Related Experiment Video
Updated: Sep 26, 2026
Automated Contraction Analysis of Human Engineered Heart Tissue for Cardiac Drug Safety Screening
Published on: April 15, 2017
3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac
Vincent Setola1, Sandra J Hufeisen, K Jane Grande-Allen
1Department of Biochemistry, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106-4935, USA.
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.
Insights
MDMA and its metabolite MDA activate the 5-HT2B receptor, similar to fenfluramine. This suggests long-term MDMA use may cause valvular heart disease (VHD), highlighting the need for drug screening.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Neuroscience
Background:
- The 5-hydroxytryptamine 2B (5-HT2B) receptor is implicated in valvular heart disease (VHD) and pulmonary hypertension linked to fenfluramine.
- Fenfluramine and its metabolite norfenfluramine are known to cause VHD through 5-HT2B receptor activation.
Purpose of the Study:
- To investigate whether MDMA and its metabolite MDA interact with the 5-HT2B receptor.
- To assess the potential of MDMA and MDA to induce VHD-like cellular responses.
- To validate a screening system for predicting VHD-inducing medications.
Main Methods:
- Large-scale screening of the receptorome to identify compounds binding to the 5-HT2B receptor.
- Assessing the binding and activation of human recombinant 5-HT2B receptors by MDMA and MDA.
- Evaluating the mitogenic responses of human valvular interstitial cells upon activation of 5-HT2B receptors.
Main Results:
- MDMA and MDA were found to preferentially bind to and activate human 5-HT2B receptors.
- Both MDMA and MDA elicited prolonged mitogenic responses in valvular interstitial cells, similar to fenfluramine.
- Pergolide and dihydroergotamine also potently activated 5-HT2B receptors, validating the assay's predictive capability for VHD.
Conclusions:
- Long-term MDMA use may lead to fenfluramine-like VHD due to 5-HT2B receptor activation by MDMA and MDA.
- These findings have significant public health implications given the widespread abuse of MDMA.
- Screening drugs for 5-HT2B receptor agonist activity is crucial before human use to prevent VHD.
