3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro

Mol Pharmacol. 2003 Jun;63(6):1223-9. doi: 10.1124/mol.63.6.1223.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3,4-Methylenedioxyamphetamine / pharmacology
  • Animals
  • COS Cells
  • Cell Division / drug effects
  • Cells, Cultured
  • Fenfluramine / pharmacology*
  • Heart Valve Diseases / pathology
  • Humans
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Norfenfluramine / pharmacology
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism
  • Serotonin Agents / pharmacology*

Substances

  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • Serotonin Agents
  • Norfenfluramine
  • Fenfluramine
  • 3,4-Methylenedioxyamphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine