CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals
Yasmin Schmid, Patrick Vizeli, Cédric M. Hysek, Katharina Prestin, Henriette E. Meyer zu Schwabedissen, Matthias E. Liechti
Pharmacogenetics and Genomics June 2, 2016 DOI: 10.1097/fpc.0000000000000231 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pooled analysis of eight double-blind, placebo-controlled crossover studies Peer reviewed |
|---|---|
| Sample size | 139 |
| Population | Healthy individuals |
| Intervention | MDMA |
| Topics | MDMA |
| Keywords | Cyp2d6 Pharmacology Pharmacokinetics Active metabolite Pharmacogenetics Pharmacodynamics Cmax Crossover study Placebo Cytochrome p450 Genotype Metabolism |
| Citations | 52 |
| Key points | Polymorphic CYP2D6 activity alters MDMA disposition and effects, but the impact is small due to autoinhibition of CYP2D6. |
Abstract
The role of genetic polymorphisms in cytochrome (CYP) 2D6 involved in the metabolism of 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy) is unclear. Effects of genetic variants in CYP2D6 on the pharmacokinetics and pharmacodynamic effects of MDMA were characterized in 139 healthy individuals (70 men, 69 women) in a pooled analysis of eight double-blind, placebo-controlled crossover studies. In CYP2D6 poor metabolizers, the maximum concentrations (Cmax) of MDMA and its active metabolite 3,4-methylene-dioxyamphetamine were +15 and +50% higher, respectively, compared with extensive metabolizers and the Cmax of the inactive metabolite 4-hydroxy-3-methoxymethamphetamine was 50-70% lower. Blood pressure and subjective drug effects increased more rapidly after MDMA administration in poor metabolizers than in extensive metabolizers. In conclusion, the disposition of MDMA and its effects in humans are altered by polymorphic CYP2D6 activity, but the effects are small because of the autoinhibition of CYP2D6.