John K. Fallon

Low-dose MDMA (“ecstasy”) induces vasopressin secretion

p=0·025, one tail). Mean initial cortisol concentration was 331·4 nmol/L (range 208·8–603·4 nmol/L), which increased, although not significantly (p>0·05), to 377·2 nmol/L (range 268·4–583·3 nmol/L) at 2 h. Street “ecstasy” frequently contains more than 100 mg of MDMA. In this study, a single relatively small dose caused an acute rise in AVP concentration at a time of day when it would not be expected to change. The rise in AVP was accompanied by a small fall in plasma sodium concentrations. The hyponatraemic illness experienced by some users is thus likely to be linked to the drug’s ability to stimulate secretion of AVP. Hence, if fluid intake is excessive, even a relatively small dose of MDMA could lead to symptoms of hyponatraemia. The rise in AVP does not seem to be part of a generalised stress response because there was no significant change in plasma cortisol concentration. It therefore seems that MDMA-induced hyponatraemia is unlikely to be due to a rare and idiosyncratic reaction, but results from a pharmacological effect compounded by excessive fluid ingestion. Animal studies show that MDMA stimulates the output of serotonin by serotonergic neurones, and AVP secretion is regulated by serotonergic pathways. The message is that those who take “ecstasy” or similar drugs may be at risk of hyponatraemia and should, therefore, avoid drinking fluid in excess of the body’s requirements. This may be difficult for users to estimate because MDMA reduces perception of thirst and impairs judgment.

The effect of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus

Methylenedioxymethamphetamine (MDMA, “ecstasy”), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. Release of both oxytocin and vasopressin from isolated hypothalami obtained from male Wistar rats was determined under basal conditions and following potassium (40 mM) stimulation. The results were compared with those obtained for basal and stimulated release in the presence of MDMA or metabolites in the dose range 1 μM to 100 pM (n=5 – 8) using Students t‐test with Dunnetts correction for multiple comparisons. All compounds tested affected neurohypophysial hormone release, HMMA (4‐hydroxy‐3‐methoxymethamphetamine) and DHA (3,4‐dihydroxyamphetamine) being more active than MDMA, and DHMA (3,4‐dihydroxymethamphetamine) being the least active. The effect on vasopressin release was greater than that on oxytocin. In the presence of HMMA the ratio test:control for basal release increased for vasopressin from 1.1±0.16 to 2.7±0.44 (s.e.m., P<0.05) at 10 nM and for oxytocin from 1.0±0.05 to 1.6±0.12 in the same hypothalami. For MDMA the ratio increased to 1.5±0.27 for vasopressin and to 1.28±0.04 for oxytocin for 10 nM. MDMA and its metabolites can stimulate both oxytocin and vasopressin release in vitro, the response being dose dependent for each drug with HMMA being the most potent.

Action of MDMA (Ecstasy) and Its Metabolites on Arginine Vasopressin Release

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.

Arginine vasopressin release in response to the administration of 3,4-methylenedioxymethamphetamine (“ecstasy”): is metabolism a contributory factor?

The aim of this investigation was to examine the effect of 3,4‐methylenedioxymethamphetamine (MDMA) administration on arginine vasopressin (AVP) release. (R,S)‐MDMA (40 mg) was administered to eight normally hydrated healthy male volunteers (22–32 years) and blood samples were collected up to 24 h. Plasma was assayed for AVP and cortisol by radioimmunoassays, and for MDMA and the N‐demethylated metabolite, MDA, by gas chromatography‐mass spectrometry. Sodium concentrations and osmolality were also determined. Plasma AVP increased in all subjects after MDMA administration and a significant negative correlation was observed between concentrations of AVP and both single and total enantiomer MDMA at 1 h (r < −0.91, P < 0.01). This had disappeared by 2 h (P > 0.7). Compared with basal values, no significant change was observed for osmolality or cortisol at 1 h after drug administration. In conclusion, plasma AVP concentrations increase after MDMA administration, but the increase is not part of a generalized stress response since cortisol did not increase concurrently. A significant negative correlation between plasma MDMA and AVP was observed soon after administration. The possibility that a pharmacological effect of MDMA is primarily mediated via one or more metabolites, rather than by the parent drug, should be considered.