About 300 million people globally live with some form of depression, including major depressive disorder and bipolar disorder. Although antidepressant medications can be effective for many individuals, a subset does not respond despite repeated treatment attempts. This condition—known as treatment-resistant depression (TRD)—is often accompanied by cognitive impairments, such as memory and attention difficulties, that standard therapies fail to address.
Psilocybin—a psychedelic and psychoactive compound colloquially known as “magic mushrooms”— has shown promise in improving mood symptoms in TRD in previous studies. Unlike conventional antidepressants, psilocybin can re-wire and form new connections in the brain—a process called neuroplasticity. These neuroplastic effects suggest psilocybin could also improve cognitive impairments in TRD. However, to date, research in patient populations has been very limited and results have been mixed.
In a recent clinical trial, researchers from UHN’s Krembil Brain Institute (KBI), led by Dr. Joshua Rosenblat, explored whether psilocybin could improve both mood and cognition in 26 patients with TRD. The team administered a single dose of psilocybin and assessed cognition one day and two weeks later using two standard tests: the Trail Making Test (TMT), and the Digit Symbol Substitution Test (DSST). These tests are used to measure the brain’s processing speed and executive function—skills that you use to manage everyday tasks.
Results indicated that psilocybin improved cognition modestly over time, as early as one day post-treatment. Importantly, these improvements occurred even when changes in depressive symptoms were considered, suggesting that the cognitive improvements were not just a byproduct of people feeling less depressed.
Although this was an encouraging group-level effect, only a minority of individual patients exhibited a change large enough to be considered clinically meaningful and the number of individuals who improved did not exceed what would be expected by chance alone. More studies are necessary to determine whether these changes were due to psilocybin specifically or more general factors.
Reflecting on this early-stage work, Dr. Rosenblat notes, “even though the results of our study should be interpreted cautiously, this is an invaluable first step in identifying and introducing a new treatment that could revolutionize care for TRD.” These results highlight the need for larger, controlled studies to determine whether initial findings are reproducible and whether psilocybin has a meaningful and reliable impact on cognition.
You can read the results of the original clinical trial that this study was based on here.
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Danica Johnson is the first author of this study. She is a Graduate Research Appointee at UHN’s Poul Hansen Family Centre for Depression (formerly the Mood Disorders Psychopharmacology Unit) and a PhD Candidate at the University of Toronto’s Institute of Medical Science.
Dr. Joshua Rosenblat is the senior author of this study. He is a Clinician Investigator at UHN’s Krembil Brain Institute, and an Associate Professor and a Clinician Scientist at the University of Toronto’s Temerty Faculty of Medicine.
This work was supported by the Brain and Cognition Discovery Foundation and UHN Foundation. The Usona Institute and Braxia Health (formerly the Canadian Rapid Treatment Centre of Excellence, CRTCE) provided in-kind support.
Dr. Rosenblat receives funds from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion, and COMPASS for speaking, consultation, and research beyond this work. During the completion of this study, Dr. Rosenblat was also the Chief Medical Officer for Braxia Health (formerly CRTCE). He is no longer associated with Braxia Health. For a complete list of the other authors’ competing interests, see the publication.
Johnson DE, Meshkat S, Kaczmarek ES, Rabin JS, Brudner RM, Chisamore N, Doyle Z, Bawks J, Riva-Cambrin J, Mansur RB, Lipsitz O, McIntyre RS, Lanctôt KL, Rosenblat JD. Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression: A post-hoc analysis of a randomized, waitlist-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2025 Dec 20;143:111565. doi: 10.1016/j.pnpbp.2025.111565.