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Search for genetic variation in early-onset alcoholism

By Bijal P. Trivedi

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Whether alcoholism is the result of a weak character or a real biological disease with a genetic component has long been debated. But now scientists have shown that ondansetron, a drug originally approved for treating chemotherapy-induced nausea, can reduce the urge to drink in alcoholics who become problem drinkers before age 25. The drug is not effective for late-onset forms of alcoholism. The ability to specifically treat one form over another lends credence to the idea that there is a solid biological basis to the disease.

While the researchers are not exactly sure how the drug works, they believe it compensates for a genetic defect that causes an imbalance of two critical neurotransmitters, serotonin and dopamine, triggering a craving for alcohol.

"The hope and dream is that we could offer alcoholics a genetic test to see whether they would respond to ondansetron," says Bankole Johnson, of the University of Texas Health Science Center in San Antonio, the leader of the study.

Early-onset is the most severe form of alcoholism and the most difficult to treat. The patients are young, more heavily addicted, generally do not respond to psychotherapy and have a history of antisocial behavior.

During the past five years 271 alcoholics participated in Johnson's 11-week study. They were given either ondansetron or a placebo twice a day. The most effective dose reduced the number of drinks consumed by half; early-onset alcoholics who took the drug drank one and a half drinks per day, while those who received a placebo drank more than three. Ondansetron was also more effective at promoting abstinence. Those taking it abstained from drinking during 70 percent of the study, those taking the placebo abstained only 50 percent of the time. The report appears in the current issue of the Journal of the American Medical Association.

Johnson believes that a genetic variation in the promoter region—the on-off switch—of the serotonin transporter gene may predispose people to early-onset alcoholism. In the next five years his team will scan the early-onset alcoholics and their families to determine which variant may be the most important in causing the disease. He will also screen about ten other genes that are part of the serotonin and dopamine signaling systems to look for variations that are linked to the disease.

"Alcohol is a dirty drug that affects many systems in the brain, and alcoholism is a complex disease that is about 60 percent genetic, and involves possibly 10 to 20 genes which all interact with each other. It is going to be very difficult to find one gene or one variation that stands out," says Ola Blomqvist, of the Alcohol Research Center at the University of Connecticut.

Johnson's research raises expectations that genetic studies will reveal subtypes of alcoholism that can be treated specifically.

Johnson, B.A. et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients. JAMA 284, 963-971 (August 23/30, 2000).

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