Endocrine Abstracts

Importance: 3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a trending recreational drug but also has potential to enter clinical practice. Acute hyponatremia is a serious complication arising from ingesting even a single dose of MDMA. The assumed aetiology is a vasopressin release inducing the syndrome of inappropriate anti-diuresis combined with increased thirst causing polydipsia and thus water intoxication.

Methods: Pooled analysis of experimental MDMA-sessions of four placebo-controlled cross-over trials in 96 healthy participants conducted at the University Hospital Basel, Switzerland. The aim was to investigate the incidence and severity of hyponatremia after a single dose of MDMA, underlying mechanisms of action, and potential effect of fluid restriction on lowering the risk of hyponatremia. Single oral dose of 100 or 125 mg MDMA. 81 participants were not restricted to fluid intake, while in 15 participants, fluid intake was controlled. Plasma oxytocin, copeptin (surrogate marker of vasopressin), and sodium were measured repeatedly within 360 minutes after drug intake.

Results: At baseline, the mean (SD) sodium level was 140 mmol/l (±3) and decreased in response to MDMA by 3 mmol/l (±3), leading to hyponatremia in 31%(n=33/96) of the participants. Among hyponatraemic participants, the mean sodium level was 133 mmol (±2). In participants not restricted to fluid intake, at baseline, the plasma sodium was 140 mmol/l (±3) and decreased in response to MDMA by 4 mmol/l (±3), leading to hyponatremia in 41% (n=33/81). In contrast, in participants restricted to fluid intake, at baseline, the plasma sodium was 141 mmol/l (±1) and decreased only slightly in response to MDMA by 1 mmol/l (±2), leading to no hyponatremia (n=0/15), suggesting that fluid restriction significantly prevented hyponatremia (P=0.002). At baseline, plasma oxytocin was 87 pg/ml (±45) and increased in response to MDMA by 474 pg/ml (±309). At baseline, plasma copeptin was 4.9 pmol/l (±3.8) and only slightly decreased in response to MDMA by 0.3 pmol/l (±1.1). The decrease in sodium levels was significantly correlated with the increase in oxytocin (r=-0.4; P<0.001), while no correlation was observed between the change in sodium and copeptin (r=-0.1; P=0.220).

Conclusion: We report a high incidence of acute and mainly mild hyponatremia in response to MDMA, which can effectively be prevented by fluid restriction. Hyponatremia is associated with acute strong oxytocin but not copeptin release - this challenges the current hypothesis of direct vasopressin release and rather indicates that the increase in oxytocin mimics the effect of vasopressin in the kidneys due to close structural homology.