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Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release
J K Fallon1, D Shah, A T Kicman
1Drug Control Centre and Department of Pharmacy, King's College London, Franklin-Wilkins Building, London SE1 9NN, UK.
Abstract:
3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause hyponatraemia, which appears to result from inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). After administration of a low dose of (R,S)-MDMA (40 mg) to eight healthy drug-free male volunteers, concentrations of AVP in plasma increased significantly at 1, 2, and 4 hours. Although no relation between plasma MDMA and AVP was found on an examination of the entire data set over the 24-hour study period, a statistically significant negative correlation was observed at 1 hour. As this occurred at a time when both AVP and MDMA concentrations were rising, it was postulated that a metabolite, or metabolites, could primarily be responsible for the increase in AVP. To test this hypothesis we examined the effect of MDMA and five of its metabolites, in the dose range 0.1-1,000 nM, on AVP release from the isolated rat hypothalamus. All compounds tested were found to increase AVP release (using 10 nM and 1,000 nM concentrations), with 4-hydroxy-3-methoxymethamphetamine (HMMA), the major metabolite of MDMA, being the most potent, and 3,4-dihydroxymethamphetamine (DHMA) the least potent. Each compound (1,000 nM), with the exception of DHMA, also enhanced the response to 40-mM potassium stimulation. Our findings confirm that metabolites of MDMA, in addition to the parent drug, contribute to AVP secretion in vitro. Further work will demonstrate whether this is also true in vivo.
Insights
MDMA metabolites, not just the parent drug, increase arginine vasopressin (AVP) secretion. This finding helps explain how MDMA causes hyponatremia and provides targets for future research.
Area of Science:
- Pharmacology
- Endocrinology
- Neuroscience
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA) is linked to hyponatremia, potentially due to inappropriate arginine vasopressin (AVP) secretion.
- Previous studies suggest a connection between MDMA administration and increased plasma AVP levels in humans.
Purpose of the Study:
- To investigate the role of MDMA metabolites in AVP release.
- To determine if MDMA metabolites contribute to MDMA-induced hyponatremia.
Main Methods:
- In vivo study: Healthy male volunteers received a low dose of (R,S)-MDMA, with plasma AVP and MDMA levels monitored over 24 hours.
- In vitro study: The effect of MDMA and its metabolites on AVP release from isolated rat hypothalamus was examined at various concentrations.
- Potassium-stimulated AVP release was also assessed in the presence of MDMA and its metabolites.
Main Results:
- In vivo, plasma AVP levels increased significantly post-MDMA administration, with a notable negative correlation at 1 hour.
- In vitro, all tested MDMA metabolites increased AVP release, with 4-hydroxy-3-methoxymethamphetamine (HMMA) being the most potent.
- Most metabolites also enhanced potassium-stimulated AVP release, indicating a direct effect on the secretory mechanism.
Conclusions:
- MDMA metabolites, alongside the parent drug, contribute to arginine vasopressin (AVP) secretion.
- These findings support the hypothesis that MDMA metabolites play a significant role in the drug's association with hyponatremia.
- Further in vivo studies are warranted to confirm these in vitro observations.
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