MB-PAT for Demoralization in Advanced Cancer ('PAT-MIND') Trial

PAT-MIND is a multi-site, phase IIb pilot feasibility and therapy-optimization trial of psilocybin-assisted therapy in adults with advanced cancer. The study uses a wave-randomized 2×2 factorial design to examine two intervention components: psilocybin dose and psychotherapy intensity. Participants will be enrolled in small waves, and each wave will be randomized to one of four combinations: high-dose psilocybin plus mindfulness-based psilocybin-assisted therapy, high-dose psilocybin plus standard psilocybin-assisted therapy, low-dose psilocybin plus mindfulness-based psilocybin-assisted therapy, or low-dose psilocybin plus standard psilocybin-assisted therapy.

The psilocybin dose comparison is blinded. Participants will receive either 25 mg or 5 mg psilocybin during a monitored in-person group dosing session. The psychotherapy intensity comparison is not blinded. Participants will receive either mindfulness-based psilocybin-assisted therapy or standard psilocybin-assisted therapy, depending on their randomized intervention combination. Preparation and integration sessions will be delivered using a hybrid format, with some sessions conducted in person and some virtually, depending on the session type and site logistics.

The primary aims of this pilot trial are to assess the feasibility, acceptability, and safety of hybrid group-based psilocybin-assisted therapy in adults with advanced cancer, and to explore therapy-optimization signals for psilocybin dose and psychotherapy intensity to inform a future definitive trial. Exploratory objectives include participant experience, demoralization, secondary psychological outcomes, health-related quality of life, health-economic measures, and exploratory biomarker outcomes.

Study procedures include screening, informed consent, trial-specific questionnaires, group and individual preparation and integration sessions, a monitored psilocybin dosing day, dried blood spot collection, stool sample collection, optional wearable device data collection, and medical chart review. Participants will complete online questionnaires at protocol-defined timepoints, including measures of demoralization, psychological distress, quality of life, treatment experience, and resource use.

Safety will be monitored throughout the study, including adverse event monitoring during and after the dosing session.

Inclusion criteria

• Written informed consent provided before any study-specific procedures.
• Age 18 years or older.
• Diagnosis of advanced cancer: Stage III-IV or metastatic solid tumor. Stage II cancer may be eligible if the treating oncologist confirms advanced/refractory disease with clinically significant existential burden, defined as a Demoralization Scale-II (DS-II) score ≥11.
• Clinical life expectancy of at least 6 months. Borderline cases of approximately 5-6 months may be considered based on Principal Investigator judgment and documentation.
• Demoralization Scale-II (DS-II) total score ≥4 at screening, or DS-II total score ≥3 with documented clinical impression of significant existential distress.
• Willing and cognitively able to complete at least 2 preparation sessions, 1 in-person dosing session, and at least 2 integration sessions over approximately 6-8 weeks.
• Sufficient spoken and written English proficiency to provide informed consent, participate in group therapy, and complete participant-reported outcome measures.
• Not pregnant or lactating. Participants of childbearing potential must have a negative pregnancy test at screening and comply with protocol-specified contraception requirements.
• A responsible adult, such as a family member, friend, or caregiver, must be available to accompany the participant or be on-call for at least 12 hours following the dosing session.

Exclusion criteria

Psychiatric/Psychological:

• Active or high-risk suicidality, defined as Columbia-Suicide Severity Rating Scale (C-SSRS) item 4 or 5 within the past 4 weeks, or a suicide attempt within the past 12 months. Passive death wishes and suicidal ideation without intent are not exclusionary.
• Current psychotic disorder or active psychotic symptoms, including schizophrenia, schizoaffective disorder, hallucinations, delusions, or thought disorganization. Historical psychosis in sustained remission may be considered on a case-by-case basis by the Principal Investigator.
• Current manic or mixed-state episode. Stable, euthymic bipolar disorder on maintenance pharmacotherapy may be permitted with Principal Investigator judgment and documentation.
• Moderate-to-severe active alcohol, stimulant, or opioid use disorder within the past 12 months. Severe uncontrolled cannabis use disorder is exclusionary; stable prescribed cannabis use is permitted.

Pharmacological/Drug Interactions:

• Use of concomitant medications that does not meet the requirements of the protocol-specified Concomitant Medications Policy.
• Known allergy, anaphylaxis, or serious hypersensitivity to psilocybin, psilocin, related tryptamines, or capsule excipients.

Medical:

• Severe hepatic impairment, defined as a current unstable diagnosis of liver disease with AST or ALT >5 times the upper limit of normal and clinical symptoms.
• Severe renal impairment, including current unstable acute kidney injury or advanced kidney disease (CKD Stage 4) with eGFR <30 mL/min/1.73 m².
• Unstable cardiovascular disease, including myocardial infarction or stroke within the past 3 months, decompensated heart failure (NYHA III-IV), or uncontrolled arrhythmia. Elevated blood pressure on dosing day may require dosing deferral and reassessment according to protocol-defined thresholds.
• Seizure within the past 12 months or currently uncontrolled epilepsy. Well-controlled epilepsy with no seizures for more than 12 months on stable therapy may be permitted with monitoring.
• Uncontrolled diabetes, including unstable Type 1 diabetes with diabetic ketoacidosis within the past 3 months, or Type 2 diabetes with HbA1c >11% and symptomatic hyperglycemia.
• Any medical, neurological, or psychiatric condition, or concurrent cancer-directed therapy, that in the Principal Investigator's clinical judgment would materially increase risk or prevent meaningful protocol participation.

Cancer Treatment-Related:

• Systemic anti-cancer therapy that does not meet protocol requirements. Chemotherapy, immunotherapy, and targeted therapy are permitted when the regimen is stable, treatment-related toxicities are CTCAE Grade 2 or lower, and protocol-specified timing requirements before psilocybin dosing are met.
• Opioid analgesic or corticosteroid use that does not meet protocol requirements. Opioids must be on a stable dose for at least 1 week without opioid-induced delirium or clinically significant respiratory compromise. Corticosteroids must generally be stable for at least 2 weeks; high-dose dexamethasone for acute central nervous system edema requires dosing to be deferred until clinically stable.