Users of widely prescribed diet pills may suffer irreversible loss of brain serotonin nerve terminals, possibly resulting in symptoms of anxiety, depression, cognitive and sleep problems, suggests the first author of a newly published report on fenfluramine side effects. National Institute of Mental Health researcher Una McCann, M.D., and colleagues, report on their review of 90 animal studies on serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and its chemical cousin dexfenfluramine, in the August 27 issue of the Journal of the American Medical Association.
An estimated 50 million people have taken the drugs, often in combination with phentermine (hence "fen/phen"), an amphetamine-like diet drug that counteracts the fenfluramines' tendency to induce drowsiness. The study cautions that if the animal findings apply to humans, the brain damage "would be expected to occur in almost everyone taking a dose sufficient to achieve weight loss."
"I think there is cause for concern that people who take fenfluramines are at risk for a host of problems," said McCann, chief of anxiety disorders research in the NIMH Biological Psychiatry Branch, Bethesda, MD. "A dose comparable to that prescribed to reduce weight in humans causes neurotoxicity in monkeys."
"It might be justifiable for someone who is morbidly obese and hence at risk for serious health problems, but not for a person who just wants to lose a few pounds for cosmetic reasons," explained McCann. "Many people who try diet pills quickly regain their weight after they stop taking the drugs, so they might be tempted to continue taking them. We won't know the long-term risks of these drugs until controlled studies are completed in humans."
In one study reviewed, monkeys' brains continued to show signs of damage 17 months after taking a course of the drug. Much like the branches of a tree, neurons contain extensions called axons that transport messenger chemicals like serotonin and form synapses -- connections with other neurons. Fenfluramines damage serotonin-secreting neurons by pruning these axons, which do not grow back in monkeys, although studies show that they do in rodents. And since human brains are more like those of monkeys, any such damage in humans would also likely be permanent, according to McCann.
"However, the neurotoxic potential of fenfluramines in humans has not been systematically evaluated," write the researchers. Moreover, "the functional consequences of brain serotonin neurotoxicity are largely unknown," even though the neurotransmitter is thought to be important "in a variety of brain functions, including cognition and memory and the regulation of mood, anxiety, impulsivity, aggression, sleep and neuroendocrine function."
In fact, McCann cites case reports that some users have experienced psychiatric disorders, which, she points out, tend to be under-diagnosed in clinical practice. Studies also document that fenfluramines increase the risk for developing primary pulmonary hypertension, a rare, but incurable and life threatening illness.
The researchers advise doctors to be vigilant for both behavioral and cardiopulmonary side effects, and that patients be apprised of the risks and benefits of fenfluramines for weight loss.
Also participating in the study were: Lewis Seiden, Ph.D., University of Chicago; Lewis Rubin, M.D., University of Maryland; George Ricaurte, M.D., Ph.D., Johns Hopkins University. The study was supported by the NIMH Intramural Research Program and grants from the National Institute on Drug Abuse (NIDA).
NIMH and NIDA are components of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services.
Journal
JAMA