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Departments of Biochemistry (V.S., S.J.H., B.L.R.) and the National Institutes of Mental Health Psychoactive Drug Screening Program (S.J.H., B.L.R.), Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, (K.J.G.-A., I.V.); Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia (R.A.G.); Chemistry and Life Sciences Group, Research Triangle Institute International, Research Triangle Park, North Carolina (B.B.); and Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (R.B.R.)
Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and norfenfluramine in vivo (i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans.
Address correspondence to: Bryan L. Roth MD, PhD, Department of Biochemistry; RM W438, School of Medicine, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106-4935. E-mail: roth{at}biocserver.cwru.edu
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