Cognitive outcomes following psilocybin-assisted therapy in treatment-resistant depression: A post-hoc analysis of a randomized, waitlist-controlled trial

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.