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.
Frontiers in Psychiatry
January 1, 2022
S Parker Singleton, Julie B. Wang, Michael C Mithoefer et al.
36 citations
In nine veterans and first-responders with chronic PTSD, MDMA-assisted therapy (MDMA-AT) did not significantly increase amygdala-hippocampus resting-state functional connectivity as hypothesized, showing only a trend. After treatment, brain activation during trauma memory recall decreased in the cuneus. Recovery from PTSD correlated with changes in four functional connections during autobiographical memory recall: left amygdala with left and right posterior cingulate cortex and left insula, and left isthmus cingulate with left posterior hippocampus. These findings suggest that amygdala, hippocampus, and insula functional connectivity may be a target of MDMA-AT, highlighting regions involved in memory processes.
Science
June 1, 2003
Michael C Mithoefer, Lisa Jerome, Richard Doblin et al.
36 citations
This work reviews evidence on whether MDMA (ecstasy) causes neurotoxicity in humans. The authors examine clinical and observational studies assessing the drug's effects on the brain's serotonin system. They conclude that MDMA use is associated with lasting changes in serotonergic function, including reduced serotonin transporter density and altered neurotransmitter activity, suggesting potential neurotoxic effects. However, the review notes limitations in human studies, such as confounding factors and lack of definitive causal evidence. The findings indicate that while MDMA can produce neurobiological alterations, the extent and clinical significance of neurotoxicity remain uncertain.
European Journal of Psychotraumatology
January 1, 2024
Richard J. Zeifman, Hannes Kettner, Stephen Ross et al.
34 citations
Therapeutic alliance—the quality of the relationship between therapist and client—predicts improvement in PTSD symptoms after MDMA-assisted psychotherapy. Among 22 adults with chronic PTSD who received MDMA during a clinical trial, stronger therapeutic alliance measured at sessions 4 and 9 (but not before the third session) was associated with lower clinician-assessed PTSD severity after treatment, even after accounting for initial symptom severity. Self-reported PTSD severity was also predicted by alliance at baseline, session 4, and session 9, though the baseline finding did not survive correction for multiple comparisons. These results provide initial evidence that common psychotherapeutic factors like alliance contribute to outcomes in MDMA-assisted therapy.
Medical Hypotheses
January 1, 2021
Timothy D Brewerton, Adele Lafrance, Michael C Mithoefer
28 citations
Eating disorders remain difficult to treat, especially when accompanied by posttraumatic stress disorder. MDMA-assisted psychotherapy for treatment-resistant PTSD shows promise, with two-thirds of participants achieving full remission at one year or more follow-up. The authors hypothesize this therapy will be effective for both eating disorder and PTSD symptoms in people with both conditions. MDMA's effects—reduced fear, enhanced wellbeing, increased sociability, reduced self-criticism, increased compassion, interpersonal trust, and alert consciousness—may counteract avoidance and hyperarousal in therapy. Other features like body image distortion, cognitive rigidity, and socio-emotional difficulties may also improve. Personal accounts describe benefit, but risks and challenges are noted.
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.
Am J Psychiatry
January 1, 2024
Michael Alpert, Kelley C. O’donnell, Casey Paleos et al.
22 citations
Psychotherapy is a necessary component of psychedelic treatment, providing safety and evidence-based support. The text argues that integrating structured psychological guidance with psychedelic sessions enhances therapeutic benefits and improves mental health outcomes. This combined approach fosters a supportive journey, leading to transformative mental health care and healing potential.
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.
medRxiv Preprint Server
May 25, 2022
S. Parker Singleton, Julie B. Wang, Michael C Mithoefer et al.
9 citations
preprint
In nine veterans and first-responders with chronic PTSD, MDMA-assisted therapy did not significantly increase amygdala-hippocampus resting-state functional connectivity as hypothesized, only showing a trend. After treatment, activation in the cuneus decreased when recalling traumatic versus neutral memories. The amount of PTSD recovery correlated with changes in four functional connections during autobiographical memory recall: left amygdala with left and right posterior cingulate cortex and left insula, and left isthmus cingulate with left posterior hippocampus. These findings suggest that MDMA-AT may alter functional connectivity in brain regions involved in memory and fear processing, but more research is needed to determine if these effects are specific to MDMA-AT compared to other PTSD treatments.
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.
Journal of psychopharmacology (Oxford, England)
June 10, 2025
Torsten Passie, Anja Loizaga-Velder, Alicia Danforth et al.
4 citations
A consensus-based model curriculum for education and training in substance-assisted psychotherapy (SAP) covers theoretical topics and practical components including apprenticeship observation, ongoing clinical supervision, and self-experience for trainees. The model, developed by authors with extensive SAP experience, also addresses peer and conventional supervision, respect for intercultural differences, and teachings about indigenous use of related substances. It is largely adapted to western industrialized countries with established graduate-level psychotherapy training. The curriculum may be valuable for psychedelic researchers, those training therapists for research studies, and those preparing for clinical work outside research settings.
Nat Med
November 1, 2024
Jennifer Mitchell, Marcela Ot’alora G., Bessel Van der Kolk et al.
4 citations
No Summary
medRxiv Preprint Server
January 3, 2023
Bessel Van der Kolk, Julie B. Wang, Rachel Yehuda et al.
2 citations
preprint
A Phase 3 clinical trial tested MDMA-assisted therapy (MDMA-AT) against placebo with therapy for severe PTSD. 85% of participants reported early childhood trauma, linked to deficits in emotional coping. MDMA-AT significantly improved alexithymia, self-compassion, and altered self-capacities compared to therapy alone. These changes address transdiagnostic mental processes that often hinder treatment response.
Archives of Clinical Neuropsychology
August 31, 2016
Michael Wagner, Michael C Mithoefer, Ann T Mithoefer et al.
1 citation
In a Phase II clinical trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD, increases in Openness and decreases in Neuroticism personality traits were linked to greater symptom reduction, regardless of treatment condition. Participants receiving MDMA showed the largest gains in Openness, which predicted lower PTSD severity. The authors propose that MDMA, combined with psychotherapy, may facilitate a reorganization of mental experience through altered brain pathways, rather than through psychological learning alone.
Frontiers in Psychology
January 1, 2024
Kelley C O'Donnell, Lauren Okano, Michael Alpert et al.
A conceptual framework for MDMA-Assisted Therapy for PTSD centers on the participant's inner healing intelligence as the primary agent of change, with the therapeutic relationship as the core facilitative condition. This inner-directed, holistic, self-directed, relational, and trauma-informed approach includes a non-pathologizing stance toward embodied experiences, such as intense emotional expression, multiplicity, suicidal ideation, and transpersonal experiences. Therapists bring psychodynamic, somatic, and transpersonal awareness, empathic attunement, relational skillfulness, and cultural humility. MDMA with this psychotherapy outperformed placebo with psychotherapy in Phase 2 and 3 trials, though significant symptom reduction also occurred in the placebo group, supporting the psychotherapy model itself.
Psychedelics as Psychiatric Medications
March 1, 2023
Michael C Mithoefer, David E. Presti
MDMA was first synthesized by Merck in 1914 but not studied in humans until the 1970s–80s, when it was reported to reduce anxiety and increase emotional openness, making it a possible catalyst for psychotherapy. In 1985, after recreational use in dance scenes attracted media attention, the US government placed MDMA in Schedule 1, banning it for medical use. MDMA's pharmacological effects include releasing serotonin and other monoamines and raising oxytocin levels. Research on its effects is evolving, and links between its physiology and user experiences remain speculative. Controlled clinical trials of MDMA-assisted psychotherapy began in 2004, focusing on PTSD.
Kelley C O'Donnell, Michael Alpert, Lauren Okano et al.
preprint
MDMA-Assisted Therapy for PTSD uses a short-term, intensive psychotherapy model that includes three sessions facilitated by MDMA along with non-drug therapy sessions. The MDMA helps recall and process traumatic memories and enhances learning in social contexts, integrating top-down and bottom-up trauma care. This paper describes the psychotherapeutic concepts and theories behind this approach, centering on the participant's inner healing intelligence as the main agent of change, with the therapeutic relationship as a core facilitative condition. Phase 2 and 3 trials showed MDMA with therapy outperformed placebo with therapy in reducing PTSD symptoms, though significant symptom reduction also occurred in participants who received only therapy.