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A Systematic Review of the Evidence

Una D. McCann, MD; Lewis S. Seiden, PhD; Lewis J. Rubin, MD; George A. Ricaurte, MD, PhD

JAMA. 1997;278(8):666-672.

Abstract
Objectives.
—Obesity is an important clinical problem, and the use of dexfenfluramine hydrochloride for weight reduction has been widely publicized since its approval by the Food and Drug Administration. However, animal and human studies have demonstrated toxic effects of fenfluramines that clinicians should be aware of when considering prescribing the drugs. Our purpose was to systematically review data on brain serotonin neurotoxicity in animals treated with fenfluramines and the evidence linking fenfluramines to primary pulmonary hypertension (PPH).

Data Sources.
—Archival articles and reviews identified through a computerized search of MEDLINE from 1966 to April 1997 using "fenfluramine(s)," "serotonin," "neurotoxicity," "behavior," "anorexigens," "weight loss," and "primary pulmonary hypertension" as index terms.

Study Selection.
—Reports dealing with long-term effects of fenfluramines on brain serotonin neurons, body weight, and pulmonary function in animals and humans.

Data Extraction.
—Reports were reviewed by individuals with expertise in serotonin neurobiology, neurotoxicity, neuropsychiatry, and pulmonary medicine and evaluated for appropriateness for inclusion in this review.

Data Synthesis.
—Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration used. Doses of fenfluramines that produce signs of brain serotonin neurotoxicity in animals are on the same order as those used to treat humans for weight loss when one takes into account known relations between body mass and drug clearance. However, no human studies have been conducted, and the pathological and clinical potential for neurotoxicity in humans is unknown. Appetite suppressants—most commonly fenfluramines—increase the risk of developing PPH (odds ratio, 6.3), particularly when used for more than 3 months (odds ratio, >20).

Conclusions.
—Fenfluramine and dexfenfluramine have been demonstrated to damage brain serotonin neurons in animal studies. It is not known if such damage occurs in humans or if there are clinical consequences. Use of fenfluramines is associated with an increased risk of PPH. Future studies should address the long-term consequences of prolonged use of fenfluramines.

Author Affiliations
From the Unit on Anxiety Disorders, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Md (Dr McCann); Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Ill (Dr Seiden); Department of Medicine, University of Maryland School of Medicine (Dr Rubin), and the Department of Neurology, Johns Hopkins University School of Medicine (Dr Ricaurte), Baltimore, Md.

Footnotes
Reprints: Una D. McCann, MD, Unit on Anxiety Disorders, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bldg 10, Room 3N212, MSC 1272, 10 Center Dr, Bethesda, MD 20892-1272 (e-mail: umccann@helix.nih.gov).

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