Catalyst for change: Psilocybin's antidepressant mechanisms-A systematic review

Abstract

Background: Recent clinical trials suggest promising antidepressant effects of psilocybin, despite methodological challenges. While various studies have investigated distinct mechanisms and proposed theoretical opinions, a comprehensive understanding of psilocybin's neurobiological and psychological antidepressant mechanisms is lacking.

Aims: Systematically review potential antidepressant neurobiological and psychological mechanisms of psilocybin.

Methods: Search terms were generated based on existing evidence of psilocybin's effects related to antidepressant mechanisms. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, 15 studies were systematically reviewed, exploring various therapeutic change principles such as brain dynamics, emotion regulation, cognition, self-referential processing, connectedness, and interpersonal functioning.

Results: Within a supportive setting, psilocybin promoted openness, cognitive and neural flexibility, and greater ability and acceptance of emotional experiences. A renewed sense of connectedness to the self, others, and the world emerged as a key experience. Imaging studies consistently found altered brain dynamics, characterized by reduced global and within default mode network connectivity, alongside increased between-network connectivity.

Conclusions: Together, these changes may create a fertile yet vulnerable window for change, emphasizing the importance of a supportive set, setting, and therapeutic guidance. The results suggest that psilocybin, within a supportive context, may induce antidepressant effects by leveraging the interplay between neurobiological mechanisms and common psychotherapeutic factors. This complements the view of purely pharmacological effects, supporting a multileveled approach that reflects various relevant dimensions of therapeutic change, including neurobiological, psychological, and environmental factors.

Keywords: Psilocybin; common factors of psychotherapy; connectedness; default mode network; depression; experiential avoidance; functional connectivity; mechanisms of change.

Figure 1.

PRISMA flow diagram. PRISMA: preferred reporting items for systematic reviews and meta-analysis.

Figure 2.

Conceptualization of review findings and candidates for antidepressant mechanisms. Note. Aspects of set and setting according to Hartogsohn (2017). Common factors of psychotherapy according to Norcross and Lambert (2018) and Wucherpfennig et al. (2024). The key outcomes on the right correspond to the primary domains identified in this review. ↑ = increasing effect; ↓ = decreasing effect; ↕ = mixed or dose-dependent effect.