Archives of Toxicology

, Volume 87, Issue 1, pp 111–122 | Cite as

The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines?

  • Diana Dias da Silva
  • Helena Carmo
  • Elisabete Silva
Toxicokinetics and Metabolism


The recreational and illicit use of amphetaminic designer compounds, specially 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy), is of concern worldwide. Such psychostimulating drugs are frequently present as complex mixtures in ‘rave’ pills, making concomitant polysubstance use a common trend. However, the understanding of possible combination effects with these substances is still scarce. The present study was aimed at predicting the cytotoxic effects of mixtures of four amphetaminic derivatives: MDMA, methamphetamine, 4-methylthioamphetamine and d-amphetamine in a human hepatoma cell line. Concentration–response curves for all single-mixture components were recorded by the MTT assay. Data obtained for individual agents were then used to compute the additivity expectations for mixtures of definite composition, using the pharmacological models of concentration addition (CA) and independent action. By comparing the predicted calculations with the experimentally observed effects, we concluded that CA accurately predicts the combination of amphetamines, which act together to generate additive effects over a large range of concentrations. Notably, we observed substantial mixture effects even when each drug was present at low concentrations, which individually produced unnoticeable effects. Nonetheless, for all tested mixtures, a small deviation from additivity was observed towards higher concentrations, particularly at high effect levels. A possible metabolic interaction, which could explain such deviation, was investigated, and it was observed that at higher mixture concentrations increased MDMA metabolism could be contributing to divergences from additivity. In conclusion, the present work clearly demonstrates that potentially harmful interactions among amphetaminic drugs are expected when these drugs are taken concomitantly.


3,4-methylenedioxymethamphetamine (ecstasy, MDMA) Amphetamine-related toxicity Hepatocytes Combination effects Concentration addition (CA) Independent action (IA) 


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Diana Dias da Silva
    • 1
    • 2
    • 3
    • 4
  • Helena Carmo
    • 3
  • Elisabete Silva
    • 4
  1. 1.Faculdade de MedicinaUniversidade do PortoPortoPortugal
  2. 2.UCL School of PharmacyUniversity College LondonLondonUK
  3. 3.REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de FarmáciaUniversidade do PortoPortoPortugal
  4. 4.Institute for the EnvironmentBrunel UniversityKingston Lane, Uxbridge, MiddlesexUK

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