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In the 30 years that Tim Campbell, 44, has been smoking, a month was the longest time he’s stayed away from cigarettes.
In the 30 years that Tim Campbell, 44, has been smoking, a month was the longest time he’s stayed away from cigarettes. (Mark Wilson/ Globe Staff)

Nicotine fight aims at brain receptors

Vaccine, drug in development

Smokers are about to get some radically different methods to help them quit, based in large part on scientists' progress in attacking nicotine addiction where it happens: in the smoker's brain.

Last week, patients in a clinical trial at Massachusetts General Hospital received their first doses of an experimental vaccine that keeps most nicotine from entering the brain. By late summer, Pfizer expects to begin selling a new pill that partially blocks a receptor -- a type of on-off switch -- in the brain that seems to be the central culprit in smoking addiction.

Also on its way, researchers say, is an experimental drug that targets receptors first discovered in research on marijuana and the ``munchies." By damping down areas of the brain involved in craving, this drug may help smokers quit without gaining much weight, initial studies suggest.

For the first time in 10 years, ``we have completely new approaches for smoking cessation," and there is hope that the new drugs, because they better target the brain's addiction response, could prove more effective than current treatments," said Dr. Nancy Rigotti, director of Mass. General's Tobacco Research and Treatment Center. She cautioned, though, that none of the new treatments ``is a magic bullet."

New tools to help quit smoking are desperately needed, federal health authorities say. Among the 44 million Americans who smoke, about 70 percent would like to quit and 40 percent really try. But in a given year, fewer than 5 percent of would-be quitters actually succeed, a National Institutes of Health panel said last week.

Current drug treatments are moderately effective, on average doubling the success rate of smokers trying to quit compared with those who attempt to break their addiction without any pharmaceutical assistance, said Rigotti.

The arsenal for quitters includes various types of counseling, nicotine replacement in forms ranging from patches to lozenges to inhalers, and Zyban, an antidepressant found to help smokers kick the habit.

None of these has helped Tim Campbell, 44, of Ipswich. Despite endless urging from his wife and six children, and a half-dozen attempts to quit that have included Zyban, nicotine gum, the patch, and hypnosis, he just cannot beat his pack-a-day habit. In 30 years of smoking, the longest he has ever stayed away from cigarettes was about a month. Cigarettes are the first thing on his mind every morning; he smoked even during a cancer walk with his sister.

``I do want to quit, but I can't," Campbell said.

With the rate of relapse still so abysmal, researchers have been struggling to develop radically new approaches.

In the field, ``Vaccine therapy is really the newest kid on the block," said Dr. Victor Reus, a professor of psychiatry at the University of California at San Francisco, who is overseeing a small clinical trial of the ``NicVax" vaccine like the one at Mass. General. Scientists have been trying for a generation to try to harness the body's immune system to fight addiction, but those efforts are only now beginning to pay off, with at least three companies developing anti-nicotine vaccines.

Reus said drugs of abuse -- such as nicotine or cocaine -- are made of small molecules that easily slip across the ``blood-brain barrier," which is essentially a filter meant to protect the brain from potentially damaging substances. With the vaccine, patients develop antibodies to nicotine, so that when they smoke, the antibodies attach to the nicotine and make the resulting molecule too big to pass into the brain. The result: Smoking stops being pleasurable.

The vaccine is still highly experimental, Reus emphasized, given to only 150 or 200 people nationwide so far, and the current set of clinical trials at nine sites around the country is still trying to determine basic questions like the size of the optimal dose and the best number of injections.

But initial studies showed promise, he said, and there's ``a lot of interest, not just for nicotine vaccines but for cocaine and methamphetamine vaccines, which are also being investigated right now."

There is certainly interest among smokers. Rigotti and Reus both said that as soon as they put out word that their clinical trials were starting, they were swamped with hundreds of would-be patients for the two-dozen spots. Rigotti said she is still seeking patients with vascular disease for a safety trial of another smoking-cessation drug, the new Pfizer pill called Chantix.

Chantix, which received US Food and Drug Administration's approval last month, stems from decades of research into how addictive drugs act inside the brain.

With time, it became ever clearer that a particular receptor in the brain with the cumbersome name of the ``alpha-four-beta-two nicotinic receptor subtype," was absolutely central to nicotine addiction, to the point that mice engineered to lack it cannot become addicted. When the receptor was restored in experiments, the mice returned to normal levels of addiction.

A number of experimental drugs now target this receptor, said Dr. Marina Picciotto, a Yale associate professor of psychiatry involved in scientific work on the receptor but not in the drug's development.

Based on the research, she said, companies decided, ``Let's try to tweak it [the receptor] in a way that will allow us to get smokers to have some stimulation of that receptor without having the addiction." With that limited stimulation, the thinking goes, smokers would not go through withdrawal.

Chantix, the drug Pfizer developed, might be compared to a 40-watt bulb that replaces the flickering 100-watt bulb that is nicotine, said Jotham W. Coe, Pfizer's main inventor of the drug or, as he puts it, the chief ``molecular carpenter and architect."

Nicotine, like other drugs, causes a sudden surge of dopamine, a brain chemical associated with pleasure and reward, but the surge quickly gives way to plummeting dopamine levels, which makes smokers feel bad and crave another cigarette. ``Chantix is like a 40-watt bulb that stays on all the time," he said. ``Chantix really is a shield from the vicious cycle of nicotine addiction."

In initial studies, one in five smokers who used Chantix for 12 weeks remained tobacco-free after one year, Pfizer says.

The drug has been approved for up to six months, and its main side effect is mild nausea, Rigotti said. Yet another drug worth watching, she said, is Rimonabant, which was developed to fight obesity but is also being tested for smoking cessation. Its maker, Sanofi-Aventis, has applied to the FDA for approval, for both obesity and smoking. The drug's brand name would be Acomplia.

Research into how marijuana works in the brain yielded discovery of the ``endocannabinoid system," which appears to be involved with feelings of reward and satiety, Rigotti said. Rimonabant acts to block that system, and in initial reports of its results, one of its great appeals is that the people who use it to stop smoking tend to gain very little weight, she said.

Still more research is being done. Dr. Nora Volkow, director of the National Institute on Drug Abuse, predicts that within five years, enough will be known about the genetics of addiction that it will be possible to test children and determine which are at particular genetic risk of becoming addicted to cigarettes or other drugs. Then -- and this is speculation at this point -- the question could arise of whether such children should be vaccinated against nicotine, or whether some other method might prevent them from getting hooked.

Ultimately, researchers said, it seems likely that smokers who want to quit will be offered a menu of various aids, from nicotine replacement to stop the withdrawal symptoms to -- perhaps -- the vaccine to prevent relapse and other drugs to stem cravings.

Carey Goldberg can be reached at goldberg@globe.com.

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