Connectedness as a Mechanism of Change in Psilocybin-Assisted Cognitive Behavioral Therapy for Major Depressive Disorder
Lorenzo Miller, Cordelia Kuiper-Rauch, Keren Chen, Nicholas J. Jackson, David J. Miklowitz, Marc J. Weintraub
Psychedelics October 1, 2026 DOI: 10.1016/j.psyche.2026.100044 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized Open-label Peer reviewed |
|---|---|
| Topics | Depression Psilocybin |
Abstract
Background: Psilocybin-assisted therapy has shown robust antidepressant effects among individuals with major depressive disorder (MDD); however, mechanisms of the treatment remain unclear. Depression has been associated with diminished feelings of connectedness to oneself, others, and the world, and psilocybin is thought to facilitate connectedness. This analysis of an open-label trial of psilocybin-assisted cognitive behavioral therapy (PA-CBT) examined changes in connectedness over treatment and its associations with depressive symptoms and psychosocial functioning.
Methods: Adults with MDD were enrolled in PA-CBT, which included twelve psychotherapy sessions and two psilocybin sessions (10 mg, 25 mg) over 4 months and were followed for 3 months post-treatment. Linear mixed-effects models examined changes over time in feelings of connectedness and its associations with depressive symptoms and psychosocial functioning. Connectedness was also examined as a mediator in the relationship between psychedelic effects (mystical experiences and psychological insights) and depressive symptoms.
Results: Among fifteen participants, connectedness increased significantly from baseline (M = 41.8) to post-treatment (M = 56.6; Hedges' g = 0.62), but was not sustained at three-month follow-up (M = 50.7). Increased connectedness from baseline to post-treatment predicted improved depressive and functioning outcomes at follow-up, controlling for baseline scores. There was preliminary evidence of connectedness as a mediator between psychedelic effects and depressive symptom improvement.
Conclusion: This study provides preliminary evidence that feelings of connectedness may be a mechanism underlying psilocybin's benefits for individuals with MDD. Larger randomized controlled trials comparing psilocybin to other active control conditions are needed to clarify whether connectedness functions as a treatment-specific mechanism.