PSILOCYBIN FOR ANHEDONIA: A SYSTEMATIC REVIEW OF CLINICAL AND PRECLINICAL EVIDENCE

Background

Anhedonia is a debilitating core feature of major depressive disorder (MDD) and bipolar depression (BD) and is associated with significant burden on both functioning and quality of life. Psilocybin has recently emerged as a novel antidepressant treatment in MDD, yet its effects on anhedonia specifically have yet to be systematically reviewed. This review evaluates available clinical and pre-clinical research, exploring whether psilocybin influences anhedonia outcomes in animal models and individuals with depression.

Methods

A systematic search was conducted of PubMed and Ovid databases from inception to June 10th 2025, using search terms related to psilocybin, anhedonia/reward-related processes, and MDD/BD. Studies were screened independently by two reviewers. Risk of bias was also conducted independently by the same two reviewers.

Results

The systematic search initially identified 428 records. After removing duplicates, 345 records were screened, resulted in the inclusion of eleven studies, including five clinical studies and six animal studies. Across clinical studies, reductions in anhedonia were consistently observed following psilocybin-assisted psychotherapy wherein two randomized clinical trials reported greater improvements in anhedonia relative to control or comparator groups. Changes in anhedonia were primarily assessed using the Snaith-Hamilton Pleasure Scale (SHAPS), with one study utilizing a validated MADRS anhedonia factor. Three included studies additionally incorporated neuroimaging measures, examining associations between changes in anhedonia and emotional expression. Results from animal studies demonstrated improved reward sensitivity and motivation after psilocybin exposure.

Conclusion

Initial pre-clinical and clinical studies suggest that psilocybin may be beneficial for anhedonia. Despite encouraging early findings, interpretation is limited by heterogeneity in dosing strategies, small samples sizes, and variability in the manner of which anhedonia was measured, with most clinical studies assessing only consummatory pleasure. While current evidence suggests psilocybin may meaningfully ameliorate anhedonia, further controlled research evaluating anhedonia as a primary outcome, using comprehensive and standardized measures, is needed.