Lancet Psychiatry
May 1, 2018
Michael C Mithoefer, Ann T Mithoefer, Allison A. Feduccia et al.
443 citations
A randomized, double-blind, phase 2 clinical trial tested MDMA-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers. Participants were randomly assigned to receive different doses of MDMA during psychotherapy sessions. The findings revealed that the active dose of MDMA led to significant and lasting reductions in PTSD symptoms compared to the lower dose, indicating that this innovative therapeutic approach can effectively treat this condition and provide significant relief for individuals with profound trauma.
Psychopharmacology
September 1, 2019
Michael C Mithoefer, Allison A. Feduccia, Lisa Jerome et al.
364 citations
A pooled analysis of six phase 2 trials found that MDMA-assisted psychotherapy significantly reduced PTSD symptoms in adults. Participants receiving active MDMA (75-125 mg) during manualized therapy sessions showed a large treatment effect (Cohen's d = 0.8) compared to those receiving placebo or low doses (0-40 mg). After two sessions, 54.2% of the active group no longer met PTSD diagnostic criteria versus 22.6% of the control group. Depression symptoms also improved more in the active group, though this difference was not statistically significant. MDMA was well tolerated with expected side effects. These findings supported advancement to phase 3 trials and FDA Breakthrough Therapy designation.
Psychopharmacology
November 1, 2018
Alicia Danforth, Charles S. Grob, Christopher M Struble et al.
284 citations
Autistic adults with severe social anxiety who received MDMA-assisted psychotherapy showed significantly greater improvement in social anxiety symptoms compared to those given an inactive placebo. The improvement was rapid and durable, with effects still present at a six-month follow-up. The study used two eight-hour psychotherapy sessions with either MDMA (75–125 mg) or placebo, plus three non-drug sessions after each. The effect size was very large at the primary endpoint and remained large at follow-up. Social anxiety stayed the same or continued to improve for most in the MDMA group after treatment ended. Initial safety and efficacy support larger studies.
Journal of psychopharmacology (Oxford, England)
December 1, 2018
Marcela Ot'Alora G, Jim Grigsby, Bruce Poulter et al.
232 citations
MDMA-assisted psychotherapy reduces posttraumatic stress disorder symptoms more than a low dose, with effects lasting at least 12 months. In a double-blind trial, 28 people with chronic PTSD received either 100 mg, 125 mg, or 40 mg of MDMA during psychotherapy sessions. The active dose groups showed larger reductions in Clinician-Administered PTSD Scale scores one month after two sessions, with mean changes of -26.3 for 125 mg, -24.4 for 100 mg, and -11.5 for 40 mg. At 12-month follow-up, 76% no longer met PTSD criteria. No serious adverse events occurred, and the treatment was well-tolerated.
Progress in neuro-psychopharmacology & biological psychiatry
June 8, 2018
Allison A. Feduccia, Michael C Mithoefer
213 citations
MDMA-assisted psychotherapy for PTSD has advanced to Phase 3 trials and received FDA Breakthrough Therapy designation. Phase 2 trials showed it is effective and safe, with 68% of participants achieving durable remission from PTSD. This review explores how MDMA may work by enhancing memory reconsolidation and fear extinction. MDMA boosts serotonin, norepinephrine, dopamine, oxytocin, cortisol, and BDNF, which modulate emotional memory circuits. It reduces activity in fear-related brain regions like the amygdala and insula while increasing amygdala-hippocampus connectivity, potentially allowing reprocessing of traumatic memories. The authors suggest a neurobiological rationale for MDMA's large effect sizes in treating PTSD.
Frontiers in Psychiatry
September 12, 2019
Allison A. Feduccia, Lisa Jerome, Berra Yazar-Klosinski et al.
172 citations
MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD) shows a large effect size in pooled analyses, substantially improving safety and efficacy over approved medications paroxetine and sertraline, which have only small to moderate effects. The treatment involves up to three monthly 8-hour sessions with MDMA administered under direct observation, plus preparatory and integrative psychotherapy. Dropout rates are lower than in medication trials, and risks of diversion, overdose, or withdrawal are minimal. Breakthrough Therapy Designation from the FDA has accelerated phase 3 trials, with a planned submission for approval in 2021.
Scientific Reports
November 24, 2020
Julane Andries, Lisa Jerome, Evan Sola et al.
170 citations
A randomized controlled trial tested MDMA-assisted psychotherapy for anxiety in people with life-threatening illnesses. Participants received either MDMA (125 mg) or placebo during two 8-hour psychotherapy sessions. At one month after the second session, the MDMA group showed a greater average reduction in anxiety scores (23.5 points) compared to the placebo group (8.8 points), but the difference did not reach statistical significance. The treatment was well tolerated. After the trial, all participants received open-label MDMA sessions. These preliminary results suggest MDMA-assisted psychotherapy may be a promising approach, but larger trials are needed to confirm its effectiveness.
Psychopharmacology
August 1, 2020
Lisa Jerome, Allison A. Feduccia, Julie B. Wang et al.
163 citations
PTSD symptoms significantly decreased after MDMA-assisted psychotherapy, and the improvement continued for at least 12 months after the final MDMA session. Participants received two to three doses of MDMA (75-125 mg) during psychotherapy sessions. The average reduction in PTSD symptom scores from before treatment to 1-2 months after the last MDMA session was 44.8 points on the CAPS-IV scale, a large effect. Symptoms further decreased slightly over the following year. The proportion of participants who no longer met PTSD diagnostic criteria rose from 56% at treatment exit to 67% at long-term follow-up. Most participants reported benefits such as improved relationships and well-being, while a minority reported harms.
European Journal of Psychotraumatology
December 7, 2020
Candice M Monson, Anne C Wagner, Ann T Mithoefer et al.
90 citations
A small pilot study tested whether adding MDMA to cognitive-behavioural conjoint therapy (CBCT) for PTSD is safe and effective. Six couples, where one partner had PTSD, completed a condensed 7-week CBCT protocol that included two sessions where both partners received MDMA. No serious side effects occurred. PTSD symptoms improved substantially, as rated by clinicians, patients, and partners (effect sizes d = 1.85–3.59). Patients also showed improvements in depression, sleep, emotion regulation, and trauma-related beliefs. Relationship adjustment and happiness improved for both patients and partners (d = 0.64–2.79). MDMA may enhance CBCT's benefits for individuals with PTSD and their partners.
Expert Review of Clinical Pharmacology
June 1, 2020
Kyle T. Greenway, Nicolas Garel, Lisa Jerome et al.
87 citations
Combinations of psychotherapy with antidepressants and psychedelic-assisted psychotherapy both work through complex, interactional mechanisms. A review of therapeutic mechanisms behind conventional and psychedelic paradigms, including the evolution of this knowledge and explanatory frameworks, finds that the contextual model of common factors in psychotherapy provides a powerful perspective on psychotherapy, antidepressants, psychedelics, MDMA, and ketamine. Conventional antidepressants and especially psychedelics may improve psychotherapy's efficacy via neurochemical changes and increased environmental sensitivity. Combined treatments hold significant promise for advancing knowledge and treatment of many forms of psychopathology.
Psychopharmacology (Berl)
November 20, 2017
Allison A. Feduccia, Julie Holland, Michael C Mithoefer
79 citations
Posttraumatic stress disorder (PTSD) is often treated with daily medication, but such pharmacotherapy does not provide definitive treatment and side effects are problematic. Trauma-focused psychotherapies are more likely to achieve remission but have high dropout rates and are ineffective for many patients. Research into drugs that might increase the effectiveness of psychotherapy is a logical next step. The most promising drug studied as a catalyst to psychotherapy for PTSD is MDMA (Ecstasy), which stimulates release of hormones and neurochemicals affecting key brain areas for emotion and memory processing. Phase 2 clinical trials of MDMA-assisted psychotherapy for PTSD show favorable safety outcomes and large effect sizes, warranting expansion into multi-site phase 3 trials set to commence in 2018. Brain imaging and animal models are elucidating neural mechanisms, though much remains unknown.
Journal of Traumatic Stress
February 19, 2020
Ingmar Gorman, Alexander Belser, Lisa Jerome et al.
43 citations
MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD) not only reduces symptoms but also promotes posttraumatic growth (PTG)—positive changes in self-perception, relationships, and life philosophy. Pooled data from three phase 2 clinical trials with 60 participants showed that those receiving active MDMA (75–125 mg) had significantly more PTG and larger reductions in PTSD symptom severity at the primary endpoint compared to the control group (0–40 mg MDMA). At 12-month follow-up, PTG remained higher, symptom severity lower, and two-thirds of participants no longer met PTSD criteria. These large-magnitude effects suggest PTG may be a new mechanism of action for this treatment.
Journal of Traumatic Stress
August 1, 2021
Linnae Ponté, Lisa Jerome, Scott Hamilton et al.
42 citations
Sleep disturbances are common and hard to treat in PTSD. In four randomized controlled double-blind studies, 63 participants received either active MDMA (75-125 mg) or placebo/control MDMA (0-40 mg) during psychotherapy sessions. At the primary endpoint 1-2 months after sessions, PTSD symptoms dropped more with active MDMA than placebo (CAPS-IV score change -34.0 vs. -12.4). Sleep quality also improved more with active MDMA (PSQI score change -3.5 vs. +0.6). Sleep quality continued to improve from treatment exit to 12-month follow-up. These data provide evidence that MDMA-assisted psychotherapy benefits sleep disturbances in PTSD.
Psychopharmacology (Berl)
November 21, 2020
Allison A. Feduccia, Lisa Jerome, Michael C Mithoefer et al.
39 citations
In four phase 2 trials of MDMA-assisted psychotherapy for PTSD, participants who tapered off antidepressant medications before treatment had worse outcomes than those who did not taper. The non-taper group had significantly lower PTSD symptom scores (mean 45.7 vs. 70.3) and depression scores (mean 12.7 vs. 22.6) at the primary endpoint, and 63.6% no longer met PTSD criteria compared to 25.0% in the taper group. Recent exposure to antidepressants that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy.
Journal of Affective Disorders
July 1, 2023
Allison A. Feduccia, Gabby Agin-Liebes, Collin M Price et al.
38 citations
Psychedelic substances are being studied in drug development programs, with clinical trials showing evidence for safe and effective use of psychedelic therapies for mental health conditions. With anticipated FDA approval of MDMA-assisted therapy for PTSD in 2023 and psilocybin therapy for depression disorders soon after, the medical community should become informed on best practices and participate in developing standards of care. Gold standards in medicine distinguish treatments as the highest quality for comparison. This article reviews the origins of psychedelic-assisted therapy, minimum requirements for safe use, criteria for gold standards in mental health, and nuances in establishing gold standards in psychedelic medicine to guide clinical decision making.
Focus (American Psychiatric Publishing)
July 1, 2023
Allison A. Feduccia, Lisa Jerome, Berra Yazar-Klosinski et al.
24 citations
Two FDA-approved medications for PTSD, paroxetine and sertraline, show only small to moderate effects over placebo. Pooled analyses of Phase 2 studies indicate that MDMA-assisted psychotherapy—combining the drug with three monthly 8-hour therapy sessions plus preparatory and integrative sessions—produces a large effect size and lower dropout rates than the approved medications. The treatment also carries minimal risk of diversion, overdose, or withdrawal because MDMA is administered under direct observation. This review describes the data that earned MDMA-assisted psychotherapy Breakthrough Therapy Designation from the FDA, which has accelerated Phase 3 trials toward a planned 2021 submission for FDA approval.
Journal of Humanistic Psychology
June 23, 2021
Julie B. Wang, Jessica Lin, Leah Bedrosian et al.
22 citations
MDMA-assisted therapy (MDMA-AT) can be scaled across multiple clinic sites while maintaining high treatment fidelity. In an open-label study across 14 North American sites, cotherapist dyads were trained in a manualized protocol and administered three experimental sessions to participants with severe PTSD. Adherence to the therapy protocol was high across both dyads and sites. PTSD symptom severity, measured by the CAPS-5, decreased substantially after three sessions at 18 weeks. MDMA was well tolerated. These results indicate that the benefits of MDMA-AT for PTSD can be achieved in a multi-site, real-world clinical setting.
Psychopharmacology (Berl)
November 1, 2024
Lisa Jerome, Allison A. Feduccia, Julie B. Wang et al.
10 citations
This is a retraction note for a previously published article on the long-term outcomes of MDMA-assisted psychotherapy for PTSD. The original article reported a longitudinal pooled analysis of six phase 2 trials, but it has been retracted. The retraction does not provide any findings or data about the treatment's efficacy or long-term effects.
Psychopharmacology (Berl)
November 1, 2024
Michael C Mithoefer, Allison A. Feduccia, Lisa Jerome et al.
9 citations
This is a retraction note for a previously published article about MDMA-assisted psychotherapy for PTSD. The original article described the design and rationale for phase 3 trials, which were based on a pooled analysis of six phase 2 randomized controlled trials. The retraction indicates that the original article should not be relied upon, but the note itself does not provide any findings or data about the treatment's effectiveness.
Psychopharmacology (Berl)
November 1, 2024
Allison A. Feduccia, Lisa Jerome, Michael C Mithoefer et al.
6 citations
Taking certain reuptake-inhibitor medications (such as SSRIs) before MDMA-assisted psychotherapy can affect how well the treatment works. Discontinuing these medications appears to alter patients' therapeutic outcomes. The original article that reported this finding has been retracted.
BMJ Open
May 11, 2026
Julia Colcott, Alexandre A. Guerin, Olivia Carter et al.
A new tool, the MDMA-Assisted Psychotherapy Side Effects Tool (M-SET), was developed to systematically capture side effects during MDMA-assisted psychotherapy. Experts in MDMA-AP and neuropsychopharmacology participated in a two-round online Delphi process to refine a list of 165 items across four questionnaires covering screening, baseline, medication session days, and follow-up. The tool aims to improve safety monitoring and build a more robust evidence base on the tolerability of MDMA-AP for research and clinical use.