Safety pharmacology and pharmacogenetics of 3,4-methylenedioxymethamphetamine (MDMA)

Psychoactive substances such as the ring substituted phenylethylamine 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”) are widely used in recreational settings. Additionally, recent research highlights substance-assisted psychotherapy as potential new effective treatment for various psychiatric disorders, e.g. post-traumatic stress disorder (PTSD). MDMA releases and inhibits the uptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) via an interaction with the respective monoamine transporter. Additionally, MDMA increases blood levels of the hormone oxytocin. Through these mechanisms, MDMA produces autonomic and distinct psychological effects such as increased empathy and sociability - effects that may prove to be helpful in psychotherapy. Despite the widespread recreational use and growing interest in using MDMA for medical purposes, interindividual differences in the response to MDMA are not elucidated. Genetic variants, such as single-nucleotide polymorphisms (SNPs) may influence the individual effects of MDMA. To address this matter, we used a uniquely large population of up to 166 subjects assembled from pooled but highly standardized phase I MDMA studies and conducted in-depth analyses on the clinical safety and on the influence of different genetic variations on the effects of MDMA.
The first part of the present thesis was to evaluate the clinical safety pharmacology of single-dose administrations of 75 or 125 mg of MDMA. In up to a third of the subjects, administration of MDMA showed notable increases in maximum systolic blood pressure (>160 mmHg), heart rate (>100 bpm), and body temperature (>38 °C). Those effects on autonomic measures were significantly greater in subjects receiving 125 mg of MDMA. Acute and subacute adverse reactions such as headache, bruxism or lack of appetite were also dose-dependent and more frequent in women than men. However, no extreme outliers were observed, and the use of MDMA was considered as safe in controlled clinical settings. Nevertheless, we suggest a lower therapeutic dose for women. Due to the sympathomimetic stimulation, risks of MDMA might be higher in patients with cardiovascular diseases and should be further investigated in psychiatric patients with comorbidities.
In the second part of this thesis focus was laid on the identification of pharmacogenetic roles in the effects of MDMA. Specifically, the influence of genetic variants within genes coding for relevant cytochromes P450 (CYPs), and pharmacodynamic targets such as the 5-HT, NE, and DA system, and oxytocin receptors, on the response to MDMA was tested. We found that CYP2D6 poor metabolizers (PMs) exhibited increased plasma levels of MDMA, leading to accelerated cardiovascular and psychostimulant responses to acute MDMA administration. Polymorphisms in CYP2D6, CYP1A2, CYP2C19, and CYP2B6 altered the metabolism of MDMA to 3,4-methylenedioxyamphetamine (MDA), but showed no clinical relevance. In additional analyses, moderating effects for MDMA-induced feelings of trust and desire for company between variations of an oxytocin receptor single nucleotide polymorphism (SNP OXTR rs1042778) were shown.
To our knowledge, investigations assessing the influence of the monoamine system gene variations on the effects of MDMA were mostly the first on this matter. Subsequently, results had to be rigorously corrected for statistical errors and tested for specific hypothesis. Most of the tested genetic polymorphisms in the 5-HT (7 SNPs and 1 repeat polymorphism), NE (5 SNPs), and DA (10 SNPs and 1 repeat polymorphism) systems did not alter the effects of MDMA when adjusting for multiple comparisons. Only SNPs in the NE transporter gene SLC6A2 (rs1861647, rs2242446, and rs36029) significantly altered the acute MDMA-induced cardiovascular response.
In summary, apart from variations within CYPs, genetic polymorphisms seem to play a subordinate role in the acute MDMA effects and are unlikely to sum up all interindividual variations.
Results from the present thesis showed that MDMA was overall safe and well-tolerated with only moderate adverse effects in a clinical setting. Furthermore, pharmacogenetic analysis highlighted possible relevant genetic variations for the pharmacokinetic and pharmacodynamics effects of MDMA and point out targets of interest, which can define the scope of future studies with MDMA.