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

  • Toxicokinetics and Metabolism
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Abstract

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.

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Acknowledgments

The authors would like to kindly thank Renata Silva (Faculty of Pharmacy, University of Oporto, Portugal) and Paula Guedes (Faculty of Pharmacy, University of Oporto, Portugal) for technical support with cell culture and GC–MS techniques, respectively. Félix Carvalho (Faculty of Pharmacy, University of Oporto, Portugal), Martin Scholze and Andreas Kortenkamp (The Institute for Environment, University of Brunel, London) are also greatly acknowledged for their criticisms and suggestions. This work was supported by the Portuguese Research Council Fundação para a Ciência e para a Tecnologia (FCT) [SFRH/BD/45617/2008 to D.D.S.] and cofounded by the European Community financial support Programa Operacional Factores de Competitividade do Quadro de Referência Estratégico Nacional (QREN POFC).

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    Diana Dias da Silva

  2. UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK

    Diana Dias da Silva

  3. REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha n.º 164, 4050-047, Porto, Portugal

    Diana Dias da Silva & Helena Carmo

  4. Institute for the Environment, Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH, UK

    Diana Dias da Silva & Elisabete Silva

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  1. Diana Dias da Silva
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  2. Helena Carmo
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  3. Elisabete Silva
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Correspondence to Elisabete Silva.

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Dias da Silva, D., Carmo, H. & Silva, E. The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines?. Arch Toxicol 87, 111–122 (2013). https://doi.org/10.1007/s00204-012-0929-9

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