3,4-Methylenedioxymethamphetamine-assisted... — Research Summary & Context

3,4-Methylenedioxymethamphetamine-assisted... — Research Summary & Context | Blossom

Abstract

Background

Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms.

Aims

This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams.

Methods

Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session.

Results

In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of −26.3 (29.5) for 125 mg, −24.4 (24.2) for 100 mg, and −11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set ( p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up ( p<0.001) with 76% ( n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated.

Conclusions

Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.

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Research Summary of '3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress dis - order: a randomized phase 2 controlled trial'

Methods

R. and colleagues conducted a randomised, double-blind dose–response pilot trial assessing MDMA-assisted psychotherapy in people with chronic post‑traumatic stress disorder (PTSD). Twenty-eight participants with chronic PTSD were randomised to receive two blinded eight-hour psychotherapy sessions with MDMA at one of three dose levels: 125 mg, 100 mg (both considered active doses), or a low dose of 40 mg. Treatment sessions incorporated a manualised psychotherapeutic approach delivered by therapist pairs; active dose groups received one additional open‑label MDMA session, whereas the 40 mg group crossed over to receive three open‑label active‑dose sessions. A 12‑month follow‑up assessment was performed after participants had completed their final MDMA session. The primary outcome was change in Clinician‑Administered PTSD Scale for DSM‑IV (CAPS‑IV) total score from baseline to one month after the second blinded session. Secondary outcomes included measures of depression (BDI‑II), sleep quality (PSQI), and dissociation (DES‑II). Analyses were specified for an intent‑to‑treat (ITT) set (participants who received at least one MDMA session and completed a post‑baseline outcome) and a per‑protocol (PP) set (participants completing both blinded sessions, the primary outcome assessment, and without major protocol deviations). Safety analyses included all participants who received at least one dose of MDMA. The primary statistical test was analysis of variance (ANOVA) with α=0.05, followed by preplanned t‑tests when ANOVA indicated significant main effects; within‑subject t‑tests examined changes after open‑label or additional sessions. Cohen’s d (independent‑groups pretest–posttest design) was used to estimate effect sizes. Peak vital signs averaged across blinded sessions were compared by one‑way ANOVA and t‑tests.

Results

The ITT analysis showed larger mean reductions in CAPS‑IV total scores at the primary endpoint for the active MDMA dose groups compared with the low (40 mg) dose. Reported mean (standard deviation) changes one month after the second blinded session were −26.3 (29.5) for 125 mg, −24.4 (24.2) for 100 mg, and −11.5 (21.2) for 40 mg. Statistical significance for the primary outcome was reached only in the PP set (p=0.03), not in the ITT set. Responder analyses indicated that over half of participants in the ITT set who received active MDMA doses achieved a ≥30% reduction in CAPS‑IV total score, compared with 16.7% in the 40 mg group. After the blinded phase, active dose groups showed the largest reductions and a pattern consistent with a dose response. Examination of an additional (third) experimental MDMA session found further reductions in CAPS‑IV scores for the 100 mg and 125 mg groups, suggesting an incremental benefit from a third active session. The 40 mg group, after crossing over to active dosing, showed a large treatment response after two open‑label active sessions with little additional change after a third session; the authors note individual variation in time to respond may influence these patterns. At 12‑month follow‑up (after all participants had received active MDMA in blinded or open‑label sessions), PTSD symptom reductions were maintained relative to baseline (p<0.001), with 76% (n=25) of participants no longer meeting diagnostic criteria for PTSD. Secondary outcomes (depression, sleep quality, dissociation) also showed significant reductions at 12 months compared with baseline. Medication use at 12 months was low for PTSD specifically (one participant), with nine participants taking medications for other conditions such as insomnia, depression, anxiety or ADHD. Safety analyses found no drug‑related serious adverse events. Adverse event frequency and intensity, including psychiatric symptoms and suicidal ideation, were reported as similar to prior studies. Transient increases in anxiety were noted, typically early in sessions or later when traumatic memories were processed; the authors report vital signs increased in a dose‑dependent manner to levels comparable to moderate exercise but were well tolerated. Baseline participant characteristics indicated a severely affected sample: participants had moderate to extreme PTSD, prior failures of psychotherapy (including CBT and EMDR) and pharmacotherapy, 96.4% had lifetime suicidal thinking, 46.4% reported serious suicidal ideation, and 28.6% had a history of suicidal behaviour. The study was underpowered to detect small to medium effects and was designed to detect large effects only.

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RESULTS

Power calculations were performed using results from a completed randomized, inactive-placebo controlled study of MDMAassisted psychotherapy. The current pilot study was underpowered to detect small to medium effect sizes, but could possibly detect a large effect. Efficacy analyses for all measures were performed on the intent-to-treat (ITT) set, consisting of all who had at least one MDMA session and completed an outcome assessment after baseline. CAPS-IV data were also analyzed in the per protocol (PP) set, which included all participants who completed both blinded sessions, primary outcome assessment, and did not experience a major protocol deviation. Participants who completed the open-label crossover were included in the crossover ITT set. Safety analyses included all participants who received at least one dose of MDMA. The primary efficacy outcome was the change in CAPS-IV Total scores from baseline to one month after the second blinded session, analyzed using an analysis of variance (ANOVA) with α=0.05. Preplanned t-tests compared dose groups when significant main effects were found. Secondary measures (BDI-II, PSQI, DES-II) were analyzed with the same method. Cohen's d independent-groups pretest-posttest design was used for comparator-subtracted effect size estimates. Descriptive statistics display the percentage of participants not meeting PTSD criteria on CAPS-IV (diagnostic score) and those attaining a ⩾30% decrease in scores post-treatment. For the open-label crossover, within-subjects t-tests compared scores on all measures at one-month after two open-label sessions to the primary endpoint. To explore whether a third active dose MDMA session produced further benefit, within-subjects t-tests of individual treatment groups compared scores of two vs three sessions. Peak vital signs averaged across the two blinded MDMA sessions were analyzed by a one-way ANOVA with t-tests to comparing groups. All statistical analyses were conducted using SPSS, version 20.0 (IBM Corporation, Armonk, New York, USA).

CONCLUSION

Consistent with prior research, this study provides supportive evidence that MDMA-assisted psychotherapy can be safe and efficacious in individuals with chronic PTSD refractory to medication and/or psychotherapy. This is the first trial to employ multiple therapy teams with newly trained therapists implementing the manualized approach, which is encouraging regarding the likelihood that other newly-trained providers may replicate these findings in phase 3 trials. Although significant group differences were detected only in the PP set for the primary outcome, over half of participants in the ITT set who received active MDMA doses reached a 30% or greater drop in CAPS-IV total scores compared to 16.7% in the 40 mg group. After two blinded MDMA sessions, active dose groups had the largest reductions in CAPS-IV total scores with more participants attaining clinically significant improvements in PTSD symptoms relative to the 40 mg group, supporting a dose response. To understand if three experimental sessions were more beneficial than two sessions, outcomes were evaluated again two months after the third (last) MDMA session. After the third experimental session, both the 100 mg and 125 mg groups showed further reductions in CAPS-IV scores, providing evidence that an additional session significantly improved PTSD outcomes. On the other hand, after the 40 mg group crossed over, a large treatment response resulted after two open-label sessions with little change after the third. The difference in time to respond is likely due to individual variation in the small samples, although there may have been a small additional therapeutic effect from the initial two low-dose sessions. Importantly, the gains were maintained over a 12-month follow-up after all groups had received active doses of MDMA in either blinded or open-label sessions, with 76% (n=25) of individuals not meeting the criteria for a diagnosis of PTSD. The fact that CAPS scores continued to improve between the two-month and 12-month follow-up visits lends support to the hypothesis that MDMA helps to catalyze a therapeutic process that continues long after the last drug administration. Moreover, the secondary outcome measures (depression, sleep, and dissociation) all showed significant reduction of symptoms at 12 months compared to baseline. At the 12-month visit, only one participant was taking a medication for PTSD; nine others were taking medications for insomnia, depression, generalized anxiety disorder, attention deficit/hyperactivity disorder (ADHD), and anxiety. These findings are noteworthy given that participants had moderate to extreme PTSD and had previously failed to benefit from psychotherapy, including approaches thought to be relatively effective (cognitive behavioral therapy (CBT) and eye movement desensitization reprocessing (EMDR)), and pharmacological treatment, including medications for depression and anxiety. At baseline, 96.4% of participants reported suicidal thinking at some point in the past; for 46.4% the suicidal ideations were serious, and 28.6% reported a history of suicidal behavior. Thus, the participants were severely impacted by symptoms before study participation, and the sample was not restricted to exclude people who had previously experienced suicidal thinking, as is common practice in many clinical trials of psychiatric drugs. Safety outcomes for MDMA-assisted psychotherapy in a controlled clinical setting strongly suggest a favorable benefit to risk ratio. Frequency and intensity of adverse events, reactions, and suicidal ideation were similar to previous reports. The greater number of psychiatric symptoms in active dose groups, such as anxiety, depression, or suicidal ideation, could be caused by the psychotherapeutic process of recalling and discussing experiences, thoughts, and emotions related to traumatic events, and also possibly be a direct pharmacological effect of MDMA. Available data is not adequate to identify a causal relationship, but increased transient anxiety has been detected in studies of healthy individuals after MDMA and is likely due to the MDMA-stimulated release of cortisol. The most common time for mild to moderate anxiety related to drug onset to occur is in the first hour after administration; anxiety associated with painful or stressful memories typically occurred later in the session. Therapists encourage diaphragmatic breathing and other stress inoculation techniques that are discussed during the non-drug preparatory sessions. Participants may be able to continue the therapeutic processing of trauma memories, even when facing anxiety, because of the support of two therapists, and reduced amygdalar activitythrough the pharmacological effects of MDMA. Vital signs after MDMA generally increased in a dose-dependent manner to values similar during moderate exercise, and were well tolerated in these participants. There were no SAEs related to the treatment, adding to the evidence that MDMA can safely be administered to patients with PTSD. Possible mechanisms for the treatment effect demonstrated in this sample are theorized based on the pharmacological effects of MDMA and its actions in the context of psychotherapy. Subjective effects of MDMA that bolster prosocial feelings and behaviorsmake unpleasant memories more tolerable, and enhance empathy, self-compassion,, and trusting in the pace of processing the experience, could all be beneficial in promoting a strong therapeutic alliance and inducing an optimal state of engagement for effectively processing traumatic memories. Healthy volunteers also report that MDMA can change the significance or meaning of perceptions. MDMA-assisted psychotherapy is meant to maintain the optimal "window of tolerance"). An enhanced therapeutic alliance combined with reduced anxiety or discomfort around difficult memories, increased self-compassion, and openness to expanding meaning of thoughts, feelings or experiences may all contribute toward therapeutic effects. Similar therapeutic procedures that include attention to setting, a pair of therapists offering nondirective, supportive care and substances that alter consciousness, are also used in psilocybin and ayahuasca research in people with depression. Other proposed models include an explicit role for experiential "regression" and re-examination of past experiences, and non-ordinary or transpersonal experiences in MDMA-assisted psychotherapy. MDMA-stimulated decrease in amygdalaand insular cortex activitymay allow for emotional engagement without overwhelming anxiety during processing of painful traumatic memories. In healthy humans, MDMA acutely modulates brain circuitry important for memory and affective processing, and implicated in the pathophysiology of PTSD, including increased resting state functional connectivity between the hippocampus and amygdala and decreased coupling of the medial prefrontal cortex with the hippocampus and posterior cingulate cortex. Given that MDMA modulates emotional memory, neural pathways, fear extinction and memory reconsolidation might play a role in the underlying mechanisms for the positive treatment response.

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Study Details

Study Type
individual
Population
humans
Characteristics
double blindrandomizedparallel groupdose findingfollow upplacebo controlled
Journal
Journal of Psychopharmacology
Compound
MDMA
Topics

Discussion

The authors interpret the findings as supportive of earlier pilot work showing that MDMA‑assisted psychotherapy can reduce PTSD symptoms and be administered safely in a controlled clinical setting. They highlight that the active dose groups demonstrated larger symptom reductions after two blinded sessions and that an additional third active session produced further benefit for the 100 mg and 125 mg groups. The durability of effects is emphasised: symptom reductions persisted and in some measures continued to improve up to 12 months after the final MDMA session. R. and colleagues position these results in the context of prior research by noting concordance with earlier positive findings and by stressing that this trial is the first to deploy multiple therapy teams with newly trained therapists using a manualised protocol, which they suggest increases the likelihood that other providers could replicate the approach in Phase III trials. They discuss plausible mechanisms grounded in MDMA pharmacology and neurobiology: facilitation of prosocial feelings, reduced amygdala and insular activity, modulation of memory and affective circuitry, and possible roles for fear extinction and memory reconsolidation. Such effects are proposed to enhance therapeutic alliance and enable emotional engagement with traumatic memories without overwhelming anxiety. The authors acknowledge limitations and uncertainties. The trial was a small pilot and underpowered for small–medium effects; the primary outcome reached statistical significance only in the per‑protocol set. The available data do not permit determination of causal mechanisms for transient increases in psychiatric symptoms seen around sessions, which could reflect either the psychotherapeutic processing of traumatic material or direct pharmacological effects of MDMA (for example, transient cortisol‑linked anxiety). The small sample size and individual variability in treatment response are noted as factors that may influence interpretation. Safety observations are tempered by these sample limitations, though no treatment‑related serious adverse events were observed. The authors suggest implications for further research and clinical development: replication in larger, adequately powered Phase III trials, evaluation of the optimal number of MDMA‑assisted sessions, and continued monitoring of safety and mechanisms. They also indicate that the manualised therapy and multi‑team implementation used here support feasibility of broader training and deployment if efficacy is confirmed.

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3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress dis - order: a randomized phase 2 controlled trial

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