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3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro

Vincent Setola, Sandra J. Hufeisen, K. Jane Grande-Allen, Ivan Vesely, Richard A. Glennon, Bruce Blough, Richard B. Rothman and Bryan L. Roth
Molecular Pharmacology June 2003, 63 (6) 1223-1229; DOI: https://doi.org/10.1124/mol.63.6.1223
Vincent Setola
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.)
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Sandra J. Hufeisen
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.)
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K. Jane Grande-Allen
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.)
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Ivan Vesely
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.)
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Richard A. Glennon
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.)
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Bruce Blough
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.)
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Richard B. Rothman
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.)
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Bryan L. Roth
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.)
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Abstract

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.

  • Received February 10, 2003.
  • Accepted March 18, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (6)
Molecular Pharmacology
Vol. 63, Issue 6
1 Jun 2003
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3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro

Vincent Setola, Sandra J. Hufeisen, K. Jane Grande-Allen, Ivan Vesely, Richard A. Glennon, Bruce Blough, Richard B. Rothman and Bryan L. Roth
Molecular Pharmacology June 1, 2003, 63 (6) 1223-1229; DOI: https://doi.org/10.1124/mol.63.6.1223

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3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro

Vincent Setola, Sandra J. Hufeisen, K. Jane Grande-Allen, Ivan Vesely, Richard A. Glennon, Bruce Blough, Richard B. Rothman and Bryan L. Roth
Molecular Pharmacology June 1, 2003, 63 (6) 1223-1229; DOI: https://doi.org/10.1124/mol.63.6.1223
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