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

Abstract

Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT 2B ) 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-HT 2B 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-HT 2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT 2B 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-HT 2B receptors for agonist actions before their use in humans.

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

“…These results are similar to those obtained in a recent progressive ratio study (Lile et al 2005) where MDMA maintained significantly lower break points than did cocaine. Although R(−)-MDMA exhibits markedly lower activity in an assay of inhibition of dopamine uptake (Steele et al 1987), and a 25-fold lower affinity for the dopamine transporter than its S(+)-enantiomer (Setola et al 2003), no obvious differences in drug potency or effectiveness in maintaining contingent responding have been observed for the MDMA stereoisomers in self-administration experiments. Indeed, the finding that R(−)-MDMA functions as a reinforcer at all is puzzling.…”

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

“…However, 5-HT 2B receptors have been implicated in substance-induced heart valve fibrosis (Bhattacharyya et al, 2009;Setola et al, 2003), and the 2C and NBOMe drugs may therefore have cardiac toxicity if used chronically.…”

Estimating the relative reinforcing strength of (±)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine

“…Because MDMA is a more potent releaser of 5-HT than DA, it was hypothesized that MDMA would be a weaker reinforcer than MA. Additionally, because (−)-MDMA is more selective for 5-HT release than MDMA or (+)-MDMA (Rothman et al 2001;Setola et al 2003), we hypothesized that (−)-MDMA would be a weaker reinforcer than MDMA and (+)-MDMA. It is interesting to note that both isomers have been reported to function as positive reinforcers in monkeys responding under a fixed-ratio schedule (Fantegrossi et al 2002(Fantegrossi et al , 2004.…”