This multicenter, triple-blind, phase 2, randomized controlled trial will evaluate the efficacy and safety of psilocybin therapy compared to an active control in treating demoralization in adults near the end of life (≤2 years life expectancy).

After providing written informed consent, participants deemed eligible for this trial will be randomized to a brief course of talk therapy plus 1 dose of oral psilocybin vs the same brief course of talk therapy plus 1 dose of oral ketamine (the active control). Participants' degree of demoralization and other clinical outcomes (e.g., depression, anxiety) will be assessed at 1, 2, and 5 weeks after the study drug administration. After completing the study, participants will have the option of being told which study drug they took (aka, "unblinded"); those who were randomized to the active control will be offered another brief course of talk therapy plus 1 dose of oral psilocybin, and the same sequence of outcome assessments.

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

Data from this study may be requested from other researchers 2 years after the completion of the primary endpoint by contacting the study sponsor.

Data will become available 2 years after completion of the primary endpoint.

Data will be made available to qualified investigators who agree to the data sharing policies of the study.

A Multicenter Triple-blind Phase 2 Randomized Controlled Trial.