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
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
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.
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