MEDICATION REDUCES METABOLISM OF NICOTINE, DECREASING URGE TO SMOKE

Researchers at the University of Toronto have found that a medication that partially blocks the body's ability to break down nicotine significantly improves the effectiveness of oral nicotine replacement in reducing a smoker's urge for nicotine. In addition, when smokers on the medication do light up, they take fewer and shorter puffs on each cigarette, the scientists say.

"This research opens up an exciting new avenue of treatment that can help smokers substantially reduce their exposure to the deadly particles of tobacco smoke while they overcome the addiction to nicotine that makes it so hard to quit," says Dr. Alan I. Leshner, director, National Institute on Drug Abuse (NIDA). Dr. Edward Sellers and colleagues at the University of Toronto describe the research in the July 2000 issue of "Clinical Pharmacology and Therapeutics".

Smokers who are addicted to nicotine try to maintain the concentration of nicotine in their blood at a level that prevents the discomfort of withdrawal. When nicotine levels drop, smokers light up to increase the concentration. Many smokers who are trying to quit use nicotine replacement -- a patch or gum -- to maintain nicotine levels without smoking.

Dr. Sellers and his colleagues found that methoxsalen, a compound used to treat skin disorders, reduces the activity of an enzyme (CYP2A6) that metabolizes nicotine. This makes more nicotine -- whether from a cigarette or nicotine replacement -- available in the blood and keeps it there longer, Dr. Sellers says.

In earlier studies, the researchers found that individuals with a genetic deficiency in CYP2A6 metabolism are less likely to start smoking, and smoke less if they do start, than individuals with normal CYP2A6 activity. Building on this knowledge, the scientists tested more than 200 medications to find compounds that decreased CYP2A6 activity. "We found that methoxsalen, which is approved for use in humans, is a potent CYP2A6 inhibitor," Dr. Sellers says.

The researchers conducted two studies of methoxsalen's effect on nicotine. In one study, 17 regular smokers with normal CYP2A6 metabolism received methoxsalen (3.5, 10, or 30 mg tablets) or placebo in combination with oral nicotine replacement (4 mg capsules). Blood levels of nicotine were measured in samples taken at 30-minute intervals for three hours. Participants who received 10 mg or 30 mg doses of methsoxsalen had mean nicotine levels roughly twice as high as those given placebo or 3.5 mg methoxsalen. Participants who received the higher methoxsalen dose also reported far less desire to smoke.

In a second study, participants received either methoxsalen (30 mg) or placebo in combination with nicotine or placebo and after a 60-minute abstinence were allowed to smoke at will for 90 minutes. Smokers who received methoxsalen plus nicotine smoked fewer cigarettes, had longer intervals between cigarettes, and took fewer puffs on each cigarette.

"These results suggest that inhibiting the activity of CYP2A6 may represent a potential component of a potent new treatment for nicotine dependence," Dr. Sellers says.  "CYP2A6 inhibition could reduce smokers' exposure to the harmful constituents of tobacco smoke while serving as part of a step-by-step program of reduction leading to cessation of smoking."

Methoxsalen has not been proven safe for long term use in humans, Dr. Sellers notes, and would have to undergo additional trials before it could be used as part of any smoking cessation treatment.

The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports more than 85 percent of the world's research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to ensure the rapid dissemination of research information and its implementation in policy and practice.

Fact sheets on the health effects of drugs of abuse and other topics can be ordered free of charge in English and Spanish by calling NIDA Infofax at 1-888-NIH-NIDA (644-6432) or 1-888-TTY-NIDA (889-6432) for the deaf. These fact sheets and further information on NIDA research and other activities can be found on the NIDA home page at http://www.drugabuse.gov.