Nature Medicine
June 1, 2021
Jennifer Mitchell, Michael P. Bogenschutz, Alia Lilienstein et al.
965 citations
A phase 3 clinical trial tested MDMA-assisted therapy against placebo for severe PTSD. Participants received manualized therapy with either MDMA or placebo alongside preparatory and integrative sessions. At two months after the last session, the MDMA group showed a significantly greater reduction in PTSD symptoms (average 24.4-point drop on the CAPS-5 scale) compared to the placebo group (13.9-point drop), with a large effect size. Functional impairment also improved more with MDMA. No serious safety issues such as abuse potential, suicidality, or heart rhythm problems were observed. The findings suggest MDMA-assisted therapy is highly effective and safe for severe PTSD, including in people with common co-occurring conditions.
J Psychopharmacol
July 19, 2010
Michael C Mithoefer, Mark T Wagner, Ann T Mithoefer et al.
672 citations
In a pilot randomized controlled trial, MDMA-assisted psychotherapy reduced PTSD symptoms more than placebo therapy in people with chronic, treatment-resistant posttraumatic stress disorder. The treatment was well tolerated, with no serious adverse events. These results suggest that MDMA-assisted psychotherapy may be a safe and effective intervention for this difficult-to-treat population, warranting further investigation.
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.
Nature Medicine
October 1, 2023
Jennifer Mitchell, Marcela Ot’alora G., Bessel Van der Kolk et al.
400 citations
In a phase 3 trial, MDMA-assisted therapy reduced PTSD symptoms and functional impairment more than placebo with therapy in 104 participants with moderate to severe PTSD. The average decrease in PTSD symptom severity was 23.7 points with MDMA-assisted therapy versus 14.8 points with placebo, and functional disability improved by 3.3 versus 2.1 points. Participants were ethnoracially diverse, with 27% identifying as Hispanic/Latino and 34% as other than White. Severe side effects occurred in 9.4% of the MDMA group and 3.9% of the placebo group; no deaths or serious adverse events were reported. The treatment was generally well tolerated.
Journal of psychopharmacology (Oxford, England)
January 1, 2013
Michael C Mithoefer, Mark T Wagner, Ann T Mithoefer et al.
377 citations
In a long-term follow-up of the first completed trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD, all 19 original participants took part, and 16 completed all outcome measures 17 to 74 months after their final MDMA session (average 45.4 months). The mean CAPS score at follow-up (23.7) was nearly identical to the mean score at study exit (24.6), indicating that the substantial symptom relief achieved during the trial was maintained over time. Although two participants relapsed, the majority sustained clinically significant improvements, and no one reported harm from participation.
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.
Lancet Psychiatry
April 5, 2016
Michael C Mithoefer, Charles S. Grob, Timothy D Brewerton
237 citations
Psilocybin and MDMA, known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research over the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and anxiety in patients with advanced cancer. MDMA shows encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, not as stand-alone treatments. This model offers a possible alternative to existing pharmacological and psychological treatments, though further research is needed.
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.
Journal of psychopharmacology (Oxford, England)
August 1, 2017
Mark T Wagner, Michael C Mithoefer, Ann T Mithoefer et al.
163 citations
Traumatic events can lead to lasting personality changes, especially increased neuroticism. In a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD, changes in openness—but not neuroticism—moderated the link between reduced PTSD symptoms and the treatment. Patients showed increased openness and decreased neuroticism from baseline to long-term follow-up. These preliminary findings suggest MDMA-assisted psychotherapy may alter personality structure beyond just relieving PTSD symptoms, leading to enduring personality change.
Focus (American Psychiatric Publishing)
July 1, 2023
Jennifer Mitchell, Michael P. Bogenschutz, Alia Lilienstein et al.
97 citations
A phase 3 clinical trial tested MDMA-assisted therapy for severe PTSD. In 90 participants randomized to receive either MDMA or placebo alongside therapy, those receiving MDMA showed a significantly larger reduction in PTSD symptoms, with an average decrease of 24.4 points on the CAPS-5 scale compared to 13.9 points in the placebo group. Functional impairment also improved more with MDMA. No serious safety issues like abuse potential or suicidality were observed. The treatment was effective even for patients with common co-occurring conditions such as depression or substance use history. The authors conclude MDMA-assisted therapy is a safe and highly effective treatment for severe PTSD.
Journal of Psychoactive Drugs
January 1, 2019
Anne C Wagner, Michael C Mithoefer, Ann T Mithoefer et al.
92 citations
Combining Cognitive Behavioral Conjoint Therapy for PTSD (CBCT) with MDMA-assisted psychotherapy in a small pilot trial can reduce PTSD symptoms and improve relationship satisfaction. A case study of one couple with a severe trauma history, representative of the trial participants, details the integrated methodology and the couple's treatment experience. The article describes how these two therapeutic modalities were merged and demonstrates that the combination produces positive outcomes, including symptom reduction and enhanced relationship functioning.
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.
Journal of Psychiatric Research
May 1, 2022
Timothy D Brewerton, Julie B. Wang, Adele Lafrance et al.
81 citations
Among 89 individuals with severe PTSD enrolled in a placebo-controlled trial of MDMA-assisted therapy, 15% had eating disorder symptoms in the clinical range and 31.5% in the high-risk range at baseline, despite no active purging or low weight. After treatment, participants who received MDMA-assisted therapy showed significantly greater reductions in eating disorder symptoms compared to those who received placebo, especially among women with elevated baseline scores. The findings suggest that eating disorder psychopathology is common in severe PTSD and that MDMA-assisted therapy may reduce these co-occurring symptoms.
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.
Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)
January 1, 2021
Alvaro V Jardim, Dora V Jardim, Bruno Rasmussen Chaves et al.
54 citations
In Brazil's first clinical trial of MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), three patients with PTSD from sexual abuse completed treatment. The protocol involved 15 weekly therapy sessions, with three sessions including orally administered MDMA combined with psychotherapy and music, spaced about a month apart. Two months after the final MDMA session, all three patients showed clinically significant improvement, with CAPS-4 scores dropping by more than 30% from baseline. Final scores were 61, 27, and 8, down from 90, 78, and 72. No serious adverse events occurred; common side effects were somatic pains and anguish. Secondary outcomes also improved. MDMA-assisted psychotherapy could become a viable PTSD treatment in Brazil.
PLoS One
January 10, 2024
Rachel Yehuda, Leah Bedrosian, Charlotte Harrison et al.
52 citations
In a randomized, double-blind, placebo-controlled Phase 3 trial of 90 participants with severe PTSD, MDMA-assisted therapy produced significantly greater improvements than therapy with placebo on measures of emotional coping and self-experience. Participants receiving MDMA showed larger gains on the Toronto Alexithymia Scale, the Self-Compassion Scale, and most factors of the Inventory of Altered Self-Capacities, including affect regulation and interpersonal functioning, with identity diffusion being the only exception. Most participants had histories of developmental trauma and multiple traumas. These findings suggest that MDMA-assisted therapy enhances psychological capacities that are often linked to poor treatment outcomes, offering insight into how psychedelic agents may reduce PTSD symptoms.
Hum Psychopharmacol
March 1, 2014
Rick Doblin, George Greer, Julie Holland et al.
48 citations
This article responds to and critically re-evaluates a prior review of 25 years of empirical research on MDMA (ecstasy). It argues for a more balanced understanding of the drug's effects, emphasizing that controlled therapeutic contexts can yield positive psychological outcomes and beneficial subjective experiences, contrary to earlier conclusions that focused predominantly on harms. The response highlights the need to separate recreational use from clinical applications and calls for nuanced interpretation of prior data to inform mental health research.
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.
JAMA Network Open
June 3, 2024
Amy L. Mcguire, I Glenn Cohen, Dominic Sisti et al.
41 citations
A consensus statement from a 2023 meeting of 27 experts identifies 20 points of consensus across five ethical issues for integrating psychedelic medicines into mainstream medical practice: reparations and reciprocity, equity, and respect; informed consent; professional boundaries and physical touch; personal experience; and gatekeeping. The meeting included clinicians, researchers, Indigenous groups, industry, philanthropy, veterans, retreat facilitators, training programs, and bioethicists. The statement focuses on government-approved medical use in the US and abroad, emphasizing that policymakers must address challenges ahead while acknowledging the hopeful moment.
Frontiers in Psychiatry
December 6, 2023
Elliot Marseille, Manish Agrawal, Paul Thambi et al.
40 citations
Group psychedelic-assisted therapy, compared with individual therapy, reduces clinician costs by 50.9% for MDMA treatment of PTSD and 34.7% for psilocybin treatment of major depressive disorder, saving $3,467 and $981 per patient respectively. Using 2023 data from two trial sites and published prevalence estimates, treating all eligible U.S. adults with PTSD or MDD over ten years with group therapy would require 6,711 fewer full-time clinicians for MDMA-PTSD and 1,159 fewer for psilocybin-MDD, saving up to $10.3 billion and $2.0 billion. Adopting group protocols could lower costs, ease clinician shortages, and expand patient access.
Frontiers in Psychiatry
January 1, 2021
Anne C Wagner, Rachel E Liebman, Ann T Mithoefer et al.
40 citations
Healing from trauma happens in relationships, and PTSD affects more than just the diagnosed individual. In a pilot trial of Cognitive Behavioral Conjoint Therapy (CBCT) for PTSD combined with two MDMA psychotherapy sessions, six romantic couples where one partner had PTSD showed improvements across multiple areas. Both partners reported increases in post-traumatic growth, relational support, and social intimacy. Partners also reported less behavioral accommodation and conflict, while patients with PTSD reported better psychosocial functioning and empathic concern. These gains lasted through a 6-month follow-up. The findings suggest that combining CBCT with MDMA can improve relational and growth outcomes, supporting a dyadic approach to holistic trauma recovery.