Depending on Cigarettes, Counting on Science

Courtesy of California Department of Health Services Faster than an injection, more reinforcing than crack cocaine: Smoking a cigarette speeds nicotine to the brain faster than any other delivery method, giving smokers precise control over their exact nicotine dose with each puff they take. It turns out that those two attributes--speed and control--greatly enhance nicotine's addictive effect on the brain. "It's not just the drug, but how you take it,"

By | March 24, 2003

Courtesy of California Department of Health Services

Faster than an injection, more reinforcing than crack cocaine: Smoking a cigarette speeds nicotine to the brain faster than any other delivery method, giving smokers precise control over their exact nicotine dose with each puff they take. It turns out that those two attributes--speed and control--greatly enhance nicotine's addictive effect on the brain. "It's not just the drug, but how you take it," says Timothy Baker, associate director, University of Wisconsin Center for Tobacco Research and Intervention. "Cigarette smoking introduces nicotine to the pulmonary beds of the lungs, which means it gets to the brain in seconds, without achieving general venous circulation."

Nicotine mimics the neurotransmitter acetylcholine, binding to and activating a subset of receptors (the nicotinic acetylcholine receptors). Nicotine affects the brain in much the same way as cocaine, opiates, and amphetamines do; it is hard to say which drugs are more addictive. Animals can be trained to self-administer nicotine, just as they do other drugs; yet even though nicotine can be fatal, animals will not dose themselves to death, as they will with cocaine.

But once hooked, people cling to their cigarettes: Researchers have asked those with multiple addictions which drug is hardest to give up; nicotine is often the answer. "They all activate key brain regions that seem to be involved in addiction, like the nucleus accumbens and the ventral tegmental area [VTA]," says Baker.

THE BIOLOGY OF ADDICTION Once it reaches the brain, nicotine quickly spreads the love--the activated brain regions are part of a reward, memory, and learning center. Nicotine stimulates nicotinic acetylcholine receptors in the VTA, which has projections into the nucleus accumbens where the firing receptors cause the release of dopamine, a neurotransmitter associated with pleasure and addiction. Smoking may also keep brain dopamine levels high by reducing enzymes such as monoamine oxidase B, which breaks down dopamine, or by increasing the expression of molecules such as nitric oxide, which inhibits dopamine reuptake. Nicotine also influences a host of other neurotransmitters, including acetylcholine (excitatory when responding to nicotine), gamma aminobutyric acid (a dopamine regulator), serotonin (involved in mood), norepinephrine (involved in feelings of energy), and glutamate (involved in memory). Furthermore, nicotine increases the number of its own nicotinic acetylcholine receptors. "The brain becomes used to having nicotine on board, and if someone quits smoking they experience withdrawal symptoms," says Caryn Lerman, Department of Psychiatry, University of Pennsylvania.

Withdrawal symptoms are not the only thing that makes a substance addictive; long-lasting neurological changes, such as alterations in dopamine signaling, also play a role. For example, one result of these neurological changes, an effect called reinstatement, increases an ex-addict's desire for drugs after reexposure to just a small amount. Researchers say that it is usually the relentless long-term cravings, rather than the relatively short-term withdrawal symptoms, that catch up with addicts and lure them back.

In other words, smoking is a remarkably difficult habit to kick. Researchers are using knowledge about the biology of addiction to study specific genes that might predispose or protect people from getting hooked, with the hope of keeping future generations from inhaling.

WHO GETS ADDICTED "Many studies suggest that as much as 50% of the variability in smoking initiation, and 70% of the variation in nicotine dependence, may be attributable to genetic factors," says Lerman. "There may be genes in general pathways, such as the dopamine-reward pathway or the serotonin pathway, that may increase risk for drug dependence in general ... [there may be] other genes that play a role in addiction to particular substances, such as genes that play a role in the metabolism of specific drugs or brain receptors for the drugs," she adds. For example, genes in the dopamine pathway could predispose to addiction in general, whereas variants in enzymes that metabolize nicotine could predispose specifically to nicotine addiction.

The dopamine receptor gene (D2) could play a role in general addiction. A 2002 study showed that individuals having many D2 receptors didn't like an intravenous stimulant as much as did individuals with fewer receptors. "There's a differential vulnerability to even liking a drug, and it's related to the D2-receptor density," says Frank Vocci, National Institute on Drug Abuse. "There's some suggestion that when you look at people across addictions, people who are obese, alcoholics, cocaine addicts, methamphetamine addicts, etc., they all have low levels of D2 receptors." Vocci points out that D2-receptor density is influenced by environment as well as genetics. For example, taking cocaine can downregulate D2 levels, and social interactions can also affect receptor levels, at least in monkeys. Studies have implicated other neurotransmitter genes involved in general drug-response pathways in either smoking initiation or high levels of cigarette consumption, including those involved in serotonin biosynthesis (tryptophan hydroxylase),1 serotonin reuptake (5-HTTLPR),2 and dopamine metabolism (monoamine oxidase, dopamine beta hydroxylase).3

As for the genes for nicotine metabolism, Lerman's group has been studying whether polymorphisms in a gene called CYP2B6 predict success in smoking cessation programs. When nicotine levels are high, the CYP2B6 protein metabolizes nicotine to inactivate cotinine in the brain; smokers with less active CYP2B6 enzymes reported more cigarette cravings and had higher relapse rates.4 "These smokers may have higher brain levels of nicotine that could result in greater neuroadaptive changes that promote nicotine dependence," she speculates.

WHY ANTIDEPRESSANTS? Besides nicotine replacement therapy, the only FDA-approved drug for treating nicotine dependence is the antidepressant bupropion (Zyban). But Zyban's effectiveness doesn't come from simply curing depression--Zyban clinical trials were conducted on nondepressed people. Furthermore, Zyban seems to help schizophrenics quit smoking; nicotine addiction rates among this group are extraordinarily high. "You don't see a lot of smoking-naïve schizophrenics," says Gregory Dalack, an associate professor of psychiatry, University of Michigan. The relationship is complex, but people with schizophrenia seem to respond differently to nicotine. Unlike others, they do not puff less when supplemented with nicotine patches, and one (unconfirmed) study showed that their brains have fewer nicotinic acetylcholine receptors.5

Although its mechanism of action is largely unknown, researchers think Zyban could help treat a broad array of addictions. "We're testing Zyban in cocaine addiction, and it is also in Phase I [trials] ... for methamphetamine dependence," says Vocci. "There's a lot of speculation about what it's doing. It may directly involve some nicotine receptor effects, and there may be other effects too."

At a descriptive level, Zyban may dull the negative emotions associated with quitting. In addition to depression, these can include anxiety, sadness, anger, and irritability. "The worse the mood, the more likely the person is to go back to using tobacco," says Baker. People with a history of depression (but who are not so when they try to quit) tend to experience more severe emotional symptoms, making it harder to avoid cigarettes. "Smoking may have a certain ability to mask or ameliorate negative moods," says Baker.

Courtesy of National Cancer Institute
 CESSATION IRRITATION: Cartoon from Harper's Weekly circa 1890.

If Zyban's efficacy comes directly from its effect on depression, then other antidepressants should have similar effects, but the jury is still out on that question. Baker says nortriptyline (which affects norepinephrine and serotonin levels) works well, but studies investigating selective serotonin-reuptake inhibitors have been mixed.

Interestingly, Zyban is metabolized by CYP2B6, the same enzyme involved in nicotine metabolism. Yet, researchers are unsure how Zyban acts at a molecular level to ease smoking cessation; it may increase dopamine concentrations, but this is far from proven. Still, such links between genes and drugs promise to help identify the best treatment for individual smokers. "In the future, with more agents available, we will be better able to match particular kinds of smokers with particular kinds of pharmacotherapy," says Baker.

However, Lerman cautions that because some genes involved in smoking behavior also have been linked to mental disorders, genetic testing to individualize cessation treatment could reveal information about predisposition to psychiatric conditions, a problem that would greatly complicate informed consent. For example, genes in the dopamine pathway have been linked to attention deficit hyperactivity disorder, and serotonin-regulation genes have been linked to anxiety and depression.

Despite the relational complexity between smoking and depression, a link exists. Smokers with a history of depression are about half as likely to quit as others; smokers are more apt to be depressed than nonsmokers; and depressed teens are more susceptible to cigarette ads than their counterparts. For example, one recent study showed that depressed teens are more likely to have a favorite cigarette ad or own clothing with cigarette logos.6

% Change
Adult Men
Adult Women
High School Seniors
College Educated Americans
Americans without a High School Degree

Source: National Conference of State Legislatures "A Report on The States' Allocation of The Tobacco Settlement Dollars-2002"

BUZZ KILLERS Two companies, Xenova Group and Nabi Biopharmaceuticals, are taking a vaccine approach to block nicotine's action on the brain. "Using a vaccine as a treatment rather than a preventive is a slightly different way of thinking about vaccines," says Doreen Wood, product manager at Xenova. Rather than generating an immune response that clears away nicotine, both companies' vaccines create antibodies that bind nicotine in the blood and prevent it from crossing the bloodbrain barrier. The result: Nicotine can't stimulate the brain's reward centers--no buzz. Thus, there is little, if any, reason to smoke. The nicotine molecule is so small that the immune system doesn't notice it, says Robert Naso, senior vice president at Nabi Biopharmaceuticals. The challenge then, was to make nicotine immunogenic; in both cases this was achieved by chemically linking nicotine to a larger immunogenic molecule.

In preclinical studies, vaccinated animals were interested less in self-administering intravenous nicotine. However, it's unclear if the vaccines will work against the faster and stronger effect of nicotine delivered by smoking. So far, human trials have measured only safety, yet both companies are hopeful. "We think this will be very helpful to somebody who ... needs protection from falling off the wagon," says Naso.

Courtesy of Vector Tobacco
 A NICOTINE VACCINE: NicVAX vaccine is another smoking cessation method designed to inhibit nicotine from crossing the blood-brain barrier.

Xenova is developing a similar vaccine against cocaine addiction, although Vocci is concerned that a vaccine might not sweep up the large amounts of cocaine that users get into their system. "Average [blood] nicotine levels are 1/10th to 1/100th the concentration of cocaine levels," he says.

Whether used against cocaine or nicotine, the vaccines could be especially helpful in blocking reinstatement. With a vaccine, even if an ex-smoker stumbles a bit, if that nicotine doesn't reach the brain, then the reinstatement molecules that normally would ratchet up cravings may not be activated. They may have smoked lettuce for all the reward they'll get.

As long as nearly 33 million smokers in the United States alone want to quit,7 interest in nicotine addiction therapies is likely to remain high. Vocci says he's studying other drugs such as small-molecule D1 dopamine receptor agonists and drugs that affect the glutamate system to block an effect called priming, whereby researchers reexpose previously addicted animals to a drug, inducing a reinstatement response. Both Dalack and Lerman think future studies--such as comparing schizophrenic patients who smoke with those who do not, or stratifying smokers according to their biological response to nicotine on brain scans or blood tests--will provide finer resolution of the smoking phenotype.

Mignon Fogarty ( is a freelance writer in Santa Cruz, Calif.

1. C. Lerman et al., "Tryptophan hydroxylase gene variant and smoking behavior," Am J Med Genet, 105:518-20, 2001.

2. S. Hu et al., "Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior," Mol Psychiatry, 5:181-8, 2000.

3. E.F. McKinney et al., "Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers," Pharmacogenetics, 10:483-91, 2000.

4. C. Lerman et al., "Pharmacogenetic investigation of smoking cessation treatment." Pharmacogenetics, 12:627-34, November 2002.

5. S. Leonard et al., "Smoking and schizophrenia: abnormal nicotinic receptor expression," Eur J Pharmacol, 30:237-42, 2000.

6. K.P. Tercyak et al., "Interacting effects of depression and tobacco advertising receptivity on adolescent smoking." J Pediatr Psychol, 27:145-54, 2002.

7. American Lung Association, "Trends in tobacco use," 2002, available online at

Of $21.3 billion (US) distributed throughout the tobacco settlement through 2002, the states spent $949 million on biomedical research. The top eight spenders in the research realm and how much they've spent are presented below:

$235.5 million, including equity investments in health care startups

$192 million, including research grants to six different universities

$143 million, including research grants to state universities

$88.5 million, including HIV programs

$35.1 million, including a biomedical research fund

New Jersey
$25 million, including cancer research

$21.6 million, including biomedical research

$20.1 million, including substance abuse research

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