April 26, 1994
Media Contact: Joann Rodgers
Phone: (410) 955-8659
A diet drug that more than 5 million people have taken may produce lasting changes or damage in parts of the brain regulating appetite and mood, according to a new animal study by researchers at Johns Hopkins, the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA).
The study concludes that dexfenfluramine, prescribed often in Europe to curb appetite in persistently obese people, causes extensive damage to nerves in the brains of test monkeys as long as a year and a half after a short course of the drug.
The results, published in the May 11 issue of the Journal of Pharmacology and Experimental Therapeutics, verify and extend an earlier study that showed brain damage occurs within a few weeks of drug exposure.
There is definite cause for concern that humans treated with dexfenfluramine may be at risk of brain injury," says a Hopkins assistant professor of neurology, George Ricaurte, M.D., Ph.D. "We're still unsure what dose in humans would be enough to produce the damage we see in the lab animals," says Ricaurte, "because the four-day experimental dose in the animals was high, compared with a typical daily dose for humans. But dexfenfluramine stays in human tissues about seven times longer than it does in animals. That, coupled with the fact the people may take the drug twice a day for a half-year or more, gives us concern that toxic doses could be reached," Ricaurte says.
Dexfenfluramine is widely used in Europe, and the FDA is currently evaluating the drug in the United States. Fenfluramine (trade name Pondimin), a sister drug that contains both dexfenfluramine and its molecular mirror image, is currently approved for use in the United States. More than 20 million people have used fenfluramine by prescription in the 26 years it has been on the market, say industry representatives.
Both dexfenfluramine and fenfluramine target nerves in the brain that release the chemical messenger serotonin. "These are nerves with a role in regulating mood, appetite, sleep, impulse control, sexual activity, aggression and some hormone action," says Ricaurte.
Any behavioral changes due to nerve damage are probably subtle, says Ricaurte. "Changes in personality, for example, might even be in a positive direction, and these things are often terribly difficult to tease out," he says. For example, users of ecstasy, a street drug that, also affects serotonin neurons in the brain, score lower than controls in personality tests for impulsiveness and aggression, he says.
In the study, the researchers injected squirrel monkeys with dexfenfluramine twice a day for four days. Either 14 or 17 months later, they checked the animals' brains for levels of serotonin or its byproducts -- an indirect sign of nerve health. The scientists also examined slices of the brains microscopically after pretreating them to expose serotonin nerves.
"By every sign, dexfenfluramine produced persistent and possibly permanent damage in these specific nerves in the monkeys," Ricaurte says.