Caffeine provokes adverse interactions with MDMA and related psychostimulants

Combining caffeine with other drugs can be more dangerous, sometimes lethally, than using separately

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    Study Author(s):
    N Vanattou-Saïfoudine, R McNamara and A Harkin
    Journal Name:
    British Journal of Pharmacology
    Publication Date:
    October 8, 2012
    Full title:
    Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) and related psychostimulants: mechanisms and mediators

    Many common psychostimulant drugs of abuse, including both illicit substances such as cocaine, MDMA, and MDA, and those in clinical use such as dextroamphetamine and methamphetamine, are known to have neurotoxic effects, either directly or by inducing circumstances which are neurotoxic. Caffeine, a legal psychostimulant, is generally considered to be safe on its own; however, forensic analysis of samples of seized illicit drugs reveals caffeine to be a common adulterant.

    It is known from previous studies in rats that co-administering caffeine with certain stimulants (cocaine, dextroamphetamine, MDMA, MDA) significantly increases neurotoxic effects, sometimes resulting in death, as compared to administration without caffeine. However, as most studies have focused on the influence of caffeine on other drugs' abuse liability, not much is known about the specifics of the adverse interactions between caffeine and other drugs of abuse, such as dosing levels required, the neurochemical or other systems involved, or the mechanisms of action through which neurotoxicity occurs.

    If lab results with rats from those few studies that have examined caffeine's influence on neurotoxicity are translatable to humans, the potential for overdose or death appears to be significant. Therefore, closer examination to determine and understand the interactions between caffeine and other drugs, and the mechanisms by which they occur, is needed in order to more effectively treat acute toxicity and improve patient outcomes. This study is primarily focused on the interaction between caffeine and MDMA, but also examines several other drugs' interaction with caffeine.


    Concomitant consumption of caffeine with recreational psychostimulant drugs of abuse can provoke severe acute adverse reactions in addition to longer term consequences. 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-related drug interactions, placing a particular emphasis on an adverse interaction between caffeine and the substituted amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), which has been most recently described and characterized. Co-administration 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-administration of caffeine enhances the long-term serotonergic neurotoxicity induced by MDMA. Observations to date support an interactive model of drug-induced toxicity comprising MDMA-related enhancement of dopamine release coupled to a caffeine-mediated antagonism of adenosine receptors in addition to inhibition of PDE. These experiments are reviewed together with reports of caffeine-related drug interactions with cocaine, d-amphetamine 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-related toxicity, resulting from concomitant caffeine consumption.