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

In recent years there has been renewed interest in the therapeutic potential of classical psychedelics such as psilocybin for a range of neuropsychiatric conditions, including major depressive disorder (MDD). Earlier phase trials have reported rapid and sometimes long-lasting antidepressant effects after one or two doses, but the mechanisms that explain both the rapid onset and persistence of benefit remain uncertain. Proposed mechanisms include neurobiological changes (for example, neuroplasticity), acute subjective experiences (such as mystical-type experiences), and psychological or behavioural processes including increased psychological flexibility, experiential acceptance, connectedness, and revision of high-level beliefs. Sloshower and colleagues set out to examine psychological flexibility as a potential mechanism of change within an exploratory, placebo-controlled, within-subject clinical trial of psilocybin-assisted therapy for moderate to severe MDD. Specifically, the study tested whether psilocybin dosing sessions embedded in an Acceptance and Commitment Therapy (ACT)-informed psychotherapy protocol would produce changes in psychological flexibility, mindfulness facets, and values-congruent living, and whether changes in psychological flexibility or experiential acceptance were associated with reductions in depressive symptoms.

The study was conducted under institutional and regulatory approvals, including an FDA Investigational New Drug application and DEA Schedule I licence, and was registered on ClinicalTrials.gov. A placebo-controlled, within-subject, fixed-order design was used: each participant received placebo first and, approximately four weeks later, psilocybin (0.3 mg/kg, maximum 35 mg). The fixed-order design aimed to reduce functional unblinding and carryover given the strong and potentially durable effects of psilocybin. Dosing sessions were embedded within an eight-session psychotherapy protocol grounded in ACT principles. Participants were followed for 16 weeks. Eligibility required adults aged 18–65 meeting DSM-5 criteria for MDD with a current moderate to severe episode (GRID-HAM-D-17 ≥ 17) of at least six weeks’ duration and failure of at least one adequate antidepressant trial during the current episode. Individuals had to be off conventional antidepressant or antipsychotic medications for at least two weeks (four weeks for fluoxetine). Exclusions included primary psychiatric diagnoses other than MDD, active substance use disorders, personal or family history of psychotic or bipolar disorder, unstable medical or neurological disease, or recent psilocybin exposure. Interventions comprised two dosing sessions conducted at a VA research site: an identical opaque capsule containing microcrystalline cellulose (placebo) at the first session and a capsule with psilocybin at the second. Psychotherapeutic support included two-hour preparatory sessions before each dosing and two debriefing/integration sessions after each dosing (1 day and 1 week later), plus two additional integration sessions after primary outcome collection; therapists used a manualised ACT-based framework. Outcome measures relevant to this substudy were psychological flexibility (Acceptance and Action Questionnaire-II, AAQ-II), mindfulness (Kentucky Inventory of Mindfulness Skills, KIMS, with subscales Observe, Describe, Awareness, Accept Without Judgment), and values-congruent living (Valued Living Questionnaire, VLQ), collected at baseline, week 2 (post-placebo), week 6 (post-psilocybin) and week 16. Depression severity was measured repeatedly with the QIDS-SR-16 through week 16. Adverse events and vital signs were monitored. Analyses were performed on the intention-to-treat population of participants who completed at least one dosing session. Linear mixed models assessed change over time, with time as a within-subjects factor for outcomes through week 16. Associations between changes in depressive symptoms (QIDS-SR-16) and changes in AAQ-II and the KIMS Accept Without Judgment scale were examined using Spearman correlations from before to two weeks after each dose. Given the exploratory nature and small sample, tests used two-tailed alpha = 0.05 with no correction for multiple comparisons.

Of 949 individuals initially assessed, 42 were screened in person and 22 were enrolled; 19 participants completed at least one dosing session and 15 completed both. Baseline participant characteristics were reported in a table (not reproduced here). The parent trial reported primary outcomes related to depression, anxiety and quality of life elsewhere. Psychological flexibility, as measured by the AAQ-II (where lower scores indicate greater flexibility), showed a significant time effect (F(3,35) = 8.74, p < 0.001). AAQ-II scores were significantly lower following psilocybin than after placebo, and this reduction was maintained through week 16. Values-congruent living (VLQ) increased over time (F(3,36) = 2.99, p = 0.044). VLQ scores were significantly higher two weeks after psilocybin compared to baseline, and the increases persisted to week 16, but VLQ changes after psilocybin were not significantly different from post-placebo scores. No significant VLQ change was observed after placebo alone. For mindfulness subscales (KIMS), significant time effects were observed for Describe (F(3,36) = 2.87, p = 0.05) and Accept Without Judgment (F(3,36) = 3.38, p = 0.029). Both Describe and Accept Without Judgment increased significantly two weeks after psilocybin compared to baseline and remained elevated through week 16; these subscales did not change significantly after placebo. There were no significant changes over time in the Observe (F(3,36) = 0.72, p = 0.548) or Awareness (F(3,36) = 2.02, p = 0.129) scales. Depressive symptoms (QIDS-SR-16) decreased following both placebo and psilocybin. After placebo, mean QIDS-SR-16 decreased from 16.79 (SE = 0.95) to 11.74 (SE = 1.49), Δ = 5.05, p = 0.005; however, change in depression during the placebo-to-post-placebo interval was not significantly correlated with change in AAQ-II (Spearman’s rho = 0.30, p = 0.295) or Accept Without Judgment (rho = -0.42, p = 0.140). Following psilocybin, QIDS-SR-16 decreased from 11.71 (SE = 1.49) to 6.27 (SE = 1.38), Δ = 5.47, p = 0.016. Reductions in depression after psilocybin were strongly associated with reductions in psychological inflexibility (AAQ-II) (Spearman’s rho = 0.88, p < 0.001) and with increases in Accept Without Judgment (Spearman’s rho = -0.64, p = 0.014). Adverse event and safety data were monitored, but safety results are reported elsewhere.

Sloshower and colleagues interpret their findings as evidence that psilocybin-assisted therapy administered within an ACT-informed psychotherapeutic frame produced significant and durable improvements in psychological flexibility, certain mindfulness facets (Accept Without Judgment and Describe), and values-congruent living in participants with long-standing, predominantly treatment-resistant MDD. Improvements in psychological flexibility were significantly greater two weeks post-psilocybin than two weeks post-placebo and persisted to three months. Importantly, the investigators found strong correlations between reductions in depressive symptoms and improvements in psychological flexibility and experiential acceptance following psilocybin. The authors situate these results within prior observational research that linked classic psychedelic use to increased psychological flexibility, and note that this study extends those findings into a clinical trial context. They also point out that the associations observed between psychological flexibility and clinical improvement occurred despite a lack of significant correlation between the strength of mystical-type experiences and antidepressant response in the parent trial, suggesting that other acute or post-acute processes (for example, psychological insight, emotional breakthrough, or increased psychological flexibility) may be more predictive of treatment outcomes. Several limitations acknowledged by the investigators temper causal interpretation. The within-subject, fixed-order design prevents a clean separation of effects attributable to placebo dosing, psilocybin dosing, and the ACT-based psychotherapy; carryover from the placebo phase and expectancy effects are possible contributors. The sample was small and the study was not primarily powered for the clinical and psychological outcomes reported here. Measurement issues are also noted: the AAQ-II has recognised validity concerns, including overlap with distress measures and limited multidimensionality, so the authors recommend future work include alternative measures such as the Multidimensional Psychological Flexibility Inventory. The researchers suggest future directions including intensive longitudinal methods to better establish temporal relationships, dose-response studies varying psilocybin dose and psychotherapy dose, and direct comparisons of different psychotherapeutic models or levels of support. Blinding challenges and expectancy effects remain broader methodological issues in psychedelic research, which the authors acknowledge as affecting interpretation.

This exploratory, placebo-controlled, within-subject trial found that a moderate dose of psilocybin delivered within an ACT-based psychotherapeutic protocol was associated with significant improvements in psychological flexibility, two facets of mindfulness (Accept Without Judgment and Describe), and values-congruent living in people with moderate to severe MDD. Improvements in psychological flexibility were greater after psilocybin than after placebo, and increases in psychological flexibility and experiential acceptance were strongly associated with reductions in depressive symptoms. The investigators conclude these results support integrating psilocybin dosing with psychotherapeutic approaches that target psychological flexibility and add to evidence that psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for depression.