Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects

Abuse of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been linked to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and symptomatic hyponatraemia, with most clinical reports describing affected individuals as female. Case series and poison-centre data indicate a disproportionate number of women among ecstasy-associated hyponatraemia cases, and a small non-blinded laboratory study in eight men reported MDMA-induced increases in plasma arginine vasopressin (AVP). AVP measurement is technically challenging, so copeptin — the stable C-terminal fragment of the AVP precursor that is released in equimolar amounts and easier to assay — can serve as a surrogate marker of AVP secretion. Serotonergic and noradrenergic systems regulate AVP release, and MDMA produces transporter-mediated release of both monoamines, a process that can be blocked by serotonin–norepinephrine transporter inhibitors such as duloxetine. Simmler and colleagues set out to determine whether MDMA administration increases AVP and copeptin in healthy male and female subjects and whether pretreatment with duloxetine (to block MDMA-induced monoamine release) would prevent any such effect. The primary hypothesis was that MDMA would raise AVP and copeptin, particularly in women, and that duloxetine would attenuate or abolish this response.

The investigators used a randomized, placebo-controlled, crossover design with four treatment conditions in balanced order: placebo–placebo, duloxetine–placebo, placebo–MDMA, and duloxetine–MDMA. Washout periods between sessions were 10–14 days. Duloxetine (120 mg total, given as two 60 mg doses) or matched placebo was administered twice, at 16 and 4 hours before MDMA (125 mg) or placebo. MDMA was given as a single absolute oral dose of 125 mg in gelatin capsules. Because dosing was absolute rather than weight-adjusted, the resulting relative MDMA doses were higher in women than men (men: 1.6 ± 0.23 mg/kg, range 1.4–2.1 mg/kg; women: 2.1 ± 0.25 mg/kg, range 1.8–2.5 mg/kg). Sixteen healthy volunteers (eight women, eight men) participated. Mean ages were 29.0 ± 7.1 years for women and 23.3 ± 3.1 years for men; mean body weight was 59.0 ± 6.9 kg for women and 79.5 ± 9.8 kg for men. Female subjects were studied during the follicular phase (days 2–14) to reduce menstrual-phase effects on amphetamine reactivity and osmotic sensitivity. Exclusion criteria included age <18 or >45 years, pregnancy, BMI <18.5 or >25 kg/m2, personal or first-degree family history of psychiatric disorder, regular medication use, acute or chronic illness, smoking, lifetime illicit drug use >5 times (except THC), recent illicit drug use within 2 months, and positive urine drug screens on test days. Subjects rested in hospital beds in a temperature-controlled environment and received a small standardised breakfast at the start of each session. Fluid intake was ad libitum up to 2000 ml during the session and was recorded from 4 hours before to 120 minutes after MDMA/placebo administration. An intravenous saline infusion (100 ml/h) was run from 0 to 120 minutes to keep blood-draw catheters patent. Plasma copeptin was measured at baseline (4 h before) and at 60 and 120 minutes after MDMA/placebo; AVP was measured at baseline and 120 minutes. Plasma and urine osmolality and sodium were measured 4 hours before and 120 minutes after MDMA/placebo. Assays were performed in duplicate in a blinded single batch: AVP by radioimmunoassay (lower limit 0.82 pmol/l, intraassay precision 6.0%) and copeptin by immunoassay (lower limit 0.4 pmol/l, intraassay CV <5%). For statistical analysis, repeated-measures ANOVA was used with factors drug (four-level) and time (baseline, 60, 120 min), stratified by sex and followed by Tukey pairwise post hoc tests. Non-normally distributed variables were log-transformed before ANOVA. Correlations used Spearman rank coefficients across all available values (n = 128). All tests were two-tailed with significance set at P = 0.05.

ANOVA revealed a significant three-way interaction of drug × time × sex on plasma copeptin levels [F(6,84) = 3.93; P = 0.0017]. In women, MDMA (125 mg) produced significant elevations in plasma copeptin at 60 minutes (P < 0.001) and at 120 minutes (P < 0.01) compared with placebo. In men, copeptin was not significantly altered by MDMA. Pretreatment with duloxetine prevented the MDMA-induced copeptin increase in women at both 60 minutes (P < 0.001) and 120 minutes (P < 0.01). AVP showed a similar directional trend in women after MDMA, but the drug effects on AVP did not reach statistical significance in the extracted text. Oral fluid intake differed across treatment conditions (main effect of drug: F(3,42) = 8.62; P < 0.001) but did not differ by sex (no drug × sex interaction). Mean (± SEM) oral intake from 4 h before to 120 min after administration was 612 ± 50 ml after placebo–placebo, 1267 ± 118 ml after duloxetine–placebo (P < 0.001 vs placebo–placebo), 1198 ± 130 ml after placebo–MDMA (P = 0.001 vs placebo–placebo), and 807 ± 83 ml after duloxetine–MDMA (P = 0.02 vs duloxetine–placebo and P = 0.051 vs placebo–MDMA). Urine osmolality decreased significantly over time [main effect of time: F(1,14) = 62.69; P < 0.001]. There was a near-significant drug × time interaction for urine osmolality [F(3,42) = 2.70; P = 0.058], with urine osmolality tending to be higher after placebo–MDMA or duloxetine–MDMA than after placebo–placebo or duloxetine–placebo. A similar near-significant trend was seen for urine sodium [drug × time interaction: F(3,42) = 2.33; P = 0.088]. There were no significant drug effects on plasma sodium concentrations or plasma osmolality. Circulating copeptin correlated with AVP (all subjects: rs = 0.34, P < 0.001; women: rs = 0.53, P < 0.001; men: rs = 0.28, P < 0.05). Copeptin also correlated with plasma and urine osmolality (rs = 0.22, P < 0.05; and rs = 0.68, P < 0.001, respectively). The extracted text reports additional correlations with plasma and urine sodium but the numeric values are incomplete in the extraction and cannot be reliably quoted here.

Simmler and colleagues interpret the findings as evidence that MDMA activates the AVP system in women but not in men, based on the observed rises in circulating copeptin in female subjects. They note this sex difference aligns with clinical observations that ecstasy-associated hyponatraemia occurs predominantly in women and with other reported sex differences in responses to MDMA. The prevention of the copeptin response by duloxetine suggests that MDMA-induced AVP (copeptin) secretion is mediated, at least in part, by transporter-mediated release of serotonin and norepinephrine. This interpretation is consistent with preclinical data implicating central serotonergic and noradrenergic pathways in AVP regulation and with clinical associations between serotonergic medications and SIADH. The authors further point out that copeptin and AVP are stress-related hypothalamic hormones and that MDMA also activates other neuroendocrine axes (for example, increases in corticotropin and cortisol), which could interact with fluid and electrolyte balance. The investigators acknowledge several limitations. The sample size was small (n = 16), and only single doses of MDMA and duloxetine were tested. MDMA was administered as an identical absolute dose to all participants, producing higher mg/kg exposures in women; although the authors report no correlation between relative dose and copeptin response within each sex, they concede they cannot fully exclude a dose-contribution to the sex difference. Differences in fluid intake across treatment conditions may have counteracted or modulated MDMA effects on AVP secretion. Baseline urine osmolality and AVP-related activation were higher in men at study start, which could have influenced differential responses. The authors also discuss discrepancies with a prior study that found AVP increases after a lower MDMA dose in men, attributing differences to experimental context (free fluid intake, physical activity, resting conditions) and study design. Overall, the authors conclude that MDMA increases copeptin, a marker of AVP secretion, in women but not men under the study conditions, and that this effect is likely mediated by MDMA-induced release of serotonin and norepinephrine. They suggest this mechanism may contribute to the higher incidence and severity of ecstasy-associated hyponatraemia reported in women, while noting that multiple personal and environmental factors also influence risk.