Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial

Abstract

Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.

Figure 1

Study design and flow.

Figure 2

Changes in psychological inflexibility and valued living. (A) Significant reductions in psychological inflexibility 2 weeks post-psilocybin relative to baseline and 2 weeks pre-psilocybin. (B) Significant increases in valued living at 2 weeks and 4 weeks post-psilocybin relative to baseline. Note. Statistical significance relative to baseline = *p < .05, **p < .01, ***p < .001. Statistical significance relative to previous time point = ^##p < .01.

Figure 3

Changes in mindfulness domains. (A) Significant increases in Acceptance Without Judgment at 2 weeks and 4 weeks post-psilocybin relative to baseline. (B) Significant increases in Awareness at 2 weeks post-psilocybin relative to baseline. (C) No significant changes in Observe. (D) Significant increases in Describe at 2 weeks and 4 weeks post-psilocybin relative to baseline. Note. Statistical significance relative to baseline = *p < .05, **p < .01, ***p < .001. Statistical significance relative to previous time point = ^##p < .01.

Figure 4

Association between post-psilocybin changes in depression severity and psychological inflexibility/Accept Without Judgment. (A) Significant positive association between reductions in psychological inflexibility and depression severity. (B) Significant negative association between increases in Acceptance Without Judgment inflexibility and reductions in depression severity.