Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects
In a randomised placebo‑controlled crossover study, MDMA (125 mg) significantly raised plasma copeptin—a stable surrogate for AVP—in women but not men, with a nonsignificant AVP rise and evidence of increased renal water retention. These effects were blocked by duloxetine, implicating MDMA‑induced serotonin and noradrenaline release in the sex‑specific AVP/copeptin response and offering a mechanism for the higher incidence of hyponatraemia in female ecstasy users.
Authors
- Matthias Liechti
- Cédric Hysek
Published
Abstract
Background
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) misuse is associated with hyponatremia particularly in women. Hyponatremia is possibly due to inappropriate secretion of plasma arginine vasopressin (AVP).
Objective
To assess whether MDMA increases plasma AVP and copeptin in healthy male and female subjects and whether effects depend on MDMA-induced release of serotonin and norepinephrine. Copeptin, the C-terminal part of the AVP precursor preprovasopressin, is cosecreted with AVP and can be determined more reliably.
Methods
We used a randomized placebo-controlled crossover design. Plasma and urine osmolalities as well as AVP and copeptin levels were measured in 16 healthy subjects (eight female, eight male) at baseline and after MDMA (125 mg) administration. In addition, we tested whether effects of MDMA on AVP and copeptin secretion can be prevented by pretreatment with the serotonin and norepinephrine transporter inhibitor duloxetine (120 mg), which blocks MDMA-induced transporter-mediated release of serotonin and norepinephrine.
Results
MDMA significantly elevated plasma copeptin levels at 60 min and at 120 min compared with placebo in women but not in men. The copeptin response to MDMA in women was prevented by duloxetine. MDMA also nonsignificantly increased plasma AVP levels in women, and the effect was prevented by duloxetine. Although subjects drank more water after MDMA compared with placebo administration, MDMA tended to increase urine sodium levels and urine osmolality compared with placebo, indicating increased renal water retention.
Conclusion
MDMA increased plasma copeptin, a marker for AVP secretion, in women but not in men. This sex difference in MDMA-induced AVP secretion may explain why hyponatremia is typically reported in female ecstasy users. The copeptin response to MDMA is likely mediated via MDMA-induced release of serotonin and/or norepinephrine because it was prevented by duloxetine, which blocks the interaction of MDMA with the serotonergic and noradrenergic system.
Research Summary of 'Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects'
Introduction
Abuse of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been linked to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and symptomatic hyponatraemia, with most clinical reports describing affected individuals as female. Case series and poison-centre data indicate a disproportionate number of women among ecstasy-associated hyponatraemia cases, and a small non-blinded laboratory study in eight men reported MDMA-induced increases in plasma arginine vasopressin (AVP). AVP measurement is technically challenging, so copeptin — the stable C-terminal fragment of the AVP precursor that is released in equimolar amounts and easier to assay — can serve as a surrogate marker of AVP secretion. Serotonergic and noradrenergic systems regulate AVP release, and MDMA produces transporter-mediated release of both monoamines, a process that can be blocked by serotonin–norepinephrine transporter inhibitors such as duloxetine. Simmler and colleagues set out to determine whether MDMA administration increases AVP and copeptin in healthy male and female subjects and whether pretreatment with duloxetine (to block MDMA-induced monoamine release) would prevent any such effect. The primary hypothesis was that MDMA would raise AVP and copeptin, particularly in women, and that duloxetine would attenuate or abolish this response.
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Study Details
- Study Typeindividual
- Journal
- Compound
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- APA Citation
Simmler, L. D., Hysek, C. M., & Liechti, M. E. (2011). Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects. The Journal of Clinical Endocrinology & Metabolism, 96(9), 2844-2850. https://doi.org/10.1210/jc.2011-1143
References (1)
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