Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial

Persistent, clinically significant anxiety and/or depressive symptoms affect a substantial proportion of patients with cancer and are associated with poorer medical and psychosocial outcomes, including increased healthcare use, reduced quality of life, greater hopelessness and higher suicide risk. Existing pharmacological and psychosocial treatments for cancer-related psychological distress have mixed efficacy, delayed onset for antidepressants, notable side effects, and no approved medications specifically for this indication. Previous open-label and early controlled trials with serotonergic psychedelics suggested potential benefits for cancer-related existential distress, and growing evidence links higher existential/spiritual wellbeing with better psychological outcomes in cancer care. Ross and colleagues set out to test whether a single moderate oral dose of psilocybin (0.3 mg/kg), administered alongside a manualised psychotherapy platform, would reduce anxiety and depression in patients with life‑threatening cancer compared with an active control (niacin 250 mg) plus the same psychotherapy. The trial aimed to assess both immediate effects and durability up to several months, and to examine whether the intensity of mystical-type subjective experiences mediated clinical outcomes.

This was a double-blind, randomised, placebo-controlled crossover trial in which 29 patients with cancer-related clinically significant anxiety or depression were allocated to one of two dosing sequences: psilocybin first then niacin, or niacin first then psilocybin. The single-dose psilocybin was 0.3 mg/kg orally and the active control was oral niacin 250 mg. Drug administration dose 1 occurred about 2–4 weeks after baseline assessment, and the crossover (dose 2) took place 7 weeks after dose 1. The total study participation lasted approximately 9 months, with assessments at multiple time points including 1 day pre-dose, several post-dose visits (1 day, 2 weeks, 6 weeks, 7 weeks) and a long-term follow-up 26 weeks after dose 2. Participants were recruited primarily from an academic cancer centre; of 108 pre-screened, 42 consented and 29 were randomised and treated. Inclusion required a SCID-derived anxiety-related diagnosis (90% met criteria for an adjustment disorder, 10% for generalized anxiety disorder) and no current psychotropic medication. Nearly two-thirds had stage III/IV cancer and 59% had prior antidepressant or anxiolytic treatment but were off psychotropics at enrolment. Outcomes comprised co-primary clinical measures of anxiety and depression assessed repeatedly: Hospital Anxiety and Depression Scale (HADS) anxiety and depression subscales and total, Beck Depression Inventory (BDI), and Spielberger State‑Trait Anxiety Inventory (STAI) state and trait scales. Secondary measures assessed cancer-related existential distress (Demoralization, Hopelessness, Death Anxiety, Death Transcendence), quality of life (WHO-BREF), spiritual wellbeing (FACIT-SWB), persisting effects (PEQ), and subjective drug effects including the Mystical Experience Questionnaire (MEQ 30). Safety monitoring included adverse events and cardiovascular measures during sessions. Statistical analyses used mixed-effect repeated measures (MMRM) regressions with an AR(1) covariance structure for continuous longitudinal outcomes, reporting planned between-group comparisons prior to the crossover as primary tests. Between-group effect sizes were calculated with Cohen's d. Clinically significant response was prespecified as ≥50% reduction on relevant scales; antidepressant remission required ≥50% reduction plus HADS D ≤7 or BDI ≤12. Additional analyses included within-group comparisons, ANOVA to compare magnitude of change across psilocybin sessions, chi-square tests for categorical response rates, Spearman correlations between MEQ scores and clinical change, partial correlations controlling for rated intensity, and bootstrap mediation analyses (PROCESS macro) to test whether MEQ total mediated treatment effects.

Sample characteristics: Twenty-nine participants completed the first dosing session; mean age was 56.3 years (range 22–75), 62% were women and 90% Caucasian. Cancer types were predominantly breast/reproductive (59%), gastrointestinal (17%) and haematologic (14%); 62% had stage III/IV disease. About 45% reported prior hallucinogen use and 52% reported some organised religious faith. The two dose-sequence groups did not differ significantly on demographic or clinical variables. Safety and tolerability: No serious adverse events (medical or psychiatric) were attributed to psilocybin or niacin. During psilocybin sessions common medical adverse events included transient, non-clinically significant elevations in blood pressure and heart rate (76%), headaches/migraines (28%) and nausea (14%). Psychiatric adverse events were mostly transient anxiety (17%) and brief psychotic-like symptoms in two participants (7%). Cardiovascular effects peaked around 180 minutes post-dose; peak mean systolic/diastolic BPs in the psilocybin-first group were 142/83 mmHg and peak mean heart rate was 71 bpm at 300 minutes. No participants required pharmacologic rescue during sessions, developed dependence, had prolonged psychosis or required psychiatric hospitalisation. Primary outcomes: Prior to the crossover (the primary between-group comparison window), psilocybin produced immediate, substantial and sustained reductions in anxiety and depression relative to niacin across all six primary measures (HADS total, HADS anxiety, HADS depression, BDI, STAI state, STAI trait). Between-group effect sizes (Cohen's d) were large at 1 day, 2 weeks, 6 weeks and 7 weeks post-dose 1. Within-group analyses showed that the psilocybin-first group had significant reductions from baseline at each post-baseline time point, with effects remaining significant up to the final assessment (26 weeks after dose 2, ~8 months post‑psilocybin). The niacin-first group showed little or transient change prior to crossover but, after receiving psilocybin in session 2, demonstrated significant within-group improvements that persisted to study end. Categorical response rates were notable: at 7 weeks after dose 1, 83% of the psilocybin-first group met BDI-defined antidepressant response versus 14% in the niacin-first group; anxiolytic response (HADS A) was 58% versus 14%. At the 6.5-month follow-up (after both groups had received psilocybin), approximately 60–80% of participants maintained clinically significant reductions in depression or anxiety. Secondary outcomes and persisting effects: Two weeks after dose 1, psilocybin versus niacin produced reductions in cancer-related demoralization and hopelessness, and increased spiritual wellbeing and several domains of quality of life (physical, psychological, environmental). Many of these benefits were sustained at the 26-week post-dose 2 follow-up. Measures of death anxiety did not show short-term or long-term reductions, although death transcendence (attitudes/adaptations towards death) improved significantly at the 26-week follow-up in the psilocybin-first group. Persisting Effects Questionnaire responses indicated that psilocybin sessions yielded lasting positive changes in attitudes, mood, social behaviour and spirituality; at 26 weeks after dose 2, 52% and 70% of participants rated the psilocybin session among the single most or top-five most spiritually significant or personally meaningful experiences of their lives, and 87% reported increased life satisfaction or wellbeing attributed to the experience. Mystical experience and mediation: Psilocybin produced higher MEQ 30 scores than niacin. MEQ total at 7 hours post-dose 1 correlated with change scores from baseline to 6 weeks post-dose 1 on several primary measures (for example, BDI r=0.49, P=0.01; HADS total r=0.39, P=0.04; STAI state r=0.42, P=0.03). Partial correlations controlling for participant-rated intensity maintained significant associations for most measures. Bootstrap mediation analyses indicated that MEQ total significantly mediated a portion of the psilocybin versus niacin effect on four primary outcomes with point estimates (ab) and bias-corrected 95% CIs reported for HADS total (ab=0.46, 95% CI 0.01–0.97), HADS depression (ab=0.43, 95% CI 0.01–1.23), BDI (ab=0.79, 95% CI 0.23–1.29) and STAI state (ab=0.65, 95% CI 0.13–1.16).

Ross and colleagues interpret the findings as showing that a single moderate dose of psilocybin, given alongside a targeted psychotherapy platform, produced rapid, robust and durable reductions in cancer-related anxiety and depression. They highlight the novelty that one medication administration produced immediate clinical effects that persisted for weeks to months, noting that within-group reductions occurred after psilocybin in both dosing sequences and that between-group differences prior to crossover were substantial. The authors situate their results within prior work, noting consistency with historical psychedelic studies in cancer patients and with recent open-label trials reporting enduring antidepressant effects after single or limited dosing of serotonergic psychedelics. They contrast the durability observed here with the typically shorter-lived effects of single-dose ketamine, and they place the observed high response rates in the context of meta-analyses that have generally found limited antidepressant efficacy in cancer populations with conventional antidepressants. Safety observations are emphasised: no serious adverse events attributed to psilocybin occurred, and the observed transient cardiovascular and psychological effects were consistent with previous controlled studies. The investigators stress the need to monitor and manage transient difficult psychological states during sessions but report no cases of prolonged psychosis, hallucinogen persisting perceptual disorder or addiction in this cohort. Acknowledged limitations include the small sample size, a predominantly Caucasian and female sample limiting generalisability, the crossover design that complicates attribution of sustained effects after crossover, and the use of an active control (niacin) that provided imperfect blinding. The authors note it is unclear whether sustained benefits arise from psilocybin alone or from interactions between psilocybin and the psychotherapy platform, and they recommend future studies to disentangle these contributions and to replicate findings in larger, more diverse samples. Regarding mechanisms, the discussion summarises both neurobiological and psycho-spiritual hypotheses advanced by the authors. Neurobiological possibilities mentioned include 5-HT2A receptor modulation, downstream effects on glutamatergic transmission, AMPA receptor activation and brain-derived neurotrophic factor (BDNF) expression, and acute changes in medial prefrontal and default mode network activity observed in imaging studies. Psycho-spiritual mechanisms focus on the mystical-type experiences occasioned by psilocybin; the magnitude of these experiences correlated with and statistically mediated portions of clinical improvement, suggesting they are one plausible pathway through which psilocybin may produce therapeutic benefit. The authors emphasise that the mystical experience is likely one of several mediators and call for further research into which experiential dimensions predict clinical response and how to promote them safely.

The investigators conclude that, when administered with appropriate psychotherapy, a single moderate dose of psilocybin was safely given to patients with cancer-related psychological distress and produced rapid and sustained reductions in anxiety and depression, decreased existential distress, increased spiritual wellbeing and quality of life, and improved attitudes toward death. They report that mystical-type experiences mediated part of the anxiolytic and antidepressant effects. The authors recommend further empirical research to definitively establish safety and efficacy and to clarify the relative contributions of the pharmacological agent and the psychotherapeutic context.