This double-blind placebo-controlled trial (n=35) found that psilocybin-assisted psychotherapy (25mg) significantly reduced depression and anxiety symptoms in adults with life-threatening illnesses compared to an active placebo (100mg niacin), with benefits sustained at 26 weeks and improvements in spiritual well-being, quality of life, demoralisation, and death anxiety.
Papers cited by this study that are also in Blossom
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.
A life-threatening diagnosis commonly produces profound psychological and existential distress, worsening symptoms such as pain, nausea and insomnia and reducing quality of life. Previous research has shown only modest benefit from existing pharmacological and psychological interventions in palliative populations, and spiritual well-being has been identified as an important target for reducing existential distress. Early trials of psilocybin in cancer patients reported rapid reductions in depression, anxiety and death-related distress, but evidence remains limited for people with non-malignant life-threatening illnesses and for mixed diagnostic samples. Ross and colleagues designed a Phase 2b, double-blind randomized controlled trial to test whether a single 25 mg dose of psilocybin, delivered alongside manualised preparatory and integration psychotherapy, reduces depression and anxiety in adults with life-threatening illness compared with an active placebo (100 mg niacin) plus the same psychotherapy. The trial also included an open-label extension in which all participants received psilocybin, enabling comparison of one versus two psilocybin doses and assessment of durability of effects up to 26 weeks. Secondary and exploratory aims addressed quality of life, death attitudes, mystical experiences and other measures of spiritual and existential well-being.
The study was a single-site, double-blind, placebo-controlled RCT with an open-label extension, conducted at St Vincent's Hospital Melbourne between January 2020 and October 2023 under Good Clinical Practice standards. Ethical approval was obtained and written informed consent provided by participants. Eligibility criteria required adults (18–80) with an advanced life-threatening illness (malignant or non-malignant) and clinically significant depression and/or anxiety; screening included phone triage, SCID-5 screening questions and a semi-structured DSM-5 interview by a study psychiatrist. Participants needed a minimum score of 8 on either HADS subscale. Key exclusions included personal or first-degree family history of psychosis or bipolar disorder. Participants on antidepressants tapered under supervision with a two-week washout where required. After baseline electronic self-report measures and at least 6 hours of preparatory psychotherapy, participants were randomised 1:1 to receive a single double-blind dose of either 25 mg psilocybin or 100 mg niacin (active placebo) in identical capsules. Randomisation used permuted blocks (sizes 2–6) generated by an unblinded monitor; allocation was concealed by prelabelled containers. Niacin was chosen to produce flushing and therefore help preserve blinding. The dosing protocol implemented a standardised set-and-setting approach: 2–3 preparatory sessions, a supervised dosing day with eye-shades and music, and three integration sessions after each dose; a consistent therapist dyad supported each participant. Therapists were experienced clinicians trained in a manualised protocol combining psychodynamic therapy with acceptance and commitment therapy (ACT) techniques, somatic resourcing and creative arts methods. Qualitative interviews were collected but are not reported here. Primary efficacy assessments targeted change on the Hospital Anxiety and Depression Scale (HADS) depression and anxiety subscales from baseline to 6–7 weeks post-dose 1, with primary timepoints at Day -1, Day +1, 3 weeks and 6/7 weeks. Key secondary measures were the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory—state version (STAI-s); additional instruments included the Death Attitude Profile–Revised (DAP-R), WHOQOL-BREF, Mystical Experience Questionnaire (MEQ) and Persisting Effects Questionnaire (PEQ). Safety was monitored using CTCAE v5 criteria with systematic recording of treatment-emergent adverse events, and cardiac observations were performed on dose days. The open-label extension used the 6/7-week assessment as the new baseline and repeated the same schedule after a second psilocybin dose. Statistical planning aimed for a sample of 40 to detect a 50% reduction in primary outcomes, but the study enrolled 35 participants. Primary outcomes were hypothesis-tested with a Bonferroni-adjusted α of 0.025 to control type I error across two primary endpoints. Analyses employed marginal mean models with robust standard errors and exchangeable correlation structures for longitudinal data; MEQ was analysed with linear regression. Missing data were handled with multiple imputation using MICE with predictive mean matching under a missing-at-random assumption. Analyses were performed in Stata v17 and reported as point estimates with 95% confidence intervals; secondary and exploratory outcomes were described without multiplicity-adjusted hypothesis testing.
Sample size was based on detecting a 50 % reduction in primary outcomes at six weeks post-first dose, with 16-28 participants per group required. A total sample of 40 was targeted to allow for attrition. Primary outcomes were ≥ 50 % reductions in HADS-D (depression) and HADS-A (anxiety), with Cohen's d > 0.5. Standard deviations and baseline estimates were derived from. Key secondary outcomes-BDI-II (depression) and STAI-s (state anxiety)-were included to complement the HADS measures, offering greater psychometric sensitivity and broader dimensional assessment of mood and anxiety symptoms. These outcomes were analysed using the same statistical approach as the primary measures. To control type I error, a Bonferroni correction (α = 0.025) was applied to each primary outcome. Secondary and exploratory outcomes were not hypothesis tested. Descriptive statistics summarized baseline characteristics. Raw scores were presented numerically and graphically across time points. Phase 1 (double blind) outcomes were analysed using marginal mean models with robust standard errors and exchangeable correlation structures. MEQ (Day 1) was analysed via linear regression; PEQ outcomes (Weeks 3 and 6) used marginal mean models. Phase 2 (open-label extension) applied the same models, with new baseline set at 6 weeks post-dose 1. Analyses assessed within-group changes (psilocybin group) and pre/post changes in the former control group. Treatment effects were reported as point estimates with 95 % CIs. Only primary outcomes were subject to hypothesis testing with multiplicity adjustment. Multiple imputation was performed using the Multivariate Imputation by Chained Equations (MICE) algorithm with predictive mean matching to handle missing data under the assumption that values were missing at random (MAR), preserving the observed data distribution and reducing bias in parameter estimates. All analyses were performed using Stata v17, with details provided in the supplementary material. Qualitative interview data was obtained at baseline, 3 weeks post dose 1 and 3 weeks post dose 2, although will not be reported here.
Psilocybin treatment rapidly reduced depressive and anxiety symptoms, with improvements observed within a day in both the randomized controlled trial and open-label phases. Therapeutic gains persisted up to six months, suggesting durable benefits. While the HADS-Depression scale showed statistically superior improvements, the BDI-II indicated more significant reductions in depressive symptoms for the psilocybin condition. Pre-treatment, participants had a mean depression score of 21 (moderate severity), which shifted to a non-clinical range (mean 9.23) by weeks 6-7 post-dose 1. Given that a 26 % BDI-II score reduction is considered clinically meaningful for moderate depression (minimally clinical important difference MCID), the observed >50 % reduction for more than 50 % of the cohort well surpasses this threshold, indicating robust clinical improvement. These effects remained at both 6/7 weeks post-dose 1, and six-months post-dose 2. Although HADS-Anxiety scores trended downward for the psilocybin group, they did not reach statistical significance between the groups. However, the STAI-s showed a significant, sustained reduction in anxiety symptoms at 6/7 weeks for the psilocybin condition. A Bonferroni correction was applied to control for multiple comparisons across two primary outcomes; while rigorous, this conservative approach may have reduced statistical power and contributed to the non-significant finding for HADS-Anxiety despite both showing improvments. The discrepancy between anxiety measures may also stem from scale differences: the HADS-Anxiety subscale (7 items) assesses general anxiety over the past week, while the STAI-s (20 items) captures a more detailed range of current symptoms potentially more sensitive in smaller samples. The HADS recall period may have masked immediate post-dose effects, reflecting an aggregate weekly response which could have included predose anxiety states. The HADS was selected for consistency with prior studiesand suitability for medically ill populations. However, the STAI-s demonstrated greater nuance in detecting acute anxiety symptoms. Death anxiety, demoralization, and hopelessness score reductions were also more rapid, pronounced, and sustained in the psilocybin condition. Beyond symptom reduction, the psilocybin condition experienced increases in quality of life and spiritual well-being, and much higher reports of mystical experiences (e.g., awe, unity, oceanic boundlessness), states rarely achieved in conventional therapy. Unlike many palliative medications which tend to sedate patients, psilocybin appeared to elicit vivid, meaningful & enlivening psychological states. The treatment's impact on spiritual well-being was supported by qualitative data and clinician reports. 1 Given the prevalence of existential suffering in terminal illness, improvements in both spiritual and psychiatric symptoms suggest psilocybin-assisted therapy may be a valuable intervention. This aligns with the WHO's definition of palliative care, emphasising psychological and spiritual support at the end of life. These findings also reinforce prior research showing that psychedelics can induce profound, personally meaningful, and spiritually significant experiences. While 50 % of participants in the psilocybin condition experienced a ≥ 50 % reduction in BDI-II depression scores, this was lower than reported in previous cancer studies. This may reflect the greater heterogeneity of the current sample, which included individuals with both malignant and non-malignant advanced illness, a wider range of psychiatric diagnoses and severity, and generally more medically unwell participants. Unlike previous studies involving patients with earlierstage or curable cancers, many participants in this study were in an advanced state of illness, experiencing expected medical setbacks during follow-up, which potentially overshadowed sustained benefit. Nevertheless, notable improvements in psychological distress, quality of life, and spiritual wellbeing highlight the therapeutic promise of psilocybinassisted psychotherapy in this population. Findings suggest most therapeutic gains may stem from a single psilocybin session, as no significant differences were observed between the one and two-dose groups at 26 weeks. The placebo group improved after receiving psilocybin. However, the initial dose reduced scores to non-clinical ranges, limiting measurable change after the second dose. Qualitative interviews may provide further insights into any additional effects from the second session. Interestingly, several outcomes continued to improve over time, potentially reflecting ongoing psychological integration. The treatment demonstrated a strong safety profile, even among participants with advanced illnesses. This study was the first to administer psilocybin-assisted psychotherapy to individuals with conditions not previously represented in the literature, including advanced motor neurone disease (ALS), kidney dialysis, non-invasive ventilation dependency, and advanced cardiac failure. With trained personnel addressing medical considerations, no serious treatment-emergent adverse events occurred. Mild side effects (e.g., nausea, headache, transient hypertension) aligned with prior research. Balancing protocol exclusions with ethical inclusion was a key consideration. One amendment refined exclusions for taxol chemotherapy, commonly used in palliative care for stage 4 cancers. After consulting medical experts, it was deemed safe to administer psilocybin with a 3-day washout during taxol-free weeks, enabling broader participant inclusion without compromising safety.
Create a free account to open full-text PDFs.
Raison, C. L., Sanacora, G., Woolley, J. D. et al. · JAMA (2023)
Davis, A. K., Barrett, F. S., May, D. G. et al. · JAMA Psychiatry (2021)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Griffiths, R. R., Johnson, M. W. · Journal of Psychopharmacology (2016)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Agin-Liebes, G. I., Malone, T., Yalch, M. M. et al. · Journal of Psychopharmacology (2020)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
MacLean, K. A., Leoutsakos, J. S., Johnson, M. W. et al. · Journal for the Scientific Study of Religion (2012)
Lewis, B. R., Garland, E. L., Byrne, K. et al. · Journal of Pain and Symptom Management (2023)
Agrawal, M., Richards, B. D., Richards, W. A. et al. · Cancer (2023)
Of 106 individuals prescreened, 55 consented and 35 were randomised to the double-blind phase (17 to psilocybin, 18 to niacin). Baseline characteristics showed a mean age of 60.9 (sd 11.5) years in the psilocybin arm and 51.3 (sd 13.9) in the niacin arm; 54.3% of the total sample were female. Most participants were Australian-born, none identified as Aboriginal or Torres Strait Islander, and 11 reported prior psychedelic use. The majority had moderate functional impairment and 46% had comorbid depression and anxiety. Thirteen participants tapered antidepressants prior to enrolment. During the double-blind phase three participants in the psilocybin arm did not complete the 6/7-week follow-up (one due to disease progression, one withdrew because of anxiety during dosing, and one died from their terminal illness); no participants withdrew from the niacin arm during the double-blind phase. All placebo participants proceeded to the open-label psilocybin dose; four participants from the psilocybin arm did not proceed to the open-label dose for medical, family or COVID-related reasons. By 26 weeks, two participants had died and one was lost to follow-up, leaving 25 participants (9 originally randomised to psilocybin and 16 originally randomised to niacin) who completed both doses and follow-up. On primary outcomes at 6–7 weeks post-dose 1, the psilocybin group showed significantly greater reductions in HADS depression compared with control (β = -2.49, p = .02) with a large effect size (d = 1.12). HADS anxiety reductions did not reach statistical significance between groups (p = .07). Complementary measures demonstrated robust effects: BDI-II scores reduced significantly in the psilocybin arm (β = -7.56, p = .004; d = 2.87), and STAI-state anxiety showed a significant reduction (β = -12.59, p = .005; d = 4.51). The authors report that pre-treatment mean BDI-II was approximately 21 (moderate severity) and decreased to a non-clinical mean of about 9.23 by weeks 6–7 post-dose 1. Secondary and exploratory outcomes indicated meaningful improvements in death-related attitudes, demoralization and hopelessness, and increases in quality of life and spiritual well-being. Following their open-label psilocybin dose, former placebo participants showed significant within-group increases in PEQ positive mood (β = -1.65; 95% CI -2.68 to -0.63; p = .002; d = -0.87) and improvements in altruism and positive attitudes with similar effect sizes. At 6/7 weeks after the open-label dose and at the 26-week follow-up, there were no significant differences between participants who had received two psilocybin doses and those who had received one dose; therapeutic gains were generally sustained through 26 weeks. Safety data showed no treatment-emergent serious adverse events attributed to psilocybin. Eight serious medical events unrelated to the investigational product occurred during the study period, including three deaths expected from terminal illness and five hospitalisations for intercurrent medical issues. Treatment-emergent adverse events were reported more frequently in the psilocybin arm (100%) than in the niacin arm (61.1%); common events included transient hypertension during dosing, headache and nausea. Short-lived psychiatric events in the psilocybin group included transient anxiety (23.5%), transient paranoia (5.9%) and passive suicidal ideation (5.9%), all of which resolved within the session or within 48 hours with clinical support. Cardiac observations noted expected, transient, asymptomatic increases in blood pressure on dose days.
Ross and colleagues interpret their findings as showing rapid and durable reductions in depressive and some anxiety symptoms following psilocybin-assisted psychotherapy in people with life-threatening illness. Improvements were detectable within a day and persisted up to six months. The BDI-II demonstrated particularly large reductions in depressive symptoms, with more than 50% of participants in the psilocybin arm achieving ≥50% BDI-II score reductions; HADS-Depression also showed significant between-group benefit while HADS-Anxiety trended in the same direction but did not reach the corrected significance threshold. The authors note that applying a Bonferroni correction across two primary outcomes, while conservative, may have reduced power to detect anxiety effects on HADS, and that scale differences (HADS-A’s one-week recall versus STAI-s’s focus on current state) may explain discrepant findings. Beyond symptom scores, the study observed reductions in death anxiety, demoralisation and hopelessness, alongside increases in spiritual well-being, quality of life and reports of mystical-type experiences. The investigators highlight that many participants reported enlivening, meaningful psychological states rather than sedation, which aligns with the goals of palliative care to address psychological and spiritual needs. The open-label phase showed that participants initially allocated to placebo improved after receiving psilocybin, and no sustained differences were found between one- and two-dose groups at 26 weeks, suggesting most gains may accrue after a single session for this sample. The authors acknowledge several important limitations. The study enrolled 35 participants rather than the planned 40, leaving it underpowered for some comparisons and precluding detailed subgroup analyses (for example, examining effects of antidepressant tapering). Blinding was difficult to maintain: retrospective file audits suggested many participants receiving psilocybin correctly inferred their allocation, and no formal blinding integrity assessment was performed, raising the possibility of expectancy effects. The small sample size may have inflated effect size estimates for some measures, and limited demographic diversity and an uneven mix of malignant and non-malignant diagnoses constrain generalisability. Practical considerations for wider implementation are noted: the intensive 2:1 therapist model may be resource-intensive and future work should explore scalable delivery options, recruitment of more diverse populations, and formal evaluation of dose-frequency effects with larger samples. Despite these caveats, the authors conclude that psilocybin-assisted psychotherapy had an acceptable safety profile in a medically unwell cohort and produced clinically meaningful improvements in psychological and existential outcomes.
This Phase 2b randomised controlled trial with an open-label extension found that a single 25 mg dose of psilocybin administered with structured preparatory and integration psychotherapy produced rapid, clinically meaningful reductions in depressive symptoms and improvements in spiritual well-being among people with life-threatening illness. Benefits were maintained up to 26 weeks, no treatment-emergent serious adverse events were attributed to psilocybin, and adverse effects were transient and manageable. The investigators conclude that psilocybin-assisted psychotherapy shows safety and therapeutic promise as an intervention for end-of-life psychological and existential distress, while emphasising the need for larger, more diverse trials and exploration of scalable therapeutic models.