Examining the effects of psilocybin-assisted psychotherapy on anhedonia in treatment-resistant depression

Psilocybin therapy may help people with treatment-resistant depression experience joy again.

This new paper reports a secondary analysis of data from a randomized, waitlist-controlled trial examining how psilocybin-assisted psychotherapy (PAP) affects anhedonia - the diminished ability to experience pleasure in people with treatment-resistant depression (TRD). Participants included adults with either Major Depressive Disorder or Bipolar II Disorder who had not responded to standard treatments.

“Anhedonia, a core symptom of depression, is often resistant to conventional treatments and significantly impacts quality of life. This secondary analysis aimed to evaluate the effects of psilocybin-assisted psychotherapy (PAP) on anhedonia severity in individuals with treatment-resistant depression (TRD). Participants (n = 30) with TRD and a primary diagnosis of Major Depressive Disorder or Bipolar II Disorder received at least one 25 mg dose of oral psilocybin with psychotherapy as part of a randomized, waitlist-controlled trial (NCT05029466).

The primary outcome of the present secondary analysis was changes in anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Exploratory analysis examined whether changes in anhedonia were mediated through changes in overall depression severity, measured by the Montgomery-Asberg Depression Rating Scale (MADRS). A mixed ANOVA, adjusted for sex and age, revealed a statistically significant reduction in SHAPS scores following PAP at the 2-week primary endpoint (F(8, 143.48) = 3.43, p = 0.001, n = 29) with clinically significant improvements observed at 3-month and 6-month secondary endpoints.

Our findings from this preliminary analysis suggest that PAP may offer a promising intervention for addressing anhedonia in TRD, but further research with larger, placebo-controlled trials are needed to confirm these effects and elucidate potential mediators. This study adds to a growing body of evidence supporting the therapeutic potential of PAP.”

Notes

Participants showed statistically significant reductions in anhedonia severity (measured by the Snaith-Hamilton Pleasure Scale or SHAPS) after receiving PAP by the primary study endpoint (~2 weeks).

Effects not entirely explained by overall depression improvement. Exploratory analyses indicated that reductions in anhedonia were not solely mediated by decreases in overall depressive symptom severity. This suggests that PAP might target reward-related aspects of depression more directly, rather than just general mood symptoms

Psilocybin-assisted psychotherapy may be a promising intervention for a core, treatment-resistant symptom of depression (anhedonia), which is often poorly treated by standard antidepressants.

These results support growing evidence that psychedelic-assisted therapies (like psilocybin) could have a unique therapeutic profile for mood disorders, possibly engaging neurobiological mechanisms distinct from traditional pharmacotherapies.

Kaczmarek ES, Rodrigues NB, Chisamore N, Doyle Z, Meshkat S, Blainey MG, Brudner R, Ali S, Teopiz KM, McIntyre RS, Rosenblat JD. Examining the effects of psilocybin-assisted psychotherapy on anhedonia in treatment-resistant depression. J Affect Disord. 2026 Feb 12;403:121385. doi: 10.1016/j.jad.2026.121385. Epub ahead of print. PMID: 41690631. Read Paper

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