ACS Pharmacology & Translational Science
March 18, 2021
Stephen Ross, Gabrielle Agin-Liebes, Sharon L. Lo et al.
133 citations
People with advanced cancer face elevated risks of desire for hastened death, suicidal ideation, and completed suicide. Loss of meaning, a component of demoralization, predicts these outcomes. In a randomized controlled trial, psilocybin-assisted psychotherapy produced rapid and sustained improvements in depression, demoralization, and hopelessness. Secondary analyses showed that among participants with elevated suicidal ideation at baseline, reductions in suicidal ideation appeared as early as 8 hours and persisted for 6.5 months. Large reductions in loss of meaning emerged 2 weeks after treatment and remained significant at 6.5 months and at 3.2 and 4.5 year follow-ups. The findings suggest psilocybin-assisted psychotherapy may be an effective antisuicidal intervention for cancer patients due to its positive impact on hopelessness and meaning-making.
Neuropharmacology
December 27, 2022
Robin Carhart‐Harris, Shamil Chandaria, David Erritzøe et al.
106 citations
A theoretical model proposes that psychopathology arises from a defensive process called canalization, which narrows an individual's range of thoughts, feelings, and behaviors by increasing precision or reducing variance in neural responses. This contrasts with an early form of plasticity, TEMP (Temperature or Entropy Mediated Plasticity), which increases variance and learning rate. Canalization entrenches pathology as the agent develops expertise in their disorder, while TEMP, combined with gentle psychological support, may counter this entrenchment. The model distinguishes adaptive from maladaptive canalization and suggests concrete experiments to test its hypotheses.
Frontiers in Psychiatry
August 7, 2020
Richard J. Zeifman, Anne Catherine Wagner, Ros Watts et al.
104 citations
In two prospective studies with convenience samples of people planning to use a psychedelic (total N=358), participants completed questionnaires before use and at 2 and 4 weeks afterward. Across both studies, significant decreases occurred in experiential avoidance, depression severity, and suicidal ideation after psychedelic use. Decreases in experiential avoidance were significantly associated with decreases in depression severity and suicidal ideation. These results suggest that psychedelics may reduce experiential avoidance, depression severity, and suicidal ideation, and that reduced experiential avoidance may be a transdiagnostic mechanism in psychedelic therapy. Integrating psychedelics with therapies targeting experiential avoidance, such as acceptance and commitment therapy, may enhance outcomes.
Frontiers in Pharmacology
November 19, 2019
Richard J. Zeifman, Fernanda Palhano-Fontes, Jaime E. C. Hallak et al.
79 citations
A single dose of ayahuasca, compared with placebo, was associated with medium-to-large reductions in suicidality among 29 adults with treatment-resistant depression. Suicidality was assessed by a psychiatrist before the intervention and at one, two, and seven days afterward. The between-group effect sizes (ayahuasca versus placebo) were medium at each time point (Cohen's d = 0.58, 0.56, and 0.67), and the within-group effect sizes for those receiving ayahuasca were large (Cohen's d = 1.33, 1.42, and 1.19). The group-by-time interaction was not statistically significant, suggesting the findings should be interpreted cautiously. The authors conclude that ayahuasca may hold potential as an intervention for suicidality, while noting important limitations and the need for further research.
ACS Pharmacology & Translational Science
March 11, 2021
Richard J. Zeifman, Nikhita Singhal, Leah Breslow et al.
60 citations
Classic psychedelics such as psilocybin, ayahuasca, and LSD are being used more often and studied as a potential mental health treatment. Suicidality is a safety concern with these substances, yet they may also help reduce suicidal thoughts. A systematic review of 64 articles found mixed results for non-clinical use: some studies showed positive, negative, or no link between lifetime psychedelic use and suicidality. Early psychedelic therapy had some suicide cases, but it was unclear if therapy caused them. Recent clinical trials found no increased suicidality and preliminary evidence for acute and sustained decreases after treatment.
Journal of Psychopharmacology
March 1, 2022
Gabrielle Agin-Liebes, Richard J. Zeifman, Jason B. Luoma et al.
51 citations
People who participated in ayahuasca retreats in Central and South America reported reduced negative mood and increased positive mood and psychological flexibility three months later. Acute experiences of cognitive reappraisal during the ceremony were the strongest predictor of improvements in positive mood and flexibility. Increases in psychological flexibility statistically accounted for the link between acute psychological factors, including reappraisal, and later mood improvements. The findings suggest that acute reappraisal and subsequent gains in psychological flexibility are key mechanisms behind psychedelic-assisted therapy's benefits, supporting the integration of mindfulness-based and third-wave therapy approaches with such interventions.
Scientific Reports
August 22, 2023
Hannes Kettner, Stephen Ross, Richard J. Zeifman et al.
31 citations
Co-using a low dose of MDMA with psilocybin or LSD is associated with less intense challenging experiences—such as grief and fear—and increased feelings of self-compassion, love, and gratitude, compared to using psilocybin or LSD alone. In a survey of 698 people planning to use these substances, the 27 who also took a low dose of MDMA reported these benefits without a reduction in mystical-type experiences or compassion. Medium-to-high MDMA doses did not show the same effects. The findings suggest MDMA may buffer against some difficult aspects of psychedelic experiences, but the study's small, non-experimental convenience sample limits certainty.
American Journal of Psychiatry
January 1, 2025
Noam Goldway, Snehal Bhatt, Stephen Ross et al.
23 citations
Psilocybin-assisted therapy (PAT) produced lasting changes in personality, indicating a normalization of abnormal personality trait expression in people with alcohol use disorder. The findings suggest that PAT may reduce impulsiveness, or that impulsive individuals may inherently respond better to the therapy. Further research is needed to clarify the mechanism.
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.
The Journal of Clinical Psychiatry
January 13, 2022
Richard J. Zeifman, Dengdeng Yu, Nikhita Singhal et al.
18 citations
A meta-analysis of 7 psychedelic therapy clinical trials found that, relative to baseline, psychedelic therapy was associated with large decreases in suicidality acutely (80–240 minutes) and at 1 day, 1–8 weeks, and 3–4 months (standardized mean differences ranging from −1.48 to −2.36). At 6 months, the effect was medium (SMD = −0.65). Reductions were significant at all time points except 7–8 weeks. Acute and post-acute elevations in suicidality were rare (6.5% and 3.0%, respectively). The authors note limitations including heterogeneous samples and interventions, and suggest that controlled trials specifically evaluating psychedelic therapy for suicidality may be warranted.
July 7, 2022
Richard J. Zeifman, Meg J. Spriggs, Hannes Kettner et al.
13 citations
preprint
The Relaxed Beliefs Under pSychedelics (REBUS) model suggests that psychedelics reduce the strength of deeply held beliefs. In a preliminary test of this idea, 11 healthy adults received a low (1 mg) and a high (25 mg) dose of psilocybin four weeks apart. Confidence in negative self-beliefs decreased after the high dose but not after the low dose. Greater brain signal entropy and stronger subjective effects during the high dose correlated with larger decreases in negative belief confidence, both during the session and four weeks later. Reduced confidence in negative beliefs was strongly linked to improved well-being at the four-week follow-up. These findings provide initial psychological support for the REBUS model, though replication in larger and clinical samples is needed.
PLoS ONE
January 17, 2025
Shakila Meshkat, Wendy Lou, Rakesh Jetly et al.
10 citations
A new pilot study will test whether a single 25 mg dose of psilocybin combined with one week of massed cognitive processing therapy (CPT) is feasible, tolerable, and effective for chronic posttraumatic stress disorder (PTSD), which affects 3.9% of the general population. Fifteen participants with chronic PTSD will receive 12 CPT sessions, two psilocybin-related psychotherapy sessions, and one dosing session over 7 days. Feasibility and tolerability will be measured by recruitment, withdrawal, data completion, adherence, and adverse events. Preliminary efficacy will assess reductions in PTSD severity and explore mechanisms of change, with 12 weeks of follow-up and wearable device data. Results will guide a future large-scale randomized trial.
Nature Mental Health
October 7, 2024
Petros Petridis, Jack Grinband, Gabrielle Agin-Liebes et al.
10 citations
No Summary
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.
Research Square
August 22, 2025
Richard J. Zeifman, George Danias, Gabrielle Agin-Liebes et al.
2 citations
Psychedelics can acutely induce mystical experiences and elevated positive mood, which may contribute to the potential benefits of psychedelic therapy. However, there remains limited understanding of the occurrence and importance of specific positive emotional experiences within psychedelic therapy. Therefore, we examined the effects of psychedelics on positive emotional experiences and their association with improvements in mental health. Methods: Study 1 was an observational study of naturalistic psychedelic use. Study 2 used data from a clinical trial that compared psilocybin with escitalopram in individuals with major depressive disorder.
The Journal of Clinical Psychiatry
May 9, 2022
Richard J. Zeifman, Dengdeng Yu, Nikhita Singhal et al.
2 citations
correction
In a meta-analysis of patient-level data on psychedelics and suicidality, two serious adverse events occurred that the original study authors deemed unrelated to the drug. One participant in a very low-dose psilocybin condition (1 mg/70 kg) completed suicide 11 days after administration, having reported boredom and left the session early. Another participant attempted suicide about two months after an active psilocybin dose (21–25.2 mg/70 kg), following a partner's sudden death and subsequent methamphetamine and crack cocaine use, with a brief psychotic episode. These events highlight the need for close monitoring of all participants during and after psychedelic therapy trials.
June 10, 2025
Gabrielle Agin-Liebes, Petros Petridis, Richard J. Zeifman et al.
1 citation
preprint
In a trial where adults with alcohol use disorder received either psilocybin or an active placebo alongside psychotherapy, psilocybin-assisted therapy robustly increased compassionate self-responding and decreased uncompassionate self-responding, with the largest effects on reducing self-judgment, isolation, and over-identification. Across all participants, small but significant correlations linked improvements in self-compassion to reduced drinking. However, in the psilocybin group alone, no significant association emerged between self-compassion gains and drinking reductions, while the control group showed moderate associations. These between-group differences were not statistically significant. Self-compassion appears clinically relevant for alcohol use disorder treatment but may not mediate outcomes when psilocybin is part of therapy.
Psychedelic Medicine
June 16, 2026
Max Wolff, Samuli Kangaslampi, Richard J. Zeifman et al.
Therapeutic alliance likely plays a meaningful role in shaping both the psychedelic experience and clinical outcomes, contrary to a recent analysis that concluded it did not. This commentary argues that the reported results actually support a meaningful role for alliance when contextualized properly, and that methodological decisions obscured relevant effects. Unexplained deviations from the study protocol also warrant scrutiny. The findings underscore the importance of accurately characterizing psychological and contextual factors in psychedelic treatment research and call for more transparent analyses of psychotherapeutic processes.
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.
October 14, 2024
Terence J. Lyons, Merle Spriggs, Leevi Kerkelä et al.
preprint
A single high dose of psilocybin (25 mg) produced lasting functional and anatomical brain changes in healthy, psychedelic-naive adults, detected from one hour to one month later. Diffusion imaging showed decreased axial diffusivity in prefrontal-subcortical tracts, correlating with reduced brain network modularity, which in turn correlated with improved well-being. Increased cortical signal entropy shortly after dosing predicted better psychological well-being at one month, with next-day psychological insight mediating this relationship. No such effects occurred with a 1 mg placebo dose. Cognitive flexibility, psychological insight, and well-being also increased at one month.