Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial

Importance Psilocybin-assisted psychotherapy may offer a novel approach to treating depression, anxiety, and existential distress in individuals with life threatening illnesses, where current treatments show limited efficacy.Objective To evaluate the efficacy and safety of psilocybin-assisted psychotherapy versus active placebo and psychotherapy in adults with life-threatening illnesses.Design Double-blind, randomized controlled phase 2b trial (RCT) with an open-label extension and 6-month follow-up (January 2020 - October 2023).Setting Single-site study at a tertiary hospital's palliative care department (St. Vincent's Hospital Melbourne affiliated with the University of Melbourne).Participants Adults aged 18-80 with a life-threatening illness and clinically significant depression and/or anxiety.Interventions Participants were randomized to receive 25 mg psilocybin or 100 mg niacin (active placebo), alongside three preparatory psychotherapy and six post-dose integration psychotherapy sessions. After 6-7 weeks post double blind dose, all participants received 25 mg psilocybin in an open-label extension, enabling a two dose versus one dose group comparator. Participants were followed up to 26 weeks post open label dose.Main outcomes and measures Primary outcome was change in depression and anxiety symptoms, assessed using the Hospital Anxiety and Depression Scale (HADS), from baseline to 6-7 weeks post-dose. Key secondary outcomes included the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory - State version (STAI-S), which provided complementary, dimensional measures of depression and anxiety over the same time period. Additional secondary outcomes included Death Attitudes Profile, WHOQOL-BREF, State-Trait Anxiety Inventory (STAI-Trait scale), Mystical Experiences Questionnaire, and Persisting Effects Questionnaire. Exploratory outcomes included spiritual well-being, hopelessness, demoralization, and HADS-Trait scores.Results Thirty-five participants (mean age 56.0; 54.3 % female) were randomized (psilocybin: n = 17; placebo: n = 18). At 6-7 weeks, psilocybin produced significantly greater reductions in HADS depression (B = -2.49; P = .02; d = 1.12), BDI-II (B = -7.56; P = .004; d = 2.97), and STAI-State anxiety (B = -12.59; P = .005; d = 4.51) compared to placebo. Benefits were sustained at 26 weeks. Exploratory outcomes demonstrated enhanced spiritual well-being, quality of life, and significant reductions in demoralization, death anxiety and hopelessness. No serious treatment-emergent adverse events occurred. Psilocybin was associated with more mild-to-moderate adverse events. One participant withdrew due to anxiety during dosing.Conclusions and relevance Psilocybin-assisted psychotherapy appears safe and may offer durable relief from depression and anxiety in individuals with a life-threatening illness.