Fluid restriction effectively prevented 3,4-methylenedioxymethamphetamine-induced hyponatremia, according to an analysis of four randomized, placebo-controlled trials. The study also implicated oxytocin, rather than vasopressin, as a potential mediator.

The analysis included 96 healthy adults (mean age, 29 years; 65% male) who received a single oral dose of 100 or 125 mg of 3,4-methylenedioxymethamphetamine (MDMA) between 2017 and 2022. Among 81 participants with unrestricted fluid intake, 31% developed hyponatremia (plasma sodium <135 mEq/L), with sodium levels decreasing by a mean of 4 mEq/L. No cases of hyponatremia occurred in the 15 participants with restricted fluid intake, who consumed a maximum of 250 mL of intravenous saline (P = .002). The difference in sodium reduction between groups was 4 mEq/L (95% CI, 2-5; P < .001).

Mechanistically, plasma oxytocin levels increased by 433% on average, from 87 pg/mL at baseline to 474 pg/mL, and negatively correlated with plasma sodium levels (R = −0.4; P < .001). Copeptin, a vasopressin surrogate, showed no significant changes, challenging the hypothesis that vasopressin drives hyponatremia. The findings suggested that oxytocin mimicked vasopressin’s antidiuretic effects on the kidneys due to structural similarities.

The study, conducted at the University Hospital Basel and published in JAMA Network Open, emphasized monitoring fluid intake to mitigate risks associated with MDMA. Limitations included the small size of the fluid-restricted group and the absence of urinalysis for SIAD patterns. These results may be relevant to both recreational MDMA use and therapeutic settings, such as MDMA-assisted psychotherapy for posttraumatic stress disorder.

Full disclosures can be found in the published analysis.