2026 ECNP Congress

PS01-1161

Psilocybin treatment and cognitive outcomes in treatment-resistant depression: results from a randomized controlled trial

Laura Kärtner — M. Spangemacher, T. Buchborn, T. Riemer, T. Majic, M. Wolff, R. Evens, H. Adolphi, C. Schmitz, C. Timmermann, L. Färber, A. Meijer, M. Koslowski, F. Betzler, H. Jungaberle, M. Berger, G. Gründer, L. Mertens · Central Institute of Mental Health, Molecular Neuroimaging, Mannheim, Germany

2026 ECNP Congress

Background. Psilocybin-assisted therapy has demonstrated rapid and sustained antidepressant effects in treatment-resistant depression (TRD) [1]. Cognitive dysfunction is a core feature of TRD and an important determinant of functional outcomes, yet the effects of psilocybin on cognition remain insufficiently understood. Serotonergic psychedelics are hypothesized to influence cognitive processes through neuroplastic and brain network-level mechanisms, including changes in cognitive flexibility and affective processing [2]. While emerging evidence suggests potential pro-cognitive effects, particularly in domains related to cognitive control [3], findings are inconsistent and data on longer-term neurocognitive outcomes in clinical populations are scarce.

Objective. This study aimed to characterize psilocybin-associated changes in global cognition and domain-specific emotion-independent (“cold”) and emotion-dependent (“hot”) cognitive processes in TRD at predefined endpoints six weeks after each dosing session, with sessions administered six weeks apart.

Methods. This prespecified secondary analysis of a randomized, double-blind, active placebo-controlled trial included 144 participants with TRD [4]. Participants received two dosing sessions six weeks apart in a 2:2:1:1 allocation: (1) active placebo (100 mg nicotinamide) + 25 mg psilocybin, (2) 5 mg + 25 mg psilocybin, (3a) 25 mg + 5 mg psilocybin, or (3b) 25 mg + 25 mg psilocybin. Cognitive performance was assessed using the Brief Assessment of Cognition in Affective Disorders (BAC-A) at baseline and six weeks after each dosing session. Outcomes included a composite score of global cognition as well as individual subtests capturing cold and hot cognitive domains. Multivariable linear regression models were used, adjusting for baseline cognitive performance, baseline depressive symptom severity, education, and study centre.

Results. Six weeks after the first dose, no between-group differences were observed in global cognition. At the subtest level, both psilocybin groups showed improvements in a colour-naming subtest. Exploratory analyses at week twelve, after all participants had received at least one 25 mg dose, indicated convergence of global cognitive performance across treatment groups. There was no evidence for cumulative cognitive effects following two 25 mg doses compared to a single exposure. Earlier exposure to 25 mg psilocybin (week 0 vs. week 6) was associated with numerically higher global cognition scores at week twelve. At the subtest level, some cold cognitive measures reflecting working memory and processing speed showed nominal group effects, although patterns were not consistently directional across comparisons and should be interpreted cautiously. Changes in global cognition were not associated with concurrent or subsequent depression severity.

Conclusion. This is the largest study examining neurocognitive outcomes after psilocybin in TRD that found no robust evidence of global or subtest-level cognitive changes. Findings indicate no detectable adverse cognitive effects and provide hypothesis-generating observations on domain-specific pro-cognitive effects. These findings provide no evidence of adverse cognitive effects of psilocybin therapy in TRD, while highlighting the need for adequately powered studies targeting specific cognitive domains and clinically meaningful functional outcomes.

Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT04670081), NCT04670081.

References

  1. Goodwin GM, Aaronson ST, Alvarez O, et al. (2023) Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life. Journal of affective disorders 327: 120-127.
  2. Doss MK, Považan M, Rosenberg MD, et al. (2021) Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational Psychiatry 11(1): 574.
  3. Sayalı C, Truesdale A, Rosen DS, et al. (2026) Cognitive control as a transdiagnostic mechanism of action in psychedelic effects. Cognitive, Affective, & Behavioral Neuroscience 26(1): 1–15.
  4. Mertens LJ, Koslowski M, Betzler F, et al. (2026) Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial. JAMA Psychiatry. Epub ahead of print 18 March 2026. DOI: 10.1001/jamapsychiatry.2026.0132.