Diet Drugs May Kill Brain Cells, Studies Suggest

Barely a month after doctors linked popular weight-reducing drugs to dangerous heart problems, the prescription medications are under fire again for possibly destroying brain cells.

In a new analysis of 71 previous studies on laboratory animals, National Institute of Mental Health researchers say that fenfluramine, part of the combination called fen-phen, and dexfenfluramine, or Redux, appeared to kill off portions of some brain cells at doses roughly comparable to those that people take.

About 50 million people worldwide take the drugs, which suppress appetite, evidently by altering how brain cells release the neurotransmitter serotonin.

It is not known whether the drugs affect human beings the same way, but the researchers say that the brain damage observed in lab animals--especially monkeys--is cause for caution.

In the same report, which appears today in the Journal of the American Medical Assn., the researchers summarize the largely accepted clinical evidence that the drugs dramatically raise a person’s risk of impaired blood circulation in the lungs, a rare but sometimes fatal disorder called primary pulmonary hypertension.

“We wanted people who are considering taking [these medications] to be aware of the possible adverse effects,” said the study’s lead author, Dr. Una McCann. Given such risks, she said it might be justifiable only for people who are “morbidly obese” to take the drugs if all other weight loss therapies have failed. About 300,000 Americans a year reportedly die of complications of obesity.

The manufacturer of Redux, Wyeth-Ayerst Laboratories, said that the neurotoxicity data was “nothing new” and that millions of people have taken Redux in the last decade without showing signs of brain damage.

Still, the company announced last week that it will begin a long-range study to monitor mental and neurological changes in people taking the drug.

A neuroscientist who has studied the diet drugs’ effects on animal brain tissue, James O’Callaghan of the National Institute for Occupational Safety and Health, said the evidence did not support the conclusions of McCann and her co-workers. “I’ve done many, many experiments on these compounds . . . and never found any evidence that the compound causes brain damage,” he said.

In a way, the controversy is largely a matter of interpretation. Many studies have found changes in the brains of animals fed or injected with fenfluramine and dexfenfluramine. Among those changes is a markedly diminished ability of the spindly branches of certain brain cells to respond to serotonin, as shown in neurochemical tests of autopsied brain tissue.

The question is whether such changes represent lasting or permanent damage to the animals’ brain cells, as McCann and her colleagues suggest. In one experiment highlighted by the researchers, a squirrel monkey was injected with 3 milligrams of dexfenfluramine twice a day for four days. An antibody test 17 months later showed a paucity of serotonin activity compared with tissue from an untreated monkey.

The lack of neurotransmitter activity more than a year after ceasing the drug indicated that the nerve cells were “undergoing death,” said Lewis Seiden, a University of Chicago pharmacologist and a co-author of the new analysis.

But critics like O’Callaghan dispute that. “You can’t call that brain damage,” he said. “It’s probably just a biochemical effect” that may correct itself in time. Wyeth-Ayerst echoed that idea, saying “neurochemical changes were generally found to be reversible when administration of the drug ceased, and were likely to be the result of the high doses used in such studies.”

McCann and co-authors said, however, that the drug doses used in many of the animal studies were generally in the range of typical human doses. Patients usually start on Redux by taking 30 milligrams a day.

Fenfluramine, the form of the drug often combined with phentermine as “fen-phen,” was approved in the 1970s by the Food and Drug Administration for limited use. But the FDA approved Redux, long available in Europe, only last year, after what some researchers believe was a shallow review of the adverse effects.

FDA panels met twice in late 1995 to review evidence on the drug’s safety and effectiveness. At the first meeting, in September, at which Seiden and others presented evidence on the neurotoxic effects of Redux on animals, panelists voted not to approve the drug. But at a second meeting, in November, where neurotoxicology data was not emphasized, panelists voted 6 to 5 to approve the drug.

Seiden complained to the agency about the lack of neurotoxicology evidence weighed by the subsequent FDA review panel. He proposed another hearing so that “input from the neurosciences community can be given a fair representation in the evaluation” of Redux.

The FDA did not respond to a request for comment on the new study.

Also, the Mayo Clinic doctors who went public in July with their study of 24 women who developed damaged heart valves after taking the fen-phen said Tuesday that they have learned of 61 more cases, 16 of which have been directly confirmed by the medical center, said Dr. Michael McGoon, a Mayo Clinic cardiologist. “The take-home message is that physicians who prescribe the medication need to be extremely cautious” about using it only in patients with obesity that is “life-threatening,” he said. In such patients, heart signs need to be closely monitored, he added.

“Physicians who prescribe the drug for marginal reasons”--like losing a few pounds in a hurry--”are probably on thin ice,” he said.