This pre-print review and meta-analysis (2023) of randomised controlled trials (RCTs) assessed the effectiveness of MDMA-assisted psychotherapy (MDMA-AP/AT) for treating Post-Traumatic Stress Disorder (PTSD) and its impact on quality of life and physiological effects. The analysis found that MDMA-AP significantly improved dissociation, depression, and functional impairment in PTSD patients compared to controls, but not sleep quality.
Post-Traumatic Stress Disorder (PTSD) causes broad impairments affecting quality of life. However, despite current treatment many people with PTSD do not fully recover. MDMA assisted psychotherapy has emerged as a new therapy for PTSD and its comorbidities. We aimed to analyse the current evidence for MDMA assisted psychotherapy in PTSD and associated quality of life, and physiological effects, by conducting a systematic review and metanalysis of randomised controlled trials. ClinicalTrials.gov, MEDLINE, PsycINFO, PsycARTICLES, and Cochrane Library database were searched from inception to July 2022. We included both published and unpublished randomized control trials comparing MDMA assisted psychotherapy (MDMA-AP) with control. Meta-analysis of primary and secondary outcome measures was performed using Review-Manager software. Effect sizes were calculated using Standardised Mean Difference for CAPS scores and Mean Difference for secondary measures. MDMA-AP significantly improves dissociation, depression, and functional impairment, compared to controls, but not sleep quality. This data supports the use of MDMA-AP for PTSD with an improvement found in PTSD core symptoms and quality of life measures. While these findings are limited by small samples sizes in currently available clinical trials, this study provides empirical evidence to support development of MDMA-AP in PTSD.
PTSD is a common and often persistent disorder characterised by intrusive memories, avoidance, negative alterations in cognition and mood, and marked changes in arousal. Population surveys report a 12-month prevalence averaging 1.1% internationally and a lifetime prevalence around 8%, with substantially higher rates in some groups such as combat veterans. Despite evidence-based behavioural therapies (for example, cognitive processing or exposure therapies) and pharmacotherapies (SSRIs and SNRIs), a substantial proportion of patients remain symptomatic or develop chronic, treatment-resistant PTSD, creating a demand for novel treatments. This study set out to synthesise randomised controlled trial evidence on MDMA-assisted psychotherapy (MDMA-AP) for PTSD and its associated outcomes. Building on prior trials sponsored largely by the Multidisciplinary Association for Psychedelic Studies (MAPS) and mechanistic theories that MDMA may enhance cognitive flexibility, memory reactivation/reconsolidation, and fear extinction when combined with psychotherapy, Green and colleagues performed a systematic review and meta-analysis to quantify effects on clinician-rated PTSD severity (CAPS) and a set of secondary outcomes including dissociation, functional impairment, depression, sleep quality and physiological measures.
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Bird, C. I. V., Modlin, N. L., Rucker, J. · International Review of Psychiatry (2021)
Emerson, A., Ponté, K. L., Jerome, L. et al. · Journal of Psychoactive Drugs (2014)
Feduccia, A. A., Mithoefer, M. C. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)
Illingworth, B. J. G., Lewis, D. J., Lambarth, A. T. et al. · Journal of Psychopharmacology (2020)
Green and colleagues conducted a systematic review and meta-analysis of randomised controlled trials comparing MDMA-AP with psychotherapy-alone control conditions. Eligible studies enrolled adults with a PTSD diagnosis and used the Clinician-Administered PTSD Scale (CAPS-IV or CAPS-5) as the primary outcome. Trials were excluded if they were preclinical, animal, non-English, reviews, or enrolled children/adolescents. The search covered MEDLINE, PsycINFO, PsycARTICLES, the Cochrane Library and ClinicalTrials.gov from inception to 8 July 2022, and included trial registries to identify unpublished studies. Two reviewers screened titles and abstracts, with a third reviewer resolving disagreements. Data extraction used a customised Covidence template and only intention-to-treat participants were included in analyses. The internal validity (risk of bias) of included trials was independently assessed and results were stratified by study quality; the quality assessment did not determine whether studies were included. For synthesis the investigators used Review Manager v5.4.1 and a random-effects model to allow for between-study heterogeneity. Outcomes measured on the same scale were combined as mean differences (MD); outcomes on different scales used standardised mean differences (SMD; Hedges' g). Ninety-five percent confidence intervals, two-tailed p-values, Tau-squared and I2 were calculated to quantify heterogeneity, and prediction intervals were computed for MD outcomes. The authors interpreted Hedges' g using conventional thresholds (0.2 small, 0.5 medium, 0.8 large).
Six randomised psychotherapy-alone control comparisons were included, with individual study sample sizes ranging from 8 to 91 middle-aged adults and a pooled n reported for primary outcome analyses of 169. Trials spanned 2011 to 2021 and included one unpublished RCT identified via registries. On the primary outcome of PTSD severity (CAPS), the meta-analysis found a large and statistically significant effect favouring MDMA-AP: Hedges' g = 0.93 (95% CI, 0.60 to 1.25; p < .001), with a prediction interval reported as 0.52 to 1.38. Between-study heterogeneity for this outcome was negligible (Q(5) = 1.87; p = 0.87; tau2 = 0.00; I2 = 0%). Secondary outcomes largely favoured MDMA-AP. Dissociation severity (DES-II) showed a significant mean difference of -9.70 (95% CI, -13.39 to -6.12; p < .001; n = 38) with low heterogeneity (I2 = 7%). Functional impairment demonstrated a large standardised effect (g = 0.82; 95% CI, 0.10 to 1.73; p = 0.03; n = 118) with moderate heterogeneity (I2 = 52%). Comorbid depression decreased significantly (MD = -11.13; 95% CI, -19.35 to -2.92; p = 0.008; n = 137) though heterogeneity was substantial (I2 = 72%). Sleep disturbance did not reach statistical significance at the primary endpoint (MD = -3.67; 95% CI, -7.70 to 0.36; p = 0.07; n = 46; I2 = 65%), though authors note improvements at follow-up. Physiological measures indicated an acute increase in heart rate during treatment sessions (MD = 12.88 bpm; 95% CI, 0.97 to 24.79; p = 0.03; n = 32) with no significant pooled increases reported for diastolic or systolic blood pressure or body temperature; heart rate heterogeneity was low (I2 = 0%). Assessments of confidence in the evidence characterised internal validity of the included studies as moderate to high. Excluding two studies judged high risk of bias produced the same primary outcome effect size (reported as g = 0.93 with a 95% CI presented in the extracted text as 1.27 to 0.58; note: the confidence interval ordering in the extraction appears reversed). Egger's regression for publication bias yielded p = 0.07, and one identified RCT was not journal published.
Green and colleagues interpret their findings as evidence that MDMA-AP produces substantial reductions in clinician-rated PTSD severity within a small number of treatment sessions (typically two to three). They highlight the magnitude of the pooled effect on CAPS and emphasise improvements in secondary domains that matter for patients, including dissociation, depression and daily functioning. The authors note that these multi-domain effects may reflect MDMA's hypothesised facilitation of psychotherapeutic processes such as memory reactivation and reconsolidation, enhanced cognitive flexibility, and facilitated fear extinction. Compared with earlier meta-analyses, the present synthesis incorporates two additional RCTs and an unpublished trial and uses a standardised mean difference approach to accommodate CAPS versions (DSM-IV versus DSM-5). The study team reports consistency of the primary effect after excluding higher risk-of-bias trials and found no clear evidence of publication bias on Egger's test. The authors also draw attention to the temporal profile of benefit, reporting maintenance of PTSD symptom reduction in follow-up periods ranging from one to 3.8 years in the included trials. Safety considerations are discussed with respect to acute cardiovascular effects: pooled analyses showed an average heart rate increase of approximately 13 beats per minute during sessions, which the authors interpret as indicative of sympathetic activation and a potential concern for participants with pre-existing cardiac vulnerability. They state this finding does not, in their view, undermine the treatment's safety in the studied samples but argues for caution in populations with cardiac risk. Limitations acknowledged by the investigators include small pooled sample sizes (with only one Phase III trial large enough to be well powered), the single-sponsor nature of the evidence base (MAPS), and the lack of independent standardisation or replication of the specific nondirective psychotherapeutic approach used in these trials. They point out that MDMA-AP has not been tested head-to-head against established psychotherapies such as cognitive processing therapy, trauma-focused CBT or EMDR, nor directly compared with approved pharmacological treatments, which limits conclusions about comparative effectiveness. The authors call for independent, larger RCTs including active comparator arms and further standardisation of the psychotherapeutic component.
The authors conclude that combining MDMA (reported dosing 120–125 mg) with psychotherapy is very effective in reducing PTSD severity on CAPS and produces significant improvements in associated outcomes including dissociation, depression and functional quality of life; sleep quality may improve but did not reach statistical significance at the primary endpoint. They recommend further independent randomised trials with larger cohorts and direct comparisons to established evidence-based psychotherapies and pharmacological treatments, and they stress the need to identify and evaluate an appropriate evidence-based psychotherapeutic approach to pair with MDMA in future studies.
Post-traumatic stress disorder (PTSD) is a devastating condition that develops in some individuals who fail to recover from exposure to extreme threatening situations, including actual or threatened death, serious injury, or sexual violence. Symptoms include intrusive thoughts, avoidance, negative alteration in cognitions and mood, and marked alterations in arousal and reactivity. Epidemiologic studies of international population data from 20 countries in a WHO World Mental Health Survey Initiative showed 12-month PTSD prevalence averaged 1.1%, ranging between 0.2-3.8%. While the aggregate lifetime prevalence of PTSD is estimated to be approximately 8%, the rate is substantially higher in certain populations. In United States veterans following combat in Iraq, prevalence rates vary from 9% to 31%. Despite its prevalence rate, unfortunately many patients do not recover from PTSD. Approximately one-fifth of patients develop an unremitting condition. Current treatment protocols include behavioural therapies (cognitive processing therapy and exposure therapy) usually over a 12-week period, and pharmacological therapies using SSRI and SNRI based treatments (fluoxetine, sertraline, paroxetine, and venlafaxine) these options do not provide complete recovery in all patients. Given the prevalence, impact, and lack of recovery in some patients, new and more successful treatment options for PTSD are urgently needed. Psychedelics have been experimented with to assist psychotherapy since the 1970s and are currently ongoing a resurgence in interest for therapeutic use, including recent approval for use in PTSD by the Australian Therapeutic Goods Administration (TGA). 3,4-Methylenedioxy methamphetamine (MDMA) was first synthesised in 1912 and is used as an illicit recreational drug commonly referred to as 'ecstasy'. A lack of new treatments for PTSD has compelled renewed interest in psychedelic pharmacological research (John H. To date the Multidisciplinary Association for Psychedelic Studies (MAPS) is the only sponsor of global MDMA RCTs. MAPS have developed their own manualized MDMA assisted psychotherapeutic approach (MDMA-AP), involving 2 -3 sessions of treatment. A key element of the therapy is its non-directive approach (for full details see). They hypothesised the pharmacokinetic action of MDMA, in combination with unique psychotherapy stimulates cognitive flexibility and reduces barriers to treating traumatic memories. The mechanism of change is theorised to include memory reactivation, reconsolidation, and facilitated fear extinction. Previous metaanalyse find MDMA-AP reduces PTSD symptoms in treatment-resistant and severe PTSD populations and included analysis of safety and adverse events. Data indicates the MDMA treatment effect is long-lastingand is effective in participants who are non-response to SSRI treatments
We considered RCTs whose primary outcome variable was measured with the clinically administered PTSD scale (CAPS-IV, or CAPS-5) with either an active control or placebo comparator. Studies were included with adult participants diagnosed with PTSD. MDMA must have been clinically administered with psychotherapy to reduce PTSD symptoms. Comparison interventions were limited to psychotherapy alone. Studies were excluded if they were pre-clinical, animal, non-English, review articles, and infant or adolescent participants. Information Sources and Study Selection MEDLINE, PsycINFO, PsycARTICLES, Cochrane Library database, and ClinicalTrials.gov were searched from inception until Friday, July 08, 2022. A specific approach was adopted using a highly sensitive search strategy (J. P.for identifying RCTs indexed with associated medical subject headings (MeSH) termsClinical trial registries were included in our search strategy to identify studies that have not been published in a journal to identify publication bias and selective reporting. Three researchers including one non-content expert, were assigned as reviewers to minimise review author bias. Two reviewers: (W.G., F.H.) screened the title and abstract, and selected studies were full text reviewed. Discrepancies were resolved by discussion. A third reviewer: (L.J.) resolved conflicts. Full texts were prepared for data extraction. Six measures were identified for data collection and obtained after last treatment session. Effects of treatment were determined by using the difference in score following treatment. independently assessed the included study's internal validity. To determine the risk, we checked if the included study authors reported the method used to address RoB in the journal or protocol publication. The quality assessment did not influence the decisions to synthesise any data.
Where studies assessed the outcome of the dependent variable on the same measurement scale we combined the mean change score, standard deviation, and intention to treat sample size to calculate the mean difference (MD). Where the outcome of the dependent variable was assessed on different measurement scales, a standardised mean difference (SMD) model was used (J. P.. The SMD is defined by Hedges (adjusted) g.
Covidence v2930, a web-based collaboration software program that streamlines the production of systematic reviews to administer the included studies was used with a customised template v2.0 to extract data. Only intention to treat participants were included. A meta-analysis for each primary and secondary outcome measure was performed using Review Manager v.5.4.1. We set a random effects model because it is assumed there is sample heterogeneity. We calculated 95% confidence intervals and two-tailed p-values. The between-study variance was estimated with Tau 2 . Heterogeneity was calculated with a chi-squared test producing an I 2 statistic to assess the observed variance assuming all sampling errors could be removed. We considered an I 2 value using the following thresholds: (a) 0% to 40%, might not be important; (b) 30% to 60%; may represent moderate heterogeneity, (c) 50% to 90%, may represent substantial heterogeneity; (d) 75% to 100%, considerable heterogeneity (J. P.. To measure the true variance, we calculated prediction intervals with the CMA prediction interval program using the MD. In SMD models we used Cohan's rule of thumb to interpret Hedges g: (a) 0.2 = small; (b) 0.5 = medium; (c) 0.8 = large.
The study selection procedure is shown in Figure. 82 records were identified of which 27 reports sought for retrieval met the eligibility criteria. Six randomised psychotherapy-alone control comparisons were included for data extraction. Sample sizes ranged from 8 to 91 middle-aged adults. Tableand
A large effect of MDMA-AP occurring in 2-3 treatments sessions was observed on primary outcomes (PTSD symptoms: g = 0.93; 95% CI, 0.60 to 1.25; p<.001; PI, 0.52 to 1.38; n = 169). There was no significant amount of heterogeneity (Q(5) = 1.87; p = 0.87; tau 2 = 0.00; I 2 = 0.00%). For most secondary measures the outcome was significant and with similarly large effect sizes. For, independently measured, dissociation severity the mean difference (MD) was -9.7; 95% CI, -13.39 to -6.12; p<.001; n = 38. For, independently measured, daily functioning the standardised mean difference calculate effect size was g = 0.82; 95% CI, 0.10 to 1.73, p = 0.03; n = 118. For, independently measured, comorbid depression the mean difference (MD) was, -11.13; 95% CI, -19.35 to -2.92; p = 0.008; n = 137. The observed result was smaller and not significant in sleep disturbance severity (MD, -3.67; 95% CI, -7.70 to 0.36; p = 0.07, n = 46). Of physiological measures heart rate was observed to increase (MD, 12.88; 95% CI, 0.97 to 24.79; p = 0.03; n = 32). Heterogeneity varied (dissociation severity: I 2 = 7.00%; comorbid depression: I 2 = 72.00%; functional disability: I 2 = 52.00%; sleep disturbance: I 2 = 65.00%; heart rate: I 2 = 0.00%). See Figure.
Internal validity of the included studies was moderate to high. Results were stratified by study quality, see figure. The same effect on the primary outcomes emerged with a small broadening of confidence intervals was observed after two high RoB studies were excluded from the analysis (g = 0.93; 95% CI, 1.27 to 0.58; p<.001). There is no evidence of publication bias measured with Eggars Regression (p = 0.07). One study not journal published was detected. However, MDMA use protocol requires clinical trials to be registered therefore there is no reason to believe other null or weaker studies exist. This meta-analysis is the most current and complete assessment of MDMA-AP in people diagnosed with severe or treatment resistant PTSD, synthesizing six RCTs conducted between 2011 and 2021. Importantly, we also include the first comprehensive analysis of secondary outcome measures and find MDMA-AP significantly improves dissociation, depression, and functional impairment, finding large effect sizes compared to controls, but not for sleep quality. This study is also the first meta-analysis to examine the effect of MDMA-AP in RCTs on physiological measures of heart rate, diastolic and systolic blood pressure, and body temperature, finding participants experience a significant increase in heart rate during treatment sessions. Together, these new results provide evidence for broad therapeutic advantages of MDMA-AP across the PTSD symptom profile. The present meta-analysis finds MDMA-AP has effects on PTSD symptoms within a few treatment sessions. Traditional therapies including Cognitive Processing Therapy and SSRI treatments take weeks to months for symptom relief to occur. In contrast, in the studies identified in this systematic review and meta-analysis we find MDMA-AP symptoms improvements can occur within 2-3 treatment sessions. Participants were previously unsuccessful using current treatment approaches however they reported a significant reduction in PTSD symptoms and comorbid conditions after MDMA-AP. Therapies with effects in minimal treatment sessions are likely to get more compliance with increased satisfaction. In addition to having rapid effects on PTSD symptoms measured with CAPS, we find MDMA-AP also acts on key secondary measures of PTSD in randomised clinical trials. Dissociation is a hallmark of severe PTSD and is characterised by depersonalisation and derealisation symptoms. Our results indicate MDMA-AP treatment significantly reduces DES II scores compared to control. This suggests the treatment reduces dissociation severity and is likely because MDMA enhances the psychotherapeutic process that reduces the intense emotions associated with PTSD. The result is clinically useful because almost half of PTSD diagnoses include dissociation incidents. The current meta-analysis shows MDMA-AP reduces comorbid depression. Treatment guidelines for PTSD advise treatment efficacy is limited by severe depression. However, this result supports the rationale that psychedelics reduce both PTSD symptoms and comorbid depression. The present meta-analysis includes two more RCTs and contradicts a previous meta-analysis bywhich showed MDMA-AP does not reduce depression. This result identifies a reduction in severe comorbid depression in PTSD. Decreasing PTSD symptoms and comorbid conditions has been shown to improve cognitive capacity, daily functioning, and quality of life. As individuals' ability to mobilise the help they require increases, their health conditions decrease. The present meta-analysis demonstrates participants treated with MDMA-AP experience improvements in daily functioning across psychological, social, and occupational domains compared to controls. Furthermore, following treatment, participants report their PTSD symptom improvement remains stable from one to 3.8 years, implying a similar long-term improvement in daily functioning. A cardinal feature of PTSD is sleep disturbance. Correspondingly, decreasing PTSD symptoms increases sleep quality to improve quality of life. Our results indicate MDMA-AP reduces PQSI scores used to measure sleep quality however the reduction in score was not statistically significant (p = 0.07). Sleep quality is observed to improve at follow-up. Perhaps the result was not significant because sleep disturbance is assessed at the primary endpoint when the acute effect of MDMA on participants is extant. PTSD symptom, comorbid condition and functional disability improvement may result in a delayed reduction in sleep disturbance. The meta-analysis showed MDMA-AP increases heart rate during treatment sessions but not diastolic blood pressure or body temperature. Results indicate the treatment's acute effect increases heart rate by an average of 13 bpm compared to controls. This finding supports a relationship between cardiac-specific effects and the risk of cardiac dysfunction. MDMA is known to increase sympathetic nervous system activation and therefore increase cardiac vulnerability in PTSD. The result does not challenge the intervention's safety in people with treatment-resistant PTSD. Instead, it suggests caution as future participants with underlying cardiac vulnerability may be at risk. In addition to our findings on PTSD symptoms and secondary measures, this meta-analysis has several important strengths. In this study we have advanced our understanding of MDMA-AP by including the results of an unpublished RCT and our meta-analysis has allowed for variation in CAPS scales. While both the construct (PTSD) and the measure (CAPS) were consistent across studies, we identified that different studies used different versions of CAPS (DSM-IV versus DSM-5) with a different score range. While previous meta-analyseshave used the mean difference to compare RCT our use of the standardized mean difference approach accounts for version differences of CAPS. The results of this study indicate benefits of MDMA-AP for the treatment of PTSD, however there are limitations of the findings of this meta-analysis. In its current form, MAPS nondirective psychotherapy has not been tested as a stand-alone therapy against established psychotherapies (for example, CPT, Trauma focused CBT, EMDR). Moreover, this therapy has not been independently standardised and replicated outside of MAPS and requires more research on PTSD patients worldwide. An additional limitation is the single study sponsor for all studies, highlighting the need for independent replication. An additional limitation of the findings is the small sample sizes that do not provide sufficient power to measure the secondary and primary outcomes in all studies except the single Phase 3 RCT.
Evidence indicates that combining MDMA (120mg -125mg) with psychotherapy to be very effective in reducing PTSD CAPS scores as well as significantly improving secondary PTSD measures and co-morbidities including dissociation, depression, quality of life and may also improve sleep quality. Together, this evidence provides a wide and comprehensive clinical picture for PTSD symptom improvement using MDMA-AP. Independent research groups need to assess the effect in more RCTs including comparisons with existing evidencebased therapies, existing FDA approved pharmacological treatments and in larger cohorts to increase the certainty of the findings. Most importantly, the type of psychotherapy practised in these trials is a substantial limiting factor in the clinical utility of this breakthrough treatment, a suitable evidence-based psychotherapy to combine with MDMA must be identified and evaluated in future trials. Funding acknowledgement: We acknowledge University of Tasmania, College of Health and Medicine for funding and support.
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Mithoefer, M. C., Feduccia, A. A., Jerome, L. et al. · Psychopharmacology (2019)
Mithoefer, A. T., Mithoefer, M. C., Feduccia, A. A. et al. · Lancet Psychiatry (2018)
Ot'alora G, M., Grigsby, J., Poulter, B. et al. · Journal of Psychopharmacology (2018)
Passie, T., Benzenhöfer, U. · Journal of Psychoactive Drugs (2016)
Ponte, L., Jerome, L., Hamilton, S. et al. · Journal of Traumatic Stress (2021)