Oxytocin and fluid restriction may mitigate MDMA-Induced life threatening Hyponatremia: JAMA

A significant incidence of acute hyponatremia was observed following MDMA use, with fluid restriction potentially helping to mitigate this condition. The study, published in JAMA Network Open, found that hyponatremia was linked to elevated oxytocin levels rather than copeptin, challenging the existing theory that vasopressin release directly causes hyponatremia. Instead, the findings suggest that oxytocin, due to its structural similarity to vasopressin, may mimic its effects on the kidneys, contributing to water retention and the development of hyponatremia.

MDMA, commonly known as ecstasy, is a popular recreational drug that can lead to a range of physiological responses, including a sharp drop in sodium levels, known as hyponatremia. This condition can be life-threatening if left unaddressed, particularly due to its association with water retention and altered kidney function. The presumed cause has been the release of vasopressin, which triggers the syndrome of inappropriate antidiuresis, coupled with increased thirst, leading to polydipsia and water intoxication.

Against the above background, Cihan Atila, Department of Clinical Research, University of Basel, University Hospital Basel, Basel, Switzerland, and colleagues examined the occurrence and severity of hyponatremia following a single dose of MDMA, explored the underlying neuroendocrine mechanisms at play, and assess the potential impact of fluid restriction in reducing the incidence of hyponatremia.

For this purpose, the researchers conducted a secondary analysis using data from four placebo-controlled crossover randomized clinical trials at the University Hospital Basel in Switzerland, involving 96 participants who received experimental doses of MDMA between March 1, 2017, and August 31, 2022. Participants were given a single oral dose of 100 or 125 mg of MDMA, with 81 not having fluid intake restricted and 15 having their fluid intake restricted.

The main outcomes measured were plasma oxytocin, copeptin (a marker of vasopressin), and sodium levels, which were taken at multiple intervals within 360 minutes after MDMA intake. The researchers specifically examined the relationship between plasma oxytocin or copeptin levels and plasma sodium levels at 180 minutes, which corresponded to the peak MDMA concentration.

The key findings are as follows:

• The study involved 96 participants with a mean age of 29 years, 65% of whom were men.
• 41% of participants received a 100-mg dose of MDMA, and 59% received a 125-mg dose.
• At baseline, the mean plasma sodium level was 140 mEq/L, which decreased by 3 mEq/L after MDMA administration.
• Hyponatremia occurred in 31% of participants, with a mean sodium level of 133 mEq/L.
• Among 15 participants with restricted fluid intake, there were no cases of hyponatremia. In contrast, 37% participants developed hyponatremia among 81 participants with unrestricted fluid intake.
• Fluid restriction was associated with a significant difference in plasma sodium levels (4 mEq/L), suggesting it may reduce the risk of hyponatremia.
• At baseline, the mean plasma oxytocin level was 87 pg/mL, which increased by 388 pg/mL (a 433% increase) 180 minutes after MDMA intake.
• The mean copeptin level at baseline was 4.9 pmol/L, showing a slight decrease of 0.8 pmol/L after MDMA intake.
• Changes in plasma sodium levels correlated negatively with changes in oxytocin (R = -0.4) and MDMA (R = -0.4), but no correlation was found with changes in copeptin levels.

This secondary analysis of four randomized clinical trials revealed a high incidence of acute hyponatremia following MDMA administration, which could potentially be reduced through fluid restriction.

"The results suggest that oxytocin, rather than vasopressin, may play a key role in mediating the hyponatremic response to a single dose of MDMA. Additionally, fluid restriction appears to help mitigate this risk," the researchers concluded.

Reference:

Atila C, Straumann I, Vizeli P, et al. Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia: A Secondary Analysis of 4 Randomized Clinical Trials. JAMA Netw Open. 2024;7(11):e2445278.

doi:10.1001/jamanetworkopen.2024.45278