Role of serotonin transporter and receptor gene variations in the acute effects of MDMA in healthy subjects

This pooled analysis of randomized, double-blind, placebo-controlled studies (n=124) explored the effects of genetic variants within selected genes in physiological and subjective response to MDMA (125 mg) compared with placebo. The study concluded that none of the tested genetic polymorphisms had any significant effect on the response to MDMA, thus, interindividual differences in the activation of the serotonin system (5-HT) may play only a marginal role when MDMA is used for recreation or therapy.

Abstract

“Methylenedioxymethamphetamine (MDMA; ecstasy) is used recreationally and has been investigated as an adjunct to psychotherapy. Most acute effects of MDMA can be attributed to activation of the serotonin (5-hydroxytryptamine [5-HT]) system. Genetic variants, such as single-nucleotide polymorphisms (SNPs) and polymorphic regions in 5-HT system genes, may contribute to interindividual differences in the acute effects of MDMA. We characterized the effects of common genetic variants within selected genes that encode the 5-HT system (TPH1 [tryptophan 5-hydroxylase 1] rs1800532 and rs1799913, TPH2 [tryptophan 5-hydroxylase 2] rs7305115, HTR1A [5-HT_1A receptor] rs6295, HTR1B [5-HT_1B receptor] rs6296, HTR2A [5-HT_2A receptor] rs6313, and SLC6A4 [serotonin transporter] 5-HTTLPR and rs25531) on the physiological and subjective response to 125 mg of MDMA compared with placebo in 124 healthy subjects. Data were pooled from eight randomized, double-blind, placebo-controlled studies that were conducted in the same laboratory. TPH2 rs7305115, HTR2A rs6313, and SLC6A4 5-HTTLPR polymorphisms tended to moderately alter some effects of MDMA. However, after correcting for multiple comparisons, none of the tested genetic polymorphisms significantly influenced the response to MDMA. Variations in genes that encode key targets in the 5-HT system did not significantly influence the effects of MDMA in healthy subjects. Interindividual differences in the 5-HT system may thus play a marginal role when MDMA is used recreationally or therapeutically.”

Authors: Patrick Vizeli, Henriette E. Meyer zu Schwabedissen & Matthias E. Liechti

Summary

MDMA (ecstasy) affects the serotonin (5-HT) system and may cause differences in acute effects between individuals.

Methods: We tested the effects of common genetic variants within selected genes that encode the 5-HT system on the physiological and subjective response to 125 mg MDMA compared with placebo in 124 healthy subjects.

MDMA is a popular psychedelic drug that induces empathic and euphoric effects. Pharmacological inhibition of the 5-HT transporter and 5-HT2A receptors can reduce the effects of MDMA. The 5-HT system is involved in the acute effects of MDMA, but little is known about how genetic variations of genes that encode targets that are implicated in the mechanism of action of MDMA or its metabolism influence the response to MDMA.

4 SERT comprises two variants with long (L) and short (S) alleles, and one important SNP variant. Individuals with the L allele and G variant of rs25331 present the same low-expressing phenotypes as S-allele carriers, but the efficacy of MDMA depends on activity of the SERT. Therefore, individuals with the LG or short 5-HTTLPR allele may present a reduction of MDMA’s effects compared with LALA carriers. MDMA indirectly and partially also interacts with 5-HT receptors 5, 10, 43, 44. The rs6295 SNP of the HTR1A gene may play a role in substance use disorder.

A SNP in the gene encoding the 5-HT1B receptor was found to influence childhood aggressive behavior, and a SNP in the gene encoding the 5-HT2A receptor was found to influence suicide, anxiety when observing pain, and communication problems. The present study investigated whether genetic variations within the serotonergic system influence MDMA’s acute subjective, emotional, empathic, cardiovascular, thermogenic, and adverse effects.

Results show that the SNPs did not significantly alter the maximum response to MDMA.

The distribution of alleles and genotypes did not differ from the distributions that were reported elsewhere in Caucasian cohorts. The tested genetic variants were consistent with Hardy-Weinberg equilibrium.

MDMA significantly altered the Emax values for all reported parameters on the VASs and AMRSs, and serotonergic system gene polymorphisms were associated with higher ratings of “good drug effect,” “trust,” AMRS “well-being,” “high-mood,” and “dreaminess” compared with homozygous G-allele carriers.

Genetic polymorphisms had no effect on MDMA’s effects on subjective Visual Analog Scale ratings.

MDMA impaired the recognition of fearful, sad, and angry faces on the FERT.

MDMA significantly increased blood pressure, mean arterial pressure, respiratory rate, and body temperature. The TPH2 rs7305115 SNP had no significant effect on these physiological parameters.

MDMA significantly increased LC scores after up to 6 h and up to 24 h, and the genetic polymorphisms TPH2 and HTR2A had no significant effect on the adverse effects of MDMA.

MDMA concentrations increased across all serotonergic system gene variants, except for the rs6295 SNP (MDMA AUC6; CG vs. GG, p 0.05) and rs6313 SNP (MDMA Cmax).

The present study investigated the effects of genetic variants in the 5-HT system on MDMA-induced mood, empathogenic, cardiovascular, thermogenic, and adverse effects. The effects were limited and none were significant.

The present study was the first to investigate the role of polymorphisms in the 5-HT system in modulating the acute effects of MDMA in healthy human subjects. The results suggest that the 5-HTTLPR polymorphism does not play an important role in modulating the acute effects of MDMA. The discrepancies between these studies may be due to the different doses of MDMA used, as the 125 mg dose produced greater good drug effects compared to the 75 mg dose. The present study, which included mostly MDMA-naive healthy subjects, showed that genetic variations of genes that encode the 5-HT system did not markedly influence the effects of MDMA in healthy subjects. Therefore, interactions between MDMA and 5-HT system genotypes may not be an important factor to consider when MDMA is used therapeutically or recreationally.

Eight double-blind, placebo-controlled, crossover studies were reviewed. A total of 136 healthy subjects received 125 mg MDMA twice, once alone and once after pretreatment with a medication.

MDMA was administered to healthy subjects in a hospital research ward for at least 7 days to exclude possible carry-over effects. Informed consent was obtained from all participants, and the studies were conducted in accordance with the Declaration of Helsinki.

A total of 136 healthy subjects were recruited from the University of Basel campus, and 124 subjects participated in the study. Forty-two subjects had prior illicit drug experiences, of which 22 subjects had previously used MDMA (1-3 times), seven subjects had previously used amphetamine or methamphetamine (1 time), 10 subjects had previously used cocaine, and six subjects had previously used psilocybin.

MDMA hydrochloride was administered orally in a single dose of 125 mg, prepared as gelatin capsules. The dose was not adjusted for body weight or sex.

Physiological effects were measured before and 0, 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 h after MDMA or placebo administration. Acute and subacute adverse effects were assessed using the list of complaints (LC), and bruxism was included in the LC that was used in 92 subjects.

The Adjective Mood Rating Scale (AMRS) was administered to 109 subjects before and after MDMA or placebo administration.

We used the Facial Emotion Recognition Task (FERT) to measure emotion recognition 90 min after drug administration. The outcome measure was accuracy (proportion correct) and misclassification (emotions that were indicated incorrectly).

The Multifaceted Empathy Test (MET) assesses the cognitive and emotional aspects of empathy. It is sensitive to oxytocin, MDMA, and other psychoactive substances, and can be performed 90-180 min after drug administration.

Genomic DNA was extracted from whole blood and genotyped using commercial TaqMan SNP genotyping assays and a ViiA7 real-time polymerase chain reaction (PCR) system. The SLC6A4 5-HTTLPR polymorphism and rs25531 SNP were also genotyped using a T100 thermal cycler. The size of the PCR products was determined by 4% agarose gel electrophoresis, and the genotypes of the rs25331 SNP were determined by PCR using Taq DNA polymerase, recombinant.

The TPH1 gene was analyzed using polymerase chain reaction (PCR) with an initial activation step of 95°C (3 min), 49 cycles of 95°C (30 s), 59.7°C (25 s), and 72°C (30 s), with final extension at 72°C (5 min). Three groups were defined: LGLG, LGS, and SS.

We performed statistical analyses using Statistica 12 software (StatSoft, Tulsa, OK, USA) and corrected for 19 subjective effects (VAS+AMRS), 3 interaction effects, and 2 time course effects.

MDMA affected 19 emotions, 5 vital parameters, 8 items in the LC, and 7 polymorphisms, leading to a corrected significance threshold of p 0.00023 to keep Type I error rate at 5%. Additionally, modulatory effects of sex were explored by adding sex as a between-subjects factor in the ANOVAs.