Safety and Efficacy of Psilocybin During Anticancer Treatment: A Phase II Trial Secondary Analysis

Depression affects a substantial proportion of people with cancer and is associated with poorer health-related quality of life. Conventional antidepressants may have delayed effects and potential drug–drug interactions, while standard psychotherapies often provide only modest benefit in oncology populations. Psilocybin, which is converted to the active compound psilocin, has produced rapid and sustained antidepressant effects in earlier cancer studies. However, most trials excluded patients receiving active systemic anticancer treatment, leaving limited evidence about concurrent use with chemotherapy, immunotherapy, hormone therapy, tyrosine kinase inhibitors, monoclonal antibodies and other systemic agents. This creates particular uncertainty for patients who may already be vulnerable to treatment-related toxicities and overlapping adverse effects.

Schaefer and colleagues conducted a secondary analysis of a Phase II, open-label, single-arm, non-randomised clinical trial (NCT04593563) carried out at a community oncology practice in Maryland between November 2020 and May 2021. The parent trial included 30 adults with a confirmed malignant neoplasm, DSM-5 major depressive disorder without psychotic features, a baseline 17-item Hamilton Depression Rating Scale score of at least 18, and an Eastern Cooperative Oncology Group performance status of 0–2. Key exclusions included current antidepressant or antipsychotic medication or medical cannabis use, and chemotherapy or radiotherapy that impaired general physical functioning.

Of the 30 participants, 17 (56.7%) had received systemic anticancer treatment within 30 days before psilocybin administration and 13 (43.3%) had not. The groups were similar in mean age, at 56 years, and approximately 70% of participants in each group were women. Participants receiving systemic treatment had more prior lines of oncology treatment and more frequently had stage IV or metastatic disease. Their systemic regimens included cytotoxic chemotherapy, hormone-based therapy, immunotherapy, tyrosine kinase inhibitors, monoclonal antibodies and combinations of these treatments.

The authors interpret the findings as indicating that antidepressant response and short-term safety were broadly similar whether or not participants were receiving active systemic anticancer treatment. The similar adverse-event patterns were consistent with earlier psilocybin research in oncology populations, and the concentration of events around dosing and the first post-dose week suggested that many reflected acute or early effects of psilocybin-assisted therapy. The authors note that events such as anxiety, crying, mood alteration, depressed mood and euphoric mood may overlap with expected psychological or emotional experiences during treatment, and recommend that future studies distinguish transient expected effects from clinically burdensome or functionally impairing events.

The authors conclude that, within the limitations of this small secondary analysis, psilocybin-assisted therapy showed a similar short-term efficacy and safety profile in patients with cancer receiving active systemic anticancer treatment and those not receiving such treatment. They consider the findings supportive of including actively treated oncology patients in future psilocybin trials, while calling for larger prospective studies stratified by treatment type, longer follow-up and dedicated evaluation of potential drug–drug interactions.