Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects
This pooled analysis (n=139) of double-blind, placebo-controlled studies reviews the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans. The research shows affirmed that these enzymes play a significant role in the metabolism of MDMA to MDA in humans and that genetic polymorphism in CYP2C19 could moderate MDMA's cardiovascular toxicity.
Authors
- Yasmin Schmid
- Patrick Vizeli
- Matthias Liechti
Published
Abstract
In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.
Research Summary of 'Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects'
Introduction
MDMA (3,4-methylenedioxymethamphetamine; ecstasy) produces prosocial and empathic effects and is used recreationally and experimentally in psychotherapy, yet its use can cause severe toxicity including agitation, hypertension and hyperthermia. Earlier work established that CYP2D6 is primarily responsible for O-demethylenation of MDMA to HHMA and subsequent metabolism, while in vitro data also implicate CYP1A2, CYP2B6 and CYP2C19 in the N-demethylation of MDMA to the minor but active metabolite MDA. The extent to which genetic polymorphisms in CYP1A2, CYP2B6 and CYP2C19 influence MDMA pharmacokinetics and pharmacodynamics in humans remained unknown. Vizeli and colleagues designed the present study to test whether common genetic variants in CYP2C19, CYP2B6 and CYP1A2 alter conversion of MDMA to MDA and whether these genotypes affect MDMA’s physiological or subjective effects. Because CYP1A2 is inducible by tobacco smoking in carriers of the rs762551 A/A genotype, the investigators also examined interactions between smoking status and CYP1A2 genotype to evaluate CYP1A2’s contribution to MDMA N-demethylation in humans.
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Study Details
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- APA Citation
Vizeli, P., Schmid, Y., Prestin, K., Meyer zu Schwabedissen, H. E., & Liechti, M. E. (2017). Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects. European Neuropsychopharmacology, 27(3), 232-238. https://doi.org/10.1016/j.euroneuro.2017.01.008
References (2)
Papers cited by this study that are also in Blossom
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2010)
Oehen, P., Traber, R., Widmer, V. et al. · Journal of Psychopharmacology (2012)
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Black, J. C., Monte, A. A., Dasgupta, N. et al. · Nature Mental Health (2024)
Poyatos, L., Lo Faro, A., Sprega, G. et al. · International Journal of Molecular Sciences (2022)
Sarparast, A., Thomas, K., Malcolm, B. et al. · Psychopharmacology (2022)
Vizeli, P., Straumann, I., Holze, F. et al. · Scientific Reports (2021)
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Nichols, D. E., Walter, H. · Pharmacopsychiatry (2020)
Vizeli, P., Meyer Zu Schwabedissen, H. E., Liechti, M. E. · ACS Chemical Neuroscience (2018)
Dunlap, L. E., Andrews, A. M. · ACS Chemical Neuroscience (2018)
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Vizeli, P., Liechti, M. E. · PLOS ONE (2018)
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Vizeli, P., Liechti, M. E. · Journal of Psychopharmacology (2017)
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