Appendices (973K)

Appendices (973K)

Appendix A: Structured Abstracts of Reports on Clinical MDMA Research Lisa Jerome, Ph.D., and Matthew Baggott, B.A. Contains: summaries of all available studies (34 published and unpublished as of June 1, 2001) in the English-language literature in which MDMA was administered to humans. Anderson et al. (1978). Absolute configuration and psychotomimetic activity. Anderson, G. M., Braun, G., Braun, U., Nichols, D. E. & Shulgin, A. T. (1978). Absolute configuration and psychotomimetic activity. NIDA Research Monograph, 22, 8-15. http://www.maps.org/publications/1978_anderson_1.pdf Purpose: Pharmacological, psychological; Comparison of effects of the R and S isomers of MDMA, and argument for placing MDMA in a classification separate from the classic hallucinogens on the basis of the profile of these isomers. Design: Non-experimental uncontrolled within-subjects design, wherein all volunteers received at least one dose of each form of MDMA; racemate, R-MDMA and S-MDMA, at doses including those of 40- 200 mg. (Also performed comparative studies on rabbits wherein hyperthermic response to racemate and each isomer of MDMA was compared with response to the phenethylamine classic hallucinogen, DOM). Subjects: Unspecified number (perhaps 6 (6 x 5)?) of human volunteers, probably including the authors, gender and ages of volunteers not provided. Information on subject recruitment not provided. Criteria for Inclusion – Prior experience with psychedelic drugs. (An unspecified number of rabbits were used in studies of drug-induced hyperthermia). Measures: An author-constructed five-point rating scale for overall drug effects, with rating dependent upon degree and intensity / intrusiveness (described as “disruptiveness”) of subjective drug effects, and open-ended narratives wherein volunteers described drug effects. (Rectal hyperthermia in rabbits). Analyses: No formal analyses were performed. Comparative drug effects of racemic MDMA, R-MDMA and S-MDMA are presented in descriptive form. Results: Volunteers reported that racemic MDMA was active at 5 mg – 150 mg. S-MDMA was reported to be effective at doses of 80 mg – 120 mg. The effective doses for R-MDMA were far higher, and even 200 mg. R-MDMA did not produce the full intoxication obtained with racemic MDMA. Most of the emotional and sensory effects reported with the racemate are present with S-MDMA, but volunteers reported that they preferred the racemate to S-MDMA alone. The physiological effects of the racemate were also present with S-MDMA, including dilated pupils (mydriasis) and jaw clenching. R-MDMA did not produce these physiological effects. However, 2 / 6 or 2 / 35 reported “color enhancement” with R- MDMA but not with S-MDMA. (These volunteers reported experiencing color enhancement with racemic MDMA). The authors conclude that the effects found with each isomer, alone or summed, did not account for the effects of racemic MDMA. (In rabbits, S-MDMA produced greater elevation in body temperature (rectal hyperthermia) than either R-MDMA or racemic MDMA). Overall Effects: S-MDMA was far more active than the R-enantiomer and moderately more active than the racemate. S-MDMA had a lower effective dose than the R-enantiomer and it seemed to produce most or all of the effects associated with racemic MDMA, including psychological effects and side effects. R- MDMA was found to have a much higher effective dose range, and it did not produce an intoxication comparable to racemic MDMA even after 200 mg R-MDMA. With the possible exception of altered perception of color, S-MDMA appeared to possess most of the effects of the racemate. Nevertheless, volunteers preferred the effects of the racemate to either R-MDMA or S-MDMA, and the authors conclude that racemic MDMA produces effects that are not simply the sum of the effects produced by each enantiomer alone. The authors argue that because the R-enantiomers of hallucinogens are typically Page 221 of 367 more potent than S-enantiomers and MDMA was more active as the S-enantiomer, MDMA should not be classed as a hallucinogen. (As with humans, studies with rabbits indicated that the S-enantiomer of MDMA was more active than the R-enantiomer, when hyperthermia is used as a test of activity). Adverse Effects: See above; an unspecified number of volunteers reported sweating and jaw clenching with racemic MDMA and with S-MDMA. Comments: This paper is the second published report of the effects of MDMA in humans, and the only report at present that describes the individual effects of the MDMA enantiomers in humans. It is unclear how many volunteers were involved in these trials or how many doses were sampled for each compound. However, this paper does offer some preliminary information about the effects of racemic MDMA and the effects R-MDMA and S-MDMA. On the basis of their findings, the authors propose that MDMA should not be classified as a hallucinogen. Boone et al. (In Preparation). Neuropsychological Effects of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy). Boone, K. B., Chang, L., Grob, C. S., & Poland, R. E. (In Preparation). Neuropsychological Effects of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy). Manuscript obtained from C. S. Grob, August, 2000. Purpose: Neuropsychological, assessment of cognitive performance; “This current study evaluates…possible chronic and subacute effects of MDMA on brain function as measured by neuropsychological tests.” (p. 2 in manuscript). Design: Randomized, double-blind, placebo-controlled within-subjects design used to compare performance on neuropsychological test battery before receiving 2 separate doses of up to 2.5 mg / kg. MDMA (combined dose =0.75-4.75 mg/kg) with performance after receiving 2 doses of MDMA from 0.75 up to 2.5 mg/kg., with all volunteers assessed pre-drug and approximately 2 wks post-drug. (Study also compares MDMA-experienced subjects’ performance on a (baseline) neuropsychological test battery with published norms matched for subject sample age or education, with comparison conducted on 14 volunteers + an additional 10 volunteers who did not take part in the pre-drug / post-drug study.) Subjects: 24 MDMA-experienced subjects, 16 men, 8 women, average age 38, underwent baseline assessment only. 14 / 24 subjects, gender and age not provided, underwent baseline and post-drug assessment 2 wks after 2 doses of MDMA. (Volunteers in pre-test / post-test study belong to same sample reported on in Grob et al., 1996, Grob, 2000). All volunteers recruited via local advertisements. Criteria for Inclusion – Good health as assessed through medical examination, psychiatric interview and neurological examination. Lack of personal or family history of major medical or psychiatric illness. No history of substance abuse (except for MDMA or nicotine) and no history of head trauma with loss of consciousness over 30 min. At least 1 mo free of psychoactive medications or illicit drugs, and pre- session urine screen free of marijuana, barbiturates, cocaine, benzodiazepines or amphetamines. Not pregnant. Measures: MRI – Performed via clinical 1.5 Tesla scanner. Neuropsychological Assessment – Test battery administered at baseline for 24 / 24 subjects, conducted 193 + / - 225.3 days after last use of MDMA / ecstasy (range 7.5-780 days). Baseline assessment contained measures of intelligence (WAIS-R), attention (digit span), information processing (Stroop, Digit Symbol), language (Boston Naming Test), constructional ability (Rey-Osterrieth Complex Figure), Memory, Verbal (Logical Memory sub-test of WMS-R, Warrington Recognition Memory Test, Words, RAVLT), Memory, nonverbal (Visual Reproduction sub-test of WMS-R, Warrington Recognition Memory Test-Faces, Rey-Osterrieth Figure, 3 minute delayed, Continuous Visual Memory Test), and executive function (Stroop, Auditory Consonant Trigrams, WCST, Controlled Oral Word Association Test - Fluency. 14 / 24 volunteers assessed again with a less extensive test battery. Post-drug assessment included Digit Span, (Attention), Auditory Consonant Trigrams (Executive function), alternate forms of Page 222 of 367 RAVLT (verbal memory), Controlled Oral Word Association – Fluency (executive function) and Continuous Visual Memory (visual memory). Post-drug assessment conducted approximately 2 wk after receiving the second of 2 doses of MDMA as part of a controlled, laboratory study. Analysis: Performance on each test scored for 24 volunteers at baseline and for 14 / 24 volunteers post- drug. Pre-drug performance compared with post-drug performance on each test via paired t-test. (24 / 24 performance scores on baseline test battery compared with published norms for each test, matched for sample age group, except for Copy and Recall scores for Rey-Osterrieth figure, matched for sample education. Spearman correlation coefficient used to assess relationship between MDMA user parameters (duration, frequency and recency of use) and performance on each assessment employed in baseline test battery.) Results: MRI – MRI scans normal for all subjects. Neuropsychological Assessment – Post-drug performance did not differ from baseline. MDMA did not reduce performance scores on measures of digit span, RAVLT, continuous visual memory, auditory trigrams, or verbal fluency when post-drug assessment was compared with baseline. (When baseline test performance matched with age-appropriate norms, MDMA users (24 / 24 subjects) found to score within normal range (25th – 74th percentile or higher) for all tests except WCST. Volunteers scored <25th percentile on several WCST scores, including

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