The metabolism of amphetamine-like psychostimulants is regulated by the polymorphic enzyme CYP2D6. Methamphetamine acts as a weak substrate and competitive inhibitor of CYP2D6, while MDMA is a high-affinity substrate and potent mechanism-based inhibitor, causing all users to phenocopy the poor metabolizer phenotype regardless of genotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than in vitro studies suggest, with other cytochrome P450 isoenzymes and renal excretion contributing significantly. Overall, the clinical relevance of CYP2D6 polymorphism is lower than predicted by in vitro findings.
A single 75 mg dose of MDMA selectively enhances emotional empathy—the ability to share and understand others' feelings—without affecting cognitive empathy (understanding others' mental states), trust, or reciprocity in social interactions. This effect was not altered by adding pindolol, a drug that blocks the 5-HT1A serotonin receptor. Oxytocin nasal spray, a hormone often linked to social bonding, had no effect on any empathy or social interaction measure. Changes in emotional empathy were unrelated to oxytocin levels in the blood. The findings suggest that MDMA's empathy-enhancing effects do not depend on peripheral oxytocin and may instead involve other receptors such as serotonin 2A or vasopressin 1A.
A single oral weight-adjusted dose of MDMA (1.4 mg/kg) produced similar plasma concentrations and positive subjective effects in healthy recreational users regardless of gender or CYP2D6 and COMT genotypes. Female subjects experienced more intense physiological effects (increased heart rate and oral temperature) and negative effects (dizziness, sedation, depression, psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality led to greater cardiovascular effects, while low-functionality genotypes were linked to negative subjective effects. The contribution of MDMA pharmacokinetics to gender differences in drug effects appears negligible; instead, 5-HTTLPR and COMT val158met genotypes play a major role.