title: Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.
abstract: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Autònoma de Barcelona (Parc de Salut Mar-UAB), Barcelona, Spain; Clinical Pharmacology Unit. Hospital Universitari Germans Trias i Pujol-IGTP, Badalona, Spain. Electronic address: mfarre@imim.es.
authors.forename: Magí
authors.initials: M
authors.lastname: Farré
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Autònoma de Barcelona (Parc de Salut Mar-UAB), Barcelona, Spain.
authors.forename: Angels
authors.initials: A
authors.lastname: Tomillero
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Autònoma de Barcelona (Parc de Salut Mar-UAB), Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Pérez-Mañá
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Pompeu Fabra (CEXS-UPF), Barcelona, Spain.
authors.forename: Samanta
authors.initials: S
authors.lastname: Yubero
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Autònoma de Barcelona (Parc de Salut Mar-UAB), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Papaseit
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Autònoma de Barcelona (Parc de Salut Mar-UAB), Barcelona, Spain.
authors.forename: Pere-Nolasc
authors.initials: PN
authors.lastname: Roset
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain.
authors.forename: Mitona
authors.initials: M
authors.lastname: Pujadas
authors.affiliation: Universitat Autònoma de Barcelona (Parc de Salut Mar-UAB), Barcelona, Spain; Institut de Neuropsiquiatria i Adiccions. Adiction Unit and IMIM, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Torrens
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Pompeu Fabra (CEXS-UPF), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Camí
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Medical Research Institute, Parc de Salut Mar, Barcelona, Spain; Universitat Pompeu Fabra (CEXS-UPF), Barcelona, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CB06/03), CIBEROBN, Santiago de Compostela, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
mesh_terms: D000328:Adult; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006213:Hallucinogens / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006728:Hormones / Q000097:blood; D006801:Humans; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D055815:Young Adult
chemical_list: D006213:Hallucinogens; D006728:Hormones; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: CYP2D6; Ecstasy; MDMA; Pharmacokinetics; Pharmacologic effects; Repeated dose