Comment on the letter by Green, Gabrielsson, Marsden, and Fone, MDMA: on the translation from rodent to human dosing

Abstract

Sir,We read with interest the manuscript ‘MDMA: On thetranslation from rodent to human dosing by Richard Greenet al. as a commentary to a recently published manuscript inthis journal by Goni-Allo et al. (2008). We subscribe allarguments of the authors pleading for preclinical studies inanimal models exploring the potential neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) whereappropriate exposure analysis coupled to parent compoundand potentially neurotoxic metabolite(s) should be incorpo-rated in order to adequately extrapolate experimentalfindings to acute and long-term effects seen in humansubjects consuming this psychoactive drug.Tenyearsago,onestudycarriedoutbyVollenweideretal.(1998) started a passionate debate on the risk of adminis-tering a low dose of MDMA (1.7 mg/kg p.o.) to healthyvolunteers due to the possible long-term neurotoxic con-sequences on the serotonergic system of humans (Gijsmanet al. 1999). Two years later, Drs. McCann and Ricaurte(2001) burst into the debate supporting Dr. Gijsman and co-worker’s concern, based on the principle of interspeciesdrug dose scaling. In their letter to the Editor, Drs. McCannand Ricaurte acknowledged that “there are some circum-stances under which the principles of interspecies scalingdo not apply (e.g., a particular animal species has a uniquemetabolic pathway involving a neurotoxic metabolite).However, these do not appear to be relevant in the case ofMDMA”. In light of current available evidence, we cannow say that this latter assumption is, at the very least,wrong.Animal studies are important for the identification andfunctional characterization of the biological mechanismsunderlying complex disorders as would be MDMA inducedneurotoxicity. However, there is a need to develop fullyvalid translational models not only to investigate MDMAtoxicity but also psychiatric and neuropsychological dis-orders (Kas et al. 2008).There are relevant differences in MDMA metabolicdisposition across species as exemplified by Green et al.(2008). Differences in pharmacokinetics are relevant interms of defining MDMA dosing in preclinical studies butan additional aspect that should be considered would bedifferences across species in enzymes regulating metabolicreactions. Several mice models expressing human CYP1A1,CYP1A2, CYP2E1, CYP2D6, CYP3A4, and CYP3A7 havebeen generated and characterized (Gonzalez 2007; Miksys