The synthetic psychostimulant MDMA (63,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin,
dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has
been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have
satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of
genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological
effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics
and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT,
and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for
CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75–100 mg) which was similar
to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed
during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma
concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration
poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6
genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral
temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT
val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low
functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of MDMA
pharmacokinetics following 1.4 mg/kg MDMA to the gender differences observed in drug effects appears to be negligible
or even null. In contrast, 5-HTTLPR and COMT val158met genotypes play a major role.
