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.
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.
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.
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.
JAMA Psychiatry
March 1, 2025
Michelle Matvey, D Parker Kelley, Ellen Bradley et al.
12 citations
In psychedelic clinical trials, participants often cannot be masked to whether they received the active drug or placebo, because the drug's effects are so noticeable. This can bias outcomes because participants' expectations influence their responses. One proposed solution is to modify the informed consent process to obscure some details of the study design, which has been used in several recent trials. However, this approach raises serious ethical concerns. The authors review the use of such modifications in trials from 2000 to 2024, discuss the regulatory landscape, and suggest ways to reduce risks. They conclude that modified consent may improve trial interpretability but has not been explicitly tested and may not be appropriate in all cases.
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.
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.
American Journal of Psychiatry
December 1, 2025
Amanda E. Downey, Marlene Tai, Ellen Bradley et al.
2 citations
Psilocybin, a hallucinogen found in certain mushrooms, shows promise in treating severe depression, with studies revealing that 70% of participants experienced significant symptom reduction after just one dose. In a sample of 200 individuals, those receiving psilocybin reported enhanced consciousness and emotional well-being compared to a control group. Additionally, the safety profile is encouraging; there were no incidents of sudden death or severe adverse effects linked to ingestion. This highlights psilocybin's potential role in modern psychiatry as a transformative medicine alongside cannabis and cannabinoid research.
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.
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.
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.