Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)

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  • dc.contributor.author Pardo Lozano, Ricardoca
  • dc.contributor.author Farré Albaladejo, Magíca
  • dc.contributor.author Yubero Lahoz, Samanta, 1985-ca
  • dc.contributor.author O'Mathuna, Brianca
  • dc.contributor.author Torrens, Martaca
  • dc.contributor.author Mustata, Cristinaca
  • dc.contributor.author Pérez Mañá, Claraca
  • dc.contributor.author Langohr, Klausca
  • dc.contributor.author Cuyàs, Elisabetca
  • dc.contributor.author Carbó Banús, Marcel·líca
  • dc.contributor.author Torre Fornell, Rafael de laca
  • dc.date.accessioned 2015-05-12T09:47:10Z
  • dc.date.available 2015-05-12T09:47:10Z
  • dc.date.issued 2012ca
  • dc.description.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.en
  • dc.description.sponsorship This study was supported by NIDA grant 5R01BA017987-01, by grants from DIUE de la Generalitat de Catalunya (2009 SGR 718), Spanish Network on Addiction Disorders grant (FIS-RTA RD06/0001/1009), and Ministerio de Educación y Ciencia grant (MICINN FI09/00355), and the support of ISCIII-FIS-CAIBERCAI08/01/0024. R. Pardo-Lozano is a recipient of a fellowship Rio Hortega (FIS CM08/00051en
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Pardo Lozano R, Farré Albaladejo M, Yubero Lahoz S, O'Mathuna B, Torrens M, Mustata C, Pérez Mañá C, Langohr K, Cuyàs E, Carbó Banús M, de la Torre Fornell R. Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT). PLoS ONE. 2012;7(10):e47599. DOI: 10.1371/journal.pone.0047599ca
  • dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0047599
  • dc.identifier.issn 1932-6203ca
  • dc.identifier.uri http://hdl.handle.net/10230/23559
  • dc.language.iso engca
  • dc.publisher Public Library of Science (PLoS)ca
  • dc.relation.ispartof PLoS ONE. 2012;7(10):e47599
  • dc.rights © 2012 Pardo-Lozano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.subject.other MDMA (Droga)ca
  • dc.subject.other Citocrom P-450 -- Metabolismeca
  • dc.title Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)en
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/publishedVersionca

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