Psilocybin-assisted therapy (PAT) shows promise for cancer-related depression, yet little research has examined how therapeutic context shapes patient experiences. While set (mindset) and setting (environment) are considered central to psychedelic treatment, empirical evidence on their role in PAT acceptability remains limited. This study explores factors influencing the acceptability of PAT from the perspective of patients with cancer and depression.

We conducted semi-structured interviews with participants in a clinical trial of psilocybin-assisted therapy. Using template analysis, we examined themes related to the acceptability of the experience and the surrounding therapeutic environment.

Participants ( n  = 28) described the psilocybin experience as intense and demanding, with therapeutic benefits closely tied to their ability to “surrender”—a term used to describe accepting and remaining open to the experience's intensity and unpredictability. A safe, supportive, and ethical environment was critical in fostering trust and engagement. Preparation and integration were key to maximizing benefit. Music played a significant but variable role, sometimes enhancing and other times distracting. While the clinical setting provided safety, ceremonial elements added meaning for many.

Findings highlight how therapeutic structure, preparation, and setting shape PAT acceptability, supporting the need for patient-centered approaches to optimize care and outcomes.