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.
AbbreviationsBAT, brown adipose tissue; BP, blood pressure; CPP, conditioned place preference; CREB, cAMP response element binding protein; CVS, cardiovascular system; CYP, cytochrome P450 enzyme; DARPP-32, cAMP-regulated phosphoprotein of 32 kDa; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; MDA, methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine; PDE, phosphodiesterase; UCP, uncoupling protein
IntroductionIn recreational drug use settings, caffeine is found in a range of commercially available products such as energy drinks that may be consumed with other drugs (Reissig et al., 2009). In addition, forensic analyses of seized illicit drug samples have reported quantities of caffeine mixed with other stimulants, including cocaine and amphetamines (Cole et al., 2011).
BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 946 British Journal of Pharmacology (2012) Such combinations may influence the toxicity of these stimulants and, consequently, investigations regarding the potential for adverse interactive effects are warranted. Interactive effects have led to concern that caffeine could have a role to play in the acute, often idiosyncratic, and long-term adverse consequences associated with the consumption of a range of psychostimulant drugs, including some agents in clinical use.
Risks associated with caffeine use in recreatio...