Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression: A post-hoc analysis of a randomized, waitlist-controlled trial
Cognitive difficulties within treatment-resistant unipolar and bipolar depression (TRD; TRBD) often do not improve with conventional pharmacotherapies. Psilocybin-assisted psychotherapy (PAP) has shown promise as a novel intervention for TRD; however, few studies have assessed its effects on cognition in this population.
The researchers in this new study were interested not just in mood improvement, but in cognitive functioning (because many depressed patients continue to suffer cognitive symptoms e.g. slowed processing, poor executive function even if mood improves). They performed a post-hoc analysis on 26 adults treated in an earlier open-label trial of Psilocybin-assisted psychotherapy (PAP).
“PAP was associated with modest, short-term improvements in performance on measures of processing speed and executive function among individuals with TRD. While these changes appeared independent of mood, they did not consistently exceed expected practice effects. These findings highlight the need for adequately powered, controlled trials to clarify whether observed cognitive changes reflect genuine procognitive effects of psilocybin or are attributable to non-specific influences such as test familiarity or concurrent mood improvements.”
Comments
The authors conclude that PAP was associated with modest, short-term improvements in processing speed and executive functions among people with TRD.
Because gains didn’t consistently exceed what might be expected from repeated testing (practice effects), it’s unclear whether these represent real “procognitive” effects of psilocybin, or simply non-specific effects (like familiarity with the tests, or improved mood). The authors stress the need for larger, well-controlled trials to determine whether psilocybin truly improves cognition separate from mood improvements or test-retest artifacts.
If a therapy like psilocybin-assisted psychotherapy could reliably improve cognition (not just mood), it could meaningfully improve quality of life, functioning, return to work, and overall recovery. This study is a first step suggesting potential but also highlights limitations and underscores the need for more rigorous research.
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 Nov 22:111565. doi: 10.1016/j.pnpbp.2025.111565. Epub ahead of print. PMID: 41285295. Link to Paper
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