This secondary analysis (n=26) of adults with treatment-resistant depression from an open-label psilocybin-assisted psychotherapy trial found statistically significant improvements in processing speed and executive function at two weeks post-treatment, with gains on Trail Making Tests remaining significant after adjusting for depressive symptoms; however, reliable change indices showed that the proportion of participants achieving meaningful improvement (4.2–12.5%) did not exceed chance expectations, suggesting observed gains may reflect practice effects rather than genuine procognitive benefits.
Abstact of Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression
“Background 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.
Methods This retrospective post hoc analysis included 26 adults with TRD or TRBD from an open-label trial of PAP. Cognition was assessed with the Digit Symbol Substitution Test (DSST) and Trail Making Test Part A and B (TMT-A/B) at baseline, one-day, and two-weeks post-treatment. Linear mixed models (LMMs) evaluated change over time, and reliable change indices (RCIs) with binomial tests assessed whether the proportion of participants showing meaningful improvement exceeded chance.
Results Significant improvements were observed on all cognitive measures over time (all p < .05). After adjusting for depressive symptoms, gains on the TMT-A (p < .001), TMT-B (p < .001), and TMTB – A (p = .005) remained significant. In contrast, DSST improvements were attenuated (p = .069). RCIs showed that 4.2 %–12.5 % of participants achieved meaningful improvement, but these rates did not significantly exceed chance expectations.
Conclusion 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.”
Authors: Danica E. Johnson, Shakila Meshkat, Erica S. Kaczmarek, Jennifer S. Rabin, Ryan M. Brudner, Noah Chisamore, Zoe Doyle, Jordan Bawks, Jeremy Riva-Cambrin, Rodrigo B. Mansur, Orly Lipsitz, Roger S. McIntyre, Krista L. Lanctôt & Joshua D. Rosenblat
Summary of Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression
Johnson and colleagues begin by outlining how common and disabling depression is worldwide, and emphasise that it is not only about low mood. A large proportion of people with depression – estimated at around 30–50% – experience noticeable problems with thinking and memory. These cognitive difficulties span attention, speed of information processing, planning and problem-solving (executive function), language, and episodic memory. Importantly, such problems often remain even when mood improves and are tightly linked to reduced social and occupational functioning, poorer quality of life, and lower productivity at work. In other words, even if a person’s mood lifts, lingering cognitive symptoms can keep them from getting fully “back on their feet”.
The authors highlight that cognitive problems appear particularly marked in treatment-resistant depression (TRD). TRD is usually defined as not responding adequately to at least two antidepressant treatments of appropriate dose and duration. Compared to people with a first depressive episode or those who respond to treatment, people with TRD tend to perform worse on tests that measure processing speed and executive function, such as the Digit Symbol Substitution Test (DSST) and the Trail Making Tests (TMT). Johnson and colleagues suggest that cognitive impairments may both contribute to, and be worsened by, treatment resistance, which supports the idea that effective treatments should ideally address both mood and cognition.
The introduction then moves into possible biological explanations. The authors describe evidence that cognitive impairments in depression may reflect reduced neuroplasticity – the brain’s ability to adapt and reorganise. Structural brain imaging has shown smaller volumes and thinner cortex in areas such as the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC) and hippocampus in people with depression. These regions are important for memory, attentional control and flexible thinking. Functional imaging shows disrupted communication within and between fronto-limbic circuits (networks linking frontal lobes with emotion-related regions like the amygdala and hippocampus). At the molecular level, lower levels of brain-derived neurotrophic factor (BDNF), downregulation of mTORC1 signalling (a pathway important for cell growth and synapse formation), and increased microglial activation are all described as mechanisms that may reduce synapse formation and circuit flexibility. This could explain why many traditional antidepressants, which do not strongly or directly drive neuroplasticity, often fail to improve cognitive symptoms even when mood improves.
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https://doi.org/10.1016/j.pnpbp.2025.111565
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Cite this paper (APA)
Johnson, D. E., Meshkat, S., Kaczmarek, E. S., Rabin, J. S., Brudner, R. M., Chisamore, N., ... & Rosenblat, J. D. (2025). Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression: A post-hoc analysis of a randomized, waitlist-controlled trial. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 111565.
Study details
Compounds studied
Psilocybin
Topics studied
Treatment-Resistant Depression
Depression
Study characteristics
Original Re-analysis
Open-Label
Re-analysis
Participants
26
Humans
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