MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
Rafael de la Torre, Samanta Yubero‐lahoz, Ricardo Pardo‐lozano, Magı́ Farré
Frontiers in Genetics 2012 DOI: 10.3389/fgene.2012.00235 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | MDMA |
| Keywords | Pharmacogenetics Cyp2d6 Methamphetamine Pharmacology |
| Citations | 108 |
| Key findings | The clinical relevance of CYP2D6 polymorphism for methamphetamine and MDMA metabolism is lower than predicted by in vitro studies due to contributions from other clearance pathways and mechanism-based inhibition by MDMA. |
Abstract
In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.
Comparable studies
Other narrative reviews on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Human Pharmacology of MDMA | 2004 | Review | |
| Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical research | 2001 | Review | |
| 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans | 1994 | Review | |
| (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals | 2000 | Review | |
| Amphetamine toxicities | 2010 | Review |
Citations in the library
Cited by 28
- Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination The International Journal of Neuropsychopharmacology October 8, 2013
- Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies Journal of Psychopharmacology April 3, 2017
- Progress and promise for the MDMA drug development program. Psychopharmacology November 20, 2017
- CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals Pharmacogenetics and Genomics June 2, 2016
- Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies Journal of Psychopharmacology March 30, 2021
and 23 more in the library
Cites 19
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study PLoS One May 4, 2012
- The Norepinephrine Transporter Inhibitor Reboxetine Reduces Stimulant Effects of MDMA (“Ecstasy”) in Humans Clinical Pharmacology & Therapeutics June 15, 2011
- Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates Pharmacogenetics August 1, 2001
- Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA Journal of Psychopharmacology May 20, 2006
and 14 more in the library