This systematic review and meta-analysis (2020) of MDMA-assisted therapy for PTSD, found that over four RCT’s (n=67), PTSD scores (CAPS-IV) were lower in the 75mg and 125mg groups (not 100mg), and depression scores (BDI) only in the 75mg group.

Abstract

“Rationale: Novel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.

Objective: To review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.

Methods: Systematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within 7 days of intervention.

Results: Four randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75 mg (MD -46.90; 95% (confidence intervals) CI -8.78, -5.02), 125 mg (MD -20.98; 95% CI -34.35, -7.61) but not 100 mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75 mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after 7 days.

Conclusion: These results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further.”

Authors: Benjamin J. G. Illingworth, Declan J. Lewis, Andrew T. Lambarth, Kate Stocking, James M. N. Duffy, Luke A. Jelen & James J. Rucker

Notes

This meta-analysis is less favorable than some/many of the reports around MDMA-assisted psychotherapy. One reason for this difference is that this study compared the intervention versus the other groups that did get (high quality) therapy, whereas usually the headline number is compared to the status quo (no improvement at all).

It should also be noted that this study (2020) predates the Phase III studies by MAPS which promise to show efficacy (and have larger samples sizes to do so).

“The results of this meta-analysis suggest that the use of MDMA in conjunction with psychotherapy is associated with a significant decrease in CAPS-IV scores at greater than 3 weeks when compared to both active (except at 100 mg) and inactive placebo groups in the treatment of treatment-resistant PTSD. MDMA-assisted psychotherapy showed no significant decreases in BDI except for at 75 mg. Subjects in these trials experienced significant physical side effects from the intervention. These included nausea (58% of sessions), low mood (17% of sessions) and jaw clenching in session (30% of sessions) and also lack of appetite within 7 days of intervention (25% of sessions).“

Summary

Post-traumatic stress disorder

Post-traumatic stress disorder is a psychiatric disorder triggered by exposure to a psychologically traumatic event. It is characterised by anxiety, sleep disturbance, hypervigilance, avoidance behaviour, and intrusive thoughts and memories about the trauma.

PTSD is a disabling condition that inflicts a large individual and societal burden. Treatment-resistance is often defined as a failure to respond to at least two evidence-based therapies, however there are many different criteria for determining treatment response.

Co-morbidity and disease burden

There are close links between PTSD and physical health, with those with PTSD having a higher risk of morbidity and mortality from a range of physical medical conditions, and self-harm and suicide being more common in those with PTSD than in the general population.

Current treatment options and their efficacies

Management of PTSD generally consists of pharmacological treatments, including selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, as well as psychotherapies that involve exposure to and processing of traumatic events. IPT is notable in that it does not require exposure to or processing of traumatic experiences.

Psychotherapy alone appears to be more effective than pharmacotherapy alone, but methodological difficulties in trials of psychotherapies mean their effectiveness may be overestimated. Despite this, a significant proportion of patients do not achieve remission regardless of the regimen used.

MDMA is a psychoactive drug that promotes feelings of empathy, relatedness and trust, as well as increased oxytocin and prolactin levels. It may also be responsible for reducing fear and negative emotions, and increasing confidence and extroversion.

MDMA produces subjective and appreciable effects, so active placebos are frequently used in trials to reduce the risk of unblinding.

MDMA may help those affected by PTSD to access and process traumatic memories by moderating fear responses.

Side-effect and toxicity profile

MDMA side effects include dry mouth, nausea, anxiety, inability to urinate, bruxism, restlessness and increases in heart rate, blood pressure and body temperature. Higher doses can cause a potentially fatal serotonin syndrome, but at the doses used in therapy, side effects are usually transient, mild and unlikely to pose any significant risk.

Summary of intervention

MDMA was administered to participants in expertly supervised clinical settings as an adjunct to a limited number of psychotherapy sessions. The feasibility of this intervention has been demonstrated in phase 1 and phase 2 clinical trials.

There have been previous systematic reviews in this area published in 2016 and 2019, but this review includes more up-to-date data and uses robust statistics to compare the effect sizes of MDMA assisted psychotherapy and prolonged exposure therapy.

Bahji et al. (2019) differ in their analysis of the primary outcome, reporting risk-ratios for loss of PTSD diagnostic status and clinical response. Our analysis complements this review by reporting mean change in CAPS-IV score at individual dosages.

Methods

We searched PUBMED, PsychINFO, EMBASE and MEDLINE for double-blinded, randomised controlled trials evaluating the efficacy and safety of MDMA-assisted psychotherapy treatment in TR-PTSD patients. Two review authors independently screened titles and abstracts and critically reviewed the full text of selected randomised trials to assess eligibility.

Two review authors independently extracted study characteristics, assessed risk of bias, extracted data on primary and secondary outcomes, and contacted authors for clarification. Discrepancies between the reviewers were resolved through discussion, contacting the authors, or consultation with a third reviewer.

We used a random-effects model to calculate summary estimates and a fixed-effects model to calculate summary estimates for secondary outcomes. We used the peto odds ratio when comparing studies with low event rates.

Results

We imported 688 references for screening. Six randomised controlled trials reporting data from 109 participants met our inclusion criteria, and four trials using 85 participants were used in the final analysis.

Primary outcomes

The intervention groups taking 75 mg and 125 mg of MDMA in conjunction with psychotherapy saw significant decreases in CAPS-IV scores, and the intervention group taking 150 mg of MDMA in conjunction with psychotherapy saw a significant improvement in BDI scores.

Secondary outcomes

MDMA caused jaw clenching, nausea, and lack of appetite more often than inactive placebo and active placebo at therapeutic doses, but not at 100mg. Low mood was more prevalent when taking MDMA than in the active placebo group.

Main findings

MDMA-assisted psychotherapy decreased CAPS-IV scores at greater than 3 weeks in subjects with treatment-resistant PTSD, but was associated with significant physical side effects, including nausea, low mood, jaw clenching, and lack of appetite.

Strengths and limitations

This prospectively registered systematic review has a comprehensive search strategy, methodological design and statistical analysis, and looks in-depth at the secondary outcomes and adverse events. It also assesses the dose differences on effect size.

This study has several limitations, including a small sample size and inconsistent reporting of outcome measures. A core outcome set for use in all future PTSD trials would be helpful, as would a set of ‘adverse events of special interest’.

The blinding of participants and investigators in all of the studies included was suboptimal, as evidenced by 95% of participants guessing which treatment arm they were in.

Interpretation

MDMA-assisted psychotherapy has been shown to have some effect on reducing CAPS-IV scores in participants with treatment-resistant PTSD.

Certain symptomatology clusters or trauma aetiologies may be more amenable to MDMA-assisted psychotherapy, although this treatment may have limited effects on depressive symptoms.

Some participants experienced a transient increase in suicidal ideation after their second 30mg session of MDMA, although no suicidal behaviour was reported. The emergence of low mood and suicidal ideation may be interpreted as a necessary part of engaging with and re-processing long-avoided traumatic experiences.

Phase 2 trials of MDMA were effective in treating symptoms of TR-PTSD at doses as low as 75mg, and as high as 125 mg. Some somatic side effects were more prevalent at lower doses, but no significant difference was detected.

Conclusion

MDMA-assisted psychotherapy is associated with significant decreases in CAPS-IV scores and little effect on BDI in subjects with TR-PTSD, indicating a potential therapeutic benefit with minimal physical and neurocognitive risk.