Pilot Study of Psilocybin-Assisted Therapy for Demoralization in Patients Receiving Hospice Care

Inclusion Criteria: * Patients enrolled in hospice care at home * Age ≥ 21 years. * Any terminal illness with respect of exclusion criteria * Palliative Performance Scale (PPS) ≥ 50 % (see Appendix A) * Moderate-to-severe demoralization as measured by Demoralization Scale-II ≥ 8 * Significant other or other caregiver present at home the night of study drug administration * No driving for 24 hours following study drug administration. * English proficiency * Ability to understand and the willingness to sign a written informed consent document. * Psilocybin is very likely to have no genotoxic effects. One study that directly focused on the mutagenic potential of psilocybin did not found this type of toxicity. However, due to the lack of clinical and non-clinical studies on the effects of psilocybin on the developing human fetus, women and men of child-bearing potential and who are sexually active must agree to use an acceptable contraceptive method (hormonal or barrier method of birth control; abstinence) throughout their participation in the study. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of psilocybin administration. Exclusion Criteria: * Current General Inpatient (GIP) hospice status * Patients currently receiving chemotherapy * Condition impairing oral intake or digestive absorption * Presence of a delirium diagnosed by the CAM * Significant suicide risk as defined by suicidal ideation with intend and a plan as endorsed on item 5 on the C-SSRS within the past month or at V0 * Current or past history of schizophrenia, psychotic disorder, bipolar disorder, delusional disorder, paranoid personality disorder, schizoaffective disorder, or borderline personality disorder, as assessed by medical history * Patients with first-degree relatives with schizophrenia or bipolar disorder * History of allergic reactions attributed to compounds of similar chemical or biologic composition to psilocybin * Other personal circumstances and behavior that would limit compliance with study requirements, or judged by the study psychiatrist and/or principal investigator to be incompatible with establishment of rapport or safe exposure to psilocybin * Potential for adverse drug-drug interactions. Concomitant medications with significant potential to interact with study medications will be exclusionary if they cannot be tapered. These include the following: * Serotoninergic antidepressants * Centrally-acting serotonergic agents (e.g. MAO inhibitors) * Antipsychotics (e.g. first and second generation) * Mood stabilizers (e.g. lithium, valproic acid) * Aldehyde dehydrogenase inhibitors (e.g. disulfiram) * Significant inhibitors of UGT 1A0 or UGT 1A10 * Any psychiatric medication will be tapered if possible in an appropriate fashion to avoid withdrawal effects. They will be discontinued long enough before the psilocybin Session to avoid the possibility of any drug-drug interaction (the interval will be at least five times the particular drug and active metabolites' half-life). * End stage liver disease or cirrhosis as primary hospice diagnosis * Patients who have elevated AST and ALT five times above the normal laboratory limit on their last available bloodwork and patients with symptoms suggestive of liver failure including confusion, asterixis or jaundice. * Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal condition or any other unstable condition that, in the opinion of the principal investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if he/she takes part in the study. This may include but is not limited to clinical symptoms or recent history of significant tachyarrhythmias; severe angina or myocardial ischemia; poorly controlled congestive heart failure; poorly controlled hypertension; poorly controlled hypo- or hyperthyroidism; uncontrolled diabetes; severe renal or liver disfunction; acute respiratory failure; sepsis; history of cerebral aneurysms; glaucoma; increased intracranial pressure and any intracranial mass. * Women who are pregnant, nursing, or planning a pregnancy.