CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of MDMA in a controlled study in healthy subjects

The role of genetic polymorphisms in cytochrome (CYP) 2D6 involved in the metabolism of MDMA (34 methylenedioxymethamphetamine ecstasy) is unclear. Effects of genetic variants in CYP2D6 on the pharmacokinetics and pharmacodynamic effects of MDMA were characterized in 139 healthy subjects (70 male 69 female) in a pooled analysis of eight double blind placebo controlled cross over studies. In CYP2D6 poor metabolizers (PMs) the maximum concentrations (Cmax) of MDMA and its active metabolite 34 methylenedioxyamphetamine (MDA) were +15 and +50 higher respectively compared with extensive metabolizers (EMs) and the Cmax of the inactive metabolite 4 hydroxy 3 methoxymethamphetamine (HMMA) was 50 70 lower. Blood pressure and subjective drug effects increased more rapidly after MDMA administration in PMs than in EMs. In conclusion the disposition of MDMA and its effects in humans are altered by polymorphic CYP2D6 activity but the effects are small because of the autoinhibition of CYP2D6.