MDMA. MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck pharmaceutical company in 1912 [40, 41]. MDMA is a monoamine releaser that has its greatest effects on serotonin, followed by norepinephrine and dopamine [42-47]. MDMA is capable of inducing unique psychopharmacological effects, including: • Decreased feelings of fear. • Increased feelings of well-being. • Increased sociability and extroversion. • Increased interpersonal trust. • Alert state of consciousness. Early observers noted increased acceptance of self and others, increased tolerance of emotionally upsetting materials and the ability to address these issues without extreme disorientation or ego loss [48-51]. In the U.S., MDMA was used as an adjunct to psychotherapy by a considerable number of psychiatrists and other therapists in the treatment of neuroses, relationship problems and PTSD [48, 49, 52, 53] before it was placed in Schedule 1 in 1985 as a result of extensive non-medical use [51, 54, 55]. Placement in Schedule 1 prohibited it for use except in a federally approved research setting. In contrast to daily administrations of SSRIs, MDMA-assisted psychotherapy consists of several drug-assisted sessions interspersed with a moderate course of non-drug psychotherapy. Thus the effects of MDMA are distinct from and go well beyond those of anti-anxiety drugs such as benzodiazepines. Furthermore, there is no evidence that MDMA creates a physical dependency, as benzodiazepines do. Previous studies of polydrug users found a small percentage of people exhibit problematic use of ecstasy, (material represented as containing MDMA) [56, 57]. Studies of regular or problematic ecstasy users indicate that on average, regular use occurs no more often than once a week [58]. Hence, MDMA may have moderate abuse potential. See the Investigator’s Brochure (IB) for a more detailed explanation.
MDMA. The study is underpowered for detection of differences of a small or moderate effect size, and it may detect differences if the effect size is large. Analyses of MAPS’ completed U.S. study of MDMA-assisted psychotherapy in 20 people with PTSD found an effect size of 1.24 for treatment efficacy, as represented by changes in CAPS score [71]. The estimated effect size for this study may be lower as a result of comparing the full dose of MDMA with a low dose of MDMA instead of with inactive placebo, small sample size and unequal distribution of conditions. The sponsor intends to pool data across studies or perform meta-analyses of CAPS scores across all pilot studies. The sponsor used Java applications created by Lenth to calculate estimated statistical power for the primary outcome measure of this study, assuming an effect size of 0.8 for the impact of two sessions of MDMA-assisted psychotherapy on symptoms of PTSD [128], reducing the effect size to account for the hypothesized effects of using a low dose of 40 mg that is higher than the 25 mg dose employed as an active placebo in a sponsor- supported study. The software calculated an estimated power of 0.24, indicating an underpowered study. Had we used the higher effect size of 1.1, power analysis still indicates that this study is underpowered, with an estimated effect size of 0.4. Statistical power estimates were not available for secondary and exploratory measures as they were previously not used in sponsor-supported studies.
MDMA. MDMA is a ring-substituted phenylisopropylamine derivative. Chemists at the Merck pharmaceutical company first synthesized it in 1912 [49, 50], though its clinical effects were not subject to formal investigation until the 1980s. MDMA is a potent monoamine releaser that has its greatest effects on serotonin, followed by norepinephrine and dopamine [51-56]. MDMA acutely decreases activity in the left amygdala [57], a brain region involved in interpretation of negative cues, and attenuates amygdalar response to angry faces [58]. This action of MDMA is compatible with its reported reduction in fear of emotional injury or defensiveness [59]. Brain imaging after MDMA indicates less reactivity to angry facial expressions and greater reward in happy faces [58]. A recent study in healthy volunteers found correlations between oxytocin (OT) levels, amygdalar volume, and extraverted personality [60]. OT is a neuropeptide associated with pair bonding and social affiliation in mammals that also attenuates amygdalar response to anxiogenic stimuli [61, 62]. OT administration is associated with increased interpersonal trust and changes in social perception, including attenuated reactivity to threatening faces [63-66]. MDMA elevates OT in peripheral blood [67-69], which is an imperfect but somewhat reliable indicator of elevated OT in the brain [62]. Findings of an association between elevated OT and detectable MDMA in peripheral blood were first reported in a naturalistic study of London nightclub attendees with and without detectable serum MDMA levels [67]. Xxxxxx and colleagues reproduced these results in humans and found that MDMA significantly elevated peripheral plasma OT levels in a placebo-controlled study in healthy volunteers [68], in addition to a positive association between elevated levels of OT and prosocial feelings. Xxxxx and colleagues replicated these results and reported that administering a serotonin reuptake inhibitor, but not a norepinephrine uptake inhibitor nor several adrenergic antagonists, attenuated the effects of MDMA on OT levels, suggesting a serotonergic mechanism in producing elevated OT [69]. The effects of MDMA on OT may influence empathy or compassion for self and others, decrease defensiveness, and strengthen therapeutic alliance. The multi-level effects of MDMA on monoaminergic signaling and OT, combined with a therapeutic setting, are more likely to provide the opportunity for a corrective emotional experience than OT alone, and could...
