This pooled double-blind, placebo-controlled analysis (n=132) appraised oxytocin receptor (OXTR) gene variations such as single-nucleotide polymorphisms (SNPs) and their influence on socio-emotional effects of MDMA in healthy participants. The study found evidence that OXTR gene variations, which are shown to contribute towards prosociality and moral cognition, may modulate characteristics of the prosocial subjective effects of MDMA in human subjects. However, OXTR SNPs did not moderate the overall subjective response to MDMA (any drug effect) or sentiments that correlate to “closeness to others”.
Methylenedioxymethamphetamine (MDMA) increases oxytocin, empathy, and prosociality. Oxytocin plays a critical role in emotion processing and social behavior and has been shown to mediate the prosocial effects of MDMA in animals. Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the oxytocin receptor (OXTR) may influence the emotional and social effects of MDMA in humans. The effects of common genetic variants of the OXTR (rs53576, rs1042778, and rs2254298 SNPs) on the emotional, empathogenic, and prosocial effects of MDMA were characterized in up to 132 healthy subjects in a pooled analysis of eight double-blind, placebo-controlled studies. In a subset of 53 subjects, MDMA produced significantly greater feelings of trust in rs1042778 TT genotypes compared with G allele carriers. The rs53576 and rs225498 SNPs did not moderate the subjective effects of MDMA in up to 132 subjects. None of the SNPs moderated MDMA-induced impairments in negative facial emotion recognition or enhancements in emotional empathy in the Multifaceted Empathy Test in 69 subjects. MDMA significantly increased plasma oxytocin concentrations. MDMA and oxytocin concentrations did not differ between OXTR gene variants. The present results provide preliminary evidence that OXTR gene variations may modulate aspects of the prosocial subjective effects of MDMA in humans. However, interpretation should be cautious due to the small sample size. Additionally, OXTR SNPs did not moderate the subjective overall effect of MDMA (any drug effect) or feelings of “closeness to others”.
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MDMA (3,4-methylenedioxymethamphetamine) produces empathogenic and prosocial subjective effects and increases peripheral oxytocin. Previous human and animal studies have implicated oxytocin in social cognition and prosocial behaviour, and animal work shows that blocking oxytocin receptors can prevent MDMA-induced prosocial effects. However, human evidence for oxytocin as a mediator is mixed: some studies report correlations between MDMA-induced oxytocin release and prosocial feelings, while others do not, and direct pharmacological blockade in humans is limited by blood–brain barrier issues. Genetic variability in the oxytocin receptor gene (OXTR) has been associated with social traits in prior work, suggesting that single-nucleotide polymorphisms (SNPs) in OXTR might moderate individual responses to MDMA. Vizeli and colleagues set out to test whether three common OXTR SNPs (rs53576, rs1042778, rs2254298) modulate the socio-emotional, empathic, and prosocial effects of a single 125 mg oral MDMA dose in healthy volunteers. The study used pooled data from eight similar double-blind, placebo-controlled, crossover Phase I studies to explore genotype-by-drug interactions on subjective ratings, emotion recognition, empathy tasks, economic prosociality measures, and plasma oxytocin and MDMA concentrations. The investigation was framed as exploratory and sought both to characterise potential moderating effects and to attempt replication of previously reported rs53576 findings.
This pooled analysis combined eight Phase I, double-blind, placebo-controlled, crossover studies conducted between 2009 and 2014, using a common MDMA-alone versus placebo comparison. In total 136 healthy subjects of European descent were recruited; genotyping and complete data were available for 132 subjects (64 men, 68 women), aged 18–44 years (mean ± SD = 24.8 ± 4 years). Most studies used two MDMA sessions per subject (125 mg each), but only MDMA-alone and placebo sessions were analysed here. Washout between doses was ≥7 days. Exclusion criteria included psychiatric or significant physical illness and substantial illicit drug history; urine screens excluded recent illicit drug use. MDMA was administered orally as a single 125 mg dose (mean dose 1.9 ± 0.3 mg/kg). Genotyping of OXTR SNPs rs53576, rs1042778, and rs2254298 was performed from whole-blood DNA using TaqMan assays; linkage disequilibrium analyses found no LD among these SNPs. Subjective effects were assessed repeatedly up to 6 h post-dose by Visual Analog Scales (VAS), including global items (“any drug effect”, “closeness to others”) and social items (“trust”, “want to be hugged”, etc.); some VAS social items were assessed in a subset of 53 subjects. Emotion recognition was measured at 90 min using the Facial Emotion Recognition Task (FERT) in 69 subjects. Empathy was assessed with the Multifaceted Empathy Test (MET) 90–180 min post-dose (n=69). Prosocial behaviour was measured with the Social Value Orientation (SVO) slider task 3–4 h post-dose (primary SVO data n=69; inequality-aversion index n=33). Plasma oxytocin was sampled at baseline and 2 h post-dose, and MDMA concentrations were measured across multiple time points up to 6 h. Subjective VAS responses were summarised as area under the effect–time curve from 0 to 6 h (AUEC6). Repeated-measures ANOVAs tested drug effects and one-way ANOVAs tested genotype group effects on MDMA-induced changes (MDMA minus placebo). Analyses incorporated MDMA plasma AUC6 and, where available, oxytocin change at 2 h as covariates; sex was included in additional models to check confounding. Multiple comparisons were addressed using the Nyholt correction, yielding an effective number of independent variables (Veff) of 28.96 and a corrected significance threshold of p < 0.0017. For rs2254298, AA and AG genotypes were pooled due to the rarity of AA.
Genotyping and sample characteristics matched expected Caucasian allele frequencies (rare allele frequencies: rs53576 A = 35%, rs1042778 T = 38%, rs2254298 A = 11%) and no linkage disequilibrium was detected among the three SNPs. MDMA produced robust subjective, behavioural, and neuroendocrine effects versus placebo across the pooled sample. Subjective effects: MDMA significantly increased AUEC6 on the VASs for "any drug effect" (F1,131 = 544, p < 0.001) and "closeness" (F1,131 = 57, p < 0.001). In the subset with social VASs (n = 53), MDMA increased "trust" (F1,52 = 33, p < 0.001), "want to be hugged" (F1,52 = 6.6, p < 0.05), "want to hug" (F1,52 = 7.6, p < 0.01), and "want to be with others" (F1,52 = 20, p < 0.001), and decreased "want to be alone" (F1,52 = 21, p < 0.001). Regarding OXTR moderation, rs1042778 TT homozygotes showed larger MDMA-induced increases in "trust" (F1,49 = 14, p < 0.001), "want to be hugged" (F1,49 = 5.3, p < 0.05), and "want to be with others" (F1,49 = 6.5, p < 0.05), and a larger reduction in "want to be alone" (F1,49 = 4.5, p < 0.05) compared with G-allele carriers. After Nyholt correction for multiple testing, only the rs1042778 effect on "trust" remained statistically significant. The rs53576 and rs2254298 SNPs did not significantly moderate VAS outcomes in the analysed samples. The rs1042778 effect on trust was observed in a small TT subgroup (reported as n = 5 in one place) versus larger GG/GT groups. Emotion recognition and empathy: On the FERT (n = 69), MDMA impaired recognition accuracy for fearful (F1,68 = 47, p < 0.001), sad (F1,68 = 14, p < 0.001), and angry (F1,68 = 16, p < 0.001) faces versus placebo. None of the three OXTR SNPs moderated these MDMA effects. On the MET (n = 69), MDMA increased explicit emotional empathy for positive stimuli (F1,68 = 7.6, p < 0.01); OXTR variants did not alter MET outcomes. Prosociality (SVO): MDMA produced a trend toward an increased SVO angle (greater prosociality) compared with placebo (F1,68 = 3.1, p = 0.08). MDMA reduced the inequality-aversion index in subjects with a prosocial orientation (F1,32 = 9.3, p < 0.01), indicating a shift toward greater inequality aversion. Some genotype interactions were reported: rs53576 AA subjects showed a larger MDMA-induced reduction in inequality-aversion than G-allele carriers (F1,31 = 9.4, p < 0.01), and rs1042778 GG subjects showed a larger reduction than T-allele carriers (F1,29 = 5.6, p < 0.05). However, these SVO-related genotype effects did not survive correction for multiple comparisons, and the inequality-aversion analyses were limited to a reduced subsample (n = 33). Plasma concentrations: MDMA significantly increased plasma oxytocin at 2 h versus placebo (placebo: 19 ± 39 pg/mL; MDMA: 74 ± 70 pg/mL; F1,99 = 62, p < 0.001). MDMA peak concentration and AUC6 across 132 subjects were 224 ± 48 ng/mL and 950 ± 207 ng×h/mL, respectively. Oxytocin and MDMA plasma concentrations did not differ between OXTR genotype groups. The authors also note evidence of acute tolerance to some subjective MDMA responses over time.
Vizeli and colleagues interpret their principal finding as preliminary evidence that OXTR genetic variation, specifically rs1042778, can modulate some subjective prosocial effects of MDMA, most notably increases in self-reported trust. They note this provides indirect support for a role of oxytocin in MDMA's subjective effects, consistent with animal studies where oxytocin mediates MDMA-induced prosocial behaviour. At the same time, the investigators failed to replicate an earlier report that rs53576 moderates MDMA-induced sociability, and they discuss methodological differences that may explain discrepancies: prior work combined several VAS items into a sociability component and used different MDMA dosing regimens (dose-dependent effects were previously observed). The authors emphasise that several of the genotype-related findings (including those on the SVO inequality-aversion index) did not survive correction for multiple comparisons and were based on small subsamples, limiting confidence. They also highlight that MDMA acts on multiple systems—serotonin, norepinephrine, dopamine, vasopressin, and corticosteroids—and that interactions among these mediators could influence social outcomes. Additional limitations acknowledged include the exploratory nature of the analysis, incomplete ascertainment of all outcome measures across the full cohort (reducing sample sizes for some tests), assessment of only three OXTR SNPs rather than broader haplotypes, and potential cultural or early-life environmental moderators of OXTR effects. The authors therefore urge caution in interpretation and call for replication in larger, well-powered studies. In terms of implications, the investigators suggest that if confirmed, OXTR genotyping might be relevant for understanding individual differences in response to MDMA and could have relevance for MDMA-assisted psychotherapy; they recommend that therapeutic MDMA trials consider genotyping OXTR variants and genes involved in MDMA metabolism.
The study concludes that the OXTR rs1042778 SNP—but not rs53576 or rs2254298—was associated with altered MDMA-induced feelings of trust, while rs53576 effects reported previously could not be replicated. After correction for multiple comparisons, OXTR SNPs did not moderate the overall subjective MDMA effect or feelings of "closeness to others" in the full sample. The authors emphasise that the results are preliminary and should be interpreted cautiously because of multiple comparisons and small genotype subgroup sizes.
Subjective drug effects on the VASs were determined as the area under the effect-time curve from 0 to 6 h (AUEC 6 ) after drug administration using the trapezoidal method in Phoenix WinNonlin (version 6.4, Pharsight, Certara L.P., St. Louis, MO, USA). The statistical analyses were performed using Statistica 12 software (StatSoft, Tulsa, OK, USA). The effects of MDMA on subjective effect ratings and plasma oxytocin concentrations were expressed as differences from placebo. Repeated-measured analyses of variance (ANOVAs), with drug (MDMA vs. placebo) as the within-subjects factor, were used to evaluate drug effects. One-way ANOVAs, with genotype group as the between-subjects factor, followed by the Tukey post hoc test were used to evaluate the effects of genotype on the effects of MDMA (differences from placebo). Additional ANOVAs including plasma concentrations of MDMA and/or oxytocin as covariates were conducted as well as sex differences were included by adding sex as an additional between-subjects factor to the analyses to exclude confounding by any of these variables. This showed that the results were not confounded by oxytocin plasma levels, or sex, or differences in plasma concentrations of MDMA, that corrects for differences in body weight, dosing, or/ and known and unknown activity differences in metabolizing enzymes. The reported results are from analysis with MDMA plasma concentration AUC 6 and oxytocin plasma concentration change at 2 h as covariates with the exception of the VAS "any drug effect" and "closeness to others" for which only MDMA plasma concentration AUC 6 was corrected due to the lack of oxytocin plasma concentration data for subjects from the first two studies. The level of significance was set to p < 0.05. The Nyholt correction method was used to account for multiple comparisons and flagged separately. We thereby corrected for the 7 VASs, 3 emotions in the FERT, emotional empathy in the MET, and 2 items in the SVO which have all been shown sensitive to the effects of MDMA and for each of the 3 tested SNPs ([7+3 +1+2] × 3), resulting in 39 variables and an effective number of independent variables (V eff ) of 28.96 according to Nyholt and a corrected significance threshold to keep Type I error rate at 5% of p < 0.0017. For the analysis of the rs2254298 SNP, the AA and AG genotypes were pooled as A allele carriers because only one subject had the AA genotype.
The main finding of this study was that the OXTR rs1042778 SNP influenced the typical empathogenic and prosocial feelings that are produced by MDMA, including enhancements of "trust". Similar modulation of the prosocial effects of MDMA was previously reported for the OXTR rs53576 SNPbut not rs1042778 SNP. These findings suggest that humans may respond differently to the typical subjective effects of MDMA, depending on their OXTR genetics. The results indirectly indicate a possible role for oxytocin in the subjective effects of MDMA, similar to its interoceptive effects in rats. Animal studies have shown that oxytocin mediates the prosocial effects of MDMA. We observed lower subjective prosociality after MDMA administration in carriers of the G allele of the rs1042778 SNP. Greater prosocialityand lower antisocial behaviorhave been associated with the G allele in the absence of treatment. Our placebo condition was unsuitable for assessing differences in prosociality between subjects in the absence of treatment. Altogether, however, the findings are consistent with the notion that subjects with lower sociality may respond more to the prosocial effects of MDMA or oxytocin. In the present study, we failed to replicate a previous finding of moderation of the subjective prosocial effects of MDMA by the rs53576 SNP. This previous study showed that carriers of the AA genotype at the rs53576 locus were not susceptible to the prosocial effect of 1.5 mg/ kg MDMA. However, this previous study assessed "sociability" as a combined outcome of several VASs, including "friendly," "sociable," "confident," "playful," and "loving" using principal component analysis. Additionally, the effect of rs53576 was observed only at a dose of 1.5 mg/kg MDMA, whereas opposite effects were observed with 0.75 mg/kg MDMA. The discrepant findings between these two studies may be partially explained by the different scales that were used. The findings may also indicate that the MDMA effect modulation by different OXTR SNPs is not very robust across studies and rather small. The effects of MDMA on the FERT and MET in the present study were consistent with studies by other researchers who used the same tests. The present study found that the rs53576, rs1042778, and rs2254298 SNPs did not influence MDMA-induced impairments in the recognition of fearful, sad, and angry faces or increases in emotional empathy. No other data are available on the effects of other OXTR gene variants on MDMA-induced changes in tests of emotion processing or empathy. In contrast to the present study, the effect of intranasal oxytocin on dynamic face recognition has previously been shown to be modulated by OXTR SNP haplotypes, including the SNPs that were studied herein. On the SVO test, MDMA produced a trend toward an increase in prosocial behavior and increased inequality aversion. We previously reported a significant increase in prosociality and a trend toward an increase in inequality aversion from a subset of the present data. A novel finding of the present study was that MDMA increased inequality-aversion and thus a preference for fairness only in subjects with the rs53576 AA or rs1042778 GG genotypes, indicating a role for these OXTR gene variants in MDMA's effect on social behavior. However, the MDMA-induced increase in preference for fairness in rs1042778 GG subjects appears to conflict with the smaller increase in trust in these subjects (S1 Table ). Additionally, rs1042778 GG individuals presented lower inequality aversion compared with T allele carriers who received placebo. Higher prosociality on the SVO test has previously been reported in G allele carriers, but differences in the inequality-aversion index were not studied because this scale was only added later to the SVO test. Furthermore, the OXTR rs1042778, rs53576, and rs2254298 SNPs had no effects in two other economic games (i.e., dictator game and trust game;). The findings in the SVO tests are conclusive but need to be interpreted with caution, since they did not survive the correction for multiple comparisons and the total number of subjects in this subset was reduced to 33 due to the limiting calculation of the inequality aversion. The present study has several limitations. First, the study was mostly exploratory and the findings would need to be confirmed in larger studies. Second, not all outcome measures were used in all of the subjects, thus limiting the sample size and also increasing the risk of Type I errors. Third, we tested only three OXTR SNPs. Other SNPs or haplotypes may also play a role. Fourth, MDMA causes the release of oxytocin, monoamines, and arginine vasopressin. The latter two are well known to influence social cognition and behavior. MDMA also increases cortisol and other corticosteroidsand oxytocin and cortisol may interact to influence the response to MDMA and these interactions need further study. Finally, cultural and early environmental background plays an uncertain role in the results of genetic studies, especially studies of OXTRs. For example, studies of the rs2254298 SNP reported different results in Caucasian and Asian subjects. The present findings of individual differences in the response to MDMA that depended on OXTR genetics need to be confirmed and might have implications for MDMA-assisted psychotherapyand may contribute to more personalized treatment. Therapeutic studies that use MDMA in patients should genotype OXTR SNPs and test for polymorphisms of the genes that regulate the metabolism of MDMA.
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