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.
Psychopharmacology
February 1, 2021
Richard J. Zeifman, Nikhita Singhal, Rafael G. Dos Santos et al.
79 citations
Suicidality is a major public health problem with few treatment options. In an open-label trial, 17 adults with recurrent major depressive disorder received a single dose of ayahuasca. Among the 15 who had suicidality at baseline, suicidality decreased acutely (within 40 to 180 minutes after administration) and remained lower at 1, 7, 14, and 21 days afterward. Post-acute effect sizes were large (Hedges' g = 1.31–1.75), with the largest effect at 21 days (g = 1.75). When administered in an appropriate context, ayahuasca may produce rapid and sustained reductions in suicidality. The authors call for randomized, double-blind studies with larger samples to confirm these early findings.
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.
Scientific Reports
April 17, 2024
Jordan Sloshower, Richard J. Zeifman, Jeffrey Guss et al.
56 citations
Psilocybin-assisted therapy improves psychological flexibility, mindfulness, and values-congruent living in people with moderate to severe major depressive disorder, and these improvements are strongly linked to reductions in depression severity. In an exploratory placebo-controlled study, participants received placebo then psilocybin (0.3 mg/kg) four weeks later, with dosing sessions embedded in Acceptance and Commitment Therapy. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved after psilocybin and were maintained through week 16. The findings suggest that increasing psychological flexibility may be a key mechanism underlying psilocybin's therapeutic effects.
Journal of Affective Disorders
August 1, 2023
Richard J. Zeifman, Anne C Wagner, Candice M Monson et al.
56 citations
In a double-blind randomized controlled trial comparing psilocybin therapy (two 25 mg sessions plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among 59 individuals with major depressive disorder, reductions in experiential avoidance mediated improvements in well-being, depression severity, suicidal ideation, and trait anxiety only in the psilocybin group. Exploratory analyses indicated that these improvements (except for suicidal ideation) occurred serially through increased connectedness. Experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance. The findings support reduced experiential avoidance as a mechanism underlying psilocybin therapy's positive outcomes.
J Psychopharmacol
March 4, 2024
Alessia Marrocu, Hannes Kettner, Brandon Weiss et al.
51 citations
About 16% of people who used psychedelics in naturalistic settings showed a clinically meaningful decline in psychological well-being four weeks later. Those with a prior diagnosis of a personality disorder were disproportionately affected: 31% were negative responders, and multivariate regression indicated a greater than four-fold elevated risk of adverse psychological responses. The findings suggest that personality disorders may represent an elevated risk for psychedelic use, and that psychological support and a good therapeutic alliance may be especially important for this population.
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
February 7, 2024
Christopher Timmermann, Richard J. Zeifman, David Erritzøe et al.
37 citations
Intravenous DMT, a fast-acting psychedelic, improved depression scores in healthy volunteers one to two weeks after administration. In a placebo-controlled comparison (13 participants) and a prospective dataset (17 participants), depression severity decreased significantly. Reductions in trait neuroticism appeared only in the placebo-controlled sample. Changes in depression and anxiety correlated with the intensity of acute peak experiences, suggesting that DMT may reduce depressive symptoms by inducing such experiences. The short half-life and flexible dosing of intravenous DMT make it a practical candidate for psychedelic medicine, though further research in clinical samples is needed.
Psychedelic Med (New Rochelle)
March 12, 2024
Alexander Wen, Nikhita Singhal, Brett D. M. Jones et al.
36 citations
Blinding is especially difficult in randomized controlled trials of psychedelics because these drugs produce noticeable changes in consciousness. This systematic review of 50 papers from 48 clinical trials published between 1963 and January 2023 found that most studies were double-blinded, used within-subjects designs, and employed inert placebos. The majority did not report on whether blinding procedures were successful, and in those that did, blinding failed. To reduce unblinding and expectancy effects, the authors recommend using active placebos and dose-response or active comparator designs.
European Journal of Psychotraumatology
January 1, 2024
Richard J. Zeifman, Hannes Kettner, Stephen Ross et al.
34 citations
Therapeutic alliance—the quality of the relationship between therapist and client—predicts improvement in PTSD symptoms after MDMA-assisted psychotherapy. Among 22 adults with chronic PTSD who received MDMA during a clinical trial, stronger therapeutic alliance measured at sessions 4 and 9 (but not before the third session) was associated with lower clinician-assessed PTSD severity after treatment, even after accounting for initial symptom severity. Self-reported PTSD severity was also predicted by alliance at baseline, session 4, and session 9, though the baseline finding did not survive correction for multiple comparisons. These results provide initial evidence that common psychotherapeutic factors like alliance contribute to outcomes in MDMA-assisted therapy.
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.
Scientific Reports
January 29, 2025
Richard J. Zeifman, Meg J. Spriggs, Hannes Kettner et al.
26 citations
A preliminary test of the REBUS model found that a high dose of psilocybin (25 mg) reduced confidence in negative self-beliefs in 11 healthy individuals, both during the acute experience and four weeks later. Greater brain signal entropy and stronger subjective effects under psilocybin correlated with larger decreases in negative self-belief confidence. Decreases in negative self-belief confidence were linked to increases in well-being. The findings provide initial evidence that relaxing and revising negative self-beliefs may underlie psilocybin's positive psychological effects, with increased neuronal entropy as a possible mechanism. Replication in larger clinical samples is needed.
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.
Focus (American Psychiatric Publishing)
October 1, 2022
Jenna M Traynor, Daniel E. Roberts, Stephen Ross et al.
14 citations
Borderline personality disorder is a complex psychiatric condition with limited and often ineffective treatment options, high variability in patient response, and frequent dropout from therapy. This review considers the potential of MDMA-assisted psychotherapy (MDMA-AP) as a new or complementary treatment. Based on MDMA-AP's promise in treating overlapping disorders like posttraumatic stress disorder, the authors propose initial treatment targets and hypothesized mechanisms of change grounded in prior literature and theory. They also outline considerations for designing clinical trials to investigate the safety, feasibility, and preliminary effects of MDMA-AP for borderline personality disorder.
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.
European Journal of Psychotraumatology
December 1, 2025
Gabrielle Agin-Liebes, Richard J. Zeifman, Jennifer Mitchell
11 citations
MDMA-assisted therapy (MDMA-AT) for severe posttraumatic stress disorder (PTSD) improves self-compassion, which may explain its therapeutic benefits. In a double-blind trial with 82 adults, MDMA-AT significantly increased compassionate self-responding (self-kindness, common humanity, mindfulness) and decreased uncompassionate self-responding (self-judgment, isolation, over-identification) compared to placebo plus therapy, with large effect sizes on most subscales. Changes in self-compassion fully mediated the reduction in PTSD severity and depressive symptoms, but not in alcohol or substance use. Self-compassion appears to be a key psychological mechanism in MDMA-AT, suggesting that targeting it could refine treatments for PTSD with co-occurring depression.
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.
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
Psilocybin-assisted psychotherapy (PAP) may treat a wider range of psychiatric symptoms in cancer patients than previously recognized. Pooled data from two phase II randomized placebo-controlled crossover trials involving 79 participants with cancer-related distress showed that PAP significantly improved anxiety, depression, interpersonal sensitivity, hostility, obsession-compulsion, and somatization. No lasting phobia, paranoia, or psychosis was induced. Improvements were consistent across both trials, suggesting PAP could serve as a comprehensive mental health treatment for this population.
PsyArXiv
October 17, 2023
Alessia Marrocu, Hannes Kettner, Brandon Weiss et al.
9 citations
preprint
About 16% of people who used psychedelics in naturalistic settings experienced a clinically meaningful decline in psychological well-being four weeks later. Those with a prior personality disorder diagnosis were disproportionately affected, making up 31% of negative responders and facing more than a four-fold elevated risk of adverse psychological responses. The findings suggest that personality disorders may heighten vulnerability to negative outcomes from psychedelic use, highlighting the need for careful screening and robust psychological support.