Purpose: Neuropsychological, psychopharmacological: "to assess psychomotor performance and subjective effects of the coadministration of MDMA and [ethanol]." (p. 237)

Design: Randomized, placebo-controlled, double-blind 2 x 2 crossed within-subjects design, with drug 1 (100 mg MDMA or placebo) serving as one factor and drug 2 (0.8 g/kg ethanol, placebo) serving as the other factor, and with measures taken over the course of each session also considered a within-subjects factor. All participants took part in all 4 conditions (placebo-placebo, MDMA-placebo, placebo-ethanol and MDMA-ethanol). Each session was scheduled to occur at least a week after a previous session. All participants underwent measures of psychomotor performance, subjective drug effects and extraocular muscular balance.

Subjects: 9 male MDMA/ecstasy-experienced and ethanol-experienced volunteers (ages 19-36, weight 59-81 kg, height 167-183 cm) recruited via "word of mouth." Criteria for Inclusion - Lack of major psychiatric or medical illness as assessed through interview and physical examination, routine laboratory tests, urinalysis and ECG. Lack of substance abuse (except for nicotine dependence), and extensive CYP2D6 metabolizers as assessed via urinary dextromethorphan/dextorphan ratio. Lack of adverse psychiatric or medical reactions to ecstasy/MDMA. All participants were required to have had taken ecstasy at least five times over a lifetime and to have experience with acute ethanol intoxication.

Measures: Alterations in Consciousness - Measured with Spanish-language ARCI and 23 author-constructed visual analog scales (VAS), with both measures administered at 0, 15, 30, 45, 60, 90 min and 2, 3, 4, 6, 8, 10, and 24 h post-drug.

Psychomotor Performance - Psychomotor performance measured via Digit Symbol Substitution Test (DSST), simple RT task and Maddox-Wing device. DSST = a test of visual pattern recognition; subjects respond to patterns presented on screen, scored as % of correct patterns keyed into computer in 90 sec. Simple RT task = measure of sensory-motor performance, scored as speed of response after stimulus and Maddox-Wing device = measure of extraocular muscular movement, scored as either exophoria (tendency of eyes to move apart from each other, divergent squint), normal activity or esophoria (tendency for eyes to move toward each other, convergent squint). DSST and simple RT task were performed at 0, 30, 60, 90 min and 2, 3, 4, 6, 8, 10, and 24 h post-drugl, and Maddox-Wing measure performed at 0, 15, 30 (immediately before beverage), 45 (immediately after beverage), 60, 75, and 90 min after drug 1 (MDMA/placebo) and at 2, 3, 4, 6, 8, 10 and 24 h post-drug 1.

Physiological Measures - Cardiovascular and neuroendocrine effects were assessed but are not reported in this paper.

Plasma MDMA and Ethanol - Blood samples were collected at 0, 15, 30, 45, 60, 75, and 90 min and at 2, 3, 4, 6, 8, and 10 h post-drug 1 (MDMA or placebo). Blood was also collected to detect ethanol, with samples collected at 0, 15, 30, 45, 60, 75, and 90 min and at 2, 3, 4, 6 h after drug 1 (-30, -15, 0, 15, 30, 45, 60, 90 min and 2.5, 3.5 and 5.5 h post-drug 2 (ethanol or placebo). MDMA concentration in plasma measured via gas chromatography, and plasma ethanol concentration measured via gas chromatography with capillary column.

Analyses: Alterations in Consciousness - Values were transformed into differences from baseline. Maximum peak effect in first 6 h and area under curve (AUC) were calculated for reach variable, with AUC calculated by using the trapezoidal rule. Transformed measures were analyzed via one-way (within-subjects) ANOVA, with drug condition (placebo-placebo, MDMA-placebo, placebo-ethanol or MDMA-ethanol) serving as a factor, and with significant differences analyzed via Tukey's test. A 2-way repeated measures ANOVA was performed to examine changes in time course of effects, with time of measurement serving as repeated measure and drug condition serving as the other factor. Tukey's test was used to compare significant differences. P was set at 0.05 for all tests of significance.

Psychomotor Performance - The same process was used as described for alterations in consciousness; data were transformed into differences from baseline, and maximum peak difference and AUC were calculated. Differences in effect across drug condition were analyzed via one-way ANOVA with drug condition as a factor, and time course of effects was analyzed via two-way repeated measures ANOVA, with time of measurement as a repeated measures factor and drug condition as second factor. Significant differences were examined post-hoc via Tukey's test.

Plasma MDMA and ethanol - Tmax (peak concentration), Tmax (time to reach peak) and AUC were all calculated for both MDMA and ethanol. AUC was calculated for 0-6 h and for 6-24 h for ethanol, and 0-24 h for MDMA, and AUC for both substances was calculated via trapezoidal rule. Paired student's t test was used to analyze differences in Cmax and AUC (between drug alone and combination), and Wilcoxon test was used to compare Tmax for both substances, with p set at 0.05.

Results: Alterations in Consciousness, MDMA Alone - MDMA produced increase in ARCI ratings of "MBG ("euphoria"), LSD ("dysphoria"), BG ("intellectual efficiency" efficiency") and A ("amphetamine-like, activated") scales, with peak changes appearing 1 to 2 h post-drug1. MDMA increased scores on VAS measures for "stimulated," "high," "changes in lights," "changed or unreal body feeling" and "different or unreal surroundings," and also "good effect" and "liking." Alterations in Consciousness, Ethanol Alone - Ethanol produced increases in PCAG ("sedation") scores, with sedation peaking 2-4 h post drug1. Ethanol produced increased scores for "drunken," "drowsy," "any effect," and "content" (non-significant).

Alteration in Consciousness, MDMA + Ethanol - When combined, MDMA + ethanol mostly produced effects similar to those produced with MDMA alone. This includes increases in ARCI MBG, LSD and BG Scores. MDMA completely reversed ethanol-induced increase in PCAG ("sedation") ARCI score. Ethanol non-significantly decreased BG ("intellectual efficiency") and A ("energy") scales when compared to MDMA alone. The combination produced a greater increase in MBG ("euphoria") ARCI score that peaked 1 h post-drug1. MDMA + ethanol produced high VAS scores for "good effect," "stimulated", "drunken," "any effect" and "high," with "stimulated," "high," "content" and "any effect" higher after combination than with MDMA alone. VAS scores relating perceptual changes were elevated after MDMA + ethanol ("changes in light," "different or unreal body feelings," "different or unreal surroundings."). MDMA reduced ethanol-induced increase in "drowsy," but not "drunken."

Psychomotor Performance, MDMA Alone - DSST - MDMA did not produce any significant changes in performance on DSST. RT - MDMA did not appear to affect simple RT task performance. Maddox-Wing - MDMA produced an increase in esophoria (convergent squint)., with effects lasting 3 to 4 h post-drug1. Psychomotor Performance, Ethanol Alone - DSST - Performance declined, with number of responses and number of correct responses decreasing after ethanol. RT - Ethanol produced a non-significant increase in decision time on simple RT task. Maddox-Wing - Ethanol non-significantly increased exophoria (divergent squint), with significant exophoria appearing only at 1.5 and 3 h post-drug1. Psychomotor Performance, MDMA + Placebo - DSST - Performance declined after MDMA + placebo, with both number of responses and number of correct responses declining after MDMA + ethanol. Impaired performance on the DSST lasted less long after MDMA + ethanol than after ethanol alone. RT - Decision time was significantly increased after MDMA + placebo, and impairment was non-significantly greater after combination than after ethanol alone. Impairment lasted for a half hour 1 to 1.5 h after drug1. Maddox-Wing - Both ethanol-induced exophoria and MDMA-induced esophoria were attenuated after MDMA + ethanol combination, with esophoria still the main effect, but lasting only 15 min (1.15-1.30 h post drug1).

Plasma MDMA and Ethanol - The addition of ethanol increased MDMA Cmax when compared with MDMA alone, with increased Cmax after MDMA + ethanol 13% higher than after MDMA alone. Ethanol did not alter MDMA Tmax or AUC. The addition of MDMA reduced plasma ethanol Cmax and AUC when compared with ethanol alone, with plasma ethanol decreasing by 15% with the addition of MDMA.

Overall Effects: The combination of MDMA and ethanol produced subjective effects that were generally comparable to those expected after MDMA alone; stimulation, euphoria and changes in thought and perception. The addition of ethanol did seem to produce greater euphoria, and higher ratings of "good effect," and "high," but the sedation reported after ethanol was not reported after the combination of MDMA and ethanol. On the other hand, ethanol influenced measures of psychomotor function, with performance on the digit-symbol substitution task after MDMA and ethanol as impaired as it is after ethanol alone. Furthermore, people took longer to respond on a simple RT task after receiving MDMA and ethanol, whereas neither substance produced decline in RT performance when administered alone. When given in combination, MDMA and ethanol cancelled out their effects on extraocular muscles, with neither convergent squint nor divergent squint prevailing. Ethanol increased peak MDMA concentrations when compared to peak plasma MDMA alone, and the addition of MDMA decreased peak plasma ethanol and ethanol AUC when compared to values produced after ethanol alone. In laboratory conditions, the combination of MDMA and ethanol was well tolerated in volunteers familiar with the effects of both substances.

Adverse Effects: None reported for this paper; DSST was impaired by ethanol, with and without MDMA.

Comments: This is the second of two papers comparing the effects of a combination of MDMA and ethanol with the effects of each drug taken alone. The same research team also recently published a paper addressing the immunological effects of this combination of substances, whereas this paper addresses pharmacokinetics and subjective and psychomotor effects. Findings from this paper suggest that while the euphoric and stimulating effects of MDMA dominate over the subjectively sedating effects of ethanol, the reduction in psychomotor function produced by ethanol is not attenuated by MDMA. It is probably less safe to drive under the influence of the two drugs combined than under MDMA alone (impaired driving capability may be equal to that of ethanol alone). There has been speculation that coadministration of MDMA and ethanol may increase risk of dehydration and, therefore, MDMA-related hyperthermia. Ethanol has dose-dependent diuretic effects, but it has not been firmly established that ethanol use significantly increases risk of MDMA-related adverse event. This paper does not present physiological and hormonal measures and therefore does not address this issue. It is hoped that the authors present relevant findings in a separate paper. This study also did not measure subjective effects thought to be unique to entactogens, such as feelings of empathy or closeness to others, and so it is unclear whether ethanol has any direct effects on the entactogenic effects of MDMA. The combination of MDMA and ethanol lead to modestly increased MDMA plasma concentrations and modestly decreased ethanol plasma concentrations compared to when each drug was administered alone. Because these changes are modest, it is not clear if they have toxicological or other clinical significance. Study findings are limited by small sample size and by the use of male subjects only.