to a lifelong friend. The very act of abstinence produces sadness, joylessness, dysphoria, melancholia—all emotional states associated with unipolar depression.

Work undertaken by Dr. Alexander Glassman and his associates at the New York State Psychiatric Institute has nailed down an unexpectedly strong relationship between prior depression and cigarette smoking, and the findings have been confirmed in other work. This sheds important light on the question of why some smokers repeatedly fail to stop smoking, regardless of the method or the motivation.  The problem, as Glassman sees it, is “an associated vulnerability between affective [mood] disorders and nicotine.”

Now a group of Canadian researchers, working out of the Centre of Addiction and Mental Health (CAMH), and the Department of Psychiatry at the University of Toronto, believe they have isolated the specific neuronal mechanisms responsible for the profound sadness of the abstinent smoker.

Writing in the Archives of General Psychiatry, the investigators, who had access to what the CAMH proudly calls the only PET scanner in the world dedicated to mental health and addiction research, gave PET scans to 24 healthy smokers and 24 healthy non-smokers. Non-smokers were scanned once, while heavy and moderate cigarette smokers were scanned after smoking a cigarette, and also after a period of acute withdrawal. Earlier research of this kind had focused on nicotine’s effect on dopamine release. But Ingrid Bacher and her coworkers in Toronto were measuring MAO-A levels in the prefrontal and anterior cingulate regions, two areas known to be involved in “affect,” or emotional responses. When patients suffering from major depressive disorders get scanned, they tend to show elevated levels of MAO-A. The so-called MAO-A inhibitors Marplan, Nardil, Emsam, and Parnate are still in use as antidepressant medications. In general, the higher the levels of MAO-A, the lower the levels of various neurotransmitters crucial to pleasure and reward. A high level of MAO-A would suggest that the enzyme was significantly altering the activity of serotonin, dopamine, and norepinephrine in brain regions involved in mood.

The researchers found that smokers in withdrawal had 25-35% more MAO-A binding activity than non-smoking controls. “This finding may explain why heavy smokers are at high risk for clinical depression," says Dr. Anthony Phillips, Scientific Director of the Canadian Institutes of Health Research's (CIHR's) Institute of Neurosciences, Mental Health and Addiction, which funded this study.

Although researchers involved in these kinds of drug studies almost always claim that the work is likely to lead to new pharmacological therapies, the plain truth is that such immediate spinouts are rare. But in this case, it does seem like the study provides a clear incentive to investigate the clinical standing of MAO-A inhibitors as an adjunct therapy in stop-smoking programs. “Understanding sadness during cigarette withdrawal is important because this sad mood makes it hard for people to quit, especially in the first few days,” said Dr. Jeffrey Meyer, one of the study authors.

As one addiction researcher noted, an associated vulnerability to depression “isn’t going to cover everybody’s problem, and it doesn’t mean that if you give up smoking, you’re automatically going to plunge into a suicidal depression. However, for people who have some problems along those lines, giving up smoking definitely complicates their lives.”


Bacher, I., Houle, S., Xu, X., Zawertailo, L., Soliman, A., Wilson, A., Selby, P., George, T., Sacher, J., Miler, L., Kish, S., Rusjan, P., & Meyer, J. (2011). Monoamine Oxidase A Binding in the Prefrontal and Anterior Cingulate Cortices During Acute Withdrawal From Heavy Cigarette Smoking Archives of General Psychiatry, 68 (8), 817-826 DOI: 10.1001/archgenpsychiatry.2011.82

Photo Credit:http://jenniferonmars.wordpress.com

Friday, June 3, 2011

For Smokers, Nowhere to Run and Nowhere to Hide


(With love and apologies to Martha and the Vandellas.)

That wonderful song goes on to declare:

'Cause I know
You're no good for me
But you’ve become
A part of me.

The song is not about cigarette addiction, but it could be. Full Disclosure: I smoked cigarettes myself for almost 25 years. And then, after several failed attempts, I quit. I out myself on this subject because a paper from the May 25 issue of the New England Journal of Medicine (NEJM) decries This post was chosen as an Editor's Selection for ResearchBlogging.orgwhat the authors call the “denormalization” of smoking—and I find myself agreeing with them, smokeless though I may be. I recently visited New York, coincidentally on the day that smoking outdoors in New York City became illegal. Okay, that’s not quite fair to say—it became illegal to smoke in Central Park, or at Brighton Beach, or along the newly pedestrian mallways of Times Square. There is no smoking along the High Line. There is no smoking at any park, beach, or pedestrian mall. As both the tobacco industry and anti-smoking activists well know, this was an iconic victory that has the potential to change smoking laws in virtually every other American city.

It’s a fascinating progression, starting in the 70s when the Civil Aeronautics Board decreed non-smoking sections on domestic airline flights, to the recent New York City Council Decision to ban smoking en plein air, so to speak. Thomas Farley, New York City Health Commissioner, summed it up as follows in a public hearing: “I think in the future, we will look back on this time and say ‘How could we have ever tolerated smoking in a park?’”

I’m not so sure on that, myself. James Colgrove, Ronald Bayer, and Kathleen Bachynski of the Mailman School of Public Health at Columbia University wrote the paper, entitled “Nowhere Left to Hide? The Banishment of Smoking from Public Spaces,” in the NEJM. The authors note that more than 500 towns and cities in 43 different states have already enacted laws banning smoking “in outdoor recreation areas.” At first, as the authors summarize the history, it all seems like a sensible compromise, built on common courtesy. First airplanes and buses, then restaurants and bars, began setting aside seats for non-smokers. By the early 90s, the first data on secondhand smoke was rolling in. Schools, convention centers, and finally even private workplaces either banned smoking or created smoke-free areas. But even then, the primary motivator, according to the researchers, was that secondhand smoke was “unpleasant and annoying,” not deadly. Smokers weren’t being asked to refrain from public smoking for the good of their own health, but as a courtesy to others.

The solid scientific evidence kept accumulating, however—even though tobacco cigarettes were, and still are, completely legal products for adult Americans to purchase and consume if they so choose. Now the arguments shifted to the innocent bystanders, those within the six-foot ring, the immediate smoke zone surrounding a smoker, and the elevated risk of lung cancer, heart disease, and asthma that smokers were subjecting them to. In 1993, the Environmental Protection Agency (EPA) classified secondhand smoke as a Class A carcinogen, and more school, stadiums and offices proscribed smoking.

So far so good, really, from a public health standpoint. But now comes the bend in the road. Suddenly, parks and beaches were being added to the no-smoking roster. “As the zones of prohibition are extended from indoor to outdoor spaces, however, the evidence of physical harm to bystanders grows more tenuous.” In 2008, the authors report, “The editor of the journal Tobacco Control dismissed as ‘flimsy’ the evidence that secondhand smoke poses a threat to the health of nonsmokers in most outdoor settings.”

This confusion was much in evidence at public hearings last fall on the proposed outdoor smoking bans. While Health commissioner Farley argued that 57% of New Yorkers showed nicotine by-products in their blood, he also argued that exposing young children to adults in the carnal act of smoking was detrimental to the public health and welfare. “Families,” he said, “should be able to bring their children to parks and beaches knowing that they won’t see others smoking.” This is really quite an astonishing assertion, given the range of bad habits youngsters are exposed to as they go about a normal day in the adult world. The authors are particularly concerned about this push to stigmatize smokers. “Given the addictive nature of nicotine and the difficultly of quitting smoking, strategies of denormalization raise both pragmatic and ethical concerns.” Furthermore:

The decline in U.S. smoking rates since the 1960s has coincided with the development of a sharp gradient along the lines of socioeconomic status. Whereas about one fifth of all Americans are smokers, about one third of those with incomes below the federal poverty level smoke. These data are especially pertinent to the question of bans in parks. Since smokers are more likely to be poor and therefore dependent on free public spaces for enjoyment and recreation, refusing to allow them to smoke in those places poses potential problems of fairness.

The anti-tobacco movement, frustrated by the slow pace of gains over several years of active efforts, with rates of smoking remaining essentially unchanged, has to face the fact that an outright ban on cigarettes is a ticket to black market, crime syndicate hell. But a de facto ban is something altogether different, and “steadily winnowing the spaces in which smoking is legally allowed may be leading to a kind of de facto prohibition.” More and more employers prohibit smoking in doorways, within ten feet of doorways, anywhere on university campuses, and so on. No one has voted to make cigarette smoking illegal. But the public space in which this legal activity can be pursued is disappearing. And here is where the tough questions start: “In the absence of direct health risks to others, bans on smoking in parks and beaches raise questions about the acceptable limits for government to impose on conduct,” the authors conclude. Not to mention issues of personal autonomy, individual choice, and the stigma attached to addictive behavior. Perhaps the ACLU will soon take an interest in the civil rights of outdoor smokers, where the only health being hazarded is the smokers’ own.

Colgrove J, Bayer R, & Bachynski KE (2011). Nowhere Left to Hide? The Banishment of Smoking from Public Spaces. The New England journal of medicine PMID: 21612464

Photo Credit: www.thinkstock.com

Friday, May 13, 2011

Does Menthol Really Matter?


Nicotine experts say menthol makes addiction more likely--but differ over what to do about it.

Back in the 1920s, Lloyd “Spud” Hughes of Mingo Junction, Ohio, was working as a restaurant cashier when, legend has it, he smoked some cigarettes that had been casually stored in a tin that contained menthol crystals. Menthol, a compound found in mint plants and also manufactured synthetically, is used medicinally, and as a food flavoring. Back in Spud’s day, menthol was mostly derived by extracting crystals from the Japanese Mint plant. What we know for certain is that the mentholated cigarettes tasted so good to Spud that he patented the mixture. In 1925, the Spud Cigarette Corporation of Wheeling, West Virginia, was born, and Spud Cigarettes quickly became the 5th best selling cigarette brand in America. 

Dr. Neal L. Benowitz, Professor of Medicine and Bioengineering & Therapeutic Sciences, and Chief of the Division of Clinical Pharmacology at the University of California in San Francisco, says that Spud Hughes had “accidentally identified an additive whose pharmacologic actions reduce the irritating properties of smoke generally and nicotine specifically.” Menthol accomplishes this because it acts on receptors involved in the detection of physical stimuli like temperature and chemical irritation. “Menthol contributes to perceptions of cigarettes’ strength, harshness, or mildness, smoothness, coolness, taste, and aftertaste.” That would seem to just about cover it. But no: In their article for the New England Journal Of Medicine—“The Threat of Menthol Cigarettes to U.S. Public Health"—Benowitz and Jonathan M. Samet also claim that “menthol has druglike characteristics that interact at the receptor level with the actions of nicotine.”

And nicotine hardly needs much help establishing its grip over addiction-prone individuals. “It’s not that it’s so intensive,” Dr. Benowitz told me some years ago, when I was researching my book, The Chemical Carousel, “it’s just that it’s so reliable. Nicotine arouses you in the morning; it relaxes you in the afternoon. It’s a drug that you can dose many times per day for the purpose of modulating your mood, and it becomes highly conditioned, more than any other drug, because it’s used every single day, multiple times per day.” Benowitz, along with Dr. Michael Siegel of the Boston University School of Public Health, recently sparked intense debate when they both championed electronic cigarettes as a safe alternative to smoking tobacco cigarettes, despite the FDA’s earlier wish to keep e-cigarettes out of the country. And last month, an advisory report for the FDA by a group that included Benowitz and Samet concluded that mentholated cigarettes were no more harmful, and no more likely to cause disease, than regular cigarettes. A study in the Journal of the National Cancer Institute of 440 lung cancer patients and more than 2,000 matched patients without lung cancer showed no correlation at all between menthol and cancer. In fact, the researchers were surprised to discover that menthol smokers appear to have a lower risk of lung cancer than other smokers. Asked whether menthol cigarettes are more toxic than non-menthol cigarettes, the study's author William Blot of Vanderbilt University definitively responded: “The answer is, no, they are not.”

However, the advisory report suggested that, while menthol cigarettes may not be more dangerous, they might be more addictive than regular cigarettes.  In the May 4 New England Journal of Medicine article, Benowitz and Samet argue that because menthol cigarettes attract younger smokers by making tobacco easier to smoke, and because more of these smokers go on to become lifelong nicotine addicts due to this same cooling effect, "menthol cigarettes increase the likelihood of addiction and the degree of addiction in new smokers." Further adding to menthol’s tendency to create lifelong smokers is the fact that “some consumers, particularly blacks, hold beliefs about implicit health benefits of menthol cigarettes that may interfere with their quitting."

This is a substantial indictment of menthol as a component of cigarettes, despite the belief among some experts that it is much ado about nothing. But if that’s the case, Benowitz and Samet suggest, why has the tobacco industry fought so ferociously to exempt menthol from the list of banned flavorings over the years? And why has the industry so consistently linked its marketing of menthol cigarettes to images of “freshness” and health? The authors estimated that “by 2020 about 17,000 more premature deaths will have occurred and two million more people will have started smoking than would have been the case if menthol cigarettes were not available.” Two million additional cigarette smokers by the end of the decade does not sound especially trivial. Nonetheless, the FDA advisory report that Benowitz helped to shape stopped short of recommending an outright ban on nicotine, saying only that removal of menthol would “benefit public health.”

While not disputing the findings of the FDA Advisory Committee, Dr. Michael Siegel of Boston University expressed dismay that “despite these conclusions, the [committee] did not recommend a ban on menthol cigarettes.” There are almost 20 million menthol smokers in the U.S., Siegel argues. If even a fraction of them quite smoking due to a ban on menthol in cigarettes, “it would have a profound effect on public health.” This is, Siegel insists, precisely why politicians managed to exempt menthol from bans on various flavor additives in the first place. The Black Congressional Caucus had “vigorously denounced the exclusion of menthol” at the time, while Lorillard, maker of Newports--the leading brand of menthol cigarettes--argued that banning menthol would result in the creation of a huge black market.  Because of all this, Seigel charges, Benowitz and the committee simply “punted the issue back to the FDA.” And if anyone harbored doubts about who benefited from this non-action, in Siegel’s view, one need only look at the fact that Lorillard’s stock enjoyed a nice run-up of about 8% after the public announcement of the FDA panel’s recommendations.

Because of all this, Siegel does not believe the FDA will ever ban menthol cigarettes. In his view, the Obama administration doesn’t need the grief of added health care complexities just now, and there is no movement in Congress to make additives an issue. And since the FDA has chosen not to demand the banning of menthol, Siegel thinks the committee’s findings will serve as a convenient smokescreen for Congress. And for the makers of menthol cigarettes, it will be business as usual. A window of opportunity on the menthol issue is now closing, says Siegel, who confesses to difficulty understanding a policy that bans “every other type of cigarette flavoring—including chocolate, strawberry, banana, pineapple, cherry, and kiwi—yet exempts the one flavoring that is actually used extensively by tobacco companies to recruit and maintain smokers… Menthol is a major contributor to smoking initiation and continued addiction, and for this reason, it will continue to enjoy the protection of a federal government that seems afraid to alienate any corporation, whether it’s part of Big Pharma, Big Insurance, or Big Tobacco.”

Tuesday, January 18, 2011

Visual Cues and Addiction


Do smoking scenes in movies make smokers want to light up?

Smokers and former smokers will understand what I mean when I say that an addiction to smoking is like a pilot light that is always lit, always ready to whoosh into full flame with the application of a few milligrams of nicotine. And they will also understand that feeling, like a bolt sliding home, of instant identification that comes from seeing someone else smoking. Especially if you are not smoking, but wish to be.

It makes sense that a smoker or former smoker who sees someone smoking might find that image to be a trigger for nicotine craving. But we have to ask whether smokers trying to quit are really endangering their newfound abstinence simply by viewing “smoking content” on TV or in the movies. It seems a bit too prudish to be true. Yet, logic would seem to suggest that some sort of behavioral effect might be expected when a smoker in withdrawal sees an image of someone smoking.  Does, say, viewing scenes of smoking in a movie produce changes in brain function robust enough to trigger relapse in the absence of any other direct cues? Are environmental cues of this nature more dangerous to newly abstinent smokers than we thought?

“Our findings support prior studies that show smokers who exit a movie that had images of smoking are more likely to crave a cigarette, compared with ones who watched a movie without them,” said Dylan Wagner of Dartmouth College, in a Society for Neuroscience Press Release. “More work is needed to show whether brain activity in response to movie smoking predicts relapse for a smoker trying to quit.”

In a small study involving 17 smokers and 17 non-smokers, scientists at Dartmouth College set out to determine what differences might show up in a functional magnetic resonance imaging (fMRI) scan of smokers and non-smokers while they watched 30 minutes of a movie with several smoking scenes. The subjects were not told that the experiment was about smoking. But when they viewed smoking scenes, the brains of smokers showed increased activity in a portion of the parietal lobe of the brain called the intraparietal sulcus. The study was published in the January 19 issue of the Journal of Neuroscience.

What does this brain region do? As it happens, the neurons in the intraparietal sulcus encode information about the position and geometrical properties of objects. This part of the brain coordinates eye movement data and reaching movements.  Using a mouse or a joystick is a good example of an activity that involves the intraparietal sulcus.

The intraparietal sulcus, or IPS, has other functions, but primarily it serves, in the words of one study, as an interface “between the perceptive and motor systems for controlling arm and eye movements in space.”  Apparently, the habitual hand gestures used in lighting and smoking a cigarette, when viewed in a movie or commercial, triggered impulses from that part charged with controlling the routine gestural aspects of smoking--if the viewer were actually smoking.

ResearchBlogging.org Other studies point to additional aspects of this event-related change in fMRI scans. Writing in the Journal of Neuroscience in 2006, Hamilton and Grafton offer evidence that the IPS is also “uniquely sensitive to the goals of other people’s hand actions.” The intraparietal sulcus seems to “know” what those hand gestures mean, in a sense. Macaques in the lab were used to demonstrate that “cells in macaque IPL were show to respond selectively to both the performance and observation of an action within a sequence leading to a specific goal and not to the same action when it was part of a sequence achieving a different goal.”

This was a strong suggestion that “the IPS is not just a relay but has a central role in representing and interpreting the goals of observed hand actions.”

Perhaps, then, the idea that strong cues can be produced by images and associations is not so far-fetched. It is, for that matter, the founding theory upon which the modern advertising industry has been built, and while the argument over advertising’s effectiveness is never-ending, cigarette scenes in films might have to be considered a form of indirect advertising beamed directly to the parietal lobe of smokers (and perhaps former smokers as well.)

Hamilton, A. (2006). Goal Representation in Human Anterior Intraparietal Sulcus Journal of Neuroscience, 26 (4), 1133-1137 DOI: 10.1523/JNEUROSCI.4551-05.2006


Thursday, December 9, 2010

Era of the Electronic Cigarette Officially Begins.


Court blocks FDA from prohibiting e-cigarettes.

It’s official: The e-cigarette is here. The right of a distributor of Chinese electronic cigarettes to market the product in the U.S. was solidly affirmed last week by a three-judge ruling in the U.S. Court of Appeals for the District of Columbia. The Food and Drug Administration’s refusal last year to allow importation of e-cigarettes by Sottera Inc. had been the basis for a lower court decision in Sottera’s favor. The earlier court ruled that e-cigarettes did not require FDA approval because they were neither new drugs nor new drug delivery devices. (The FDA is prohibited by an act of Congress from barring the sale of tobacco products outright.)

Last month, under a consent judgement worked out with California state Attorney General Jerry Brown in a related case, Florida-based Smoking Everywhere Co., another distributor of Chinese electronic cigarettes, had agreed not to target minors in its advertising, or to make claims that its products are safe alternatives to tobacco. The move came shortly after the FDA announced plans to regulated battery-powered e-cigarettes as new drug delivery devices, culminating in the Sottera lawsuit.

The legal argument before the appeals court hinged largely on semantics. The court found that electronic cigarettes are “battery-powered products that allow users to inhale nicotine vapor without fire, smoke, ash or carbon monoxide. The liquid nicotine is derived from natural tobacco plants.”

Here is the catch: “The FDA may only approve a product for marketing under the Federal Food, Drug and Cosmetic Act (FDCA) if it is safe and effective for its intended use,” the Appeals Court Justices ruled.  However, the FDA has “exhaustively documented” that tobacco products are unsafe for pharmacological use of any kind. The earlier court had concluded, stealing a page from “Alice in Wonderland”: “If they cannot be used safely for any therapeutic purpose, and yet they cannot be banned, they simply do not fit” within any conceivable regulatory scheme.

Hence the difficulties in the FDA’s attempt to regulate by agency fiat. E-cigarette manufacturers and distributors, having sensed an opening, are now ready to drive a convoy of semis right through it. This wasn’t a completely straightforward march, as the e-cigarette forces, in the appeals presentation, were required to thread the needle on such conundrums as: Does it matter that e-cigarettes do not, strictly speaking, contain “tobacco products?” Nicotine is a component of, not a product of, tobacco.

You see the problem. The relevant statutes have not been written with pure nicotine delivery devices in mind. In fact, having nicotine--but not the evil substance tobacco--in your product turned out to be a definitional advantage for the e-cigarette marketers: The court pointed out that, unlike products containing tobacco, which the FDA has found to be associated with “cancer, respiratory illnesses, and heart disease,” the FDA has manifestly NOT found that nicotine or tobacco-free products that deliver nicotine are inherently unsafe. And second, the “tobacco-specific legislation” invoked in earlier court cases “simply does not address products that deliver nicotine but contain no tobacco.”

Matthew Myers, president of the Campaign for Tobacco-Free Kids, said in a prepared statement: "This decision will allow any manufacturer to put any level of nicotine in any product and sell it to anybody, including children, with no government regulation or oversight at the present time. We urge the government to appeal this ruling."

Among the many  questions the ruling leaves open is the status of e-cigarettes under existing no-smoking regulations. That litigation has not even gotten underway.

See my earlier post on the e-cigarette question HERE.

For the full court decision, click HERE.



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