The International Journal of Neuropsychopharmacology
March 12, 2020
Erwin Krediet, Tijmen Bostoen, Joost J. Breeksema et al.
262 citations
Posttraumatic stress disorder (PTSD) often remains chronic after psychotherapy, and few effective medications exist. A promising new approach involves psychedelic drugs. This review discusses four compound types: MDMA, ketamine, classical psychedelics (psilocybin, LSD), and cannabinoids. It describes each compound's therapeutic rationale, administration setting, and current evidence for treating PTSD. Each offers unique qualities, from rapidly targeting symptoms to facilitating psychotherapy. The review outlines questions for future research.
CNS Drugs
August 17, 2020
Joost J Breeksema, Alistair R Niemeijer, Erwin Krediet et al.
217 citations
This review argues that qualitative research on psychedelic treatments can reveal unique features of different substances and uncover implications for treating specific psychiatric disorders that quantitative methods might miss. By examining subjective experiences, such studies can help tailor therapies to particular conditions and substances, offering insights into how psilocybin, LSD, or other compounds produce distinct psychological effects. The authors suggest that incorporating qualitative findings into clinical practice could enhance treatment precision and patient outcomes, highlighting the value of exploring personal narratives and emotional processes in psychedelic therapy.
Current neuropharmacology
January 1, 2024
Lisa Burback, Suzette Brémault-phillips, Mirjam J Nijdam et al.
187 citations
Chronic PTSD is a systemic disorder with high allostatic load, shaped by advances in genetics, neurobiology, and brain imaging. Current evidence-based treatments include pharmacological and psychotherapeutic approaches, but outcomes are often suboptimal due to barriers such as comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame. These challenges drive emerging novel approaches: early interventions during the Golden Hours, medication augmentation, psychedelics, and brain- and nervous-system-targeted interventions. A phase-oriented treatment framework is recognized to align interventions with the disorder's pathophysiology. Revisions to guidelines and care systems will be needed as innovative treatments gain evidence.
Journal of Psychopharmacology
August 26, 2022
Joost J. Breeksema, Bouwe Kuin, Jeanine Kamphuis et al.
171 citations
A systematic review of 44 clinical studies (34 quantitative, 10 qualitative) involving 598 patients treated with MDMA or serotonergic psychedelics (psilocybin, LSD, ayahuasca) found that treatments were generally well tolerated, though adverse events were often not systematically assessed. Common acute adverse events across diagnoses and compounds included nausea, headaches, and anxiety. Late adverse events included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious adverse event occurred during MDMA administration (increased premature ventricular contractions requiring brief hospitalization); no other events required medical intervention. Qualitative studies suggested that psychologically challenging experiences may be therapeutically beneficial. The authors conclude that adverse events are poorly defined and likely underreported due to study design and sample selection.
Scientific Reports
February 5, 2024
Alistair Niemeijer, Erwin Krediet, Jeanine Kamphuis et al.
50 citations
Patients with treatment-resistant depression who received psilocybin in a clinical trial described challenges with trust-building and expectation management, the need to navigate intense experiences often guided by music, and a desire for a more comprehensive treatment including multiple psilocybin sessions and sustained therapy. Distrust in mental healthcare generally, but trust in study therapists, was a key subtheme. The findings suggest that optimizing psilocybin treatment for this population requires individualized preparation, investment in trust-building, additional sessions, and access to ongoing psychotherapy with trusted therapists.
Journal of traumatic stress
August 1, 2021
Linnae Ponte, 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.
Frontiers in psychiatry
January 1, 2022
Joost J Breeksema, Alistair Niemeijer, Bouwe Kuin et al.
41 citations
Patients with treatment-resistant depression undergoing oral esketamine treatment often find the experience overwhelming and struggle with whether to let go or maintain control. Their ability to let go is influenced by preparation, emotional support, and the treatment setting. Better preparation, an optimized environment, and psychological support during sessions may improve patients' experiences and outcomes. The study provides recommendations for improving quality of care, including training for nurses and support staff.
Frontiers in Psychiatry
May 14, 2024
Zijia Yu, Lisa Burback, Olga Winkler et al.
38 citations
A scoping review of 24 articles found that four psychedelic drugs—ayahuasca, psilocybin, LSD, and the entactogen MDMA—consistently alter brain functional connectivity in healthy individuals. The drugs decreased connectivity within the default mode network and increased sensory and thalamocortical connectivity. These neurophysiological changes correlated with subjective experiences such as altered consciousness, mood elevation, and mystical experiences, suggesting a brain network basis for the drugs' psychological effects. The review provides a potential neural mechanism for psychedelics' subjective effects but notes that direct clinical evidence is needed to advance therapeutic outcomes.
Psychopharmacology
July 1, 2023
Joost J Breeksema, Alistair Niemeijer, Bouwe Kuin et al.
26 citations
The effects of oral esketamine for treatment-resistant depression are highly variable, and psychological distress is common. Patients report perceptual changes, detachment from body and emotions, stillness, mystical-type experiences, and fear. After sessions, many feel hungover and fatigued, while depressive mood is neutralized. Some effects, such as increased openness and detachment, may hold psychotherapeutic potential, but the frequent distress calls for additional patient support throughout treatment.
Psychiatry and Clinical Neurosciences
October 1, 2024
Shakila Meshkat, Fatemeh Gholaminezhad, Eric Vermetten et al.
24 citations
A systematic review of 20 studies with 2,959 participants found that psilocybin's effects on cognitive function are mixed. Global cognitive function and processing speed remained mostly unchanged in healthy individuals, while improvements in sustained attention, working memory, and executive function were reported in patients with treatment-resistant depression. Emotional processing and empathy were positively modified, especially in these patients, but cognitive empathy and social cognition were not significantly altered. Cognitive flexibility and creative cognition initially declined but could improve over time. Psilocybin improved semantic associations and associative learning, but effects on episodic and verbal memory were less pronounced than with other cognitive enhancers.
Pharmaceutics
March 25, 2025
Shakila Meshkat, Huda Al-Shamali, Argyrios Perivolaris et al.
22 citations
Psilocybin is rapidly converted to its active metabolite psilocin after oral intake. Psilocin reaches peak concentration in blood plasma between 1.8 and 4 hours, with maximum concentration ranging from 8.2 ng/mL in plasma to 871 ng/mL in urine, depending on dose. Its bioavailability is about 53%, and it distributes extensively into tissues, with volume of distribution between 277 and 1016 liters. Metabolism involves CYP2D6 and CYP3A4 enzymes, plus monoamine oxidase A, producing 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophol. Elimination half-life ranges from 1.5 to 4 hours. These pharmacokinetics vary with dosage, route, and species, and the role of CYP enzymes indicates possible drug interactions.
Frontiers in psychiatry
January 1, 2023
Macha Godes, Jasper Lucas, Eric Vermetten
14 citations
For people with severe PTSD, MDMA-assisted psychotherapy helps them articulate how the treatment changes their daily lives. Analysis of session transcripts from 7 participants in a Phase-II trial identified perceived mechanisms of change, showing how the therapy's proposed working mechanisms integrate into everyday functioning. The qualitative findings complement earlier quantitative results by providing real-life statements that clarify the treatment's effects.
Neuroscience and biobehavioral reviews
June 1, 2025
Shakila Meshkat, Gunjan Malik, Richard J Zeifman et al.
11 citations
Psilocybin-assisted psychotherapy may reduce alcohol consumption and help with smoking cessation, especially for alcohol and tobacco use disorders. In a systematic review of 16 published studies, most focused on alcohol or tobacco use, and over half used psilocybin combined with psychotherapy. Doses ranged from microdosing to 20–40 mg per 70 kg. Alcohol use disorder studies reported fewer heavy drinking days and higher abstinence rates, with brain scans showing normalized activity. Tobacco use disorder studies found high smoking abstinence rates, with mystical experiences predicting long-term success. Findings for other substance use disorders were mixed. The evidence is preliminary; larger clinical trials are needed.
European journal of psychotraumatology
January 1, 2024
Jerome Herpers, Natalie Maximets, Noah N N van Dongen et al.
7 citations
Experts in MDMA-assisted therapy for PTSD overwhelmingly endorse the need for training, standardization, equity, and access, while identifying impediments in national approval processes and anticipating spill-over effects in clinical settings. A survey of 68 researchers and clinicians worldwide gathered opinions on clinical practices, training, and regulation. The findings call for science-informed policy development, active regulatory involvement, and international cooperation to incorporate MDMA-assisted therapy into European mental healthcare, particularly for PTSD treatment.
Psychiatry and clinical psychopharmacology
August 11, 2025
Reinhard Janssen-Aguilar, Shakila Meshkat, Huda F Al-Shamali et al.
4 citations
Posttraumatic stress disorder (PTSD) is a severe condition that can be difficult to treat, prompting interest in innovative therapies. This systematic review of 94 studies evaluated interventional treatments including neuromodulation, rapid-acting pharmacotherapies like intravenous ketamine and esketamine, and psychedelic-assisted psychotherapies. Randomized controlled trials showed response rates ranging from 12.5% to 80% for transcranial magnetic stimulation, 17% to 67% for intravenous ketamine, and 50% to 87% for MDMA-assisted therapy. Most treatments were well tolerated with only mild, transient adverse effects. The review highlights variability in efficacy, safety, and tolerability across treatments, reflecting differences in patient populations, protocols, and comorbidities. While symptom improvement is observed, sustained efficacy varies, underscoring the need for maintenance strategies.
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.
Journal of Clinical Medicine
February 20, 2025
Shakila Meshkat, Taha Malik, Jennifer Swainson et al.
3 citations
A systematic review examined whether psychedelic therapies can rapidly reduce suicide risk. Four randomized controlled trials reported significant reductions in suicidal ideation with psilocybin (three studies) and MDMA-assisted therapy (one study), with effect sizes (Cohen's d) ranging from 0.52 to 1.25 and no safety issues. Five additional randomized trials also showed reductions. Among 24 non-randomized and cross-sectional studies, results were mixed: psilocybin reduced suicidal ideation (odds ratios 0.40–0.75), MDMA-assisted therapy for PTSD showed a pooled effect of d = 0.61, while LSD was associated with increased odds of suicidality (odds ratios 1.15–2.08). DMT studies showed no significant effects. The evidence remains inconclusive, underscoring the need for further trials.
Neurorehabilitation
September 27, 2024
Walter Dunn, Anya K. Bershad, David E. Krantz et al.
2 citations
MDMA-assisted therapy for PTSD, supported by late-stage clinical trials, may be especially beneficial for military populations. MDMA's pro-social and fear-regulating properties could enhance the therapeutic alliance and patient engagement during neurorehabilitation. The molecular mechanism of MDMA is outlined, and a novel application for neurorehabilitation is proposed. Similarities in patient-therapist dynamics between PTSD treatment and neurorehabilitation suggest that MDMA's ability to downregulate fear, increase cognitive flexibility, and improve alliance could aid military personnel both with and without PTSD.
Psychopharmacology
July 1, 2026
Sarah Ann Smith, Haseeb Mohammad, Lik Hang N Lee et al.
A review of 20 studies examined whether psychedelic drugs can affect social cognition in people with psychiatric or neurodevelopmental disorders that involve cognitive impairment. The drugs studied were ketamine, MDMA, psilocybin, LSD, and ayahuasca, tested in depressive disorders, anxiety disorders, autism spectrum disorder, and post-traumatic stress disorder. Findings included neural activation patterns suggesting that ketamine and psilocybin may modulate processes relevant to social perception, especially facial emotion processing, in depressive disorders. MDMA was linked to improvements in self-reported psychosocial functioning, self-awareness, and self-compassion in participants with PTSD. Direct evidence of improved social-cognitive functioning remains limited.
European Psychiatry
January 1, 2026
Shakila Meshkat, Qiaowei Lin, Rachel Sousa-Ho et al.
Control groups in psychedelic-assisted psychotherapy trials show substantial symptom improvement, likely due to non-specific factors such as expectancy and concurrent psychotherapy. A meta-analysis of 14 randomized controlled trials (643 participants) found that treatment groups had greater symptom reductions than control groups for depressive symptoms, PTSD symptoms, and anxiety symptoms. For PTSD, inactive placebo groups showed larger within-group improvements. The findings underscore the need for robust control conditions and careful interpretation of treatment effects in psychedelic research.
Journal of eating disorders
December 29, 2025
Michael Harkhoe, Tim Offringa, Eric Vermetten
No clinical trials of MDMA-assisted therapy have been conducted in patients with eating disorders, including anorexia nervosa. Evidence from PTSD trials suggests MDMA's pro-social, fear-reducing, and neuroplastic properties may enhance emotional processing, therapeutic alliance, and cognitive flexibility—factors that often hinder eating disorder treatment. The paper synthesizes current research on MDMA, PTSD, and eating disorders, reviewing clinical trial outcomes, neurobiological mechanisms, and therapeutic frameworks. It argues that MDMA-assisted therapy may hold promise as an adjunctive treatment for eating disorders with comorbid trauma, but rigorous validation through well-powered trials and careful ethical oversight are needed before clinical integration.