Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia: A Secondary Analysis of 4 Randomized Clinical Trials.

Importance: 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) is a recreational drug being investigated for the treatment of posttraumatic stress disorder. Acute hyponatremia is a potentially serious complication after even a single dose of MDMA. The assumed etiology has been a vasopressin release inducing the syndrome of inappropriate antidiuresis combined with increased thirst, causing polydipsia and water intoxication.

Objective: To investigate the incidence and severity of hyponatremia after a single dose of MDMA, underlying neuroendocrine mechanisms of action, and the potential effect of fluid restriction on lowering the incidence of hyponatremia.

Design, setting, and participants: This ad hoc secondary analysis pooled data from 4 placebo-controlled crossover randomized clinical trials conducted at the University Hospital Basel, Basel, Switzerland. The 96 participants received experimental doses of MDMA between March 1, 2017, and August 31, 2022.

Intervention: A single oral 100- or 125-mg dose of MDMA. Fluid intake was not restricted in 81 participants; it was restricted in 15.

Main outcomes and measures: Plasma oxytocin, copeptin (marker of vasopressin), and sodium levels were measured repeatedly within 360 minutes after MDMA intake. The association of plasma oxytocin or copeptin levels with plasma sodium level at 180 minutes (peak concentration of MDMA) was determined.

Results: Among the 96 participants, the mean (SD) age was 29 (7) years, and 62 (65%) were men. A total of 39 participants (41%) received a 100-mg dose of MDMA, and 57 (59%) received a 125-mg dose. At baseline, the mean (SD) plasma sodium level was 140 (3) mEq/L and decreased in response to MDMA by 3 (3) mEq/L. Hyponatremia occurred in 30 participants (31%) with a mean (SD) sodium level of 133 (2) mEq/L. In 15 participants with restricted fluid intake, no hyponatremia occurred, while in the 81 participants with unrestricted fluid intake, hyponatremia occurred in 30 (37%) (P = .002) with a difference in plasma sodium of 4 (95% CI, 2-5) mEq/L (P < .001) between both groups, suggesting that fluid restriction may mitigate the risk of hyponatremia. At baseline, the mean (SD) plasma oxytocin level was 87 (45) pg/mL and increased in response to MDMA by 388 (297) pg/mL (ie, a mean [SD] 433% [431%] increase at 180 minutes), while the mean (SD) copeptin level was 4.9 (3.8) pmol/L and slightly decreased, by 0.8 (3.0) pmol/L. Change in plasma sodium level from baseline to 180 minutes demonstrated a negative correlation with the changes in oxytocin (R = -0.4; P < .001) and MDMA (R = -0.4; P < .001) levels while showing no correlation with the change in copeptin level.

Conclusions and relevance: In this secondary analysis of 4 randomized clinical trials, a high incidence of acute hyponatremia was observed in response to MDMA, which may be mitigated by fluid restriction. Hyponatremia was associated with acute oxytocin but not copeptin release. This challenges the current hypothesis of direct vasopressin release and rather indicates that oxytocin mimics the effect of vasopressin in the kidneys due to structural homology.