This reanalysis of four RCTs (n=96) finds that MDMA (100mg or 125mg) induced hyponatremia in 31% of participants, with none occurring in the fluid-restricted group (n=15) compared to 37% in the unrestricted group (n=81). The study challenges previous understanding by showing hyponatremia correlates with increased oxytocin (433% increase) rather than vasopressin levels, suggesting oxytocin mimics vasopressin’s effects in the kidneys.
Abstract of Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia
“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.”
Authors: Cihan Atila, Isabelle Straumann, Patrick Vizeli, Julia Beck, Sophie Monnerat, Friederike Holze, Matthias E. Liechti & Mirjam Christ-Crain
Summary of Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia
MDMA, commonly known as “ecstasy”, is both a recreational drug and a substance being investigated for treating post-traumatic stress disorder. One of its potentially serious complications is acute hyponatraemia (abnormally low blood sodium levels), which can occur even after a single dose. Hyponatraemia develops when the body cannot properly excrete ingested water, leading to an imbalance between total body water and sodium ions.
The mechanisms behind MDMA-induced hyponatraemia have remained largely theoretical. The prevailing hypothesis suggested that MDMA’s structural similarity to serotonin increases hypothalamic serotonin and dopamine, triggering vasopressin release from the posterior pituitary gland. This leads to the syndrome of inappropriate antidiuresis (SIAD), combined with increased thirst, resulting in excessive water intake and dilution of blood sodium. Additional factors like hyperpyrexia (elevated body temperature), dry mouth, and physical activity in warm, crowded environments may exacerbate the condition.
Methods
Study Design
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https://doi.org/10.1001/jamanetworkopen.2024.45278
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Cite this paper (APA)
Atila, C., Straumann, I., Vizeli, P., Beck, J., Monnerat, S., Holze, F., ... & Christ-Crain, M. (2024). Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia: A Secondary Analysis of 4 Randomized Clinical Trials. JAMA Network Open, 7(11), e2445278-e2445278.
Institutes
Institutes associated with this publication
University of BaselThe University of Basel Department of Biomedicine hosts the Liechti Lab research group, headed by Matthias Liechti.
Compound Details
The psychedelics given at which dose and how many times
MDMA 100 - 125mg | 1x
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