This systematic review and meta-analysis (2020) found 5 trials (n=106) that found large reductions in PTSD symptoms after MDMA-assisted psychotherapy. The studies showed large improvements, but were only moderate in quality.
Abstract
“Background: Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD.
Aim: To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken.
Methods: Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane’s Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology.
Results: A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies.
Conclusions: MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted—and underway.
Authors: Anees Bahji, Ashleigh Forsyth, Dianne Groll & Emily R. Hawken
Summary
A systematic review and meta-analysis was undertaken to assess the effectiveness and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for reducing symptoms of posttraumatic stress disorder (PTSD). The results indicated that MDMA-assisted psychotherapy was well-tolerated, with few serious adverse events reported across studies.
- Background
Posttraumatic stress disorder (PTSD) is a complex mental disorder that can follow a traumatic experience, such as natural disaster, sexual violence, or other life-threatening circumstances. It has a tremendous impact on public health and the economy.
Since the wars in Iraq and Afghanistan, PTSD has become an internationally popular research topic. The most recent clinical practice guidelines include psychotherapies, antidepressant medications, or a combination of both. Several meta-analyses have shown that psychotherapy is an effective treatment for PTSD, including cognitive processing therapy (CPT), EMDR, and TF-CBT. Individual CPT treatment results in greater improvement in PTSD severity than group CPT treatment, however, rates of nonresponse are high.
The only FDA-approved medication for PTSD is selective serotonin reuptake inhibitors (SSRIs), but SSRIs are less effective than psychotherapy for PTSD. Other medications, including antipsychotics, mood stabilizers and anxiolytics, are frequently used as off-label treatments for particular symptoms in PTSD. Despite current treatment options, many patients with PTSD are nonresponders to first-line therapies, and may develop serious side effects to regular pharmacological treatment options.
High rates of emergent and treatment refractory PTSD have spurred a search for novel treatment approaches. However, propranolol and d-cycloserine have also been shown to be ineffective in other studies.
MDMA-assisted psychotherapy is a treatment approach in a different setting from illicit “ecstasy” obtained from a non-medical setting. It facilitates therapeutic techniques such as revisiting traumatic experiences with an appropriate level of emotional engagement.
Although clinical research suggests that MDMA-assisted psychotherapy is effective in individuals with treatment-refractory PTSD, MDMA has not yet been approved by regulatory agencies. However, the FDA has recently granted Breakthrough Therapy designation.
Although some doubt the efficacy of MDMA-assisted psychotherapy, a systematic review and meta-analysis of randomized controlled trials demonstrated that MDMA-assisted psychotherapy is an effective treatment for PTSD.
2.1. Searchstrategy
This systematic review was performed in accordance with the PRISMA guidelines and included studies in English and non-English languages. Selected researchers were contacted to identify unpublished study reports and conference proceedings likely to contain trials relevant to the review were also reviewed.
2.2. Eligibilitycriteria
We included studies that used MDMA in combination with psychotherapy to reduce the symptoms and signs of PTSD. These studies were conducted in either inpatient or outpatient settings and included participants diagnosed with PTSD or who were likely to have TR-PTSD.
2.3. Studyselectionanddataextraction
Four authors independently assessed the titles and abstracts of records retrieved from a systematic search and agreed on the inclusion and exclusion decisions. During the first stage, articles were excluded based on the title and abstract, and in the second stage, all authors independently reviewed the full text of articles. The key findings of studies were summarized descriptively, and the capacity for quantitative meta-analysis was considered.
- Dataanalysis
The following outcome measures were considered: number of participants showing clinically-significant response or remission at the end of treatment, intensity of PSTD symptoms, need for additional as-needed (PRN) medications, nature, incidence and frequency of adverse effects, completion of scheduled treatment, and number of participants engaged in further treatment.
Meta-analyses were performed using Review Manager 5.3 (Cochrane Systematic Reviews, 2014) and included four measures: likelihood of response, likelihood of remission, effect size, and durability of effect.
Clinical and methodological heterogeneity was assessed by comparing study characteristics, interventions, and reported outcomes. A p value of 0.05 or an I2 statistic of 50% indicated statistically significant heterogeneity.
Studies were grouped by outcome measure and moderators were not assessed due to the small number of studies included.
3.1. Assessmentofriskofbiasandstudyquality
Researchers extracted sufficient information from included studies to assess the risk of bias. The Cochrane Risk of Bias Tool was used to assess study quality, and publication basis was qualitatively evaluated.
4.1. Systematicreview
A search strategy identified 443 unique records from which 49 different studies were identified as potentially relevant to this review. Five studies with 106 participants were ultimately included in the meta-analysis.
These five studies spanned a 13 year period (2004-2017) and included participants with chronic PTSD who had failed to show a significant clinical response to at least one first-line treatment. The majority of participants had comorbid depression or anxiety, but all studies excluded participants with more severe comorbid mental illnesses.
All five studies were undertaken in primarily outpatient settings and used the same format of psychotherapy: a manualized supportive therapy modality developed by MAPS.
There was significant heterogeneity in the nature of the experimental designs across studies, which limited the extent of analysis that was possible. MDMA dosage varied from 50 mg to 125 mg, and antidepressant medications were discontinued at least one month before initiation of the course of MDMA-assisted psychotherapy.
4.2. MDMA-assistedpsychotherapyshowedtreatmentresponseforPTSD symptoms
MDMA-assisted psychotherapy was associated with a high rate of treatment response in participants with PTSD. The risk of publication bias was small, as the funnel plot was symmetric, and the results were similar when the Bouso 2008 study was omitted as part of a sensitivity analysis.
4.3. PTSDsymptomscoresimprovedfollowingMDMA-assisted psychotherapy
MDMA-assisted psychotherapy resulted in a significant reduction in the number and intensity of PTSD symptoms with the completion of treatment. The funnel plot for this meta-analysis was symmetric, indicating low risk of publication bias.
MDMA-assisted psychotherapy retained its therapeutic effect in follow-up, highlighting its potential durability. The effect of MDMA-assisted psychotherapy on the PTSD symptom score was found to be large, and the effect lasted several months after the completion of the intervention.
4.5. Dose-responseeffects
Two dose-response studies found that MDMA-assisted psychotherapy can be safely administered in a clinical setting, but the results diverged in terms of reported efficacy.
In contrast to previous studies, Mithoefer and colleagues found that 75 mg and 125 mg doses of MDMA had significantly greater decreases in PTSD symptom severity than 30 mg dose. Furthermore, in the open-label crossover with full-dose MDMA, PTSD symptoms significantly decreased in the group that had previously received 30 mg.
4.6. Adverseevents
MDMA-related serious adverse events were reported in one study, but were deemed unrelated to the study drug.
- Discussion
In this meta-analysis, participants who received MDMA-assisted psychotherapy for chronic, treatment-refractory PTSD were more likely to show a clinical response, remission, and a significant reduction in PTSD symptom scores.
MDMA-assisted psychotherapy for PTSD shows promise in several published reviews, including increased emotional tolerance when facing traumatic experiences and memories, and promote fear extinction processes. However, there is insufficient evidence to support the broad therapeutic use of MDMA-assisted psychotherapy over conventional treatments for PTSD. PTSD is thought to be related to a hyperactive sympathetic nervous system, and a dysregulated noradrenergic system, which is evidenced by an increased baseline noradrenergic tone and an increased noradrenergic response to stimuli in individuals with PTSD. Pharmacological challenge studies in humans and neuropsychological studies in patients with PTSD provide evidence that NA plays a role in PTSD. MDMA inhibits the human NA transporter more potently than the serotonin transporter.
MDMA can be used to facilitate the fear-extinction process, which is an important mechanism of MDMA-assisted psychotherapy. MDMA can also be used to facilitate the recall of traumatic memories without the user feeling overwhelmed by the negative affect that usually accompanies such memories.
MDMA-assisted psychotherapy has been shown to have comparable treatment outcomes to prolonged exposure, one of the first-line therapies for PTSD. It may help individuals with PTSD to remain emotionally and psychologically engaged to prevent individuals from becoming overwhelmed with anxiety or fear when experiencing traumatic memories.
The unique subjective effects of MDMA are likely due to its ability to boost serotonin, oxytocin, prolactin, and cortisol. MDMA may also be helpful in the treatment of major depression and depressive symptoms.
- Strengths&limitations
This study presents the first meta-analysis of MDMA-assisted psychotherapy for PTSD. The study has several strengths and limitations, including a small size and low degree of heterogeneity.
While the findings are promising, several limitations should be considered including small sample sizes and the between-study variability. Furthermore, while publication bias was generally considered low, studies with negative or neutral findings are less likely to be published. There may be other sources of bias in this study, including variability in the way chronic PTSD is defined in the literature and in clinical practice, and a lack of a control group for comparison with the long-term follow-up. Studies of MDMA-assisted psychotherapy for the management of PTSD may be lacking for several reasons, including study design issues specific to psychoactive drugs like MDMA. However, there are several ongoing trials exploring an array of MDMA-augmented psychotherapeutic strategies.
- Conclusions
We systematically reviewed and meta-analyzed five trials evaluating MDMA-assisted psychotherapy for treating chronic, treatment-refractory PTSD. The trials demonstrated significant improvements in PTSD symptoms following intervention that extended long-term with few reported adverse effects.
Contributionsofauthors
AB, AF, DG, and EH conceived and designed the study. AB drafted the manuscript, and all authors critically revised it.
Acknowledgements
The following study variables were coded: first author, funding source, sample size, country of study, description of recruitment measures, gross description of study design, description of primary and secondary outcome measures, MDMA regimen, and psychotherapy-assisted study.
Demographic variables were coded according to the following: female, ethnic group, single, married, divorced/separated, or widowed.
Psychiatric history variables included a history of alcohol, cannabis, tobacco, MDMA, psilocybin, illicit drug, or “other” drug use, a history of PTSD, a history of mood, anxiety, or eating disorder, and a history of prescribed medications.