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PTSD (Post-traumatic stress disorder)

A central target for MDMA-assisted therapy and related trauma-focused interventions.

State of the evidence

Synthesized

Synthesized from 25 studies in the library · AI-generated, grounded in the abstracts below

Found by searching the library for PTSD, post-traumatic stress disorder, traumatic stress, then ranked by relevance.

Research indicates that MDMA-assisted therapy and ketamine can reduce PTSD symptoms, with MDMA showing consistent, large effects in phase 2 and 3 trials, and ketamine showing rapid but less durable effects. However, evidence is limited by small sample sizes, short follow-up durations, and the need for more diverse populations and long-term safety data.

Confidence in the evidence

Moderate
  • Multiple phase 2 and 3 RCTs (e.g., article_id 16269, 14754) show consistent, large effect sizes for MDMA-assisted therapy, but sample sizes are modest (e.g., 90, 104 participants).
  • Ketamine studies (article_id 25630, 34433) are small (e.g., 41, 30 participants) and show rapid effects but limited durability data.
  • Long-term follow-up (article_id 16282) suggests durability of MDMA effects, but only in a small sample (n=19).
  • Systematic reviews (article_id 28489, 28654) confirm efficacy but highlight poor quality in some studies and need for more research.
How we rate confidence

Confidence reflects the strength of the underlying evidence, not whether the result is favorable. It weighs the number and size of studies, their design (randomized trials count for more than observational or single-case work), how consistently they point the same way, and their risk of bias.

Tiers run from Insufficient to High. High is rare in this field: small, early, or open-label studies land lower even when their direction is encouraging.

Evidence by study

Direction is each study's finding relative to your question: Supports, Opposes, No effect, Mixed, or Unclear.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. 2021
Supports

MDMA-assisted therapy significantly reduced PTSD symptoms (CAPS-5) and functional impairment (SDS) compared to placebo, with large effect sizes.

RCT Sample size: 90

The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. 2017
Unclear

This review discusses the therapeutic potential of psychedelic drugs but does not provide specific findings on PTSD.

review

The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. 2010
Supports

This pilot study found MDMA-assisted psychotherapy to be safe and efficacious in treatment-resistant PTSD.

RCT

Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder 2014
Supports

A single intravenous ketamine infusion significantly reduced PTSD symptom severity compared to midazolam at 24 hours post-infusion.

RCT Sample size: 41

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. 2018
Supports

MDMA-assisted psychotherapy showed dose-dependent efficacy for PTSD in first responders and military personnel.

RCT

A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD) 2012
Mixed

MDMA-assisted psychotherapy did not show statistically significant reductions on the clinician-rated CAPS but did show significant self-reported improvement on the PDS.

RCT Sample size: 12

MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. 2023
Supports

MDMA-assisted therapy significantly reduced PTSD symptoms and functional impairment compared to placebo with therapy, with a large effect size.

RCT Sample size: 104

Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. 2013
Supports

Long-term follow-up (mean 45.4 months) showed that most participants maintained clinically significant symptom relief from MDMA-assisted psychotherapy, though two relapsed.

observational Sample size: 19

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. 2019
Supports

Pooled analysis of six phase 2 trials showed MDMA-assisted psychotherapy significantly reduced PTSD symptoms compared to control, with a large effect size.

pooled analysis Sample size: 103

Theorizing that Psychedelic Assisted Therapy May Play a Role in the Treatment of Trauma-Induced Personality Disorders. 2024
Unclear

This theoretical paper proposes that psychedelic-assisted therapy may be useful for trauma-induced personality disorders, but does not provide empirical data.

theoretical

Psychedelic Psychiatry's Brave New World. 2020
Unclear

This review discusses the potential of psychedelic psychiatry but does not provide specific findings on PTSD.

review

Reviewing the Potential of Psychedelics for the Treatment of PTSD 2020
Unclear

This review discusses the potential of MDMA, ketamine, classical psychedelics, and cannabinoids for PTSD, but does not provide specific quantitative findings.

review

A PILOT STUDY OF GROUP MINDFULNESS-BASED COGNITIVE THERAPY (MBCT) FOR COMBAT VETERANS WITH POSTTRAUMATIC STRESS DISORDER (PTSD) 2013
Supports

Mindfulness-based cognitive therapy (MBCT) significantly improved PTSD symptoms compared to treatment-as-usual in combat veterans.

RCT Sample size: 37

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. 2021
Supports

Repeated intravenous ketamine infusions over 2 weeks significantly reduced PTSD symptoms compared to midazolam, with a large effect size at week 2.

RCT Sample size: 30

Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. 2016
Unclear

This review discusses psilocybin and MDMA for psychiatric disorders but does not provide specific findings on PTSD.

review

Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series. 2026
Mixed

In patients with TRD and comorbid PTSD, esketamine treatment led to trauma re-experiencing episodes; in most cases these resolved, but in some treatment was stopped.

observational Sample size: 22

A neurocognitive account of complex PTSD: self-modelling, affective dysregulation, and implications for MDMA-assisted and targeted psychotherapies. 2026
Unclear

This narrative review develops a neurocognitive account of C-PTSD and discusses MDMA-assisted psychotherapy as a potential intervention, but does not provide empirical data.

theoretical

Changes in trauma symptoms of discrimination after MDMA-assisted psychotherapy for posttraumatic stress disorder. 2026
Supports

MDMA-assisted therapy significantly reduced discrimination-related trauma symptoms, with a large effect size, but the sample was very small.

observational Sample size: 5

Dissociation and PTSD in women with a history of childhood sexual abuse: a pilot examination of a specialized inpatient unit 2026
Supports

In a specialized inpatient unit, PTSD symptoms significantly decreased after treatment, and reductions in dissociative symptoms were associated with improvements in PTSD.

observational Sample size: 108

Ketamine effects on EEG and their links to therapy differ across treatment-resistant major depression, post-traumatic stress disorder, and obsessive-compulsive disorder 2026
Unclear

Ketamine produced dose- and band-frequency-dependent EEG power changes in TR-PTSD patients, which differed from TR-MDD and TR-OCD patients.

observational Sample size: 22

MDMA-assisted PTSD and Alcohol Therapy Trial (MPATHY): study protocol for a double-blind, randomised, controlled outpatient trial of MDMA-assisted integrated exposure-based therapy for comorbid post-traumatic stress disorder and alcohol use disorder 2026
Unclear

This is a study protocol for a trial of MDMA-assisted integrated exposure therapy for comorbid PTSD and AUD; no results are reported.

protocol

Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature 2026
Supports

This systematic review found that MDMA-assisted psychotherapy reduced PTSD symptoms across studies, with some evidence for decreased dissociative symptoms at higher doses.

systematic review Sample size: 335

Ketamine-assisted psychotherapy for posttraumatic stress disorder: a systematic review and individual participant data meta-analysis of predictors of treatment effects. 2026
Supports

Individual participant data meta-analysis found that more psychotherapy sessions, more ketamine sessions, higher baseline severity, and shorter treatment duration predicted greater PTSD symptom improvement with ketamine-assisted psychotherapy.

meta-analysis Sample size: 533

At-Home Telehealth-Supported Subcutaneous Ketamine Therapy in Adults With Moderate to Severe Depression, Anxiety, or PTSD: A Real-World Observational Study of Safety, Feasibility, and Clinical Outcomes in a Large, Heterogeneous Cohort in the United States. 2026
Supports

At-home telehealth-supported subcutaneous ketamine therapy was associated with significant reductions in PTSD symptoms (PCL-5) over 6 weeks in a large real-world cohort.

observational Sample size: 3870

Acute pretrauma ethanol exacerbates PTSD-like phenotype in rats and is reversed by early intranasal ketamine 2026
Unclear

In rats, acute ethanol exposure before trauma exacerbated PTSD-like symptoms, and early intranasal ketamine reversed this effect.

preclinical

Points of agreement

  • MDMA-assisted therapy consistently reduces PTSD symptoms across multiple RCTs and a pooled analysis.
  • Ketamine, both single and repeated infusions, rapidly reduces PTSD symptoms.
  • Both MDMA and ketamine show large effect sizes in reducing PTSD symptoms.
  • Long-term follow-up of MDMA-assisted therapy suggests durability of symptom relief.

Conflicts

  • One early MDMA trial (article_id 22029) found non-significant results on the clinician-rated CAPS but significant self-reported improvement, while later trials found significant effects on both.
  • Esketamine treatment for comorbid TRD and PTSD led to trauma re-experiencing episodes in some patients, which is a potential adverse effect not reported in other ketamine studies.
  • The durability of ketamine's effects is less established compared to MDMA, with most studies focusing on short-term outcomes.

Gaps

  • Long-term durability of ketamine's effects on PTSD is not well studied.
  • Most studies have small sample sizes, limiting generalizability.
  • There is limited research on diverse populations, including racial/ethnic minorities and individuals with complex comorbidities.
  • The optimal dosing, number of sessions, and integration with psychotherapy for both MDMA and ketamine are not fully established.
  • Safety and efficacy in real-world settings, especially for at-home ketamine, require more research.
  • The role of psychedelic-assisted therapy for complex PTSD and borderline personality disorder is understudied.
Browse these studies in the library
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is PTSD, up to 25 in all. The most-cited set anchors the established evidence, and the recent set surfaces work that is too new to have gathered citations yet.

A study qualifies only when PTSD or a known alias appears in its title or keywords, so broad reviews that mention it only in passing are left out. Each study is read from its abstract, strongest evidence first, and the summary reports the direction of the results along with any conflicts and gaps.

Ask your own question in the Research Synthesis Tool

Latest monthly recap: June 2026 →

1,133 articles · 524 from the last two years · 446,523 participants across 378 studies reporting sample size

Common study designs

review 325 systematic review 59 observational cohort 35 randomized controlled trial 50 theoretical or philosophical paper 96

Research

Synthesize the evidence → Search all →

Simulated States of Consciousness: Inducing Psychedelic Experiences in Virtual Reality

Harman Brar

Virtual reality is used as a therapeutic tool for anxiety, PTSD, and depression through exposure therapy and simulated environments, but its potential to mimic psychedelic experiences has not been examined. Research suggests individuals in VR simulated psychedelic experiences undergo effects similar to those from psychedelic drugs, though the physiological impact on the brain and mind is largely unexplored. To determine whether VR can mimic psychedelics, targeting 5-HT receptor activity in the frontal lobe is proposed as a hypothesis. This paper examines drug mechanisms of psychedelics, the theoretical application of VR-based psychedelic therapy, and postulates a method to measure the effectiveness of psychedelic simulations for psychopathology.

DOI: 10.32920/23153678.v1

Evidence-Based Medicine is inadequate to develop evidence-based psychedelic therapies.

Eduardo Ekman Schenberg preprint

Between April and October 2024, expert bodies in the US and the Netherlands reached opposite conclusions on MDMA for PTSD. The FDA rejected Lykos Therapeutics' New Drug Application despite prior breakthrough therapy status, while the Dutch State Commission recommended making the treatment available as soon as possible. These contrasting decisions highlight epistemic differences in evidence assessment: the FDA's approach aligned with traditional Evidence-Based Medicine (EBM), whereas the Dutch approach resembled the newer EBM+ framework. Drawing on historical fatal examples and recent evidence-assessment debates (e.g., masking during COVID-19), the authors argue that shifting to EBM+ is essential for reliable assessments of psychedelic therapies.

DOI: 10.31234/osf.io/rzdpm

Combined Ketamine and Psychotherapy Provide No Additional Benefit Beyond Ketamine Alone in Treating Depression or PTSD: Evidence from a Help-Seeking Sample

Tyler Maxwell Moore, Kathryn Walker, Emma Tung et al. preprint

Adding psychotherapy to ketamine treatment does not significantly improve depression or PTSD symptoms more than ketamine alone over 30 days. Both approaches produced substantial, rapid symptom improvement that stabilized after 11-15 days. The study analyzed 202 help-seeking individuals (60% female, mean age 41.3 years) who received either ketamine alone or ketamine plus psychotherapy across six sessions. No significant differences in symptom trajectories emerged between the groups, though exploratory analyses suggested younger females might benefit more from combined treatment and older males from ketamine alone. The findings indicate ketamine's effects may be robust enough that concurrent psychotherapy does not enhance short-term outcomes, but longer-term and demographic-specific effects require further study.

DOI: 10.31234/osf.io/cs24j

A chromosome level reference genome of Diviners sage (Salvia divinorum) provides insight into salvinorin A biosynthesis

bioRxiv (Cold Spring Harbor Laboratory) Scott A. Ford, Rob W. Ness, Moonhyuk Kwon et al. preprint

A chromosome-level genome assembly of the diviners sage plant, which produces the hallucinogen salvinorin A, has been produced. The genome is about 541 million base pairs, diploid, and comparable to other sage species. Two gene clusters involved in diterpene biosynthesis were identified, including a gene that forms the dihydrofuran ring early in the salvinorin A pathway. Other enzyme classes likely involved in later steps are scattered across the genome. Most of these genes are not activated by methyl jasmonate treatment. This high-quality genome sequence will help uncover the remaining steps in salvinorin A biosynthesis and support exploration of its medical potential for chronic pain, addiction, and post-traumatic stress disorder.

DOI: 10.1101/2024.09.08.611878

Psychedelic Therapy: A Primer for Primary Care Clinicians – Part VII. Ketamine

Viviana D. Evans, Alejandro Arenas, Kenneth Shinozuka et al. preprint

Ketamine, originally a dissociative anesthetic, is now used for treatment-resistant depression and major depressive disorder with suicidal ideation. A single intravenous infusion shows antidepressant effects within hours, with a large effect size on depression scores. It also reduces PTSD symptom severity and suicidal ideation in emergency settings. However, therapeutic effects often subside within weeks, requiring repeated doses. Risks include temporary or persistent memory impairment, cardiovascular issues, liver toxicity, and bladder inflammation. Ketamine's opioid-sparing effect improves postoperative pain management.

DOI: 10.31234/osf.io/dtb6a

MDMA-Based Psychotherapy in Treatment-Resistant Post-traumatic Stress Disorder (PTSD): A Brief Overview of Current Evidence

Preprints.org Kainat Riaz, Sejal Suneel, Mohammad Hamza Bin Abdul Malik et al. 1 citation preprint

Half of patients with post-traumatic stress disorder (PTSD) do not respond to standard pharmacotherapy or psychotherapy. A review of six phase II randomized controlled trials indicates that MDMA-assisted psychotherapy can reduce PTSD symptoms, even in treatment-resistant cases, by increasing neurohormones such as dopamine, serotonin, norepinephrine, and oxytocin and by modulating brain regions involved in fear and anxiety. The FDA has granted MDMA-assisted psychotherapy a "Breakthrough Therapy" designation. Further research is needed to determine whether the benefits outweigh the risks and whether this approach can be integrated into existing treatment options.

DOI: 10.20944/preprints202308.1847.v1

MDMA Assisted Psychotherapy Decreases PTSD Symptoms, Dissociation, Functional Disability, and Depression: A Systematic Review and Meta-Analysis

medRxiv W. M. Green, S.b. Raut, F.l.j. James et al. 4 citations preprint

MDMA-assisted psychotherapy improves dissociation, depression, and functional impairment in people with post-traumatic stress disorder (PTSD), but does not improve sleep quality. A systematic review and meta-analysis of randomized controlled trials found that the therapy reduces core PTSD symptoms and enhances quality of life. The evidence is limited by small sample sizes in available trials, but supports further development of MDMA-assisted psychotherapy for PTSD.

DOI: 10.1101/2023.08.17.23293955

Psychedelic Therapy: A Primer for Primary Care Clinicians – Part VI. 3,4-methylenedioxy-methamphetamine (MDMA)

Kenneth Shinozuka, Burton J. Tabaac, Alejandro Arenas et al. preprint

MDMA, known as a party drug in the 1980s, is emerging as a powerful treatment for PTSD. Phase III FDA trials show MDMA-assisted psychotherapy has an effect size of 0.7-0.91, two to three times larger than existing antidepressants. Within 18 weeks, 67 to 71% of patients no longer meet PTSD diagnostic criteria. The literature is biased: animal studies used doses far above human levels, and human samples often involve recreational users of multiple substances. Only six clinical trials, all by MAPS, have been conducted, but preliminary evidence suggests MDMA is much more effective than current antidepressants for PTSD.

DOI: 10.31234/osf.io/r89k3

MDMA-Assisted Therapy for Complex-Post-Traumatic Stress Disorder: Toward a neurocognitive account

Philip Gerrans, Hugh Mgovern, Jakob Hohwy et al. 1 citation preprint

Complex post-traumatic stress disorder (C-PTSD) involves additional symptoms beyond those of PTSD, including emotional instability, negative self-concept, and interpersonal difficulties, often from prolonged trauma like childhood maltreatment or domestic violence. A novel model based on active inference and self-modelling explains these differences and identifies the insula's role in affective regulation. The model suggests that MDMA-assisted therapy may help recalibrate emotional regulation and strengthen self-model, offering a potential treatment avenue. Theoretical and clinical implications are discussed, with emphasis on further empirical research.

DOI: 10.31234/osf.io/425fd_v1

Too big to fail? Comparing effect sizes of MDMA assisted therapy to unmasking bias

Balázs Szigeti, Ellen Bradley, Joshua Woolley preprint

Unmasking bias—where participants or researchers can guess who received a treatment due to its noticeable effects—may account for the reported benefits of MDMA-assisted therapy for PTSD. Analyzing data from trials of ketamine and escitalopram, the authors found that the magnitude of unmasking bias is larger than the treatment-versus-control effect size observed for MDMA. This indicates that MDMA-AT's effect sizes are not too large to be explained by unmasking alone, though the findings do not prove that the effects are entirely or partially due to this bias.

DOI: 10.31219/osf.io/ujtpf

Clinical trials

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