MEETING BRIEF
by
What makes a smoker smoke? Researchers added pieces to the puzzle at a recent NIH conference, "Addicted to Nicotine."
To nicotine researchers, tobacco products are sophisticated drug-delivery systems, supplying nicotine in the amount and speed that maximizes its ability to addict. Hundreds of scientists gathered July 27-28, 1998, for the landmark "Addicted to Nicotine" conference at the Bethesda, Maryland campus of the National Institutes of Health to survey what is known about how and why people use tobacco, as well as to set new goals. The chief research sponsors - the National Institute on Drug Abuse and the Robert Wood Johnson Foundation - sought the maximum audience, even broadcasting the conference, videos and all, live on the Internet.
Nicotine Addiction
Nicotine dependence is stronger than that of any other drug, said Saul
Shiffman of the University of Pittsburgh. (The researchers prefer the term dependence
to addiction, which they regard as a vague and emotionally loaded term.) One out of three
people who try cigarettes becomes dependent - the state, Shiffman estimates,
in which 60% of all regular smokers end.
Nicotine may be uniquely addicting because it reaches the brain so fast.
Monkeys happily deal themselves nicotine when they get it every six seconds,
but when the dose is diffused over 100 seconds, self-administration - the
hallmark of dependence in laboratory animals - plunges, according to Kenneth
A. Perkins, also from the University of
Pittsburgh.
No other drug has so many pharmacological effects of interest to neuroscientists, said Kenneth Kellar of Georgetown University. Like all addictive drugs, nicotine boosts the mesolimbic system's dopamine levels. But it also stimulates the other neurotransmitters norephinephrine, acetylcholine, glutamate, and GABA, as well as the autonomic-system hormones vasopressin, ACTH, and prolactin.
Thus nicotine may actually have a good side. "The most successful drug
ever to reduce body weight is nicotine. There may be something we can learn
about it to help weight control," said Neal L. Benowitz of the San Francisco General Hospital at the
University of California at San Francisco. It can be a performance
enhancer, an effect shown even in Alzheimer's disease, according to Jack E.
Henningfield, Johns Hopkins
University. "It's not unreasonable to be thinking about nicotine
as a therapeutic tool," Kellar noted.
Genes and Receptors
Addiction is what geneticists call a complex trait, a new term for conditions they used to call multifactorial, arrived at through unimaginably intricate interactions among genes and nongenetic factors. To say that a complex trait is a product of nature and nurture is now regarded as a feeble approximation of the tangled reality.
From twin and adoption studies, Kenneth S. Kendler of the Medical College of
Virginia estimated that 55% of the causes of variation in liability to
smoking are genetic, 25% are the product of family environment, and 20% are
due to individual experience. He further suggested that some of the same
factors underlie both initiation of smoking and dependence on it. But once
a person is dependent, new genetic factors come into play, and their
expression is conditional on smoking. Genetic studies to date are mostly on
whites, he warned, even though smoking habits differ dramatically between
ethnic groups - and, for that matter, between the sexes.
Vulnerable genes are not, of course, necessary for addiction. As Nora Volkow of Brookhaven National Laboratory explained, people begin drug use because they like the effect, which leads to brain changes, which in turn perpetuates compulsive drug-taking even in the absence of genetic susceptibility.
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The researchers' logical working hypothesis is that at least some of the genes involved in addiction govern nicotine receptors. (See sidebar on receptors for details.)
Enzymes
"There's more to cigarettes than nicotine," said Nora Volkow. Cigarette smoke contains thousands of compounds and many mysteries. Volkow's PET studies show that both types of monoamine oxidase, the enzyme crucial for dopamine breakdown, are decreased in smokers' brains. Yet it is not nicotine that inhibits MAO B, found mostly in the brain. The 40% MAO B decrease, she argued, is not a genetic effect, but pure pharmacology, a consequence of something else in smoke.
The unknown substance that prevents dopamine breakdown may therefore accentuate the neurotransmitter's reinforcing effects. This could help explain, she suggested, why people addicted to other drugs are often smokers: by blocking dopamine breakdown, cigarette smoke may enhance the effects of those drugs too.
The human gene CYP2A6 makes the enzyme that inactivates up to 80% of
nicotine itself. Researchers have so far identified three mutant alleles
with impaired function, and their prevalence differs both within and between
ethnic groups, according to Rachel F. Tyndale of the University
of Toronto. She reported that about half of those who carry one active
and one defective allele appear to be protected against tobacco dependence -
a total of about seven million people in North America alone. Even
dependent smokers who possess a mutant allele smoke significantly less than
those with two normal alleles.
Tyndale hypothesizes that beginning smokers with impaired nicotine metabolism suffer intensely from dizziness and nausea, and so are less likely to persist to dependence. If they do persist, they can extract more bang from less nicotine than other smokers because their bodies break it down more slowly. Wild-type CYP2A6 also activates carcinogens, so those with a mutant allele may also be protected against cancer. The work, she noted, suggests a new approach to treatment: blocking nicotine metabolism might prove useful in preventing smoking, or at least reducing it.
Chippers
Smokers are not a homogeneous group. There is no better evidence than
chippers: people who smoke no more than five cigarettes per day and
no more than 4 days per week. (The term arose in heroin research to
describe those rare weekend users who could take it or leave it alone.
Chippers have now been found among regular users of all addictive drugs.)
Abstaining from nicotine doesn't seem to bother chippers. They suffer no withdrawal, despite the fact that in Shiffman's studies they were long-time users who had smoked an average of 50,000 cigarettes. It's not that chippers don't like nicotine; they do. Shiffman compares them to social drinkers who enjoy the effects of alcohol but drink mostly on specific social occasions and can get along fine without it.
The number of tobacco chippers is unknown but small. Shiffman estimates
that, at most, 10% of smokers fall into this category. Certain groups
produce proportionately more chippers, especially women and African- and
Asian-Americans of both sexes. Their pharmacological responses to nicotine
seem to be like those of dependent smokers, and most have smoked more than
enough cigarettes to get addicted. But apparently they aren't. Whether
that's a response to genes or social customs or both is unknown. Chippers
are a puzzle, one believed to hold vital clues to addiction.
Treatment
The nicotine withdrawal experience depends to some extent on the person and
the setting, but it is a definite physical state of impaired performance on
cognitive and motor tasks. Formal studies limited to nine days have found
that it persists for at least that long, and anecdotal reports suggest it
can last for weeks, said NIDA's Stephen J. Heishman.
Nicotine replacement can reverse withdrawal and is now a major treatment tool. It stabilizes brain function even though it delivers much less nicotine than cigarettes (about 1.5 mg from nicotine gum, for example, versus 13 or so from a cigarette). Nicotine replacement also comes in other forms, some of which must be prescribed, such as patches, nasal sprays, and inhalers.
Researchers are not much worried about nicotine replacement's addiction
potential because it delivers hits to blood and brain much more slowly than
smoking. Nicotine gum and nasal spray are probably mildly reinforcing,
according to John Slade of the University of Medicine and
Dentistry of New Jersey - Robert Wood Johnson Medical School. But to
date there have been no reports of compulsive use of patches. He even
wondered whether direct competition with tobacco should be encouraged.
Yet is nicotine replacement completely safe? No one knows the effects of slow administration on the brain, especially over a long time, according to William A. Corrigall of Toronto's Addiction Research Foundation. Many treatment experts believe, however, that some ex-smokers will always need nicotine to function. They see nicotine maintenance as a reasonable strategy, like methadone for heroin.
Antidepressants are also effective, especially bupropion (Zyban).
Researchers are also reporting good results with an older tricyclic,
nortriptylene. But even superior treatment programs - ones that include
nicotine replacement, antidepressants, and behavior therapy - achieve a
long-term quitting rate of 40% at best.
Comorbidity
You don't have to be depressed to find bupropion helpful when quitting tobacco. But a lot of smokers are depressed, or have other psychiatric disorders or addictions. (Smoking is actually a useful clinical marker for alcoholism, according to John Hughes of the University of Vermont: 20% of smokers are also alcoholics.) The term for these joint afflictions is comorbidity.
In the 1960s, this category accounted for a minority of smokers. Since then
many people who could quit relatively easily have done so. Today roughly
half of smokers fall into this hard-to-treat group. The fact that smoking's
prevalence is highest in this group is noteworthy, Volkow argued. She urged
more investigation of the functional significance of nicotine and other
components of smoke.
The Environment
The conference surveyed nonbiological influences on smoking, too, a domain that is also bursting with unanswered questions. Peer pressures, and perhaps ads and promotions, help persuade the young to start. Perkins argued that environmental cues must be a major cause of relapse because it commonly occurs months or even years after a relapsing smoker has gone through withdrawal. But what such cues might be remains mostly mysterious.
Some strategies seem obvious, however. Cochair Nancy J. Kaufman of the Robert Wood Johnson Foundation declared that
smoking decreases 4% among adults with each 10% increase in price, and the
decrease is almost twice as big among the young, who are poorer. Selling
tobacco to minors is against the law in all the states, but access is
ridiculously easy: two out of three of their buying attempts succeed, she
noted. The remedies are political, but not simple.
Gary E. Swan of SRI International in Menlo Park, California, urged a change in research mission. Because nicotine addiction is a complex trait, he wants to move from away single-minded pursuit of the next gene or environmental risk factor. Researchers should pursue "a multidisciplinary design that permits the identification of both genetic and environmental risk factors at the same time in the same people operating in well-characterized environments," he argued. "The public health impact of the nicotine addiction problem is so large that we cannot afford any longer to compete with each other in the pursuit of the magic bullet."
NIDA requires its principal investigators to be in contact with each other, director Alan I. Leshner noted, and said the agency does what it can to encourage coordination. Kaufman said the giant Robert Wood Johnson Foundation, which has a major interest in addiction and has sponsored interdisciplinary workshops, is hoping to signal that this is the way science needs to be done.
Tabitha M. Powledge is a longtime science and medical writer-editor who keeps an eye on the intensifying fusion of genetics and neuroscience.
Caleb Brown is an illustrator and biologist living in Montana. By day he drives a delivery van, and by night he draws pictures with his computer.
Nicotine Conference: Presentation Summaries - provides synopses of the presentations and contact information for the participants at the "Addicted to Nicotine" conference.
Kicking the Habit - a look at Zyban, one of the newest tools against nicotine addiction. From the November 24, 1997 issue of Scientific American, which focused on research into addictions.
Tobacco Information and Prevention Source - this Centers for Disease Control site has information for both the layperson and the researcher. The Research, Data, and Reports page has links to online, mainly epidemiological, data, and the New Citations page is a convenient way to keep up with the literature.
CYP2A6 - the OMIM entry for this cytochrome P450 enzyme, which is involved in metabolizing nicotine. Includes a brief section on the allelic variants.
