Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration

Dumont and colleagues introduce MDMA (ecstasy) as a recreational ‘‘club’’ drug notable for producing increased empathy, friendliness and other prosocial effects. The neurobiological mechanisms underlying these social effects are not well understood, but oxytocin—a hypothalamic neuropeptide known to facilitate affiliative behaviour in animals and humans—has been proposed as a plausible mediator. Animal studies have shown that MDMA elevates oxytocin and that blocking oxytocin receptors or 5-HT1A signalling can attenuate MDMA-induced sociability, but evidence in humans has been limited and confounded by naturalistic designs. This study therefore set out to test whether MDMA induces oxytocin release in healthy human volunteers and whether changes in peripheral oxytocin relate to subjective prosocial feelings. To address gaps in earlier observational work, the investigators used a randomized, double-blind, placebo-controlled, cross-over design to measure blood oxytocin and MDMA concentrations alongside self-reported amicability and gregariousness after a single oral dose of MDMA or placebo.

The study employed a double-blind, randomised, cross-over, placebo-controlled design. Fifteen healthy regular ecstasy users (12 male, 3 female) aged 18–24 years participated; the extracted text reports mean age 21.19 (SD 1.7). Each participant attended two study days separated by a 7-day washout and received either 100 mg oral MDMA or matched placebo on each day. Drug use was prohibited 14 days prior to the first study day, and urine drug screens were performed on each study day. One participant failed to abstain after the first session and was denied further participation; data from that first (MDMA) day were included. Two subjects experienced brief mild anxiety after MDMA, leading to partially missing data. Blood sampling was performed via an indwelling catheter. Oxytocin samples were taken at baseline and at 300 minutes post-dose, with processing on ice and centrifugation within 30 minutes; the investigators used an area under the curve (AUC) approach derived from the available time points to estimate total oxytocin release. MDMA plasma concentrations were sampled at baseline and at 15, 60, 105, 150, 240 and 300 minutes post-dose. MDMA was assayed by HPLC with diode-array detection, and oxytocin was measured in serum after C18 prepurification using an in-house radioimmunoassay; the extracted text reports assay performance metrics (within- and between-assay CVs of 2.2% and 6.6% at 7.2 pmol/l, analytical range 1–90 pmol/l, sensitivity 1 pmol/l). Plasma samples were stored frozen (the extraction indicates storage at very low temperature). Subjective prosocial effects were assessed with two items from the Bond and Lader Visual Analogue Mood Rating Scale that map to prosocial dimensions (antagonistic/amicable and withdrawn/gregarious) at baseline and at the same post-dose time points used for MDMA sampling. For statistical analysis the investigators used a mixed-model analysis of variance (drug and time as fixed factors, subject as a random factor) for subjective measures. Because of limited sample size and varying variance across time points, oxytocin analyses used AUC compared by paired t-test. The relationship between subjective ratings and biomarker concentrations was examined via a summary-statistics approach: correlations were computed for each subject between subjective scores and biomarker levels across matched time points, with group-level testing using Wilcoxon signed-rank tests to assess whether correlations differed from zero and whether correlations with oxytocin differed from those with MDMA.

Fifteen subjects completed study procedures with the MDMA condition included for the subject who later failed to abstain. Plasma MDMA kinetics, as reported in the extracted text, showed a mean maximum concentration (Cmax) of 222.7 mg/l (SEM 9.8 mg/l) at 105 minutes post-administration and a modest decline to a mean of 174.6 mg/l (SEM 10.3 mg/l) at 300 minutes. MDMA produced a marked increase in peripheral oxytocin compared with placebo when oxytocin AUC was analysed: AUC values were significantly greater in the MDMA condition, t(12) = 4.27, p = 0.001. Mean plasma oxytocin rose from a baseline average of 0.8 pmol/l (SEM 0.3) to an average maximum of 34.3 pmol/l (SEM 7.2) at about 110 minutes post-dose, declining to ~4.0 pmol/l (SEM 0.8) by 300 minutes. No treatment-order effects were reported. On subjective measures, amicability showed a significant main effect of treatment, F(1,165) = 9.7, p = 0.002, while gregariousness showed a significant main effect of time, F(6,162) = 2.6, p = 0.018. Both measures exhibited significant treatment-by-time interactions (amicability: F(6,164) = 3.5, p = 0.003; gregariousness: F(6,162) = 4.0, p < 0.001), indicating that MDMA altered the time course of prosocial feelings compared with placebo. Correlation analyses (median correlations across subjects) showed that subjective amicability correlated positively with oxytocin (median r = 0.37, p = 0.001) and with MDMA concentrations (median r = 0.23, p = 0.049). Subjective gregariousness correlated positively with oxytocin (median r = 0.29, p = 0.049) but not with MDMA (median correlation reported as 0). Wilcoxon signed-rank tests indicated that, for both amicability and gregariousness, correlations with oxytocin were significantly stronger than correlations with MDMA (p = 0.013 and p = 0.030 respectively). Adverse effects were limited: two participants experienced mild, transient anxiety resolving within 60 minutes. No other safety events are described in the extracted text.

Dumont and colleagues interpret the findings as evidence that MDMA robustly increases peripheral oxytocin and subjective prosocial feelings in healthy human volunteers, and that the temporal association between prosocial ratings and oxytocin is stronger than that between prosocial ratings and plasma MDMA. They suggest that these results are consistent with animal studies that linked MDMA, oxytocin release and increased social interaction, and with mechanistic work implicating 5-HT1A-mediated oxytocin release and downstream effects such as amygdala attenuation that could reduce social anxiety. The investigators acknowledge several important limitations. First, oxytocin was measured peripherally in blood rather than in cerebrospinal fluid; the relationship between peripheral and central oxytocin release is not clearly defined and may explain some timing differences noted between subjective peak effects (around 60 minutes) and peak plasma oxytocin (around 110 minutes). Second, prosocial effects were assessed by self-report; the authors recommend objective behavioural measures (for example economic games) in future studies to verify that perceived increases in friendliness translate into overt social behaviour. Third, to reduce variability future work should consider dosing by body weight rather than using a fixed dose and should sample oxytocin more frequently between about 20 and 95 minutes to characterise onset. Finally, although the pattern of associations is suggestive, the present design cannot establish that oxytocin mediates MDMA’s prosocial effects; this would require interaction studies using an oxytocin receptor antagonist (the authors cite atosiban as an example), noting that practical issues around blocking oxytocin receptors would need to be addressed. In conclusion, the authors present these results as tentative support for oxytocin’s involvement in MDMA’s characteristic prosocial effects and suggest that oxytocin-related mechanisms may be relevant to disorders with impaired social functioning, while emphasising the need for further mechanistic and behavioural confirmation.