The synthetic psychostimulant MDMA (±3,4-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.Trial RegistrationClinicalTrials.gov NCT01447472

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In women the pretreatment with MDMA resulted in a decrease in dextromethorphan clearance. CYP2D6 activity recovered after 10 days to 90% of baseline activity. Regarding CYP3A4 activity, there is an apparent decrease in its activity after MDMA use. In women, MDMA use has been associated with psychiatric symptoms and psychological problems that may require psychopharmacological treatment with antidepressant drugs, some of which are known CYP2D6 substrates. MDMA-induced mechanism-based inhibition of CYP2D6 is of relevance, and physicians should be advised to prescribe medications whose metabolic disposition is not regulated by CYP2D6.

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3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 in a previous study, the aim of this work was to study in humans the activity of CYP1A2 in vivo after CYP2D6 had been inhibited by MDMA, using caffeine as a probe drug. Twelve male and nine female recreational MDMA users were included. In session 1, 100 mg of caffeine was given at 0 h. In session 2, a 1.5 mg/kg MDMA dose (range 75-100 mg) was given at 0 h followed by a 100 mg dose of caffeine 4 h later. Aliquots of plasma were assayed for caffeine (137X) and paraxanthine (17X) and statistically significant differences were assessed with a one-way ANOVA. There were significant gender differences at basal condition, which persisted after MDMA administration. CYP1A2 activity was higher in both genders after drug administration, with an increase in 40% in females and 20% in males. Results show an increase in CYP1A2 activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females.