3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial
Mithoefer, M. C., Mithoefer, A. T., Feduccia, A. A., Jerome, L., Wagner, M., Wymer, J., Holland, J., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2018). The lancet. Psychiatry.
Methodology: Dose-Response RCT in Veterans and First Responders. This randomized, double-blind study used a dose-response design with three groups receiving two day-long therapy sessions. Standardized manualized psychotherapy was provided in all sessions, and after the blinded phase, participants in the two lower-dose groups were offered additional open-label sessions with full doses (100–125 mg).
Sample: 26 participants (84% veterans)
Dosage: 30 mg (low-dose control), 75 mg, or 125 mg MDMA (administered orally with a second booster dose in each session).
Key Findings:
– One month after the second session (primary endpoint), the higher MDMA doses led to dramatically greater reductions in PTSD symptoms than the low-dose control. Mean CAPS-IV (Clinician-Administered PTSD Scale) scores decreased by ≈58 points in the 75 mg group and 44 points in the 125 mg group, vs ~11 points in the 30 mg control (p=0.001).
– Effect sizes were large (Cohen’s d=2.8 for 75 mg vs control). In clinical terms, a much higher proportion of patients no longer met PTSD diagnostic criteria in the active-dose groups by follow-up. (For example, in the 75 mg group 86% no longer had PTSD, compared to 29% in the low-dose group, reflecting the robust response to active MDMA.)
– After all groups had the opportunity to receive full-dose MDMA in open-label crossover sessions, symptom improvements persisted. At 12-month follow-up (after full-dose MDMA for all), CAPS scores remained far below baseline (mean ~39 vs 87 at baseline; p<0.0001), indicating sustained remission in many participants.
– The treatment was well tolerated; while transient expected side effects occurred (e.g. elevated heart rate, blood pressure), there were no serious drug-related adverse events.
Implications:
This study provided the first rigorous evidence that MDMA-assisted psychotherapy can produce large, durable reductions in PTSD symptoms in a trauma-exposed population that typically shows poor response to standard treatments.
Citation: Mithoefer, M. C., Mithoefer, A. T., Feduccia, A. A., Jerome, L., Wagner, M., Wymer, J., Holland, J., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2018). 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The lancet. Psychiatry, 5(6), 486–497. https://doi.org/10.1016/S2215-0366(18)30135-4
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
Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2019). Psychopharmacology.
Methodology: Following several Phase 2 studies conducted at different sites, researchers pooled data from six randomized controlled Phase 2 trials (conducted 2004–2017) to inform Phase 3 design. All trials followed a similar methodology: participants received 2–3 eight-hour MDMA-assisted therapy sessions, approximately a month apart. Each MDMA session was preceded by preparatory psychotherapy and followed by multiple integrative therapy sessions, per the standardized protocol.
Sample: 103 participants (72 assigned to MDMA and 31 to placebo or very low-dose control) with chronic PTSD from various causes (both military and civilian trauma).
Dosage: 75–125 mg MDMA (full therapeutic dose) in the active groups vs. 0–40 mg (placebo or sub-therapeutic dose) in control groups.
Key Findings:
– After two blinded sessions, the MDMA groups had significantly greater reduction in PTSD severity than controls. The mean change in CAPS-IV score was about 22 points more in the MDMA group than in controls (p<0.001), with a large between-group effect size (d≈0.8).
– Clinically, over half (54%) of MDMA-treated participants no longer met PTSD criteria after two sessions, compared to 22% of the control group.
– MDMA therapy also showed a trend toward greater improvement in depression symptoms (measured by BDI-II) than therapy alone.
– No new safety concerns emerged – all doses were well tolerated, and while some expected acute reactions (e.g. anxiety, jaw tightness, temporary blood pressure changes) were more frequent with MDMA, there were no serious adverse events attributable to the drug.
Implications:
This pooled analysis concluded that MDMA-assisted psychotherapy was efficacious and well-tolerated in a relatively large sample of adults with PTSD, justifying progression to Phase 3. In fact, on the strength of these Phase 2 findings, the FDA granted MDMA-assisted therapy a “Breakthrough Therapy” designation in 2017 to expedite further research.
Citation: Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & 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. https://doi.org/10.1007/s00213-019-05249-5 (Retraction published Psychopharmacology (Berl). 2024 Nov;241(11):2405. doi: 10.1007/s00213-024-06666-x.)
MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study
Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., Ot’alora G, M., Garas, W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells, G., Klaire, S. S., van der Kolk, B., Tzarfaty, K., … Doblin, R. (2021). Nature medicine.
Methodology: Multi-site, randomized, double-blind, placebo-controlled study. Participants were randomized 1:1 to MDMA-assisted therapy (MDMA-AT) vs. placebo plus therapy, with three MDMA (or placebo) sessions administered under therapeutic guidance. The therapy protocol was the MAPS manualized approach: each participant had 3 preparatory psychotherapy sessions, 3 day-long experimental sessions (with either MDMA or placebo administered in each, alongside two therapists), and 9 integrative therapy sessions (three after each experimental session). The placebo group underwent identical therapy and received an inert placebo capsule on the same dosing schedule. Outcomes were assessed two months after the last session.
Sample: 90 adults with severe PTSD (including many with comorbid conditions like dissociative subtype PTSD, depression, and histories of substance use or childhood trauma). Importantly, this Phase 3 had a general adult population with diverse trauma backgrounds, only ~19% were veterans, while others had PTSD from civilian trauma (sexual assault, accidents, etc.).
Dosage: The MDMA dosing regimen was a flexible split-dose: in the first MDMA session, participants received ~80 mg MDMA followed by a 40 mg booster ~1.5–2 hours later; in sessions 2 and 3, the dose was typically increased to 120 mg plus a 60 mg booster (total 180 mg) if tolerated.
Key Findings:
– MDMA-assisted therapy produced significantly greater improvements in PTSD symptoms and functional impairment than therapy with placebo. The primary outcome, CAPS-5 total severity, dropped much more in the MDMA group: mean change –24.4 vs. –13.9 points in placebo by study end (among treatment completers).
– Statistically, MDMA-AT led to a robust attenuation of PTSD symptoms (p<0.0001 vs placebo), with a large effect size (d = 0.91).
– The key secondary outcome, functional impairment on the Sheehan Disability Scale (SDS), also improved more with MDMA (p=0.0116, d = 0.43).
– By the study’s end, 67% of participants in the MDMA group no longer met PTSD diagnostic criteria, compared to 32% in the placebo+therapy group (reflecting the added value of MDMA)
– The MDMA sessions did not precipitate any serious adverse events. There were no signs of increased suicidality, no cardiotoxic effects (e.g. no concerning QT prolongation), and no cases of substance abuse or addiction behaviors related to the study drug.
– Expected mild–moderate side effects (transient anxiety, jaw tension, headache, etc.) occurred but were manageable.
Implications:
Overall, the treatment was deemed safe and well-tolerated even in participants with multiple comorbidities. Investigators characterized MDMA-assisted therapy as a potential breakthrough treatment for severe PTSD, given the high efficacy observed in this trial.
Citation: Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., Ot’alora G, M., Garas, W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells, G., Klaire, S. S., van der Kolk, B., Tzarfaty, K., … Doblin, R. (2021). MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature medicine, 27(6), 1025–1033. https://doi.org/10.1038/s41591-021-01336-3
MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial
Mitchell, J. M., Ot’alora G, M., van der Kolk, B., Shannon, S., Bogenschutz, M., Gelfand, Y., Paleos, C., Nicholas, C. R., Quevedo, S., Balliett, B., Hamilton, S., Mithoefer, M., Kleiman, S., Parker-Guilbert, K., Tzarfaty, K., Harrison, C., de Boer, A., Doblin, R., Yazar-Klosinski, B., & MAPP2 Study Collaborator Group (2023). Nature medicine.
Methodology: Randomized, double-blind, placebo-controlled design and identical therapy protocol to previous study, but notably expanded the sample size and diversity.
Sample: 104 adults with moderate-to-severe PTSD were randomized (53 MDMA vs 51 placebo). Traumas ranged widely (combat, interpersonal violence, childhood abuse, etc.), and over 70% of participants had severe PTSD (CAPS-5 scores indicating severe range. This cohort deliberately included a more ethnoracially diverse population (about one-third identified as non-White, and ~27% as Hispanic/Latino) and a higher proportion of female participants than prior studies.)
Dosage: The MDMA dosing regimen was the same as in MAPP1 (80 mg + 40 mg booster in session 1, then 120 mg + 60 mg in sessions 2 and 3).
Key Findings:
– Consistent with the prior trial, MDMA-assisted therapy again showed superior efficacy to therapy alone. By the primary endpoint (18 weeks, after three sessions), the MDMA group had a significantly larger decrease in PTSD severity on CAPS-5: mean change –23.7 points from baseline, versus –14.8 in the placebo group (p < 0.001). The between-group effect size was d ≈ 0.7 (moderate-to-large).
– Importantly, functional impairment (SDS score) also improved significantly more with MDMA (mean change –3.3 vs –2.1, p = 0.03, d = 0.4).
– These outcomes closely mirrored MAPP1, confirming that MDMA-augmented therapy yields greater PTSD symptom reduction and better functional recovery than psychotherapy alone
– Population-specific notes: This trial demonstrated efficacy in a broader patient population, including survivors of prolonged childhood trauma and those with dissociative PTSD, who responded well to MDMA-AT. It also showed that results generalize across ethnic groups and both sexes.
– The overall safety profile remained favorable. There were no deaths, and no serious treatment-related adverse events.
– A small number of participants experienced what were classified as severe adverse events (SAEs) during the study (5 in the MDMA group vs 2 in placebo), but these were resolved and none were life-threatening or led to study discontinuation.
– Typical side effects of MDMA (e.g. transient blood pressure elevation, muscle tightness, or mood changes in the week after sessions) were observed but manageable.
Implications:
The authors conclude that this confirmatory trial provides strong evidence that MDMA-assisted therapy is effective for moderate-to-severe PTSD and can be delivered safely in a diverse sample.
Citation: Mitchell, J. M., Ot’alora G, M., van der Kolk, B., Shannon, S., Bogenschutz, M., Gelfand, Y., Paleos, C., Nicholas, C. R., Quevedo, S., Balliett, B., Hamilton, S., Mithoefer, M., Kleiman, S., Parker-Guilbert, K., Tzarfaty, K., Harrison, C., de Boer, A., Doblin, R., Yazar-Klosinski, B., & MAPP2 Study Collaborator Group (2023). MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature medicine, 29(10), 2473–2480. https://doi.org/10.1038/s41591-023-02565-4
MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial
Monson, C. M., Wagner, A. C., Mithoefer, A. T., Liebman, R. E., Feduccia, A. A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Doblin, R., & Mithoefer, M. C. (2020). European journal of psychotraumatology.
Methodology: This open-label pilot (uncontrolled trial) investigated MDMA as an adjunct to couples therapy for PTSD, recognizing that interpersonal relationships are an important facet of recovery. The therapy was a condensed 7-week course of Cognitive-Behavioral Conjoint Therapy (CBCT), a structured couples therapy for PTSD. The novel element was that both partners received MDMA together during two of the therapy sessions. Specifically, the protocol included 15 therapy sessions (focused on improving communication, reducing avoidance, and processing trauma together), delivered over 7 weeks, with 2 day-long sessions where MDMA was administered to both the patient and the partner in a comfortable, facilitated setting.
Sample: 6 couples in which one partner had chronic PTSD (the majority were believed to be military veterans and their spouses).
Dosage: MDMA dosing was individualized (typically in the 75–100 mg range with a possible booster) and aimed at producing empathogenic effects to enhance the therapeutic alliance and openness between partners.
Key Findings:
– All six couples completed the treatment, and no serious adverse events occurred in patients or partners, indicating the safety and tolerability of MDMA in a couples therapy context.
– PTSD symptoms improved significantly from pre- to post-therapy, as measured by independent clinician ratings as well as patient and partner reports. PTSD severity reductions were large, with within-subject effect sizes ranging from d = 1.85 to 3.59 (a very large improvement) across different PTSD measures.
– In fact, several patients no longer met PTSD criteria after the conjoint therapy. Moreover, there were notable benefits to comorbid and interpersonal outcomes: patients’ depression and sleep quality improved, emotion regulation enhanced, and trauma-related negative beliefs reduced.
– Relationship functioning also benefited, both patients and partners reported improved relationship satisfaction and adjustment after the therapy (effect sizes for relationship outcomes d = 0.64–2.79).
– Partners themselves, who did not have PTSD, reported personal growth and better understanding of the patient’s trauma.
Implications:
This pilot suggests that MDMA can be successfully integrated with evidence-based couples therapy, potentially producing broad benefits not only in PTSD symptoms but also in relationship health and partner well-being. Although uncontrolled and small, this study highlights how MDMA’s prosocial effects may amplify therapeutic processes in a family or couples setting. It holds promise for expanding MDMA treatment to dyadic formats to support both PTSD patients and their loved ones.
Citation: Monson, C. M., Wagner, A. C., Mithoefer, A. T., Liebman, R. E., Feduccia, A. A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Doblin, R., & Mithoefer, M. C. (2020). MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial. European journal of psychotraumatology, 11(1), 1840123. https://doi.org/10.1080/20008198.2020.1840123