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To the editor: brain serotonin neurotoxicity and fenfluramine and dexfenfluramine.

O'Callaghan JP; Miller DB
JAMA J Am Med Assoc 1997 Dec; 278(24):2141
In their review, Dr McCann and colleagues conclude that fenfluramines damage brain serotonin neurons. They define serotonin neurotoxicity as "axotomy (ie, preterminal axon loss) of serotonin neurons in the central nervous system." Nowhere in their review do they provide evidence that fenflurarnines do in fact cause axotomy; rather, they cite studies documenting what already is widely known: administration of high dosages of fenfluramines to experimental animals reduces forebrain serotonin and associated markers. Decrements in serotonin markers cannot be equated with damage to serotonin neurons in the absence of evidence for underlying neuropathology. The presence of gliosis constitutes 1 such index of neuropathology. In our studies, in which we observed 15% to 70% decrements in brain serotonin following high-dose dexfenfluramine regimens, we did not ob- serve increases in the content of glial fibrillary acidic protein (GFAP),a biomarker of gliosis. Contrary to the suggestions of McCann et al, our failure to observe an effect of dexfenfluramine on GF AP does not reflect a lack of sensitivity of this measure to "small serotonin lesions." Decrements in seratonin in discrete areas of the brain that result from administration of the known serotonin neurotoxicant, 5,7-dihydroxytryptamine (5,7-DHT), are associated with large increases (40%- 100%) in GFAP, findings that indicate the sensitivity ofGF AP as an index of gliosis and of chemical-induced damage to serotonin neurons. Thus, a hallmark of brain damage, gliosis, does occur following damage to serotonin neurons but is absent following exposure to fenfluramines. The available preclinical data do not support the conclusion that fenfluramines damage brain serotonin neurons. We conclude that the contention of McCann et al. that "serotonin neurotoxicity would be expected to occur in almost everyone taking a dose sufficient to achieve weight loss" is unwarranted.
Brain-matter; Brain-function; Brain-damage; Brain-disorders; Neurological-system; Central-nervous-system; Central-nervous-system-disorders
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Journal of the American Medical Association
Page last reviewed: May 11, 2023
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