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 | Open-label trial (secondary analysis) Randomized Peer reviewed |
|---|---|
| Sample size | 15 |
| Population | Adults with major depressive disorder |
| Interventions | Psilocybin cognitive behavioral therapy |
| Dose | 10 mg, 25 mg |
| Duration | 4-month treatment with 3-month post-treatment follow-up |
| Topics | Depression Psilocybin |
| Key findings | 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 predicted improved depressive and functioning outcomes at follow-up, and there was preliminary evidence that connectedness mediated the relationship between psychedelic effects and depressive symptom improvement. |
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.
In the evidence
This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.
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Connectedness rose significantly from baseline to post-treatment but was not sustained at 3 months, and greater increases predicted improved depressive and functioning outcomes at follow-up.
Synthesized
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Connectedness increased significantly from baseline to post-treatment (Hedges' g 0.62) and predicted improved depressive outcomes at follow-up, but the increase was not sustained at three months.
Synthesized
Comparable studies
Other non-randomized and open-label trials on psilocybin for depression, most cited first.
Citations in the library
Cites 20
- Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology July 1, 2008
- Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Journal of Psychopharmacology October 6, 2015
- Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression Journal of Humanistic Psychology June 19, 2017
- Psychedelics and connectedness Psychopharmacology August 9, 2017
- Transformative experience and social connectedness mediate the mood-enhancing effects of psychedelic use in naturalistic settings Proceedings of the National Academy of Sciences January 21, 2020
and 15 more in the library