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

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 b...

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Authors: Pardo Lozano, Ricardo, Farré Albaladejo, Magí, Yubero Lahoz, Samanta, 1985-, O'Mathuna, Brian, Torrens, Marta, Mustata, Cristina, Pérez Mañá, Clara, Langohr, Klaus, Cuyàs, Elisabet, Carbó Banús, Marcel·lí, Torre Fornell, Rafael de la
Format: article
Status:Published version
Publication Date:2012
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/23559
Online Access:http://hdl.handle.net/10230/23559
http://dx.doi.org/10.1371/journal.pone.0047599
Access Level:Open access
Keyword:MDMA (Droga)
Citocrom P-450 -- Metabolisme
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spelling Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)Pardo Lozano, RicardoFarré Albaladejo, MagíYubero Lahoz, Samanta, 1985-O'Mathuna, BrianTorrens, MartaMustata, CristinaPérez Mañá, ClaraLangohr, KlausCuyàs, ElisabetCarbó Banús, Marcel·líTorre Fornell, Rafael de laMDMA (Droga)Citocrom P-450 -- MetabolismeThe 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.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 CM08/00051Public Library of Science (PLoS)201520152012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/23559http://dx.doi.org/10.1371/journal.pone.0047599reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésPLoS ONE. 2012;7(10):e47599© 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 creditedinfo:eu-repo/semantics/openAccessoai:recercat.cat:10230/235592026-05-29T05:05:01Z
dc.title.none.fl_str_mv Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
title Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
spellingShingle Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
Pardo Lozano, Ricardo
MDMA (Droga)
Citocrom P-450 -- Metabolisme
title_short Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
title_full Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
title_fullStr Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
title_full_unstemmed Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
title_sort Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
dc.creator.none.fl_str_mv Pardo Lozano, Ricardo
Farré Albaladejo, Magí
Yubero Lahoz, Samanta, 1985-
O'Mathuna, Brian
Torrens, Marta
Mustata, Cristina
Pérez Mañá, Clara
Langohr, Klaus
Cuyàs, Elisabet
Carbó Banús, Marcel·lí
Torre Fornell, Rafael de la
author Pardo Lozano, Ricardo
author_facet Pardo Lozano, Ricardo
Farré Albaladejo, Magí
Yubero Lahoz, Samanta, 1985-
O'Mathuna, Brian
Torrens, Marta
Mustata, Cristina
Pérez Mañá, Clara
Langohr, Klaus
Cuyàs, Elisabet
Carbó Banús, Marcel·lí
Torre Fornell, Rafael de la
author_role author
author2 Farré Albaladejo, Magí
Yubero Lahoz, Samanta, 1985-
O'Mathuna, Brian
Torrens, Marta
Mustata, Cristina
Pérez Mañá, Clara
Langohr, Klaus
Cuyàs, Elisabet
Carbó Banús, Marcel·lí
Torre Fornell, Rafael de la
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MDMA (Droga)
Citocrom P-450 -- Metabolisme
topic MDMA (Droga)
Citocrom P-450 -- Metabolisme
description 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.
publishDate 2012
dc.date.none.fl_str_mv 2012
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/23559
http://dx.doi.org/10.1371/journal.pone.0047599
url http://hdl.handle.net/10230/23559
http://dx.doi.org/10.1371/journal.pone.0047599
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS ONE. 2012;7(10):e47599
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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