Recent warnings that the smoking-cessation drug Chantix may cause erratic behavior and suicidal thoughts provide a new window into nicotine's dark and powerful grip on the brain.

As any smoker, or ex-smoker, can attest, nicotine can rev you up if you're tired and relax you if you're stressed. It focuses the mind and smooths over irritations.

"I work two jobs — this is my little bit of paradise," said one man lighting up outside the New York Stock Exchange recently.

What makes nicotine so addictive is that it increases dopamine in the brain's reward center. "You've heard people say, 'I really want it but I'm not sure what I get out of it.' That happens a lot with smokers," says John Hughes, a professor of psychiatry at the University of Vermont and an adviser for Pfizer Inc.'s Chantix.

The warnings about Chantix underscore what all quitters should know: Nicotine withdrawal can cause wicked depression, particularly in people who've been depressed before. Indeed, experts debate whether what smokers interpret as an antidepressant effect from nicotine is a true benefit, or simply relief from mini-withdrawal since the last cigarette.

These days, 44 percent of all cigarettes in the United States are smoked by people with diagnosed mental disorders, including schizophrenics and alcoholics. It may be that such smokers are trying to "self-medicate" — or that nicotine addiction tends to feed on their emotional difficulties, speculates Daniel F. Seidman, a clinical psychologist at Columbia University Medical Center.

Either way, smokers with psychiatric illnesses weren't included in the premarketing trials for Chantix. As a result, Chantix (generic name: varenicline) is only now being used with a real-world population, which could explain some of the adverse reactions.

The Food and Drug Administration this month said it had received 420 reports of suicidal thoughts and 34 suicides among 4.5 million Chantix users in the U.S.

Pfizer suggests that some of those incidents could be due to nicotine withdrawal. Chantix doesn't contain nicotine, but does provide a low level of dopamine release, to help ease cravings. It also blocks nicotine receptors, so that if users do smoke, they get far less reward.

Increased suicides haven't been reported with other antismoking drugs, including nicotine-replacement therapies like gum, lozenges or patches, or with bupropion, marketed by GlaxoSmithKlein PLC as Zyban or Wellbutrin, though bupropion does carry the suicide warning mandated for all antidepressants.

"If you have a history of depression, you need to be careful when you stop smoking that it doesn't come back," says Dr. Hughes. "But if you've failed on the patch and are thinking about using varenicline, I would not not use it because of this concern. The risk is so small under a physician's care, and the benefit is so huge."

Chantix has beaten Zyban, nicotine-replacement therapy and placebos in various head-to-head trials of smokers after 12 weeks of treatment. In a study in this month's Thorax Online, 55.9 percent of those on varenicline were smoke-free after 12 weeks, compared with 43.2 percent on nicotine replacement. A significant number of all subjects relapse after a year, however.

Some experts say that's because beating the physical withdrawal isn't enough. "If you're used to going out for a smoke every time you get upset, you need to learn some new coping skills to handle what life throws at you," Seidman says.

He notes that many cessation programs include assertiveness training — so that people who used cigarettes to bury negative emotions learn to speak up instead.

All 50 states now have telephone quit lines that offer some counseling (contact the Arizona Smokers' Helpline by phone at 1-800-556-6222 and on the Web at www.ashline.org). Pfizer has an online GetQuit program (go to www.chantix.com) to go with Chantix.

If it still seems daunting, Hughes says that after withdrawal, many ex-smokers say they are far less depressed than they were when they smoked.

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