2009/05/01 by Richard B. Rothman, Michael H. Baumann · 1 citation
Medicine · Neuroscience · #Pharmacology and Obesity Treatment #Neurotransmitter Receptor Influence on Behavior #Hallucinations in medical conditions
paper · doi:10.1517/14740330902931524
openalex publication_date 2009/05/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
BACKGROUND: The serotonin (5-HT) releasers (+/-)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use owing to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the '5-HT hypothesis') suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease. OBJECTIVE: Here, we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease. METHODS: Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations. CONCLUSIONS: The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT(2B) receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT(2B) agonist activity.