Oxytocin receptor gene variation predicts subjective responses to MDMA

This double-blind, placebo-controlled within-subjects study (n=68) investigated the subjective effects of MDMA (52.5mg and 105 mg/70kg) in relation to genetic variation of oxytocin receptors of healthy participants. Results indicated a single nucleotide polymorphism in the oxytocin receptor gene-mediated differences in sociability and euphoria in response to the higher dose, providing further evidence that oxytocin mediates the distinct social effects of MDMA.

Abstract

“Introduction: 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) enhances the desire to socialize and feelings of empathy, which are thought to be related to increased oxytocin levels. Thus, variation in the oxytocin receptor gene (OXTR) may influence responses to the drug.

Methods: Here, we examined the influence of a single OXTR nucleotide polymorphism (SNP) on responses to MDMA in humans. Based on findings that carriers of the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behaviour, we hypothesized that these individuals would show reduced subjective responses to MDMA, including sociability.

Results: In this three-session, double-blind, within-subjects study, healthy volunteers with past MDMA experience (N = 68) received a MDMA (0, 0.75 mg/kg, and 1.5 mg/kg) and provided self-report ratings of sociability, anxiety, and drug effects. These responses were examined in relation to rs53576. MDMA (1.5 mg/kg) did not increase sociability in individuals with the A/A genotype as it did in G allele carriers. The genotypic groups did not differ in responses at the lower MDMA dose or in cardiovascular or other subjective responses.

Discussion: These findings are consistent with the idea that MDMA-induced sociability is mediated by oxytocin and that variation in the oxytocin receptor gene may influence responses to the drug.”

Authors: Anya K. Bershad, Jessica J. Weafer, Matthew G. Kirkpatrick, Margaret C. Wardle, Melissa A. Miller & Harriet de Wit

Summary

Variation in the oxytocin receptor gene may influence responses to MDMA, which is thought to be related to increased oxytocin levels. Individuals with the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behavior, and thus may show reduced subjective responses to MDMA.

MDMA is an amphetamine analogue used recreationally in social contexts. It is known for its ability to enhance mood and distinctly social feelings, such as empathy and a sense of connection with others, but the mechanism by which it produces these unique effects is not yet entirely understood.

Oxytocin is a neuropeptide involved in affiliative behavior and bonding. MDMA increases plasma oxytocin levels and is correlated with enhanced sociability, but the role of oxytocin in producing the prosocial effects of MDMA is still unclear.

MDMA reduces amygdala responses to angry faces and enhances ventral striatal responses to socially rewarding, happy faces. This is in line with studies showing that MDMA enhances identification of positive facial expressions.

Several single nucleotide polymorphisms in the oxytocin receptor gene have been associated with differences in socio-emotional behavior and social processing. The rs53576 polymorphism is associated with empathic behavior, greater sociability, and greater sensitivity to the emotion-recognition-enhancing effects of intranasal oxytocin.

Despite the evidence above, there have been no investigations of how rs53576 influences responses to prosocial drugs. We hypothesized that A/A individuals would experience reduced prosocial drug effects compared to individuals carrying the G allele.

Study design

We combined data from two studies using within-subjects, placebo-controlled designs. Subjects received placebo, 0.75 mg/kg, or 1.5 mg/kg MDMA under double blind conditions.

Participants

Healthy adults were recruited through flyers, online advertisements, and word of mouth referrals. They underwent psychiatric and medical screening, including a physical examination, electrocardiogram, and modified structured clinical interview for DSM-IV.

Procedure

Participants attended an orientation session, fasted for 2 h prior to each session, and were instructed to refrain from alcohol and over-the-counter drugs, marijuana for 7 days before and 24 h after the session, and all other recreational drugs for 48 h before and 24 h after the session.

Participants were given a capsule containing MDMA powder (0.75 and 1.5 mg/kg, maximum dose of 125 mg, with lactose filler) or placebo (lactose only). They were assessed every 30 – 60 min until discharge, provided their subjective and cardiovascular measures had returned to baseline.

Subjective responses

Subjective effects of MDMA were assessed using visual analogue scales and a drug effects questionnaire. Participants were asked which drug they thought they received, a stimulant, sedative, cannabinoid, hallucinogen, or placebo.

Data analysis

We calculated the area-under-the-curve (AUC) for each VAS measure, reduced the data into factors appropriate for analysis with genotype, and conducted single sample t-tests on the resulting scores.

We entered the change scores into principal components analyses, and calculated four distinct factors: sociability, anxiety, euphoria, and dizziness. We compared the four derived subjective effect factor scores between three groups by genotype at the OXTR SNP rs53576, and also examined the relationship between genotype and MDMA-related cardiovascular effects.

Participant characteristics

Twenty-eight participants possessed the G/G genotype, 30 A/G, and 10 A/A. All participants were Caucasian, in their twenties, with some college education, and moderate recreational drug use.

We conducted between-subjects ANOVAs to verify that baseline measures of anxiety and sociability did not differ among the three genotypes.

Drug identifications

Participants were asked which drug they thought they had received. On the placebo session, 35/64 correctly identified placebo, while the rest believed they had received a sedative, stimulant, cannabinoid, or hallucinogen.

Effects of MDMA

MDMA increased ratings of subjective measures of sociability, anxiety, euphoria, and dizziness in rats. Additionally, both doses of the drug increased heart rate, systolic blood pressure, and diastolic blood pressure.

Effects of genotype on responses to MDMA

MDMA differentially affected ratings of sociability and euphoria across genotype groups. Individuals with the A/A genotype reported smaller increases in euphoria compared to those with the G allele at the same 1.5 mg/kg dose.

Discussion

Here we report that a variation in OXTR genotype affects subjective responses to MDMA in healthy adults. Individuals with the A/A genotype had lower subjective ratings of sociability and euphoria after the higher dose compared to individuals carrying the G allele at this locus.

Previous studies have found that A allele carriers exhibit differences in social behavior, including being less sensitive to social cues, less trusting, and being judged by others to be less social. Our study showed that the genotype influenced MDMA-induced sociability at the higher dose.

Our findings suggest that individuals with the G allele at this locus in the OXTR gene may be particularly susceptible to the prosocial effects of MDMA, and thus to repeated use of the drug. Additionally, individuals may differ in the benefit derived from MDMA in therapeutic settings.

Individual differences may also contribute to the therapeutic efficacy of MDMA. These include being less sensitive to social ostracism and less likely to derive psychological benefits from social support.

The present study had some limitations, including a small sample size and a homozygote genotype group with the lowest MDMA effect on sociability and euphoria. However, future studies may benefit from using prospective genotyping to replicate the current findings.

Because we did not have a specific hypotheses regarding differential timecourse effects across genotypes, we chose to conduct analyses on the summary measure of area under the curve scores.

This study examined the relationship between OXTR variation and subjective MDMA responses in healthy adults with a very specific MDMA use history. The results suggest that individuals may differ in their sensitivity to MDMA’s therapeutic effects.

A/A genotype carriers reported less sociability and euphoria in response to 1.5 mg/kg MDMA compared to G allele carriers, suggesting that oxytocin mediates the distinct social effects of MDMA.