How Does Psilocybin Therapy Work? an Exploration of Experiential Avoidance as a Putative Mechanism of Change
Authors: Zeifman Richard 
Published: June 2024

Although psilocybin therapy is currently receiving attention as a novel intervention for a wide range of mental health concerns, limited research has examined the underlying psychological mechanisms (i.e., how) through which psilocybin therapy may bring about positive therapeutic changes. Qualitative research highlights the role of reductions in experiential avoidance (i.e., avoidance or suppression of aversive states) within psilocybin therapy. However, no quantitative research has examined experiential avoidance as a mechanism of change underlying psilocybin therapy's effects. Accordingly, the purpose of this dissertation is to investigate whether psilocybin therapy: (a) leads to reductions in experiential avoidance and (b) improved mental health (e.g., increased well-being and decreased depression severity, anxiety, and suicidal ideation) via reductions in experiential avoidance. This dissertation examined these questions within two studies that included the administration of psilocybin. Study 1 was a quasiexperimental study that examined the effect of administering 1 mg (very low-dose) psilocybin and 25 mg (high-dose) psilocybin to healthy individuals (N = 28). Relative to participants' experiential avoidance when they enrolled in the study, no significant reductions in experiential avoidance were observed throughout the study. Non-significant increases in experiential avoidance were observed following 1 mg psilocybin. Subsequently, significant reductions in experiential avoidance were observed 2 and 4 weeks after 25 mg psilocybin. These reductions in experiential avoidance following 25 mg psilocybin were significantly greater than those observed following 1 mg psilocybin. Decreases in experiential avoidance were sustained at 3 months (but not at 6 months) after 25 mg psilocybin. Reductions in experiential avoidance that occurred 2 weeks after 25 mg psilocybin (but not 1 mg psilocybin) predicted improvements in mental health (i.e., increases in well-being and decreases in depressed and anxious mood) 4 weeks after 25 mg psilocybin. Relative to 1 mg psilocybin, reductions in experiential avoidance following 25 mg psilocybin was a significantly greater predictor of changes in anxious mood (but failed to reach significance for well-being and depressed mood). Study 2 was a randomized controlled trial that compared psilocybin therapy with escitalopram (a selective serotonin
reuptake inhibitor) for major depressive disorder (N = 59). Relative to escitalopram, psilocybin therapy led to significant reductions in experiential avoidance. Within the psilocybin therapy (but
not the escitalopram) condition, reductions in experiential avoidance indirectly affected improvements in mental health (i.e., increased well-being and decreased depression severity,
suicidal ideation, and trait anxiety). These indirect effects were significantly larger in the psilocybin therapy condition (for well-being, depression severity, and trait anxiety but not for
suicidal ideation), providing evidence for the role of experiential avoidance being specific to psilocybin therapy. These results provide preliminary support for the positive effects of
psilocybin therapy on experiential avoidance and the potential role of experiential avoidance as a putative mechanism underlying psilocybin therapy’s positive therapeutic outcomes. Limitations
of the present studies include difficulties surrounding establishing temporal causality, issues with the experimental designs, relatively small sample sizes, and reliance upon self-report. The present findings may help to tailor and refine psilocybin therapy and its delivery as a transdiagnostic mental health intervention.