Psychology · Literature

Research papers on Psilocybin-assisted therapy for depression

Recent and highly-cited academic work on psilocybin-assisted therapy for depression, gathered from Semantic Scholar, CrossRef and OpenAlex.

1. The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

   Robin Carhart‐Harris, Robert Leech, Peter J. Hellyer, et al. · 2014 · Frontiers in Human Neuroscience · 1,306 citations

   Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of "primary states" is elevated entropy in certain aspects

2. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

   Alan K. Davis, Frederick S. Barrett, Darrick G. May, et al. · 2020 · JAMA Psychiatry · 1,296 citations

   Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective: To investigate the effect of psilocybin therapy in patients with MDD. Design, Setting, and Participants: This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagno

3. REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

   Robin Carhart‐Harris, Karl Friston · 2019 · Pharmacological Reviews · 1,199 citations

   This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics wor

4. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

   Guy M. Goodwin, Scott T. Aaronson, Oscar Alvarez, et al. · 2022 · New England Journal of Medicine · 1,127 citations

   BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total sco

5. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

   Robin Carhart‐Harris, Mark Bolstridge, Camilla Day, et al. · 2017 · Psychopharmacology · 989 citations

   RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, m

6. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

   Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias, et al. · 2018 · Psychological Medicine · 837 citations

   BACKGROUND: Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. METHODS: To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing. RESULTS: We observed significant antidepressant effects of ayahuasca when compare

7. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression

   Leor Roseman, David Nutt, Robin Carhart‐Harris · 2018 · Frontiers in Pharmacology · 822 citations

   Introduction: It is a basic principle of the ‘psychedelic’ treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would not. Material and Methods: Twenty patients with treatment resistant depression underwent trea

8. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future

   Robin Carhart‐Harris, Guy M. Goodwin · 2017 · Neuropsychopharmacology · 697 citations

9. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder

   Michael P. Bogenschutz, Stephen Ross, Snehal Bhatt, et al. · 2022 · JAMA Psychiatry · 687 citations

   Importance: Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. Objective: To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. Design, Setting, and Participants: In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assesse

10. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

    Robin Carhart‐Harris, Leor Roseman, Mark Bolstridge, et al. · 2017 · Scientific Reports · 602 citations

    Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases

11. Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression

    R. Murphy, H. Kettner, Rick Zeifman, et al. · 2022 · Frontiers in Pharmacology · 240 citations

    Background: Across psychotherapeutic frameworks, the strength of the therapeutic alliance has been found to correlate with treatment outcomes; however, its role has never been formally assessed in a trial of psychedelic-assisted therapy. We aimed to investigate the relationships between therapeutic alliance and rapport, the quality of the acute psychedelic experience and treatment outcomes. Methods: This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder (N = 59). This analysis focused on the psilocybin condition (n = 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychologi

12. A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

    Jason B. Luoma, Christina Chwyl, Geoff J. Bathje, et al. · 2020 · Journal of Psychoactive Drugs · 209 citations

    After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a sign

13. The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder

    Adam W. Levin, R. Lancelotta, N. Sepeda, et al. · 2024 · PLOS ONE · 74 citations

    We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final

14. Testing an App-Assisted Treatment for Suicide Prevention in a Randomized Controlled Trial: Effects on Suicide Risk and Depression

    Mia S. O'Toole, Mikkel B. Arendt, Christian M. Pedersen · 2019 · Behavior Therapy · 62 citations

15. Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial

    Jordan Sloshower, R. Zeifman, Jeffrey R. Guss, et al. · 2024 · Scientific Reports · 56 citations

    Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later.

16. Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial.

    F. Müller, H. Zaczek, Anna M. Becker, et al. · 2025 · Med · 22 citations

    BACKGROUND This trial aimed to assess the efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with moderate-to-severe major depressive disorder. METHODS This was a randomized, parallel, double-blind, low-dose controlled trial (Clinicaltrials.gov: NCT03866252). Patients were randomly assigned in a 1:1 ratio to receive supportive psychotherapy and either 100 μg + 200 μg LSD or 25 μg + 25 μg LSD in two dosing sessions. The primary endpoints were the changes in scores on the Inventory of Depressive Symptomatology, in the Clinician-Rated (IDS-C) version (assessed by the treating therapist) and the Self-Rated (IDS-SR) version, from baseline to 2 weeks after the second admin

17. Multidimensional Personality Changes Following Psilocybin-Assisted Therapy in Patients With Alcohol Use Disorder: Results From a Double-Blind, Placebo-Controlled Clinical Trial.

    B. Pagni, R. Zeifman, S. Mennenga, et al. · 2025 · The American journal of psychiatry · 21 citations

    OBJECTIVE Evidence suggests that psilocybin-assisted therapy (PAT) leads to durable shifts in personality structure. However, such changes have yet to be characterized in disorders of addiction. In this secondary analysis from a randomized controlled trial, the authors examined the effect of PAT on personality dimensions in patients with alcohol use disorder (AUD), hypothesizing that PAT would attenuate personality abnormalities in AUD and that reductions in trait impulsiveness would be associated with lower drinking. METHODS Eighty-four adults with AUD were randomized to two medication sessions of either psilocybin (N=44) or active placebo (diphenhydramine; N=40), received 12 weekly psych

18. In the New Era of Psychedelic Assisted Therapy: A Systematic Review of Study Methodology in Randomized Controlled Trials

    Paul S Soliman, Dallece E. Curley, Christy Capone, et al. · 2024 · Psychopharmacology · 18 citations

    Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention. This systematic review examines design and blinding techniques in RCTs utilizing psychedelic

19. Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial.

    Margaret Ross, R. Iyer, Martin L. Williams, et al. · 2025 · General hospital psychiatry · 16 citations

    IMPORTANCE Psilocybin-assisted psychotherapy may offer a novel approach to treating depression, anxiety, and existential distress in individuals with life threatening illnesses, where current treatments show limited efficacy. OBJECTIVE To evaluate the efficacy and safety of psilocybin-assisted psychotherapy versus active placebo and psychotherapy in adults with life-threatening illnesses. DESIGN Double-blind, randomized controlled phase 2b trial (RCT) with an open-label extension and 6-month follow-up (January 2020 - October 2023). SETTING Single-site study at a tertiary hospital's palliative care department (St. Vincent's Hospital Melbourne affiliated with the University of Melbourne)

20. Randomized Controlled Trials of Psilocybin‐Assisted Therapy in the Treatment of Major Depressive Disorder: Systematic Review and Meta‐Analysis

    V. Menon, Parthasarathy Ramamurthy, Sandesh Venu, et al. · 2024 · Acta Psychiatrica Scandinavica · 14 citations

    There is growing interest in the use of psychedelic‐assisted therapy (PAT) for major depressive disorder (MDD), including treatment‐resistant depression. We used randomized controlled trial (RCT) data to compare summary estimates of change in depression ratings with PAT versus comparator treatments in MDD. We also compared response and remission rates, and adverse effects.

21. Psilocybin for depression: Considerations for clinical trial design

    Kelley C. O’Donnell, Sarah E. Mennenga, Michael P. Bogenschutz · 2019 · Journal of Psychedelic Studies · 13 citations

    Background and aims Given the enormous global burden of depressive illness, there is an urgent need to develop novel and more effective treatments for major depressive disorder (MDD). Recent findings have suggested that psychedelic drugs may have a role in the treatment of depressive symptoms, and a number of groups are in the process of developing protocols to study this question systematically. Given the subjective quality of both the psychedelic experience and depressive symptomatology, great care must be taken when designing a protocol to study the clinical efficacy of psychedelic drugs. This study will discuss many factors to consider when designing a clinical trial

22. Psilocybin-assisted therapy for severe alcohol use disorder: protocol for a double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial

    Laetitia Vanderijst, Felix Hever, A. Buot, et al. · 2024 · BMC Psychiatry · 11 citations

    A significant number of individuals with alcohol use disorder remain unresponsive to currently available treatments, which calls for the development of new alternatives. In parallel, psilocybin-assisted therapy for alcohol use disorder has recently yielded promising preliminary results. Building on extant findings, the proposed study is set to evaluate the feasibility and preliminary clinical efficacy of psilocybin-assisted therapy when incorporated as an auxiliary intervention during inpatient rehabilitation for severe alcohol use disorder. Moreover, it intends to pinpoint the modifications in the two core neurocognitive systems underscored by dual-process models of addiction. In this doubl

23. Psychedelic-assisted therapy: An overview for the internist

    Brian S. Barnett, Erin E. Mauney, Franklin King · 2025 · Cleveland Clinic Journal of Medicine · 11 citations

    Preliminary evidence suggests that psychedelic-assisted therapy—the enhancement of psychotherapy with psychedelics such as 3,4-methylenedioxymethamphet-amine (MDMA) and psilocybin—may be efficacious for depression, posttraumatic stress disorder, substance use disorders, and other conditions. Therapeutic psychedelic research is advancing steadily, with psilocybin, MDMA, and lysergic acid diethylamide designated breakthrough therapies by the US Food and Drug Administration (FDA). However, in August 2024, the FDA declined to approve a New Drug Application for MDMA and asked its sponsor to conduct another phase 3 trial. Clinicians are urged to prepare for the possible return of psychedelics to m

24. Psilocybin-assisted group psychotherapy and mindfulness-based stress reduction for frontline healthcare provider COVID-19-related depression and burnout: A randomized controlled trial

    Benjamin R. Lewis, John Hendrick, Kevin Byrne, et al. · 2025 · PLOS Medicine · 9 citations

    Background Depression and burnout, which are common among healthcare workers, were exacerbated by the COVID-19 pandemic. Mindfulness-Based Stress Reduction (MBSR) and psilocybin have been reported to reduce depressive symptoms, but the efficacy of the combination requires comparison to an active treatment control. We sought to evaluate the safety and preliminary efficacy of psilocybin and MBSR versus MBSR alone for frontline healthcare providers with symptoms of depression and burnout related to the COVID-19 pandemic. We hypothesized that psilocybin would augment the antidepressant effects of MBSR in this population. Methods and findings We conducted a randomized controlled trial that enroll