Abstract
3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is increasingly used by young people for its euphoric and empathic effects. MDMA can be used in combination with other drugs such as selective serotonin reuptake inhibitors. A clinical trial was designed where subjects pretreated with paroxetine, one of the most potent inhibitors of both 5-hydroxytryptamine reuptake and CYP2D6 activity, were challenged with a single dose of MDMA. The aim of the study was to evaluate the pharmacodynamic and pharmacokinetic interaction between paroxetine and MDMA in humans. A randomized, double-blind, crossover, placebo-controlled trial was conducted in 12 healthy male subjects. Variables included physiological parameters, psychomotor performance, subjective effects, and pharmacokinetics. Subjects received 20 mg/day paroxetine (or placebo) orally for the 3 days before MDMA challenge (100 mg oral). MDMA alone produced the prototypical effects of the drug. Pretreatment with paroxetine was associated with marked decreases of both physiological and subjective effects of MDMA, despite a 30% increase in MDMA plasma concentrations. The decreases of 3-methoxy-4-hydroxymethamphetamine plasma concentrations suggest a metabolic interaction of paroxetine and MDMA. These data show that pretreatment with paroxetine significantly attenuates MDMA-related physiological and psychological effects. It seems that paroxetine could interact with MDMA at pharmacodynamic (serotonin transporter) and pharmacokinetic (CYP2D6 metabolism) levels. Marked decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.
Footnotes
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This work was supported by Grants FIS 97/1198, FIS 98/0181, FIS 00/0777, and FIS 01/1336 from Fondo de Investigación Sanitaria, Madrid, Spain; Grant 2001SGR00407 from Generalitat de Catalunya-Comissió Interdepartamental de Recerca i Innovació Tecnològica, Barcelona, Spain; and “Area Progetto Droga”, Instituto Superiore di Sanitá, Rome, Italy. S.A. is recipient the grant “Ayudas para contratos post Formación Sanitaria Especializada”, Instituto de Salud Carlos III, Madrid, Spain.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.129056.
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ABBREVIATIONS: MDMA, 3,4-methylenedioxymethamphetamine; SERT, serotonin membrane reuptake transporter; SSRI, selective serotonin uptake inhibitor; P450, cytochrome P450; 5-HT, 5-hydroxytryptamine; SBP, systolic blood pressure; DBP, diastolic blood pressure; DSST, digit symbol substitution task; ARCI, Addiction Research Center Inventory; VESSPA, Evaluation of the Subjective Effects of Substances with Abuse Potential questionnaire; VAS, visual analog scales; ANX, psychosomatic anxiety scale; SOC, pleasure and sociability scale; ACT, activity and energy scale; MBG, morphine-benzedrine group; LSD, lysergic acid diethylamine group; BG, benzedrine group; HMMA, 3-methoxy-4-hydroxymethamphetamine; AUC, area under the curve; ANOVA, analysis of variance; NE, norepinephrine; Pgp, P-glycoprotein.
- Received July 22, 2007.
- Accepted September 19, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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