Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)
| Autor: | Brian O'Mathúna, Ricardo Pardo-Lozano, Rafael de la Torre, Elisabet Cuyàs, Clara Pérez-Mañá, Klaus Langohr, Samanta Yubero-Lahoz, Marta Torrens, Cristina Mustata, Marcel·li Carbó, Magí Farré |
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| Přispěvatelé: | Universitat Politècnica de Catalunya. Departament d'Estadística i Investigació Operativa, Universitat Politècnica de Catalunya. GREMA - Grup de Recerca en Estadística Matemàtica i les seves Aplicacions |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Anatomy and Physiology Non-Clinical Medicine Epidemiology Psychopharmacology Dopamine Ecstasy lcsh:Medicine Matemàtiques i estadística::Matemàtica aplicada a les ciències [Àrees temàtiques de la UPC] Pharmacology Cardiovascular Toxicology Cardiovascular System Body Temperature law.invention Serotonin Agents 0302 clinical medicine Heart Rate law Sex factors lcsh:Science Serotonin Plasma Membrane Transport Proteins Clinical Neurophysiology Psychiatry Multidisciplinary Clinical pharmacology Adrenergic Uptake Inhibitors Substance Abuse Neurochemistry MDMA 3. Good health Mental Health Cytochrome P-450 CYP2D6 Behavioral Pharmacology Genetic Epidemiology Circulatory Physiology Medicine Female Citocrom P-450 -- Metabolisme Neurochemicals Psychology psychological phenomena and processes Research Article medicine.drug Adult Serotonin Drugs and Devices medicine.medical_specialty Biomatemàtica N-Methyl-3 4-methylenedioxyamphetamine Catechol O-Methyltransferase Cardiovascular Pharmacology Sexual and Gender Issues Young Adult 03 medical and health sciences Sex Factors Diagnostic Medicine Recreational Drug Use mental disorders Genetics medicine Humans Pharmacokinetics Biology Biomathematics Polymorphism Genetic Health Care Policy Population Biology 92B Mathematical biology in general Extramural Network on lcsh:R Drug administration Human Genetics 030227 psychiatry MDMA (Droga) Pharmacodynamics Pharmacogenetics lcsh:Q 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname UPCommons. Portal del coneixement obert de la UPC Universitat Politècnica de Catalunya (UPC) PLoS ONE PLoS ONE, Vol 7, Iss 10, p e47599 (2012) |
| Popis: | 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. 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 CM08/00051 |
| Databáze: | OpenAIRE |
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