The New England journal of medicine
November 3, 2022
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
1,095 citations
A single 25 mg dose of psilocybin, but not 10 mg, reduced depression scores more than a 1 mg control dose over three weeks in adults with treatment-resistant depression. In this phase 2 trial, 233 participants were randomly assigned to 25 mg, 10 mg, or 1 mg of synthetic psilocybin with psychological support. The 25 mg group showed an average 12-point drop on the MADRS depression scale versus a 5.4-point drop in the 1 mg group, a significant difference. The 10 mg group did not differ significantly from control. Response and remission rates at three weeks supported the primary result, but sustained response at 12 weeks was not significantly different.
Journal of Affective Disorders
February 3, 2023
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
168 citations
Three weeks after a single dose, 25 mg of psilocybin, and to a lesser extent 10 mg, improved patient-reported measures of depression severity, anxiety, affect, and functioning in people with treatment-resistant depression. These findings extend the primary results from the largest randomized clinical trial of psilocybin for TRD, highlighting outcomes that matter to patients.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
September 1, 2023
Guy M Goodwin, Megan Croal, David Feifel et al.
166 citations
A single 25 mg dose of synthetic psilocybin (COMP360) given alongside psychological support to adults with treatment-resistant depression who continued taking a selective serotonin reuptake inhibitor led to a mean reduction of 14.9 points on the Montgomery-Åsberg Depression Rating Scale at three weeks. Twelve of nineteen participants (63.2%) experienced mild treatment-emergent adverse events that resolved the same day, with no serious events or increased suicidal ideation. Response and remission occurred in 8 participants (42.1%). The authors suggest larger controlled trials are needed to determine whether this approach can benefit patients who cannot safely withdraw from antidepressants.
Journal of affective disorders
March 1, 2025
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
35 citations
In treatment-resistant depression, a single dose of 25 mg of psilocybin produced stronger correlations between certain psychedelic experiences and depression improvement three weeks later than lower doses. The intensity of psychedelic effects was dose-related, but scores for different doses overlapped considerably. At the 25 mg dose, dimensions of oceanic boundlessness and visual restructuralization, along with emotional breakthrough, showed the strongest correlations with reduced depression scores. The study does not establish causation and requires replication. The overlap in experience intensity across doses suggests unblinding to dose is less likely. Correlations between psychedelic experience and outcome indicate specificity in psilocybin's mechanism of action.
International journal of clinical and health psychology : IJCHP
January 1, 2023
John R Kelly, Gerard Clarke, Andrew Harkin et al.
33 citations
A systems psychiatry approach recognizes complex interactions across biological levels and requires integrated treatment strategies. Serotonergic psychedelics primarily target cortical 5-HT2A receptors, but their therapeutic mechanisms span molecular, cellular, and network levels, influenced by biofeedback from the periphery and environment. The gut microbiome, through the gut-brain axis, regulates host neurophysiology via unconscious parallel processing systems. Although psychedelic and microbial signaling operate on different timescales, the microbiota-gut-brain axis may contribute to the preparatory, acute, and integration phases of psychedelic therapy. This review examines the gut microbiome and mycobiome, pathways of the MGB axis, and potential interactions with psychedelic therapy, discussing implications for precision medicine.
Irish Journal of Psychological Medicine
November 7, 2024
Andrew Gribben, Tara Burke, Colm Harrington et al.
5 citations
A survey of 151 psychiatrists in Ireland found that most hold positive attitudes toward psilocybin therapy: 81.5% agreed it shows promise for treating psychiatric disorders, 86.8% supported funding research, 86.8% would refer a patient if licensed, and 78.1% would consider it for themselves. However, only 40.0% felt knowledgeable and just 9.9% felt adequately prepared to participate. A minority expressed concerns: 6.6% thought it unsafe under medical supervision, 21.9% considered it potentially addictive, and 15.9% reported at least one concern about evidence, effectiveness, safety, cost, or impartiality. Consultant psychiatrists were less optimistic than trainees about its role in bipolar depression and emotionally unstable personality disorder.
Acta neuropsychiatrica
July 25, 2025
Guillaume Thuery, Christopher Sheridan, Patricia Iusan et al.
4 citations
This narrative review synthesizes clinical and preclinical research on how 5-HT2A receptor psychedelics interact with the immune system. The evidence shows these compounds have direct immunomodulatory properties, including downregulation of gene regulators like NF-κB and reduced expression of cytokines such as TNF-α, IL-6, and IL-1β in both the central and peripheral nervous systems. These effects are accompanied by modulation of corticotrophin releasing hormone, adrenocorticotrophic hormone, and cortisol. The immunomodulation occurs through pathways involving serotonin receptors, the Sigma-1 receptor, and the TrkB receptor, as well as indirectly via the HPA axis. The review identifies that modulation of brain glia and glial-neuronal interactions remains to be determined, representing a promising direction for future research on the therapeutic potential of these psychedelics for mental health and brain disorders.
Journal of affective disorders
August 1, 2026
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
2 citations
In people with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support, the therapeutic alliance before dosing had only weak correlations with improvement in depression scores at three weeks. Stronger correlations were seen with the intensity of the psychedelic experience itself, particularly emotional breakthrough and visual restructuring. Path analysis suggested that therapeutic alliance helped facilitate the psychedelic experience, but it was the psychedelic experience—not the alliance—that had stronger direct effects on clinical outcomes. The alliance's direct effect on antidepressant response was limited or absent.
The international journal of neuropsychopharmacology
June 2, 2026
John R Kelly, Christopher Sheridan, Patricia Iusan et al.
Classical serotonergic psychedelics like psilocybin show emerging evidence of therapeutic potential across depression, anxiety, and substance use disorders, with indications of transdiagnostic efficacy. Early-phase studies yielded encouraging results, but recent larger-scale phase 3 trials for treatment-resistant depression have shown more modest effects. No regulatory approvals from the U.S. FDA or EMA exist, though a few countries permit psychedelic therapies in regulated clinical settings. The long-term trajectory and real-world impact within public health systems remain uncertain. This paper examines challenges for integrating psychedelic therapies into Ireland's public healthcare system, covering regulatory approval, Health Technology Assessment, service implementation, workforce capacity, and evaluation of long-term patient outcomes.