Current Neuropharmacology
January 5, 2024
Tamar Glatman Zaretsky, Kathleen M. Jagodnik, Robert Barsic et al.
73 citations
Post-traumatic stress disorder (PTSD) affects an estimated 12 million U.S. adults, and many remain symptomatic despite standard psychological and pharmacological treatments. Psychedelic compounds—including psilocybin, LSD, DMT, ayahuasca, MDMA, and ketamine—are being studied as potential therapies. This comprehensive review summarizes current PTSD treatments and their shortcomings, then examines clinical studies of psychedelic-assisted therapy for PTSD and related disorders. For each drug, the review covers history, psychological and somatic effects, pharmacology, and safety, along with proposed mechanisms for trauma treatment. It concludes with future directions to maximize therapeutic benefit and minimize risk for individuals and communities affected by trauma.
Frontiers in Neuroscience
September 20, 2021
Lauren Lepow, Hirofumi Morishita, Rachel Yehuda
70 citations
A framework is proposed for investigating how psychedelic-assisted psychotherapy (PAP) produces neurobiological changes that underlie recovery from illnesses like PTSD. The authors suggest that psychedelics may remove brakes on adult neuroplasticity, inducing a state similar to developmental critical periods (CPs) when the brain is exquisitely sensitive to environmental input. They highlight ocular dominance plasticity in the visual system as a model for characterizing CPs in limbic systems relevant to psychiatry. This CP framework may help integrate neuroscientific inquiry with the influence of the environment both in development and in PAP, moving beyond traditional focus on pharmacologic properties alone.
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.
JAMA
August 31, 2023
Rachel Yehuda, Amy Lehrner
33 citations
Interest is growing among clinicians and researchers in using psychedelic drugs to treat mental health disorders such as depression, anxiety, posttraumatic stress disorder, eating disorders, and addictions.
Frontiers in Psychiatry
February 6, 2023
Candace R. Lewis, Joseph Tafur, Sophie Spencer et al.
29 citations
Epigenetic changes in hypothalamic-pituitary-adrenal (HPA) axis genes may predict successful psychotherapy for post-traumatic stress disorder (PTSD). In a pilot sub-study of a Phase 3 clinical trial, 23 participants (16 receiving MDMA-assisted therapy, 7 receiving placebo with therapy) provided saliva samples. Methylation at 259 CpG sites across three HPA genes (CRHR1, FKBP5, NR3C1) was measured before and after treatment. Methylation changes across both groups significantly predicted symptom reduction on 37 of the sites, with two surviving false discovery rate correction. The MDMA group showed greater methylation change on one NR3C1 site compared to placebo. Therapy-related PTSD symptom improvements may be linked to DNA methylation changes in HPA genes, and such changes may be larger with MDMA-assisted therapy.
Psychedelic Medicine
May 19, 2023
Mollie Pleet, Joshua White, Joseph A. Zamaria et al.
12 citations
A helpline for people having difficult psychedelic experiences may reduce distress and prevent emergency calls. Analysis of 884 callers to a psychedelic helpline found that 65.9% reported the call de-escalated their psychological distress. Without the helpline, 29.3% said they might have been harmed, 12.5% might have called 911, and 10.8% might have gone to the emergency room. The findings suggest that such helplines can avert harmful outcomes and reduce the burden on emergency medical services.
Journal of Psychopharmacology
August 29, 2025
Niall M. Mcgowan, James Rucker, Rachel Yehuda et al.
10 citations
A single 25 mg dose of psilocybin, given with psychological support, was safe and well-tolerated in 22 adults with PTSD. No serious adverse events occurred, and most side effects (headache, nausea, crying, fatigue) resolved within a day. PTSD symptoms, measured by the CAPS-5 scale, showed a clinically meaningful average decrease of nearly 30 points at 4 and 12 weeks after the dose, and this improvement was linked to the intensity of the psychedelic experience. Functional impairment and quality of life also improved. The open-label design and small sample size mean further controlled trials are needed to confirm efficacy.
Focus (American Psychiatric Publishing)
July 1, 2023
Lauren Lepow, Hirofumi Morishita, Rachel Yehuda
9 citations
Psychedelic-assisted psychotherapy may work by reopening a critical period of heightened neuroplasticity, similar to developmental windows when the brain is especially sensitive to environmental input. The paper proposes that psychedelics could remove molecular brakes on adult neuroplasticity, creating a brain state akin to neurodevelopment. Drawing on ocular dominance plasticity in the visual system as a model, the authors suggest this framework could help explain how combining psychedelic compounds with psychotherapy produces enduring clinical improvements in conditions like PTSD. The framework integrates neuroscientific inquiry with the influence of environment both in development and in therapy.
Journal of Psychoactive Drugs
September 12, 2024
Katinka Hooyer, Rachel Yehuda, Alan K. Davis et al.
4 citations
About half of U.S. military veterans surveyed reported using psychedelics, most often for healing or treatment (70%) and spiritual purposes (48%). The vast majority (85%) said they benefited from use. Veterans who used psychedelics indicated they would be more likely to use VA services, and they expressed greater interest in psychedelic therapy compared to non-users. However, some adverse outcomes were reported, suggesting that without proper preparation and support, psychedelics may carry risks. The findings point to a potential role for psychedelic-assisted approaches in veteran mental health care.
Psychedelics
January 8, 2026
Rachel Yehuda, Amy Lehrner, Miryam Sperka et al.
2 citations
The original manual for MDMA-assisted therapy (MDMA-AT) for PTSD, developed by the Multidisciplinary Association for Psychedelic Studies (MAPS), introduced concepts like “inner healing intelligence” from transpersonal traditions, which lacked clear grounding in trauma science and were difficult to standardize. In response, a new model called Integrative MDMA-Assisted Psychotherapy (IMAP) is proposed. IMAP is a principle-guided, patient-driven approach rooted in humanistic and trauma-focused psychotherapy. It offers flexible, relationally attuned support for nonlinear therapeutic processes, drawing on contemporary PTSD theories and evidence-based trauma interventions while retaining experiential approaches. The model invites empirical study to determine essential therapeutic elements in psychedelic contexts.
EClinicalMedicine
December 1, 2025
Nadav Liam Modlin, Victoria Williamson, Guy M Goodwin et al.
2 citations
Psilocybin treatment for post-traumatic stress disorder, when delivered with standardized preparation and support, may allow patients to engage with trauma-related material indirectly through affective, somatic, and self-transcendent experiences, such as feelings of unity or dissolution of self, rather than requiring direct confrontation with traumatic memories as in standard therapies. This qualitative study, nested within a phase 2 trial involving 21 adults with PTSD, identified four core themes: non-pharmacological factors for psychological safety and trust, the experiential nature of psilocybin treatment, engagement with trauma-related material, and comparative reflections on prior therapies. The findings suggest psilocybin offers a meaningful therapeutic opportunity, but larger controlled studies are needed.
medRxiv Preprint Server
January 3, 2023
Bessel A. 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.
Psychedelic Medicine
March 10, 2026
Amy Lehrner, Miryam Sperka, Lauren Lepow et al.
1 citation
MDMA-assisted therapy for post-traumatic stress disorder has shown strong clinical effects, high response rates, and low dropout when using a principle-guided, patient-directed model that includes nondrug preparatory and integrative sessions. This perspective argues that embedding MDMA into highly structured, manualized cognitive-behavioral treatment protocols may misapprehend the therapy's synergistic nature, blunt its transformative effects, and potentially cause harm. The field should prioritize research on real-world evidence, treatment optimization, and mechanisms of action of this distinct patient-directed model rather than immediately adapting existing protocols.
The Journal of clinical psychiatry
April 2, 2025
Adriana Feder, Oneysha Brown, Sarah B Rutter et al.
Combining six ketamine infusions with a brief exposure-based psychotherapy, written exposure therapy (WET), produced large and durable reductions in PTSD symptoms for patients with chronic, severe PTSD. In an open-label trial, 13 of 14 patients completed treatment. PTSD symptom severity, measured by the CAPS-5, dropped from an average of 41.6 before treatment to 20.8 at 12 weeks, a large-magnitude improvement. Nine patients (69%) were treatment responders, and eight (61.5%) maintained improvement up to six months. The authors suggest the combined treatment may be effective but call for larger randomized controlled trials to confirm efficacy and synergy.