Pragmatic Trial of Psilocybin Therapy in Palliative Care

Inclusion Criteria: General * Provision of signed and dated informed consent form and the capacity to consent to research. * Stated willingness to comply with all study procedures and availability for the duration of the study * Is currently a patient in a study-engaged clinical site * Has a life-threatening illness and a life expectancy of ≤2 years * Has moderate-to-severe demoralization * Ability to take oral medication (capsules and liquid) Exclusion Criteria: General * Known allergic or severe reactions to the non-psychoactive components of psilocybin capsules or liquid ketamine * Treatment with another investigational drug or intervention within 1 month of signing Informed Consent Form (ICF) * If deemed by clinical judgment of the study investigators to be unsafe for undergoing the intervention Neurological * Cognitive impairment sufficient to impede the ability to complete study tasks * History of intracranial hemorrhage * Recent embolic stroke * Recent seizure * Current intracranial mass * Advanced stage of a neurologic disease that elevates risk for psychosis Cardiovascular * Uncontrolled hypertension * Clinically significant cardiac disease Respiratory * Severe pulmonary disease * Supplemental oxygen requirement Gastrointestinal * Current intractable nausea/vomiting/diarrhea * Recent, clinically significant GI bleed * Markedly abnormal liver function tests Endocrine, Renal, and Reproductive * Pregnancy or lactation * Severe renal insufficiency * Unstable insulin-dependent diabetes mellitus Prohibited Medications * Antipsychotics (with exceptions) * Antidepressants (with exceptions) * Dopamine agonists * Drugs known to have adverse interactions with psilocybin or ketamine