JAMA Psychiatry
November 4, 2020
Mary P Cosimano, Alan K. Davis, Frederick S. Barrett et al.
1,269 citations
Two doses of psilocybin (20 and 30 mg per 70 kg) combined with supportive psychotherapy produced large, rapid antidepressant effects in adults with major depressive disorder who were not taking other antidepressants. In a randomized waiting list-controlled trial with 24 completers, depression scores on the GRID-Hamilton scale dropped from a mean of 22.8 at baseline to 8.0 one week after the second session, compared with 23.8 at the same time point in the delayed-treatment group. Seventy-one percent of participants showed a clinically significant response at week 1, and 58% met remission criteria. Effects persisted through the four-week follow-up.
Journal of Psychopharmacology
February 1, 2022
Natalie Gukasyan, Alan K. Davis, Frederick S. Barrett et al.
419 citations
In patients with moderate to severe major depressive disorder, psilocybin-assisted therapy produced large and sustained decreases in depression severity through 12 months. Scores on the GRID-Hamilton Depression Rating Scale dropped substantially from baseline at 1, 3, 6, and 12 months (effect sizes of 2.3, 2.0, 2.6, and 2.4, respectively). At 12 months, 75% of participants showed a 50% or greater reduction in symptoms and 58% achieved remission. No serious adverse events linked to psilocybin occurred during long-term follow-up, and no participants used psilocybin outside the study. Ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted greater well-being at 12 months but did not predict depression improvement.
Scientific Reports
February 10, 2020
Frederick S. Barrett, Manoj K. Doss, Nathan D. Sepeda et al.
375 citations
A single 25 mg/70 kg dose of psilocybin temporarily reduced negative affect and amygdala response to negative facial expressions one week later in twelve healthy volunteers, while positive affect and prefrontal cortex responses to emotional conflict increased. One month later, negative affect and amygdala reactivity returned to baseline, but positive affect remained elevated and trait anxiety was lower. The number of resting-state functional connections across the brain increased from baseline to both one week and one month after dosing. These preliminary findings suggest psilocybin may enhance emotional and brain plasticity, with negative affect as a potential therapeutic target.
Translational Psychiatry
November 8, 2021
Manoj K. Doss, Michal Považan, Monica D Rosenberg et al.
343 citations
Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
Drugs Education Prevention and Policy
December 10, 2020
Monnica T. Williams, Alan K. Davis, Yitong Xin et al.
100 citations
Psychedelics such as psilocybin, LSD, and MDMA may reduce symptoms of racial trauma among Black, Indigenous, and other people of color (BIPOC) after a racist experience. In a cross-sectional survey of 313 diverse BIPOC in the US and Canada, participants retrospectively reported mental health symptoms 30 days before and 30 days after using a psychedelic. Analysis showed significant decreases in traumatic stress, depression, anxiety, and stress following the experience. A strong positive relationship emerged between acute psychedelic effects (mystical-type, insight, and challenging experiences) and reductions in psychopathology, even after controlling for prior discrimination and time since the experience. The findings suggest psychedelics could lessen the negative impact of racial trauma, though further research on psychedelic-assisted therapy for race-based trauma is needed.
Frontiers in Psychiatry
September 19, 2023
Hillary Jackson, Sara So, Abigail Yaffe et al.
87 citations
A large prospective survey of adults planning to take psilocybin outside clinical settings found that, on average, participants reported lasting reductions in anxiety, depression, and alcohol misuse, along with improvements in cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and decreases in neuroticism and burnout after use. However, a minority reported persisting negative effects: 11% at 2–4 weeks and 7% at 2–3 months after use, including mood fluctuations and depressive symptoms. The study included 2,833 respondents at baseline, 1,182 at 2–4 weeks, and 657 at 2–3 months post-use. Participants were primarily college-educated White men in the United States, mean age 40, who used dried psilocybin mushrooms (mean dose 3.1 grams) for self-exploration.
Chronic Stress
August 12, 2020
Alan K. Davis, Lynnette A. Averill, Nathan D. Sepeda et al.
83 citations
Among U.S. Special Operations Forces Veterans who completed a psychedelic treatment program with ibogaine and 5-methoxy-N,N-dimethyltryptamine in Mexico between 2017 and 2019, retrospective reports showed very large reductions in suicidal ideation, cognitive impairment, PTSD symptoms, depression, and anxiety from 30 days before to 30 days after treatment, along with a large increase in psychological flexibility. Increased psychological flexibility was strongly linked to reduced cognitive impairment and mental health symptoms. Most participants rated the experience among the top five most personally meaningful, spiritually significant, and psychologically insightful experiences of their lives. The findings are preliminary due to the retrospective, self-report, non-randomized design.
Chronic Stress
January 1, 2021
Alan K. Davis, Yitong Xin, Nathan D. Sepeda et al.
66 citations
Among 313 Black, Indigenous, and people of color (BIPOC), acute psychedelic effects were associated with decreases in racial trauma symptoms. Greater psychological insight and less intense challenging experiences during the psychedelic session predicted larger symptom reductions. Increases in psychological flexibility partially mediated these improvements. The findings suggest psychedelics may help reduce racial trauma in BIPOC, with psychological flexibility playing a key mediating role.
PLoS One
March 14, 2024
Adam W. Levin, Rafaelle Lancelotta, Nathan D. Sepeda et al.
65 citations
In a small randomized trial of psilocybin-assisted therapy for adults with major depressive disorder, the therapeutic alliance between participants and facilitators strengthened from the final preparation session to one week after the intervention. A stronger alliance before the psilocybin sessions predicted lower depression scores at 4 weeks, 6 months, and 12 months afterward. Stronger alliance also correlated with more intense mystical experiences and psychological insight during the drug sessions, which in turn predicted better depression outcomes. The findings suggest the therapeutic relationship is important for treatment success.
The American Journal of Drug and Alcohol Abuse
September 3, 2023
Alan Kooi Davis, Yitong Xin, Nathan D. Sepeda et al.
29 citations
Combined ibogaine and 5-MeO-DMT assisted therapy produced rapid and large improvements in mental health among trauma-exposed Special Operations Forces Veterans. In a sample of 86 male veterans, self-reported PTSD symptoms, depression, anxiety, insomnia severity, and post-concussive symptoms all significantly decreased from baseline to one-month follow-up. Satisfaction with life, psychological flexibility, and cognitive functioning also significantly improved. The therapeutic effects appeared durable up to six months. The study was a prospective clinical program evaluation conducted in Mexico, and the authors call for future controlled research to confirm these findings.
Journal of Psychedelic Studies
December 27, 2019
Nathan D. Sepeda, John Clifton, Laura Y. Doyle et al.
23 citations
People who used inhaled synthetic 5-MeO-DMT in a structured, supportive setting reported significantly more intense mystical experiences and enduring positive effects—such as greater meaningfulness, spirituality, and well-being—and fewer challenging experiences than those who used it in a non-structured context. In the structured context group, 83% had a complete mystical experience compared to 54% in the non-structured group. The findings suggest that a safe and supportive environment enhances the positive acute and lasting outcomes of 5-MeO-DMT.
Military psychology : the official journal of the Division of Military Psychology, American Psychological Association
January 1, 2024
Stacey B. Armstrong, Yitong Xin, Nathan D. Sepeda et al.
19 citations
Among 45 U.S. Special Operations Forces Veterans with risky alcohol use who completed ibogaine and 5-MeO-DMT treatment in Mexico, alcohol use dropped substantially from an average of 7.2 drinks per drinking day before treatment to 3.6 at one month and 4.0 at six months post-treatment. At one month, 24% were abstinent, 33% were non-risky drinkers, and 42% still risky drinkers; by six months, 16% were abstinent, 31% non-risky, and 53% risky. Responders (abstinent or non-risky) showed very large improvements in PTSD symptoms and cognitive functioning compared to non-responders, while demographics did not differ. The findings suggest psychedelic-assisted therapy may help those with complex trauma and alcohol misuse who have not responded to traditional treatments.
Psychedelic Medicine
May 16, 2025
Roland R. Griffiths, William A. Richards, Robert L. Jesse et al.
14 citations
In clergy from various world religions who had never used psychedelics, two supported psilocybin sessions (20 mg/70 kg, then 20 or 30 mg/70 kg) led to sustained positive changes in religious practices, attitudes about their religion, and effectiveness as a religious leader, as well as in non-religious attitudes, moods, and behavior, compared with a waitlist control group. At 16‑month follow‑up, 96% rated at least one experience among the top five most spiritually significant of their lives, 42% rated it the single most profound, and 79% reported positive effects on daily sense of the sacred. No serious adverse events occurred, though 46% rated an experience among the top five most psychologically challenging of their lives.
Journal of Affective Disorders
February 1, 2025
Grant Jones, Matthew X. Lowe, Sandeep M. Nayak et al.
12 citations
Psilocybin, the psychoactive compound in magic mushrooms, is linked to improved mental wellbeing on average, but few studies examine how effects differ by race. In a large online longitudinal study of 2,833 people planning naturalistic psilocybin use, race/ethnicity moderated changes in spiritual wellbeing, cognitive flexibility, and emotion regulation (expressive suppression) at 2–3 months post-experience, but not at 2–4 weeks. Participants of Color reported minor differences in context and subjective effects, such as being more likely to set an intention before use. Both groups showed comparable reductions in anxiety and depression, with no significant moderation by race.
Journal of Psychoactive Drugs
February 7, 2025
Amy Lehrner, Heather Jackson, David S. Mathai et al.
11 citations
Among 679 adults using psilocybin in naturalistic settings, 68.2% reported acute feelings of shame or guilt during the experience, which were difficult to predict. The ability to constructively work through these feelings predicted wellbeing 2-4 weeks later. On average, psilocybin produced a small but significant decrease in trait shame maintained 2-3 months after use (Cohen's dz = 0.37), though trait shame increased in 29.8% of participants. The activation of self-conscious emotions with psychedelics warrants further attention as a challenging experience subcategory relevant to psychological outcomes, potentially creating a unique learning condition for shame-related memory reconsolidation.
Psychedelic Medicine
August 30, 2023
Samantha Hilbert, David S. Mathai, Nathan D. Sepeda et al.
10 citations
Dissociatives like dextromethorphan may have clinical applications when used in supportive settings similar to those in psychedelic research, which prioritize optimizing psychologically valuable drug experiences. The analysis suggests that such contexts could enhance therapeutic outcomes.
Journal of Psychedelic Studies
September 4, 2025
Alan K. Davis, Meghan DellaCrosse, Nathan D. Sepeda et al.
4 citations
Over a five-year follow-up period, psilocybin-assisted therapy produced significant and sustained reductions in depression for people with major depressive disorder. Among the 18 participants who completed the study, 67% remained in remission for at least five years after treatment. Anxiety and functional impairment also improved. Qualitative interviews revealed lasting positive changes in mindset, emotional health, and relationships, including enhanced empathy, self-acceptance, and improved interpersonal relationships. No severe adverse events were reported. These findings support the long-term efficacy and safety of psilocybin-assisted therapy for reducing depressive symptoms and improving mental health.
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.
Journal of Psychoactive Drugs
July 14, 2023
Christopher Timmermann, Aki Nikolaidis, Alan K. Davis et al.
4 citations
Spanish translations of three questionnaires measuring acute psychedelic effects—the Psychological Insight Questionnaire (PIQ), Challenging Experiences Questionnaire (CEQ), and Mystical Experiences Questionnaire (MEQ)—showed good psychometric properties in a sample of 442 native Spanish speakers. Confirmatory factor analysis confirmed that the factor structures matched the original English versions, and this consistency held across subgroups who had used LSD or psilocybin. Construct validity was supported by positive associations between the PIQ and MEQ and between these measures and changes in cognitive fusion, alongside negative associations with changes in prosocial behaviors. Predictive validity was indicated by strong relationships between persisting effects and scores on the MEQ and PIQ. The Spanish versions can be reliably used in research with Spanish-speaking populations.
International Journal of Mental Health and Addiction
April 24, 2025
Jérémie Richard, Jeremy Scott, Sandeep M. Nayak et al.
3 citations
No Summary
Psychiatry Research
February 13, 2026
Sean P. Goldy, Nathan D. Sepeda, Samantha Hilbert et al.
1 citation
The acute subjective effects of psychedelics are known to predict therapeutic benefits like reduced depression and anxiety. Session facilitators—who support participants before, during, and after dosing—are a key part of the setting, but their influence on subjective effects was unclear. Analyzing data from 9 psilocybin studies with 298 participants, 670 sessions, and 60 facilitators, multilevel models showed facilitators accounted for negligible variance (0.8%) in healthy volunteers but greater variance in clinical samples (13.6%), after controlling for study and participant differences. This suggests facilitators may play a clinically meaningful role in shaping outcomes for patient populations, comparable to or exceeding therapist effects in traditional psychotherapy (~8%).
International Journal of Methods in Psychiatric Research
June 1, 2026
Kurt Stocker, Matthias Hartmann, Frederick S. Barrett et al.
The eight-factor structure of the Psychedelic Experience Scale (PES48), which includes the Mystical Experience Questionnaire (MEQ30) and additional factors for paradoxicality, connectedness, visual experience, and distressing experience, is valid for use in English. Analysis of 280 measurements from 145 healthy participants in four placebo-controlled psilocybin studies found that six subscales have high internal consistency, one good, and one acceptable. Both the MEQ30 and MEQ40 models show acceptable to good model fits, with better fits in English than in German. All six MEQ40 scale means were higher in English data, suggesting that the PES48 provides a broader conceptualization of mystical and non-mystical psychedelic experiences, and that setting may influence mystical experience.
Repository for Publications and Research Data (ETH Zurich)
April 30, 2026
Kurt Stocker, Matthias Hartmann, Frederick S. Barrett et al.
The Psychedelic Experience Scale (PES48) has an eight-factor structure that includes the well-validated Mystical Experience Questionnaire (MEQ30) plus four additional factors: paradoxicality, connectedness, visual experience, and distressing experience. This study tested whether the full eight-factor structure is valid in English, using data from 280 PES measurements from 145 healthy participants in four placebo-controlled psilocybin studies. Six of the eight subscales showed high internal consistency, one good, and one acceptable. Confirmatory factor analysis indicated acceptable to good model fits for the MEQ30 and MEQ40, with English data showing better fits than the German validation sample. The findings suggest the PES48 is a valid psychometric tool in English, enabling broader measurement of mystical and non-mystical aspects of psychedelic experience.
medRxiv Preprint Server
April 28, 2026
Sandeep M. Nayak, Nathan D. Sepeda, Matthew Nielsen Dick et al.
preprint
Psilocybin is being studied as a treatment for psychiatric and neurologic conditions, but there is limited comprehensive data on its cardiovascular safety. Current clinical trials typically exclude people with blood pressure of 140/90 mmHg or higher, a cutoff set conservatively without strong empirical evidence.
Religion Brain & Behavior
March 31, 2026
Kurt Stocker, Matthias Hartmann, Frederick S. Barrett et al.
After administration of LSD, psilocybin, mescaline, or DMT, mystical oneness—the core of mystical experience—showed dose-sensitive strong correlations with luminous light and renewal, and a moderate-to-strong correlation with ego disintegration. These findings from 386 healthy participants across 15 studies support a broader, dynamic model of mystical experience, where mystical oneness unfolds with ego disintegration, renewal, and luminous light. The results offer insights for psychedelic-assisted therapy.