Purpose: Neuroendocrine: "To examine the effects of [MDMA] administration on arginine vasopressin (AVP) release" (p. 1357) in male human volunteers.

Design: Single dose, non-blind within-subjects design, with time of measurement (baseline and post-drug) serving as a within-subjects factor, and with all participants receiving 47.6 mg MDMA hydrochloride (equivalent to 40 mg freebase) p.o. 3 of 8 participants served as non-blind controls, with measurements taken 2 wks after initial study, apparently to control for circadian rhythms in hormone values.

Subjects: 8 MDMA-naïve males, ages 22-32, 7 Caucasian, 1 Asian. No information on subject recruitment provided. (The same sample of participants appears in previous reports (Fallon 1999; Henry 1998).

Criteria for Inclusion - Male, healthy as established through medical examination, with no reported history of psychosis or substance abuse. Abstinence from alcohol 24 h prior to study day, with method of verification unreported (presumably self-report only).

Measures: AVP - Plasma concentration of AVP measured with radioimmunassay (RIA), from blood sampled pre-drug, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 1 day (24 h) post-drug, or at identical intervals 2 wks later in control sessions with 3 of 8 volunteers.

MDMA - Plasma concentration of both enantiomers of MDMA and its metabolite MDA were measured via GC-MS (capillary gas chromatography) with MDMA concentration measured from blood drawn at pre-drug, 30 min, 1, 2, 4, 6, 8 and 24 h post-drug.

Cortisol - Plasma concentrations of cortisol measured via RIA, with cortisol measured in plasma drawn at baseline (pre-drug), 30 min, 1, 2, 4, 6, 8 and 24 h post-drug or at same intervals 2 wks later in 3 / 8 volunteers serving as controls.

Sodium - Plasma sodium concentration measured via potentiomeric dry-slide method, with sodium concentration measured in plasma drawn at baseline (pre-drug), 30 min, 1, 2, 4, 6, 8 and 24 h post-drug or at same intervals 2 wks later in control sessions in 3 / 8 volunteers.

Osmolality - Plasma osmolality (sodium / fluid balance) measured via freezing-point depression, with measures taken from samples drawn at baseline (pre-drug), 30 min, 1, 2, 4, 6, 8 and 24 h post-drug, or at same intervals 2 wks later in 3 / 8 volunteers serving as controls.

Blood Pressure and Pulse - Both BP and pulse were measured at same points in time as when blood was drawn (pre-drug, 30 min, 1, 2, 4, 6, 8 and 24 h post-drug).

Analyses: All plasma concentrations - A repeated-measures analysis of variance (ANOVA) was performed, comparing plasma concentrations of AVP, MDMA, MDA, cortisol sodium, and osmolality over time, with time of measurement (pre-drug, 30 min, 1, 2, 4, 6, 8 and 24 h post-drug) serving as a within-subject variable. Contrasts were used to compare any differences found via ANOVA by comparing post-drug measurement with basal measurement.

Blood Pressure and Pulse - Not described in this report; probably analyzed via repeated-measures ANOVA with time of measure (pre-drug, 30 min, 1, 2, 4, 6, 8 and 24 h post-drug) as a within-subjects factor.

Relationship Between Plasma MDMA, Plasma MDA and AVP - The relationship between plasma MDMA and AVP values were analyzed via regression, with MDMA as the predictor and AVP as the dependent variable. Regressions were also performed separately for both the R and S enantiomers of MDMA. The relationship between maximum AVP increase and MDMA was also analyzed via regression. The same series of regressions were performed with MDA (racemic, R and S enantiomers) serving as predictor and with AVP serving as dependent measure, and a regression examining the relationship between maximum change in AVP and MDA was also conducted.

Results: AVP - There was a significant increase in plasma AVP values, as compared with baseline, between 1 and 4 h post-drug.

Cortisol - There were no significant changes in plasma cortisol up to 8 h post-drug. There was a non-significant increase in plasma cortisol 24 h after MDMA administration. Only an expected change in cortisol associated with circadian rhythm was seen in controls in samples taken at the same time of day 2 wks after the initial study.

Sodium - A small but significant decrease in plasma sodium, as compared with baseline, appeared between .5 and 2 h post-drug. (Changes in plasma sodium appeared in 6 / 8 volunteers, while 2 / 8 showed no significant change in sodium values). Plasma sodium value was significantly increased compared to baseline 24 h post-drug.

Osmolality - There were no significant changes in osmolality after MDMA administration. However, plasma osmolality was significantly increased 24 h post-drug.

MDMA - Plasma MDMA increased rapidly from after ingestion to 4 h post-drug, and decreased slowly from 4 to 8 h post-drug. There was no measurable amount of plasma MDMA 24 h post-drug.

MDA - Values for S-MDA exceeded R-MDA in all volunteers for up to 8 h post-drug, and Cmax was greater for S-MDA compared with R-MDA (also reported in Fallon et al. 1999).

Blood Pressure and Pulse - There were no significant changes in BP or pulse at any point in time after drug administration, as (apparently) compared with baseline.

Relationship between MDMA and AVP - At 1 h post-drug, there was a significant negative correlation between MDMA concentration and AVP values, with p < 0.001. Maximal change in AVP (difference score) was also significantly and inversely related to plasma MDMA. A participant with the highest MDMA concentration also had the smallest increase in AVP. At 2 h, plasma MDMA and AVP were no longer significantly related. There were significant and negative relationships between R-MDMA and AVP and between S-MDMA and AVP. There was no significant relationship between any MDA value (racemic, S or R) and AVP concentration, at any point in time (30 min to 8 h post-drug) or when using the maximal change from baseline. Because plasma MDA values were below the level of 0.0025 mg/L at 30 min post-drug, MDA at this time point was not regressed on AVP values.

Overall Effects: A single dose of 40 mg MDMA administered to 8 healthy MDMA-naïve men increased AVP at 1 to 4 h post-drug, with AVP values returning to baseline by 8 h post-drug. Plasma sodium values decreased from 30 min to 2 h post-drug, and increased to above baseline values 24 h post-drug. There were no significant changes in either plasma cortisol or plasma osmolality up to 8 h post-drug, though both cortisol and osmolality were increased 24 h post-drug. The effects of MDMA on AVP did not produce any clinically significant change in hydration or in sodium values. Plasma AVP values were inversely correlated with plasma MDMA values; an increase in MDMA was associated with a smaller increase in AVP after MDMA. This was true for both the R and S enantiomers of MDMA. Plasma values of MDA, a minor metabolite of MDMA, were uncorrelated with AVP values. Plasma AVP and sodium, and plasma osmolality, did not change significantly over time when measured during control (no MDMA) sessions in 3 of 8 participants, and the only significant change in cortisol values measured then was an expected change related to circadian rhythm.

Adverse Effects: None reported in this paper.