How does psilocybin therapy work? An exploration of experiential avoidance as a putative mechanism of change

Fifty-nine participants were randomised: 30 to the psilocybin therapy condition and 29 to escitalopram. The final sample had mean age 41.22 (SD = 10.91), was predominantly male (66.1%), white (88.1%), and highly educated (93.2% with university-level education). Mean duration of the current major depressive episode was 18.66 years. Some protocol deviations occurred: two psilocybin-condition and one escitalopram-condition participants missed the second dosing session due to COVID-19 restrictions; a small number discontinued daily capsules for suspected allocation or adverse events. Within the psilocybin therapy arm, there was a significant reduction in experiential avoidance over time (‘‘a’’ paths). Controlling for change in experiential avoidance, participants showed significant increases in well-being and decreases in clinician-assessed depression (MADRS), self-reported depression (QIDS-SR-16), and trait anxiety, but not a significant direct change in suicidal ideation (SIDAS) when controlling for the mediator (c' paths). Reductions in experiential avoidance predicted increased well-being and decreased MADRS, QIDS-SR-16, SIDAS, and STAI-Trait (b paths). The indirect (a × b) effects via reductions in experiential avoidance were significant for well-being (B = 4.51, SE = 1.98, p_boot < .001), MADRS (B = -3.32, SE = 1.49, p_boot = .010), QIDS-SR-16 (B = -1.82, SE = 0.94, p_boot = .015), SIDAS (B = -1.88, SE = 0.94, p_boot = .010), and STAI-Trait (B = -5.21, SE = 2.14, p_boot = .003). In contrast, the escitalopram condition did not show a significant reduction in experiential avoidance over time (no significant ‘‘a’’ paths). Changes in experiential avoidance did not predict changes in outcomes (non-significant ‘‘b’’ paths), and indirect effects via experiential avoidance were non-significant for well-being (B = 0.25, SE = 0.43, p_boot = .579), MADRS (B = -0.01, SE = 0.20, p_boot = .979), QIDS-SR-16 (B = -0.11, SE = 0.21, p_boot = .694), SIDAS (B = -0.08, SE = 0.21, p_boot = .738), and STAI-Trait (B = -0.38, SE = 0.62, p_boot = .542). Multiple-groups analyses testing differences in indirect effects between conditions found that the mediation via reductions in experiential avoidance was significantly larger in the psilocybin therapy arm versus escitalopram for well-being (B = 4.25, SE = 1.94, p_boot = .011), MADRS (B = -3.31, SE = 1.50, p_boot = .023), QIDS-SR-16 (B = -1.71, SE = 0.96, p_boot = .043), and STAI-Trait (B = -4.82, SE = 2.22, p_boot = .033). The difference for suicidal ideation approached but did not reach statistical significance (B = -1.80, SE = 0.96, p_boot = .058). Regarding predictors of reductions in experiential avoidance within the psilocybin condition, greater reported ego dissolution was associated with larger reductions in experiential avoidance (rs = -0.48, p = .007) as was greater psychological insight (rs = -0.38, p = .037). Mystical-type experience (rs = -0.30, p = .107) and emotional breakthrough (rs = 0.10, p = .592) were not significantly associated. No significant associations between acute-session measures and experiential avoidance changes were observed in the escitalopram arm. Exploratory serial mediation suggested that for several outcomes (except suicidal ideation), improvements via reductions in experiential avoidance were serially mediated through increases in connectedness, though the authors note caution given sample size and exploratory status.

Zeifman and colleagues interpret their findings as supporting reduced experiential avoidance as a putative mechanism by which psilocybin therapy produces improvements in a range of mental health outcomes among people with Major Depressive Disorder. They report that reductions in experiential avoidance mediated improvements in well-being, clinician- and self-rated depression severity, suicidal ideation, and trait anxiety following psilocybin therapy, whereas the same mediation pathway was not observed in the escitalopram arm. Exploratory analyses further indicated that, for most outcomes, the effect of reductions in experiential avoidance on clinical improvement occurred through increases in connectedness, suggesting a possible sequential relationship between decreased avoidance and enhanced connectedness. The authors situate these quantitative results within prior qualitative and survey-based research that described shifts from avoidance to acceptance and from disconnectedness to connectedness after psychedelic experiences. They also reference theoretical neuropharmacological distinctions between SSRIs and psychedelics, proposing that SSRIs may increase passive coping via 5-HT1A-related mechanisms while psilocybin promotes active coping and greater emotional responsiveness via 5-HT2A signalling, which could plausibly underlie differences in how each treatment affects experiential avoidance and connectedness. Several limitations are acknowledged. The reliance on self-report BEAQ at only pre- and post-treatment constrains causal inference about temporal sequencing; observer-based or ecological momentary assessments and biological or neuroimaging markers would strengthen claims about mechanism. The trial sample was modest in size and demographically limited, which reduces generalisability and limits power for complex or serial mediation models. Maintaining blinding in psychedelic trials remains challenging and expectancy or placebo effects could have influenced outcomes despite efforts to minimise them. The authors recommend future studies use larger, more diverse samples, active control drugs or methods to better preserve blinding, neuroimaging to identify treatment-specific neural changes, and designs that measure experiential avoidance more granularly. Clinically, the paper suggests emphasising therapeutic elements that reduce experiential avoidance and foster connectedness within psilocybin therapy, and exploring adjunctive combinations with interventions that target those processes (for example, elements of acceptance and commitment therapy) to potentially enhance efficacy and cost-effectiveness. The authors also note potential relevance of these mechanisms for other disorders characterised by high experiential avoidance, while cautioning that further research across different conditions is required. Overall, the study presents converging quantitative evidence that reductions in experiential avoidance—and increases in connectedness linked to certain acute experiences such as ego dissolution and psychological insight—may be important mechanisms of therapeutic change in psilocybin therapy.