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.

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.”

Authors: Patrick Vizeli, Yasmin Schmid, Katharina Prestin, Henriette E. Meyer zu Schwabedissen & Matthias E. Liechti

Summary

Genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 may moderate the cardiovascular toxicity of MDMA, and may be associated with higher CYP2C19 or CYP2B6 activities and greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes.

MDMA is metabolized by several enzymes to form different metabolites, including 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine (MDA). MDMA can be toxic if metabolized by the wrong enzymes. Limited controlled data are available on the pharmacogenetics/toxicogenetics of MDMA. Genetic variants in CYP2D6 have been shown to influence MDMA metabolism in humans, but the role of other CYPs is unknown.

Studies indicate that CYP2D6 is responsible for most of the clearance of MDMA, but CYP1A2, CYP2B6, and CYP2C19 also contribute to the N-demethylation of MDMA to MDA in humans. However, the effects of polymorphisms in these CYPs on the metabolism of MDMA in humans have not yet been investigated.

In eight double-blind, placebo-controlled, crossover studies, 142 healthy subjects were included. Polymorphisms in CYP enzymes were assessed for effects on MDMA PK.

112 subjects received MDMA at a dose of 125 mg, placebo, one of eight pretreatments plus MDMA, or the pretreatment alone in 6 studies. Washout periods between treatment periods were at least 7 days.

A total of 142 healthy European/Caucasian subjects were recruited from the University of Basel campus and participated in the study. A total of 110 subjects received 125 mg MDMA and 29 subjects received 75 mg MDMA.

MDMA hydrochloride was administered orally in a single dose of 125 or 75 mg.

Blood samples were collected from subjects 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, and 6 h after administration of MDMA or placebo. Plasma concentrations of MDMA, MDA, and HMMA were determined.

Blood pressure, heart rate, and body temperature were measured before and after MDMA or placebo administration, and the rate pressure product (RPP) was calculated. Subjective effects were measured using Visual Analog Scales.

Predicted CYP2C19 PMs included CYP2C192/2, intermediate metabolizers included CYP2C191/2 and CYP2C192/17, and extensive metabolizers included CYP2C191/1. For CYP1A2, the reduced-activity SNP rs3745274 was determined.

Pharmacokinetic analyses were performed on MDMA plasma concentrations up to 6 h after dosing to assess potential changes in MDMA plasma levels while relevant pharmacodynamics effects are present.

Statistical analyses were performed using Statistica 12 software, and body weight and dose were adjusted to account for differences in plasma levels. CYP2D6 activity was determined using the dextromethorphan/dextrorphan ratio, and sensitivity analyses were conducted using only the 125 mg MDMA dose.

The CYP2C19 genotype influenced the pharmacokinetics of MDMA in the plasma, with higher AUC6 of MDA in CYP2C19 PMs compared with IMs and UMs, but no effects on body temperature or subjective effects of MDMA.

The CYP2B6 rs3745274 SNP significantly altered the MDMA Cmax and MDMA/MDA AUC6 ratio, but had no significant effects on plasma levels of MDA or HMMA.

Smoking status interacted with CYP1A2 genotype to affect MDA Cmax and AUC6 values. No effect of CYP1A2 genotype or smoking was found on MDMA or HMMA plasma concentrations or pharmacodynamic autonomic and subjective effects.

The 125 mg dose of MDMA produced greater subjective peak drug effects and cardiovascular stimulant peak responses compared to the 75 mg dose. After dose normalization, the subjective and cardiovascular effects of MDMA did not differ between the dose groups.

The present study examined the role of CYP1A2, CYP2C19 and CYP2B6 in the disposition of MDMA in healthy human subjects. Results showed that the CYP2C19 and CYP2B6 genotypes altered MDMA concentrations later in time 3-4 hours after drug administration.

CYP2D6 function decreases over time due to auto-inhibition by MDMA, and CYP2B6 becomes more important. This may explain why subjects with slower MDMA to MDA conversion have greater cardiostimulant effects of MDMA. CYP1A2 contributes to the N-demethylation of MDMA to MDA in vitro and in humans. CYP1A2 genetics did not alter the response to MDMA, but CYP1A2 activity increased with the number of cigarettes smoked per day. The present study has several limitations, including only two subjects with the 2C19 PM genotype and only 4 light smokers with the inducible CYP1A2 genotype.

The present study did not include subjects with rare combinations that may predispose to MDMA toxicity, and only tested doses of MDMA up to 125 mg, which is in the upper range of recreational doses and identical to the dose used in clinical studies.

The CYP2C19 polymorphism affected the plasma concentrations of MDMA, MDA, HMMA and the MDMA/MDA ratio. The MDA levels increased with decreasing CYP2C19 function, indicating influence on the N-demthylation of MDMA to MDA.

Figure 2 shows that the heart rate and blood pressure increased more in PMs with the CYP2C19 polymorphism than in IMs or UMs.

Figure 3 shows that the CYP2B6 genotype influenced the plasma concentrations of MDMA, MDA, HMMA and the MDMA/MDA ratio, but had no significant effects on the plasma levels of MDA or HMMA.

The CYP1A2 SNP rs762551 was associated with increased levels of MDA in light smokers and very light smokers compared to non-smokers and non-inducible smokers.