MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials
APA citation (Click to edit): Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., ... Doblin, R. (2019). MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology, 236(9), 2735-2745. doi: 10.1007/s00213-019-05249-5
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The authors assessed six (randomized, double-blind, and controlled) phase 2 trials of MDMA-assisted psychotherapy for PTSD. These were conducted from April 2004 to February 2017 and warrant phase 3 trials. The experimental groups received 75-125 mg of MDMA, and the control groups received 0-40 mg of a placebo (a harmless pill) in two or three 8-hour therapy sessions spaced a month apart. Three, 90-minute drug-free sessions came before the first drug-exposed session, and after subsequent drug-exposed sessions. After two MDMA-assisted sessions, (1) there was a significant decrease in PTSD symptoms in the MDMA-group and (2) 54.2%% of the MDMA-group (compared to 22.6%% in the placebo group) recovered enough to no longer qualify for CAPS-IV PTSD. Symptoms of depression also improved in the MDMA-group. Thus, MDMA-assisted psychotherapy is well-tolerated (little side effects), effective, and promising for phase 3 trials.
PTSD has an estimated lifetime prevalence of about 4%% worldwide and over 8%% in the U.S. It has extremely impairing symptoms such as intrusive thoughts and flashbacks that can lead to further complications later in life (i.e., hypertension). Psychotherapies like trauma-focused CBT are effective for many PTSD patients but are inaccessible for a sizable population. Medications for PTSD have largely proven ineffective and may come along with poor side effects. Moreover, only two drugs- sertraline and paroxetine- are FDA approved, so it is important for new and effective drugs to be developed.
The combination of psychotherapy with MDMA is a promising approach to PTSD. MDMA may assist therapy by facilitating communication and connection between the therapist and client. Recreational use of MDMA in the 1980s led to the drug becoming classified as a Schedule I drug by the FDA. This made using MDMA for therapy illegal. However, after clinical trials conducted from 2004-2017 regarding the therapeutic benefits of MDMA were evaluated by the FDA, MDMA psychotherapy was granted two phase 3 trials.
Participants had chronic PTSD lasting over 6 months according to the Clinican-Administered PTSD Scale for DSM-IV (CAPS-IV) and had an inadequate response to at least one psychotherapy and/or medication (for PTSD).
Protocols and treatments
At a 1:2 ratio, participants were randomized to receive a placebo/control or active doses of MDMA (75mg, 100mg, 125mg) respectively. During the 8-hour experimental sessions, participants were invited to introspect and revisit traumatic experiences. They then slept overnight at the site and had a 90-minute integration session with the therapist discussing thoughts and feelings during the experimental session. Optional supplemental doses of MDMA (half the first dose) were offered 1.5-2.5 hours after the initial dose in the experimental sessions.
Assessments for CAPS-IV scores (primary outcome), symptoms of depression (secondary outcome), and meeting diagnostic criteria for PTSD (secondary outcome) were done at baseline (before any sessions) and at follow-up visits 1-2 months after the second or third session.
Efficacy of treatments was evaluated with a mixed-effect repeated measure model on change in CAPS-IV scores from baseline to post second and third treatment session.
The average duration of PTSD was 215.3 months. 90.9%% (179/197) of participants took the optional additional dose. 7.6%% (8/105) of participants dropped out of the study.
The active group has average CAPS-IV score drops of 30.4 compared to the control groups 10.5. The effect of the MDMA treatment was large and statistically significant.
After 1-2 months of experimental sessions. 54.2%% of the active group, compared to 22.6%% of the control group, no longer met diagnostic criteria for PTSD. There were greater improvements in symptoms of depression in the active group than the control group.
Commonly (and expectedly) reported treatment-emergent adverse events (TEAEs) during the experimental sessions included psychiatric, gastrointestinal, and general disorders. Over 40%% of participants in either group reported anxiety, dizziness, fatigue, headache, and nausea on the day of the experimental sessions. These symptoms were mild and decreased in frequency over the 7 days after the sessions. Suicidal thoughts increased and were more common in the MDMA group.
The efficacy and tolerability of this MDMA-assisted psychotherapy for PTSD among participants with different forms of trauma make the therapy generalizable. Side effects were mild and tapered off after experimental sessions, making MDMA a safe drug for therapeutic treatments. The most effective dosage (and those tailored to body weight) is not known and will be assessed in phase 3 trials. MDMA was not shown to impair cognition so neurocognitive measurements will not be taken during phase 3 trials. MDMA use in the context of trauma psychotherapy had a low potential for abuse as there were no reports of MDMA use outside of the study, and no treatments were discontinued from MDMA “cravings”.
Participants and therapists were mostly white/caucasian, so the generalizability of results to other ethnicities will be explored in phase 3 trials. Differences in study design and an inability to control for between-group comparisons are some drawbacks of pooled data analyses.