Background: The serotonin (5-HT) releasers (+/-)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use owing to increased risk of valvular heart disease.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.