white surface, with histologic evidence of a plaque-like process extending along the leaflet surfaces and encasing the chordae tendineae. These findings were similar to those in patients with heartvalve damage induced by serotonin-secreting carcinoid tumors. 1 This association of racemic fenfluramine and dexfenfluramine with valvular heart disease led to the withdrawal of both drugs from the market. Because of the observed similarity to carcinoid heart disease, and because fenfluramine and its active metabolite norfenfluramine are agonists at various serotonin (5-hydroxytryptamine, or 5-HT) receptors, Devereux urged caution “in the long-term use of other agents that act on serotonergic mechanisms.” 2 Since a large number of commonly prescribed medications, including antidepressant, antipsychotic, anxiolytic, antimigraine, and other drugs, have serotonergic mechanisms, there was concern that numerous approved drugs might also cause valvular heart disease. 2

In 2000, we and others reported that norfenfluramine is a potent agonist at 5-HT2B receptors. 3 These receptors are plentiful in human cardiac valves and appear to be essential for normal cardiac development. In contrast, norfenfluramine is devoid of appreciable activity at many other types of receptors that are plentiful in the heart, including all known biogenic amine (eg, α1-, α2-, and β-adrenergic) receptors and peptide receptors. 3 In subsequent studies, we found that ergotamine, an ergot derivative that has also been reported to induce valvular heart disease, activates 5-HT2B receptors and that methylergonovine, the active metabolite of the prototypic valvu-