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The mechanisms by which caffeine increases the toxicity of psychostimulants include changes in body temperature regulation, cardiotoxicity and lowering of the seizure threshold. Caffeine also influences the stimulatory, discriminative and reinforcing effects of psychostimulant drugs. In this review, we consider our current understanding of such caffeine\u2010related drug interactions, placing a particular emphasis on an adverse interaction between caffeine and the substituted amphetamine, 3,4\u2010methylenedioxymethamphetamine (MDMA, \u2018ecstasy\u2019), which has been most recently described and characterized. Co\u2010administration of caffeine profoundly enhances the acute toxicity of MDMA in rats, as manifested by high core body temperature, tachycardia and increased mortality. In addition, co\u2010administration of caffeine enhances the long\u2010term serotonergic neurotoxicity induced by MDMA. Observations to date support an interactive model of drug\u2010induced toxicity comprising MDMA\u2010related enhancement of dopamine release coupled to a caffeine\u2010mediated antagonism of adenosine receptors in addition to inhibition of PDE. These experiments are reviewed together with reports of caffeine\u2010related drug interactions with cocaine, d\u2010amphetamine and ephedrine where similar mechanisms are implicated. Understanding the underlying mechanisms will guide appropriate intervention strategies for the management of severe reactions and potential for increased drug\u2010related toxicity, resulting from concomitant caffeine consumption.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2012.02065.x","type":"journal-article","created":{"date-parts":[[2012,6,1]],"date-time":"2012-06-01T13:36:22Z","timestamp":1338557782000},"page":"946-959","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Caffeine provokes adverse interactions with 3,4\u2010methylenedioxymethamphetamine (MDMA, \u2018ecstasy\u2019) and related psychostimulants: mechanisms and 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