Purpose: Neuroendocrine, neuropsychological: to investigate the "physiological, subjective and hormonal changes" (p. 396) that appear after administering MDMA in a laboratory setting, and to find any relationships between subjective, physiological and neuroendocrine effects. Specific hypothesis tested - That elevated corticosteroids and dehydroepiandrosterone (DHEA) would be associated with increases in the rewarding effects of MDMA.

Design: Double blind, placebo controlled, incompletely randomized within-subjects study design, with drug dose (0.5 mg/kg MDMA, 1.5 mg/kg MDMA or placebo) serving as a within-subjects factor. Placebo dose was randomized, but low dose MDMA was always given before high dose MDMA, and sessions were scheduled to occur 7 days apart. All participants underwent assessment for physiological and neuroendocrine effects after MDMA, and all completed psychometric measures of subjective effects.

Subjects: 8 MDMA-experienced volunteers (3 women, 5 men, aged 24-39 years, mean age = 29 +/- 5) presumably residing in the San Francisco (CA) area, with participants recruited via advertisements placed in local newspapers. The same sample was described and examined in a previous publication (Lester et al. 2000).

Criteria for Inclusion - Good health as assessed via medical examination and laboratory screening. No major medical or psychiatric illness, history of drug dependence (except caffeine and nicotine), or history of adverse reactions to study drugs, and good P450 2D6, activity, as assessed through dextorphan/dextromethorphan ratio. No high risk of cardiovascular problems, cholesterol below 250 dL, smoking < 2.5 packs of cigarettes a day), no risk of induced myocardial ischemia as measured via dobutamine stress test (see Lester et al. 2000) and not pregnant.

Measures: Physiological Effects - BP, HR, respiratory rate, pupil size, and skin and core temperature all measured 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 24 and 48 h after drug administration.

Alterations in Consciousness - Alterations in consciousness were measured through modified Subjective Drug Effects Questionnaire (SDEQ), and visual analog scales (VAS). The SDEQ is a self-report measure of subjective drug effects, with sub-scales of "Autonomic Arousal," "Mood Euphoria," "Relaxation," "Tension," "Cognitive Impairment," "Cognitive Improvement," "Ambivalence," and "LSD" (giddy excitement). Scale modification consisted of replacing forced choice (absent/present) scale with 4-point likert-type scale. The SDEQ was administered 2, 7, 24 and 48 h after drug administration. VAS measures were made for "closeness to others," "talkative," "friendly," "energetic," "confident," "insightful," and "anxious" (items specifically designed to measure subjective effects of MDMA), "high," "any drug effect," "good drug effect," "bad drug effect," "drug liking," and "intoxication" (compared to previous ecstasy experiences). VAS scales were administered at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 24 and 48 h after drug administration. Participants were asked to describe any effects they experience not listed on the VAS or SDEQ, and to indicate how much they would pay for each dose in dollars. Observer-scored measures of Alterations in Consciousness - Observed changes in thought or behavior associated with psychosis were assessed via Positive and Negative Syndrome Scale (PANSS), a 30-item measure of observed "positive symptoms" (e.g. delusions, thought disorder), "negative symptoms" (e.g. social withdrawal) and general psychopathology. The PANSS was administered at baseline, 2.5 and 24 h post-drug, and at 1 and 2 wk follow-up after last (larger) dose.

Neuroendocrine Effects - Plasma values for cortisol, prolactin, DHEA and luteinizing hormone (LH) were assessed in samples drawn at baseline, at 30 min intervals after drug administration up to 6 h post-drug, and 8 h post-drug (cortisol, DHEA), or at baseline and 2 h after drug administration (prolactin, LH). Serum values of follicle-stimulating hormone (FSH), estradiol and progesterone were assessed in female participants only from blood drawn at baseline and at 2 h post-drug.

Analyses: Physiological Effects, Alteration in Consciousness (Self-Report and Observer-Scored) and Neuroendocrine Measures - All data was analyzed via repeated measures analysis of variance (ANOVA), with drug condition (placebo, 0.5 mg/kg or 1.5 mg/kg MDMA) serving as one repeated measure and time of measurement (from baseline to all subsequent time points) serving as the other repeated measure. Data collected at every time point was used in analysis except for plasma DHEA, where analysis only examined data collected at 0 to 5 h post-drug due to a postprandial (post-meal) rise in DHEA starting at 5 h. After a single F test, pairwise comparisons were performed., with p value was set at 0.05 for all analyses. Individual SDEQ items for "greater feeling of love for others" and "liking for having people around" were analyzed independently to examine potential entactogenic effects.
Neuroendocrine Effects and Peak Effects - Plasma hormone concentrations were correlated with peak physiological and subjective effects (mean peak) via Kendall's tau, a non-parametric test of association, with p. set at 0.05.

Results: Physiological Effects - 0.5 mg/kg MDMA - None of the physiological effects measured were significantly elevated above placebo levels, including measures of systolic and diastolic BP, HR, pupil size, skin and core BT. (More detailed results presented in Lester et al. 2000) Physiological Effects - 1.5 mg/kg MDMA - Systolic BP, diastolic BP, HR and pupil size were all significantly elevated after 1.5 mg/kg MDMA. While skin temperature decreased after 1.5 mg/kg MDMA, skin temperature after MDMA was not significantly lower than after placebo. (More detailed results presented in Lester et al. 2000).

Alterations in Consciousness - 0.5 mg/kg MDMA - Compared with placebo, only SDEQ "Tension," "Mood Euphoria" and "Relaxation" scores were significantly increased after 0.5 mg/kg MDMA. (As expected, values on these scales were highest 2 h post-drug, as compared with 7 or 24 h post-drug). 0.5 mg/kg MDMA did not significantly increase any VAS scale scores or PANSS scale scores ("positive symptoms," "negative symptoms" or "general psychopathology"). Few of the acute effects were reported at 7 or 24 h post-drug. Only 3/8 participants indicated this dose was worth paying for, valuing it at $10. 1/8 preferred 0.5 mg/kg to 1.5 mg/kg because felt effects were "less artificial" at lower dose. Alteration in Consciousness - 1.5 mg/kg MDMA - Values for every SDEQ scale were increased after 1.5 mg/kg, including "LSD,", "Ambivalence," "Cognitive Impairment," "Mood Euphoria," "Autonomic Arousal," "Relaxation," "Tension" and "Cognitive Improvement." Scores on measures of somatic changes also increased after 1.5 mg/kg MDMA, such as dry throat, dizziness, sweating and hot or cold sensations; see "Adverse Effects." (As expected, scale scores highest 2 h post-drug, as compared with 7 or 24 h post-drug.) Scores on these specific VAS scales were significantly greater after 1.5 mg/kg MDMA; "high," "any drug effect," "good drug effect," "bad drug effect," "drug liking," "insightful" and "confident." Scores for "closeness to others" and "friendly," while increased, were not significantly greater than placebo values. 5/8 had higher scores on "feeling of love for others" and "like having other people around" after 1.5 mg/kg. Maximum change for most VAS scale scores was between 1.5 h post-drug and 2 h post-drug, except in the case of "bad drug effect," with maximum change at 4 h post-drug. 1.5 mg/kg MDMA did not significantly increase any PANSS scale score ("positive symptoms," "negative symptoms" or "general psychopathology.") 3/8 participants reported unusual beliefs after drug administration, but 2 of 3 questioned these beliefs. Some alterations in affect or emotion were still reported by some individuals 7 and 24 h post-drug (Feeling of love for others, 3/8 at 7 h, 1/8 at 24 h compared with 0/8 pre-drug; At peace with the world, 2/8 at 7 and 24 h post-drug.) Most participants rated 1.5 mg/kg as a "medium" to "somewhat strong" dose of MDMA, though 1/8 rated 1.5 mg/kg as "somewhat weak." All participants were willing to pay for this dose, with average price of $19 +/- $4.

Neuroendocrine Effects - 0.5 mg/kg MDMA - Plasma cortisol was significantly elevated after 0.5 mg/kg MDMA, with peak values appearing at approximately 5 h post-drug. There was a trend for elevated plasma DHEA after 0.5 mg/kg MDMA, with peak plasma DHEA appearing 2 to 3 h post-drug (comparisons were not made after 5 h post-drug, see "Analyses"). There was no increase in prolactin after 0.5 mg/kg MDMA, and no increase in progesterone or LH (in female participants only). Differences in plasma FSH after 0.5 mg/kg MDMA were related to participant's menstrual phase.

Neuroendocrine Effects - 1.5 mg/kg MDMA - Elevated plasma values for cortisol, prolactin and DHEA were seen post-drug. Both cortisol and prolactin values after 1.5 mg/kg MDMA were significantly greater than values after 0.5 mg/kg MDMA. Peak values for cortisol were approximately 5 h post-drug. (Prolactin only measured at 0 and 2 h post-drug). There were no significant differences in progesterone or LH in female participants, and differences in FSH were related to participant's menstrual cycle.

Neuroendocrine Effects and Peak Effects - Increased plasma cortisol (change in cortisol) after 1.5 mg/kg MDMA was positively associated with increased HR and with VAS "Drug Liking" score. Increased prolactin after 1.5 mg/kg MDMA was directly related to rise in cortisol, and was also positively associated with increase in HR. Change in prolactin after 1.5 mg/kg MDMA was inversely related to increase in SDEQ "LSD" scale; greater prolactin release was associated with less reported "giddy excitement." Rise in DHEA was not associated with any peak change in physiological effects after 1.5 mg/kg MDMA, but it was associated with increased SDEQ "Mood Euphoria" and "total euphoria." Overall Effects: As was reported in a previous paper by the same authors, 1.5 mg/kg MDMA elevated systolic and diastolic BP, heart rate and pupil size, while 0.5 mg/kg MDMA did not produce significant changes in BP, HR or pupil size. Alterations in consciousness were reported in a small sample of MDMA-experienced volunteers, both after 0.5 mg/kg MDMA and after 1.5 mg/kg MDMA. Volunteers reported increased euphoria, relaxation and tension after 0.5 mg/kg, a dose considered weak by most of the participants. Somatic sensations, such as parasthesias and hot or cold sensations, were also reported after 0.5 mg/kg MDMA. In contrast, 1.5 mg/kg MDMA produced elevations on all scales of the SDEQ, including measures of opposing effects (e.g. "Tension" and "Relaxation," "Cognitive Improvement" and "Cognitive Impairment.") Side effects such as dry throat, difficulty concentrating, lack of appetite, parasthesias and hot or cold sensations were frequently reported after 1.5 mg/kg MDMA, a dose considered "medium" to "somewhat strong." Neither dose of MDMA produced significant increases in any PANSS scores, though a few participants at the higher (1.5 mg/kg MDMA) dose reported having unusual beliefs. Cortisol and DHEA were increased after 0.5 and 1.5 mg/kg MDMA, and prolactin was increased after 1.5 mg/kg MDMA. The cortisol increase after 1.5 mg/kg MDMA was significantly greater than that seen after 0.5 mg/kg MDMA, and there was a trend for increase in DHEA after 1.5 mg/kg to be greater than after 0.5 mg/kg MDMA. The sex hormones progesterone and FSH remained unchanged by either dose of MDMA. Increased cortisol was associated with increased heart rate and greater "drug liking." Prolactin was associated with increased heart rate and decreased "LSD" scores (giddy excitement). Increased DHEA was associated with increased euphoria, but not with any changes in physiological effects. Both doses of MDMA were well-tolerated by all volunteers. The authors' hypothesis was partially confirmed, in that cortisol and DHEA were associated with increased euphoria, but prolactin was inversely associated, and not positively correlated, with the LSD scale score.

Adverse Effects: 0.5 mg/kg 2 h post-drug - The following side effects were listed at 2 h post-drug, in order of frequency: hot or cold sensations, 4/8; dizziness, 4/8; parasthesias (tingling, numb, "funny feelings"), 3/8; body tense, 3/8; throat or mouth dry, 2/8; harder to concentrate, 2/8; own voice sounds closer/farther away, 2/8; colors brighter, 2/8; lack of appetite, 2/8; other sounds closer or farther away, 1/8; heartbeat felt faster, 1/8

0.5 mg/kg 7 h post-drug - Hot or cold sensations 1/8; body tense, 1/8; headache, 1/8; harder to concentrate, 1/8.

0.5 mg/kg 24 h post-drug - Heartbeat felt faster, 1/8; Harder to concentrate, 1/8.

1.5 mg/kg 2 h post-drug - The following side effects were listed at 2 h post-drug, in order of frequency: throat or mouth dry, 7/8; harder to concentrate, 7/8; hot or cold sensations, 6/8; own voice sounds closer/farther away, 6/8; other sounds closer or farther away, 6/8; parasthesias (tingling, numb, "funny feelings"), 6/8; dizziness, 6/8; colors brighter, 5/8; heartbeat felt faster, 5/8; sweating, 4/8; body tense, 4/8, lack of appetite, 4/8. Altogether, 5/8 reported some perceived loss of control over body, thoughts or feelings. Spontaneously reported, jaw clenching (5/8), lower back pain, 1/8; restlessness. 1/8.

1.5 mg/kg 7 h post-drug - Decreased appetite, 5/8; Throat or mouth dry, 4/8; headache, 4/8; body tense, 2/8; harder to concentrate, 2/8; hot or cold sensations, 2/8; 1/8 reported each of these side effects: heartbeat felt faster, parasthesias, sweating, own voice seems closer or farther away.

1.5 mg/kg 24 h post-drug - Decreased appetite, 2/8; 1/8 reported each of these symptoms: throat or mouth dry, hot or cold sensations Comments: This is the second of two reports published by a team of researchers at the University of California-San Francisco, with the first report focusing on the cardiac effects of MDMA. This paper is notable in its attempt to relate neuroendocrine effects with physiological and subjective effects, and for being the first to assess changes in plasma DHEA after MDMA. Surprisingly, research findings indicate that while each hormone assessed was associated with a slightly different MDMA effect, greater prolactin release was associated with less increases in "LSD" scale score, a measure of excitement or agitation. The inverse relationship between prolactin release and increased "LSD" score may indicate that prolactin is associated with less DA release, since "LSD" score presumably measure the effects of DA released through stimulation of 5HT2A activity. The authors also attempted a formal assessment of entactogenic effects by examining changes in selected SDEQ items. Though MDMA did not significantly elevate scores on items intended to measure entactogenic effects, the number of items used was almost certainly not great enough to serve as a valid measure of entactogenic effects. However, the combined SDEQ and VAS profile, including increased scores on scales measuring apparently opposite subjective effects, might serve as evidence that MDMA belongs to a unique drug class. Subjective effects reported here are consonant with previously reported findings (Cami et al. 2000; Grob et al. 1996; Tancer et al. 2001; Vollenweider et al. 1998). Study limitations include small sample size and relying on a sample of MDMA-experienced volunteers. In addition, it is possible the interval between the administration of the first and second dose of MDMA were not sufficiently long enough to eliminate changes in tryptophan hydroxylase or CYP2D6 produced by the first dose.