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.
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.
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.
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)
Papers in Blossom that reference this study
Ramaekers, J. G., Kuypers, K. P. C., Vollenweider, F. X. · Molecular Psychiatry (2026)
The study is a prospectively planned pooled analysis of eight double-blind, placebo-controlled, crossover studies in healthy subjects. Across those studies 142 European/Caucasian participants aged 18–45 years were recruited; after missing genotyping or incomplete concentration–time data the reported analyses included 139 participants (69 male, 70 female; mean age 24.9 ± 4.1 years). Seven studies used a 125 mg oral MDMA dose and one study used 75 mg; in total 110 subjects received 125 mg (mean 1.9 ± 0.3 mg/kg) and 29 received 75 mg (mean 1.1 ± 0.1 mg/kg). Washout periods between treatment periods were at least 7 days. Exclusion criteria included psychiatric or physical illness, substantial prior illicit drug use, recent illicit drug use, and concomitant use of drugs known to interact with CYP function. Heavy smokers (>10 cigarettes/day) were excluded, but very light (1–5/day) and light smokers (6–10/day) were included. MDMA (± MDMA hydrochloride) was given as a single oral dose of 75 or 125 mg. Blood samples for pharmacokinetic (PK) analysis were taken at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4 and 6 h post-dose, with plasma stored at −20°C. Plasma concentrations of MDMA, MDA and HMMA were measured; HMMA was assessed after enzymatic deglucuronidation in 76 subjects. The lower limit of quantification for analytes was 1 ng/ml. Pharmacodynamic measures included repeated assessments of blood pressure, heart rate, tympanic core temperature and subjective effects on visual analogue scales; the rate pressure product (RPP; systolic blood pressure × heart rate) was used as an index of cardiostimulant effect. Genomic DNA was extracted from whole blood and genotyping performed via commercial TaqMan SNP assays to determine variants in CYP2C19, CYP2B6 (rs3745274) and CYP1A2 (rs762551). CYP2D6 activity was assessed phenotypically by the dextromethorphan/dextrorphan ratio and sensitivity analyses were performed restricted to CYP2D6 extensive metabolisers (EMs) and after excluding intermediate (IM) and poor metabolisers (PMs) to reduce confounding. Peak plasma concentrations (Cmax) were taken from observed data and area under the curve from 0–6 h (AUC6) was calculated by the linear trapezoidal method. Plasma values were dose-normalised to the mean dose per body weight (1.7 mg/kg) and mg/kg dose was included as a covariate in pharmacodynamic analyses. Statistical analyses used one-way ANOVA with genotype as the between-subjects factor, followed by Tukey post hoc tests. Smoking status was included as a factor in analyses involving CYP1A2. Sensitivity analyses confined to the 125 mg dose group were conducted to exclude dose-level confounding.
The analysed sample comprised 139 participants (69 male, 70 female), with MDMA plasma sampling up to 6 h. HMMA was assayed in 76 subjects. Dose groups differed as expected: Cmax of MDMA was greater after 125 mg versus 75 mg (mean ± SD: 230 ± 46 vs 125 ± 29 ng/ml; F1,137 = 140.20, P < 0.001). The 125 mg dose also produced larger peak subjective effects (80 ± 23 vs 57 ± 30%; F1,137 = 21.5, P < 0.001) and greater peak cardiostimulant responses measured by RPP (14728 ± 3278 vs 12067 ± 3159 mmHg × bpm; F1,137 = 15.3, P < 0.001). After dose normalisation, subjective and cardiovascular effects did not differ between dose groups, although dose-normalised MDMA Cmax showed a trend toward being higher at 125 mg (F1,137 = 4.08, P = 0.05), suggesting near-nonlinear kinetics across the studied dose range. CYP2C19: Genotype influenced MDMA→MDA conversion. The CYP2C19 genotype significantly affected MDA AUC6 (F3,135 = 3.54, P < 0.05) and the MDMA/MDA AUC6 ratio (F3,135 = 5.55, P < 0.01). Two CYP2C19 poor metabolisers showed more rapid increases in MDMA plasma levels, but that particular effect did not reach statistical significance. Pharmacodynamically, CYP2C19 genotype altered Emax of the RPP (F3,134 = 2.92, P < 0.05), with higher RPP values in CYP2C19 PMs compared with IMs and UMs (both P < 0.05). There were no CYP2C19 effects on HMMA concentrations or on body temperature and no effects on subjective measures of MDMA. CYP2B6: The rs3745274 SNP (G/G vs G/T vs T/T) significantly affected MDMA Cmax (F2,136 = 3.72, P < 0.05) with higher Cmax in T/T versus G/G carriers (P < 0.05). CYP2B6 genotype also influenced the MDMA/MDA AUC6 ratio (F3,136 = 3.67, P < 0.05), showing higher ratios in T/T compared with G/T or G/G groups (both P < 0.05). No significant effects of CYP2B6 genotype were observed on plasma MDA or HMMA levels. Autonomic and subjective responses to MDMA were not altered by CYP2B6 genotype. CYP1A2 and smoking interaction: There was a significant interaction between smoking status and CYP1A2 rs762551 genotype (inducible A/A vs A/C and C/C) on MDA Cmax and MDA AUC6 (F5,133 = 5.56, P < 0.001 and F = 4.04, P < 0.01, respectively). Among carriers of the inducible A/A genotype, light smokers (6–10 cigarettes/day) had higher MDA formation than nonsmokers and very light smokers (1–5/day), both P < 0.001. No smoking-related differences in MDA were found in A/C or C/C genotype carriers. CYP1A2 genotype, smoking, or their interaction did not affect MDMA or HMMA plasma concentrations or the pharmacodynamic autonomic and subjective outcomes. Sensitivity analyses accounting for CYP2D6 status were performed: analyses were replicated in 111 subjects phenotyped as CYP2D6 EMs and after exclusion of 19 IMs and 9 PMs, to address potential confounding by CYP2D6 activity. The extracted text does not provide detailed numeric results of these sensitivity analyses beyond stating they were conducted.
The investigators conclude that genetic polymorphisms in CYP2C19 and CYP2B6 contribute to the N-demethylation of MDMA to MDA in humans, corroborating prior in vitro findings. Evidence came from higher MDMA/MDA AUC6 ratios in subjects with lower CYP2C19 or CYP2B6 function, and from genotype-associated differences in MDMA Cmax for CYP2B6. Additionally, an interaction between smoking and the inducible CYP1A2 rs762551 A/A genotype led to increased MDA formation in smokers with that genotype, indicating a contribution of CYP1A2 to MDMA N-demethylation under induced conditions. Although MDA is pharmacologically active in vitro and in animal models, the authors note that altered conversion to MDA did not correspond to changes in subjective MDMA effects in this dataset. Paradoxically, subjects with slower MDMA→MDA conversion (CYP2C19 PMs) showed greater cardiostimulant responses, leading the authors to suggest that MDMA itself may contribute more to the cardiostimulant effects than MDA. The authors caution that some findings require confirmation: only two CYP2C19 PMs were present, and the greater RPP in these two subjects may be a chance finding. Likewise, the CYP1A2×smoking interaction was based on only four light smokers with the inducible genotype and therefore needs replication in larger samples, ideally including heavier smokers who would be expected to show greater CYP1A2 induction. Additional limitations acknowledged include the absence of subjects with rare combinations of impaired enzymes (for example concurrent CYP2D6 PM with CYP2C19 PM and CYP2B6 T/T), which could magnify pharmacokinetic consequences; plasma sampling was limited to 6 h, though the authors argue this covers the relevant pharmacodynamic window; and only doses up to 125 mg were tested. The authors propose that combinations of impaired CYP function could pose greater risk for MDMA toxicity and that larger studies are needed to confirm and extend these pharmacogenetic observations.
3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) produces feelings of well-being, enhanced emotional empathy, and prosocialityand is used recreationally and as an adjunct to psychotherapy. The recreational use of ecstasy has been associated with potentially severe toxicity, including agitation, hypertension, and hyperthermia. Individually increased vulnerability to the clinical toxicity of MDMA may result from alterations in drug-metabolizing enzymes, such as cytochrome P450 monooxygenases (CYPs), that are involved in the metabolism of MDMA (de la. Specifically, MDMA is Odemethylenated primarily by CYP2D6 to 3,4-dihydroxymethamphetamine (HHMA), which is then O-methylated to 4-hydroxy-3-methoxymethamphetamine (HMMA) by catechol-O-methyltransferase (COMT) (de la, the main inactive metabolite of MDMA in humans. Additionally, MDMA is Ndemethylated by CYP1A2, CYP2B6, CYP3A4, and CYP2C19to the minor active metabolite 3,4-methylenedioxyamphetamine (MDA) (de la. Only limited controlled data are available on the pharmacogenetics/toxicogenetics of MDMA. The pharmacokinetics (PK) of a drug is in part determined by genetic variants in drug-metabolizing enzymes. Genetic polymorphisms in CYP2D6 have been shown to influence MDMA metabolism in humans (de labut the role of other CYPs is unknown. In vitro 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, and their role may become more important in cases of overdoseor in CYP2D6 poor metabolizers (PMs; de la. However, the effects of polymorphisms in these CYPs on the metabolism of MDMA in humans have not yet been investigated. Therefore, the aim of the present study was to explore whether genetic variants in the CYP2C19, CYP2B6, and CYP1A2 genes alter the conversion of MDMA to MDA in humans. No common CYP1A2 loss-offunction polymorphisms have been identified to date. However, CYP1A2 is inducible by tobacco smoking in subjects with the common single-nucleotide polymorphism (SNP) rs762551 A/A genotype compared with the C/A and C/C genotypes. Therefore, we tested whether MDA formation is greater in tobacco smokers who carry the A/A genotype to assess the contribution of CYP1A2 to the metabolism of MDMA for the first time in humans. Finally, we tested whether CYP2C19, CYP2B6 or CYP1A2 genotype influenced the pharmacodynamics of MDMA.
This was a prospectively designed pooled analysis of eight double-blind, placebo-controlled, crossover studies in healthy subjectsincluding a total of 142 subjects. The prespecified primary endpoint of the pooled analysis was to assess the effects of polymorphisms in CYP enzymes on the PK of MDMA in all of the studies. In seven studies each including 16 subjects, a total of 112 subjects received MDMA at a dose of 125 mg, placebo, one of eight pretreatments plus MDMA, or the pretreatment alone. In one study, 30 subjects received MDMA at a dose of 75 mg, placebo, or methylphenidate. Washout periods between treatment periods were at least 7 days. Only Informed consent was obtained from all participants included in the studies.
A total of 142 healthy European/Caucasian subjects, aged 18-45 years, were recruited from the University of Basel campus and participated in the study. One genotyping sample was missing, one participant did not give consent for genotyping, and a full concentration-time profile could not be obtained in one participant, resulting in data from 139 participants (69 male, 70 female, mean age ± SD: 24.9 ± 4.1 years; range: 18-44 years) that were included in the analysis. A total of 110 subjects (54 male, 56 female) received 125 mg MDMA (mean ± SD: 1.9 ± 0.3 mg/kg), and 29 subjects (15 male, 14 female) received 75 mg MDMA (1.1 ± 0.1 mg/kg). The exclusion criteria were a history of psychiatric disorders, physical illness, a lifetime history of using illicit drugs more than five times (with the exception of past cannabis use), illicit drug use within the last 2 months, illicit drug use during the study, determined by urine tests that were conducted before the test sessions, and the use of drugs that interact with CYP function. Tobacco smoking (> 10 cigarettes/day) was an exclusion criterion, but light tobacco smokers (6-10 cigarettes/day) and very light tobacco smokers (1-5 cigarettes/day) were included in the study. The detailed exclusion criteria were reported elsewhere.
(±)MDMA hydrochloride (Lipomed AG, Arlesheim, Switzerland) was administered orally in a single dose of 125 or 75 mg. Similar doses are found in ecstasy pillsand have been used in clinical studies. The dose range was 0.8-2.7 mg/kg (mean = 1.7 mg/kg).
Blood samples were collected in lithium heparin tubes 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, and 6 h after administration of MDMA or placebo and immediately centrifuged. Plasma was stored at -20°C until analysis. Plasma concentrations of MDMA, MDA, and HMMA were determined as previously described. HMMA concentrations were determined after enzymatic deglucuronidation in 76 subjects. The lower limit of quantification concentrations were 1 ng/ml for all analytes.
Blood pressure, heart rate, and body temperature were assessed repeatedly before and 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 5, and 6 h after MDMA or placebo administration as previously described. The rate pressure product (RPP), a measure of the overall cardiostimulant effects, was calculated as systolic blood pressure × heart rate. Core (tympanic) temperature was assessed using a GENIUS TM 2 ear thermometer (Tyco Healthcare Group LP, Watertown, NY, USA). Subjective effects were measured using Visual Analog Scales (VAS).
Genomic DNA was extracted from whole blood using the QIAamp DNA Blood Mini Kit (Qiagen, Hombrechtikon, Switzerland) and automated QIAcube system. Genotyping was performed using commercial TaqMan SNP genotyping assays
Peak plasma concentrations (C max ) were obtained directly from the observed data. The area under the concentration-time curve (AUC) from 0 to 6 h after dosing (AUC 6 ) was calculated using the linear trapezoidal method. Plasma concentrations were determined up to 6 h after MDMA administration because the aim of the study was to assess potential changes in MDMA plasma levels while relevant pharmacodynamics effects or MDMA are present.
The statistical analyses were performed using Statistica 12 software (StatSoft, Tulsa, OK, USA). Group differences were analyzed using one-way analysis of variance (ANOVA), with genotype as between-subjects group factors, followed by the Tukey post hoc test. Smoking status was included as factor with CYP1A2 genotype. To account for differences in body weight and dosing, plasma levels were dosenormalized to the mean dose per body weight (1.7 mg/kg), and the mg/kg dose of MDMA was included as a covariate in the analysis of the pharmacodynamic effects. Sensitivity analyses were also conducted using only the 125 mg MDMA dose to exclude confounding by dose level. Additionally, CYP2D6 activity was determined using the dextromethorphan/dextrorphan ratioand the analyses were replicated in 111 subjects phenotyped as CYP2D6 EMs and after exclusion of 19 IMs and 9 PMs to exclude confounding by CYP2D6 activity.
Effects of the CYP2C19 genotype on the pharmacokinetics of MDMA are shown in Figureand supplementary Table. MDMA plasma levels increased more rapidly in the two CYP2C19 PMs (Figure) but this effect was not significant. The CYP2C19 genotype significantly influenced the AUC 6 of MDA (F 3,135 = 3.54, P < 0.05, Figure) and the MDMA/MDA AUC 6 ratio (F 3,135 = 5.55, P < 0.01, Figure), but not HMMA concentrations (Figure). CYP2C19 genotype altered the E max of the RPP (F 3,134 = 2.92, P < 0.05) with higher RPP values in CYP2C19 PMs compared with IMs and UMs (both P <0.05, Figure). CYP2C19 genotype had no effects on body temperature or any of the subjective effects of MDMA.
Effects of the CYP2B6 rs3745274 SNP (G/G vs. G/T vs. T/T) on the pharmacokinetics of MDMA are shown in Figureand supplementary Table. The CYP2B6 genotype significantly altered the MDMA C max (F 2,136 = 3.72, P < 0.05, Figure), with a higher concentration in subjects within the T/T compared to the G/G genotype (P < 0.05). The CYP2B6 genotype significantly influenced the MDMA/MDA AUC 6 ratio (F 3,136 = 3.67, P < 0.05, Figure) with higher ratios in the T/T vs. G/T or G/G group (both P < 0.05), but had no significant effects on plasma levels of MDA (Figure) or HMMA (Figure). CYP2B6 genotype did not alter the autonomic or subjective effects of MDMA.
Smoking status interacted with CYP1A2 genotype (inducible rs762551 A/A vs. non-inducible A/C and C/C) to affect MDA C max and AUC 6 values (F 5,133 = 5.56, P < 0.001 and 4.04, P<0.01, respectively; Tableand Figure). Smoking status altered MDA formation only in subjects with the inducible rs762551 A/A genotype, with higher MDA formation in light tobacco smokers (6-10 cigarettes/day) compared with nonsmokers and very light smokers (1-5 cigarettes/day, both P < 0.001; Figure). No effect of smoking status on MDA levels was found in subjects with the rs762551 A/C and C/C genotypes. There were no effects of CYP1A2 genotype or smoking or interaction on the plasma concentrations of MDMA or HMMA (Table) or on the pharmacodynamic autonomic and subjective effects of MDMA.
As expected, peak plasma concentrations of MDMA were greater after the 125 mg dose vs the 75 mg dose (mean ± SD: 230 ± 46 vs. 125 ± 29 ng/ml; F 1,137 = 140.20, P < 0.001). Consistently, the 125 mg dose produced greater subjective peak drug effects (80 ± 23 vs. 57 ± 30%; F 1,137 = 21.5, P < 0.001) and cardiovascular stimulant peak responses (RPP = 14728 ± 3278 vs. 12067 ± 3159 mmHg × bpm; F 1,137 = 15.3, P < 0.001). After dose normalization, the subjective and cardiovascular effects of MDMA did not differ between the dose groups. However, dose-normalized C max values of MDMA were near-significantly greater at the 125 mg compared with the 75 mg dose (F 1,137 = 4.08, P = 0.05) indicating a trend towards nonlinear pharmacokinetics at the doses used in this study.
The present study described the pharmacogenetics of CYP1A2, CYP2C19 and CYP2B6 in the disposition of MDMA in healthy human subjects. We documented a role for CYP2C19 and CYP2B6 in the conversion of MDMA to MDA in humans, confirming in vitro metabolism studies. The MDMA/MDA AUC6 ratio was greater in subjects with low CYP2C19 or low CYP2B6 function, consistent with a contributing role for both CYP2C19 and CYP2B6 in the Ndemethylation of MDMA to MDA in humans and confirming in vitro studies. MDA is pharmacologically active in vitroand in rats. One might therefore that alterations in the conversion of MDMA to MDA should not have a relevant effect on the pharmacodynamics of MDMA. However, the present study showed greater cardiostimulant effects of MDMA in subjects with slower MDMA to MDA conversion suggesting that MDMA contributes more to the cardiostimulant effects of MDMA than MDA. Similar to CYP2C19 and CYP2B6, CYP1A2 contributes to the Ndemethylation of MDMA to MDA in vitro. CYP1A2 can be induced by tobacco smoking. CYP1A2 activity increased with the number of cigarettes smoked per dayand normalized with a half-life of 39 hours when smoking is stopped. Additionally, CYP1A2 function is greater in smokers with the inducible SNP rs762551 A/A genotype compared with smokers with the non-inducible A/C and C/C genotypes. We found higher MDA levels in tobacco smokers with the inducible vs. non-inducible genotypes and compared with nonsmokers. This finding indicates that CYP1A2 contributes to the N-demethylation of MDMA to MDA in humans. However, CYP1A2 genetics did not alter the response to MDMA. Overall, polymorphism in CYP1A2, CYP2C19, and CYP2B6 influenced the metabolism of MDMA but none of the polymorphism altered the subjective response to MDMA. The present study has several limitations. Although it is a relatively large study, it included only two subjects with the 2C19 PM genotype. While consistent with the higher concentrations of MDMA, the greater cardiostimulant response to MDMA in these two subjects may represent a chance finding. Similarly, there were only 4 light smokers with the inducible CYP1A2 genotype and this interaction of CYP1A2 and smoking in the metabolism of MDMA needs to be confirmed in a larger study. We also included only smokers (<10 cigarettes/day) and it is likely that heavy smokers would show greater CYP1A2 induction. Although impairments in CYP2C19 or CYP2B6 alone may have only small effects on MDMA pharmacokinetics and its effects, the presence of multiple enzymes with impaired function such as combinations of 2D6 PM with CYP2C19 PM and CYP2B6 T/T may result in more pronounced consequences. The present study did not include subjects with such rare combinations that may predispose to MDMA toxicity. Plasma for pharmacokinetic analyses was sampled only up to 6 hours. However, this time covers the actual pharmacodynamic effects of MDMA which are shorter than its presence in plasma due to acute tolerance. Finally, we tested only doses of MDMA up to 125 mg which is in the upper range of recreational dosesand identical to the dose used in clinical studies
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