Abstract
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
Highlights
Ecstasy (63,4-methylenedioxymethamphetamine, MDMA) is a synthetic psychostimulant derived from phenylethylamine and the third most widely consumed illegal drug in the world [1]
Height, and total MDMA dose administered were higher in men than in women, but body mass index was similar in both genders
Few differences were observed in MDMA doses in the distribution of gender and anthropometric data among the subgroups, age, varied in the 5-HTTLPR genotype subgroups
Summary
Ecstasy (63,4-methylenedioxymethamphetamine, MDMA) is a synthetic psychostimulant derived from phenylethylamine and the third most widely consumed illegal drug in the world [1]. This increase in abuse has become a growing public health concern since MDMA can produce acute toxicity and fatal episodes [2]. Several studies suggest that women are more vulnerable to drug abuse than males [7]. In some Western countries, female users present higher rates of consumption and dependence on ecstasy than men [1] and MDMA has been shown to produce stronger effects in them [8,9].
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