The mixture of "ecstasy" and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations

Daniel José Barbosa, João Paulo Capela, Renata Silva, Vania Vilas-Boas, Luísa Maria da Silva Pinto Ferreira, Paula Cristina de Sério Branco, Eduarda Fernandes, Maria Lourdes Bastos, Felix Carvalho

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41 Citations (Scopus)


The neurotoxicity of ``ecstasy{''} (3,4-methylenedioxymethamphetamine, MDMA) is thought to involve hepatic metabolism, though its real contribution is not completely understood. Most in vitro neurotoxicity studies concern isolated exposures of MDMA or its metabolites, at high concentrations, not considering their mixture, as expected in vivo. Therefore, our postulate is that combined deleterious effects of MDMA and its metabolites, at low micromolar concentrations that may be attained into the brain, may elicit neurotoxicity. Using human SH-SY5Y differentiated cells as dopaminergic neuronal model, we studied the neurotoxicity of MDMA and its MDMA metabolites alpha-methyldopamine and N-methyl-alpha-methyldopamine and their correspondent glutathione and N-acetylcysteine monoconjugates, under isolated exposure and as a mixture, at normothermic or hyperthermic conditions. The results showed that the mixture of MDMA and its metabolites was toxic to SH-SY5Y differentiated cells, an effect potentiated by hyperthermia and prevented by N-acetylcysteine. As a mixture, MDMA and its metabolites presented a different toxicity profile, compared to each compound alone, even at equimolar concentrations. Caspase 3 activation, increased reactive oxygen species production, and intracellular Ca2+ raises were implicated in the toxic effect. The mixture increased intracellular glutathione levels by increasing its de novo synthesis. In conclusion, this study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at low micromolar concentrations, which represents a more realistic approach of the in vivo scenario, elicited toxicity to human SH-SY5Y differentiated cells, thus constituting a new insight into the context of MDMA-related neurotoxicity.}
Original languageEnglish
Pages (from-to)455-473
JournalArchives Of Toxicology
Issue number2
Publication statusPublished - Feb 2014


  • 3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy")
  • MDMA metabolites
  • Neurotoxicity
  • Oxidative stress
  • SH-SY5Y differentiated cells


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