Effects of psilocybin with psychological support on anhedonia in treatment-resistant depression: A randomized controlled pilot trial

Anhedonia is a core feature of major depressive disorder (MDD) that is frequently resistant to available treatments. Psilocybin's specific efficacy for anhedonia remains unclear.

To evaluate psilocybin's efficacy for anhedonia in treatment-resistant MDD.

In this randomized, double-blind, placebo-controlled trial, 20 participants with treatment-resistant MDD received psilocybin (25 mg or 1 mg) with psychological support. The primary outcome was change in the Dimensional Anhedonia Rating Scale (DARS) score at week 1; DARS change at week 8 was a secondary outcome. The Snaith-Hamilton Pleasure Scale (SHAPS) and Montgomery-Åsberg Depression Rating Scale (MADRS) were used as additional secondary outcome measures for anhedonia and overall depression severity, respectively.

The primary outcome was not statistically significant: between-group difference in DARS change at week 1 was 11.2 (95% confidence interval [CI], -1.0 to 23.3; p = 0.073). At week 8, the secondary DARS outcome indicated greater improvement in anhedonia with 25 mg (difference, 14.7; 95% CI, 2.5 to 26.8; p = 0.018). SHAPS improvement favored 25 mg at week 1 (difference, -3.2; 95% CI, -6.1 to -0.3; p = 0.029), but not week 8 (-2.1; 95% CI, -4.9 to 0.9; p = 0.168). MADRS improvement favored 25 mg at weeks 1 (-11.9; 95% CI, -19.2 to -4.5; p = 0.002) and 8 (-11.6; 95% CI, -19.0 to -4.2; p = 0.002).

Psilocybin 25 mg did not significantly improve anhedonia at the primary week 1 endpoint. However, improvements on secondary measures suggest potential benefits for anhedonia and depression severity that warrant confirmation in larger trials.

ClinicalTrials.govNCT06230757.