title: Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT).
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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01447472.
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neuroscience Research Program, IMIM, Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pardo-Lozano
authors.forename: Magí
authors.initials: M
authors.lastname: Farré
authors.forename: Samanta
authors.initials: S
authors.lastname: Yubero-Lahoz
authors.forename: Brian
authors.initials: B
authors.lastname: O'Mathúna
authors.forename: Marta
authors.initials: M
authors.lastname: Torrens
authors.forename: Cristina
authors.initials: C
authors.lastname: Mustata
authors.forename: Clara
authors.initials: C
authors.lastname: Pérez-Mañá
authors.forename: Klaus
authors.initials: K
authors.lastname: Langohr
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.forename: Marcel lí
authors.initials: Ml
authors.lastname: Carbó
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000097:blood* / Q000494:pharmacology*; D000328:Adult; D001831:Body Temperature / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000009:adverse effects / Q000097:blood* / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D018490:Serotonin Agents / Q000009:adverse effects / Q000097:blood* / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D012737:Sex Factors; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; C493230:SLC6A4 protein, human; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D019389:Cytochrome P-450 CYP2D6; D002394:Catechol O-Methyltransferase; D018817:N-Methyl-3,4-methylenedioxyamphetamine