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.
JAMA
August 31, 2023
Charles L. Raison, Gerard Sanacora, Joshua Woolley et al.
493 citations
A single 25-mg dose of synthetic psilocybin, administered with psychological support, produced a clinically significant and sustained reduction in depressive symptoms and functional disability over 43 days in adults with major depressive disorder. In a phase 2 trial of 104 participants, those receiving psilocybin showed a mean 12.3-point greater improvement on the Montgomery-Asberg Depression Rating Scale at day 43 compared with those receiving a niacin placebo. Psilocybin also improved daily functioning and led to more sustained response, though not remission. No serious adverse events occurred, but psilocybin was associated with more overall and severe adverse events.
EClinicalMedicine
September 24, 2020
B. Anderson, Alicia Danforth, Prof Robert Daroff et al.
271 citations
Psilocybin-assisted group therapy is feasible, relatively safe, and potentially effective for reducing demoralization in older long-term AIDS survivor (OLTAS) gay men, a population with high levels of demoralization and traumatic loss. In an open-label study, participants with moderate-to-severe demoralization received 8-10 group therapy visits and one psilocybin administration (0.3-0.36 mg/kg). The primary clinical outcome showed a reduction in demoralization from baseline to end-of-treatment and to 3-month follow-up, with a moderate effect size (partial eta-squared = 0.47, 90% CI 0.21-0.60). Groups may offer an efficient model for delivering psychotherapy alongside psilocybin to patients with complex needs.
Psychopharmacology
April 1, 2022
Jacob S. Aday, Boris D. Heifets, Steven D. Pratscher et al.
214 citations
Psychedelic research faces unique methodological challenges beyond those typical of psychotherapy and pharmacology trials. The pronounced subjective effects of high-dose psychedelics make it difficult to mask participants to their treatment condition. Positive media coverage inflates participants' expectations for benefit, and unmasking combined with expectations can produce large placebo and nocebo effects. Recommendations to improve masking and reduce expectancy bias include careful study development, participant recruitment and selection, incomplete disclosure of study design, choice of active placebo, and measurement of expectations and masking efficacy. Incorporating these design elements aims to reduce bias and improve the ability to discern treatment-specific effects.
Journal of Psychoactive Drugs
March 15, 2019
Alexander Trope, B. Anderson, Andrew R. Hooker et al.
113 citations
A systematic review of English- and Spanish-language publications identified experimental studies of psychedelic-assisted group therapy, an area overlooked by prior reviews that focused on individual psychotherapy. The review characterizes these studies by clinical approach, experimental method, and outcomes. It aims to generate hypotheses for future research on psychedelic-assisted psychotherapy, group process, and interpersonal functioning, given renewed clinical interest in psychedelic medicines.
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.
ACS Pharmacology & Translational Science
December 9, 2020
Christopher S. Stauffer, B. Anderson, Kile Ortigo et al.
65 citations
Attachment insecurity, measured as anxiety and avoidance, is an early-life risk factor for psychopathology. Psilocybin-assisted psychotherapy may reduce attachment anxiety. In a study of 18 male long-term AIDS survivors with moderate-severe demoralization, attachment anxiety decreased significantly from baseline to three months after a single psilocybin session embedded in group therapy. Attachment avoidance did not change. Higher baseline attachment anxiety predicted stronger mystical-type experiences during the psilocybin session, while higher baseline attachment avoidance predicted more challenging experiences. These results suggest that psilocybin-assisted psychotherapy could be optimized by considering individual attachment styles.
Psychedelic Medicine
February 16, 2023
Zachary Skiles, Noa Eaton, Lisa Fredenburg et al.
49 citations
Most psychedelic therapists in a Usona Institute trial for psilocybin and major depressive disorder had personal experience with psychedelics: 88% had used at least one serotonergic psychedelic, most commonly psilocybin (81%), with a median of 2–10 uses and last use 6–12 months before the survey. The sample was predominantly white, female, and held doctoral degrees. All endorsed favorable views of psilocybin therapy. Experiential learning is common in psychotherapy but not psychiatry, placing psychedelic therapy between two traditions. The study was limited by a low response rate (22%) and lack of diversity. These first data on professionals' personal use inform the debate on whether such experience aids competency or introduces bias.
JAMA Psychiatry
June 1, 2023
Jacob S. Aday, Robin Carhart-Harris, Joshua Woolley
48 citations
The abstract discusses emerging challenges for psychedelic therapy, highlighting obstacles such as regulatory hurdles, accessibility issues, equity concerns, and the need for practitioner training. It underscores difficulties in integrating psychedelic treatments into mainstream healthcare, including governance, legal frameworks, and developing accessible and equitable treatment models. The text suggests that responsible integration requires addressing these barriers to ensure safe and effective mental health care.
Psychopharmacology
August 1, 2024
Jacob S. Aday, David Horton, Gisele Fernandes-Osterhold et al.
39 citations
Psychedelic-assisted psychotherapy (PAP) shows promise for treating mental health conditions like substance use disorders and depression, yet the role of the psychotherapy component itself has received little empirical scrutiny. This review examines current debates over whether PAP involves full psychotherapy or merely psychological support, and summarizes existing clinical trial models and theoretical frameworks. It draws lessons from traditional psychotherapy research, advocating for standardized treatment manuals, clear provider eligibility criteria, measurement of established mechanisms of change, and optimized trial designs such as dismantling studies and comparative efficacy trials. The authors argue that PAP is a distinct, integrative, transdisciplinary intervention requiring further research into its psychotherapeutic components to inform best practices and federal guidelines.
Journal of Affective Disorders Reports
September 22, 2021
David E. Gard, Mollie Pleet, Ellen Bradley et al.
33 citations
Psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve depression symptoms, but people with bipolar disorder have been excluded from clinical trials due to concerns about triggering mania. As psilocybin becomes more available, individuals with bipolar disorder may seek it for depression. A review of 17 published cases suggests a potential risk of activating manic episodes, warranting caution. However, the lack of systematic data indicates a need for a cautious trial using modern methods, focusing on those at lowest risk for mania, such as bipolar 2 disorder, given the significant impact of depression in this population.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 9, 2025
Ellen Bradley, Kimberly Sakai, Gisele Fernandes-Osterhold et al.
23 citations
In an open-label pilot trial, 12 people with mild to moderate Parkinson's disease plus depression or anxiety received psilocybin (10 mg then 25 mg) with psychotherapy. No serious adverse events occurred, and no worsening of Parkinson's symptoms was observed. Non-motor and motor symptoms improved, and gains in some cognitive domains were sustained one month later. Depression and anxiety scores improved to a clinically meaningful degree and remained improved three months after dosing. These first results in any neurodegenerative disease suggest psilocybin therapy for Parkinson's disease warrants further study.
Psychiatry Research
March 1, 2025
Stephanie L. Haft, Amanda E. Downey, Marissa Raymond-Flesch et al.
22 citations
A systematic review of 21 randomized controlled trials of psilocybin- and MDMA-assisted therapies (total 1034 participants) found that participant samples lack diversity. Gender was always reported, race or ethnicity in 76% of trials, and socioeconomic status in 57%. Sexual orientation (9.5%) and immigration status (4.8%) were rarely reported; no study reported gender identity. Compared to the US population and non-psychedelic clinical trials, Black/African-American participants (2.2%) and Hispanic/Latino participants (7.2%) were significantly underrepresented. MDMA trials enrolled more diverse samples than psilocybin trials. Analyses of treatment effects by demographic variables were virtually absent. The findings indicate a need for inclusive recruitment and rigorous reporting to improve generalizability.
December 1, 2021
Jacob S. Aday, Boris D. Heifets, Steven D. Pratscher et al.
20 citations
preprint
Clinical trials of psychedelic therapy face unique methodological challenges that threaten the interpretability of results. The intense subjective effects of high-dose psychedelics make it difficult to mask participants to their treatment condition, and widespread positive media coverage inflates participants' expectations for benefit. Participant unmasking and treatment expectations can interact, making psychedelic therapy highly susceptible to large placebo and nocebo effects. Recommendations to improve rigor include careful study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, and measurement of participant expectations and masking efficacy. Incorporating these design elements is intended to reduce bias and increase the ability to discern treatment-specific effects.
Journal of Eating Disorders
April 24, 2024
Amanda E. Downey, Anita V. Chaphekar, Joshua Woolley et al.
13 citations
Clinical trials are testing psilocybin therapy for anorexia nervosa (AN), but individuals with AN have unique medical vulnerabilities. This review describes how common physiologic adverse effects of psilocybin—tachycardia, hypertension, electrocardiogram changes, nausea, headache, and lightheadedness—may interact with medical complications seen in AN. It proposes risk mitigation strategies for each adverse effect. Early evidence suggests psilocybin therapy is well-tolerated in individuals with AN. Understanding AN's medical complications in relation to psilocybin's effects can help tailor strategies to enhance safety and tolerability of this novel intervention.
Psychopharmacology
August 1, 2024
Kimberly Sakai, Ellen Bradley, Joseph A. Zamaria et al.
10 citations
People who take SSRIs and use psilocybin mushrooms together often report a less intense psychedelic experience, though many report no change in intensity. About 8% of Reddit posts describing coadministration mention negative physical or psychological effects, including a small number of reports that may indicate serotonin toxicity and one possible psychotic or manic episode. The interactions appear complex and likely depend on multiple factors. Prospective studies are needed to determine whether psilocybin treatments are safe and effective for people using SSRIs.
International Journal of Eating Disorders
August 8, 2023
Maxine Boyd, Joshua Woolley, Amanda E. Downey et al.
7 citations
Healthcare providers who treat eating disorders expressed interest in psilocybin-assisted psychotherapy but raised concerns about risks to malnourished patients and those with psychological comorbidities. In focus groups with 32 participants, providers also worried about equity in access for publicly insured and non-English speaking patients. They requested continuing education about psilocybin therapy. Despite concerns, providers were hopeful about psilocybin therapy as a treatment and valued collaboration to improve long-term patient outcomes as clinical trials develop.
medRxiv
April 7, 2021
David E. Gard, Mollie Pleet, Ellen Bradley et al.
7 citations
preprint
Psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve depression symptoms, but its safety in people with bipolar disorder is unknown because they have been excluded from clinical trials. The authors reviewed 17 published case histories and found potential risk for activating a manic episode, warranting caution. However, the lack of systematic data or common case examples indicating risk suggests that a cautious trial using modern methods, focused on those at lowest risk for mania (e.g., bipolar 2 disorder), is needed given depression's impact on this population.
November 6, 2023
Jacob S. Aday, David P Horton, Gisele Fernandes-Osterhold et al.
5 citations
preprint
Psychedelic-assisted psychotherapy (PAP) combines a psychedelic substance with psychotherapeutic support, yet the specific role and necessary components of the psychotherapy itself remain understudied. This review examines current PAP clinical trial models and theoretical frameworks, then draws lessons from traditional psychotherapy research on standardizing treatments, identifying mechanisms of change, and optimizing trial designs. The authors conclude that PAP is a unique transdisciplinary intervention and call for increased research on its psychotherapeutic component to inform best practices and federal guidelines.
Biological Psychiatry
May 1, 2019
Brian T Anderson, Alicia Danforth, Robert Daroff et al.
5 citations
No Summary
May 15, 2023
Jacob S. Aday, Emily K. Bloesch, Alan K. Davis et al.
3 citations
preprint
People who attended an ayahuasca retreat showed increased engagement with aesthetic experiences—such as appreciation of art, nature, and beauty—one week and one month afterward, compared to before the retreat. The study followed 54 participants and measured aesthetic experience using a validated questionnaire. Although participants reported strong mystical-type experiences, awe, and ego dissolution during their ayahuasca sessions, none of these acute effects predicted the long-term increase in aesthetic engagement. The open-label design limits certainty, but the findings support anecdotal reports that psychedelics can enhance aesthetic appreciation and point to a new area for future research.
Front Psychiatry
June 10, 2024
Leehe Peled-Avron, Jacob S. Aday, Amilia Lydia Kalafateli et al.
2 citations
Psychedelic compounds produce profound alterations in consciousness and perception, and emerging evidence suggests they may be effective treatments for several mental health and medical conditions. This editorial introduces a collection of articles that explore the psychological and neural mechanisms underlying these effects, including how psychedelics modulate brain networks, promote neuroplasticity, and facilitate therapeutic change. The authors argue that understanding these mechanisms is crucial for developing safe and effective psychedelic-assisted therapies. They highlight the need for rigorous research to clarify how these compounds work and to optimize their clinical application.
Psychedelic Medicine
February 28, 2024
Joshua Woolley, Amanda E. Downey, Ellen Bradley et al.
2 citations
A risk stratification tool is proposed to help decide whether individuals with a family history of bipolar disorder should be included in psilocybin therapy trials. The authors argue for caution due to the potential for serious adverse events, but they recommend against outright exclusion. The tool allows for more nuanced inclusion and exclusion criteria, balancing the need for effective treatments against safety concerns.
Scientific Reports
November 29, 2025
Leehe Peled-Avron, Jacob S. Aday, Madeline M. Pantoni et al.
1 citation
MDMA enhances emotional empathy but reduces accuracy in recognizing negative facial expressions such as sadness, fear, and anger. No significant effects were found on cognitive empathy or recognition of happy expressions. These findings come from a meta-analysis of studies using the Multifaceted Empathy Test and the Facial Emotion Recognition Task. Understanding these nuanced effects may help optimize therapeutic applications and safety considerations for MDMA-assisted psychotherapy, which is currently under regulatory review for post-traumatic stress disorder.
August 25, 2024
Stephanie L. Haft, Amanda E. Downey, Marissa Reymond-Flesch et al.
1 citation
preprint
Limited participant diversity in mental health intervention research perpetuates health disparities, a concern especially relevant to psychedelic-assisted psychotherapy (PAT). This systematic review of 21 randomized controlled trials of psilocybin- and MDMA-assisted therapies (total 1,034 participants) found that gender (100%) and race or ethnicity (76%) were frequently reported, while socioeconomic status was sometimes reported (57%) using varied measures. Sexual orientation (9.5%) and immigration status (4.8%) were rarely reported, and no studies reported gender identity. Black/African-American (12.2%) and Hispanic/Latino (7.2%) participants were significantly underrepresented compared to the US population and non-psychedelic clinical trials. MDMA trials enrolled more diverse samples than psilocybin trials. Analyses of treatment effects by sociodemographic variables were virtually nonexistent, highlighting the need for inclusive recruitment and rigorous reporting to improve generalizability.