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Catalyst for change: Psilocybin’s antidepressant mechanisms—A systematic review

Summary

This research review examines how psilocybin, a compound from certain mushrooms, may help treat depression by creating changes in both brain function and psychological experience. Within supportive therapeutic settings, psilocybin appears to increase cognitive flexibility, help people better process emotions, and restore a sense of connection to themselves, others, and the world. The antidepressant benefits seem to work through a combination of direct brain changes and psychotherapeutic factors, rather than through pure pharmacological action alone.

Background

Depression is characterized as a disease of disconnection from self, others, environment, and emotions. Recent clinical trials suggest psilocybin may have promising antidepressant effects, though comprehensive understanding of its neurobiological and psychological mechanisms remains lacking. Treatment-resistant depression affects approximately 30% of depressed individuals, highlighting the need for novel therapeutic approaches.

Objective

To systematically review potential antidepressant neurobiological and psychological mechanisms of psilocybin. The review explores therapeutic change principles including brain dynamics, emotion regulation, cognition, self-referential processing, connectedness, and interpersonal functioning.

Results

Studies found psilocybin promoted openness, cognitive and neural flexibility, and greater emotional acceptance within supportive settings. Imaging revealed reduced global and within-network DMN connectivity alongside increased between-network connectivity. A renewed sense of connectedness to self, others, and world emerged as a key therapeutic experience, with sustained antidepressant effects and minor adverse events.

Conclusion

Psilocybin appears to induce antidepressant effects through interplay between neurobiological mechanisms and common psychotherapeutic factors within supportive contexts. The findings support a multileveled approach integrating neurobiological, psychological, and environmental factors rather than purely pharmacological effects, emphasizing importance of set, setting, and therapeutic guidance.
  • Published in:Journal of Psychopharmacology,
  • Study Type:Systematic Review,
  • Source: PMID: 39829391, DOI: 10.1177/02698811241312866
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