Psilocybin With Psychotherapy for Improving Chronic Pain in Cancer Patients Requiring Opioids

Inclusion Criteria: * Age ≥ 18 and ≤ 75 years old * Diagnosis of active cancer, any stage * Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Estimated prognosis of ≥ 3 months at the time of enrollment, determined by participant's primary oncologist or palliative physician * Diagnosis of moderate to severe pain (reported average pain score ≥ 4 on the 11-point Numerical Rating Scale) that is chronic (≥ 3 months) and secondary to cancer or cancer treatment * Pain regimen has been escalated to opioid therapy * Participants must be on stable pain regimen for at least one month prior, with no intention to adjust pain regimen during the study period * Participants must be ≥ 4 weeks beyond treatments/procedures that, in the opinion of the study physician, would significantly affect outcomes related to pain and physical function (e.g., surgery or radiation). Participants may otherwise receive cancer-directed treatment throughout the study period * Have no known procedures/treatments scheduled in advance that would prohibit patient from completing or significantly delaying completion of the study * The participant has no vacations or plans to be out of town during their study enrollment * Participants must not plan for additional treatments/procedures that, in the opinion of the study physician, would significantly affect outcomes related to pain and physical function (e.g., surgery or radiation) for ≥ 4 weeks following psilocybin treatment initiation. Participants may otherwise receive cancer-directed treatment throughout the study period * No use of other illicit substances (excluding cannabis) within the past year based on self-report at screening and routine urine toxicology screen * Participants must be able to read, write, and speak English * Participants must be able to swallow pills * Agree to refrain from using any unprescribed psychoactive drugs, including alcoholic beverages, ≤ 24 hours of before each psilocybin administration. Exceptions include: * Daily use of caffeine or nicotine * Prescribed benzodiazepine medications and non-benzodiazepine sleeping medications will be allowed to continue through the study period for participants who have been on a stable dose of such a medicine for ≥ 6 weeks prior to screening * Participants using cannabis, including legal cannabis, for any purpose must agree to refrain from use beginning at two weeks before dosing and one week following completion of dosing (7-8 weeks total, dependent on frequency of prior use) * Participants will not be withdrawn from the trial for a positive cannabis result during the initial screening drug test. However, participants who test positive for cannabis at the second drug test on visit 10 will be withdrawn from the trial * Participants must agree to be driven home after each experimental session and not drive or operate heavy machinery ≤ 16 hours of ingesting psilocybin * Participants must provide an emergency contact (relative, spouse, close friend, or other support person) willing and able to be reached by the investigators if the participant is unreachable by study staff or in an emergency * The participant agrees to take part in all study procedures, including the assessments, psychological evaluations, and dosing day requirements * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure Exclusion Criteria: * Participants who are pregnant or breast-feeding * Participants of childbearing potential who decline to use a highly effective dual contraceptive method for the duration of the study * Participants with a condition impairing oral intake or digestive absorption * Cognitive impairment as defined by Montreal Cognitive Assessment (MOCA) score \< 23 * Medical conditions or serious abnormalities of complete blood count, chemistries, or electrocardiography (ECG) that in the opinion of the study physician would preclude safe participation in the trial. Some examples include: congestive heart failure, valvular heart disease, recent acute myocardial infarction or evidence of ischemia, clinically significant arrhythmias (e.g., ventricular fibrillation, torsades) or clinically significant ECG abnormality (e.g. corrected QT interval using Fridericia's Correction Formula \[QTcF\] interval \> 450 in males and \> 470 in females), uncontrolled hypertension (systolic blood pressure \[BP\] ≥ 140 or diastolic BP ≥ 90 on three separate occasions), congenital long QT syndrome, renal dysfunction (i.e. creatinine clearance \[CrCl\] \< 40 mL/min), liver cirrhosis or hepatic dysfunction (indicated by gamma-glutamyltransferase \[GGT\], aspartate aminotransferase \[AST\], or alanine aminotransferase \[ALT\] \> 3 x ULN \[upper limit of norm\] or total bilirubin \[bili\] \> 3.0 mg/dl, or Child Pugh over class C), paraneoplastic syndrome, respiratory failure, dementia, delirium, known cerebral aneurysm, seizure disorder, stroke/transient ischemic attack (TIA) in past year, cancer with known central nervous system (CNS) involvement, previously treated brain metastasis, or other major CNS disease * Participants who have a personal history of, or a current diagnosis of the following: primary psychotic disorder, major depressive disorder with psychotic features, bipolar affective disorder type 1 or history of or current dissociative identity disorder * Participants who have an ongoing substance use disorder (defined as active in the past year) * Participants with first-degree relatives with schizophrenia or bipolar disorder may be eligible depending on their age and personal and family psychiatric history. The decision will be made by the principal investigator and study psychiatrist or on-call psychiatric provider based on risk assessment * Active suicidal behavior (interrupted or aborted attempt; preparatory acts) as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) connotating either passive or active suicidal intent; OR one of the following: * History of suicide attempt(s) within the past year (≤ 365 days) * Have any suicidal ideation or thoughts, in the opinion of the study physician or principal investigator (PI), that presents a serious risk of suicidal or self-injurious behavior * Any contraindications to undergoing an fMRI scan, including having metal implants or metal fragments in the body * Participants who have hypersensitivity to the ingredients of the IMP (Investigational Medicinal Product) listed below: * Indol alkaloids including psilocybin and psilocin * Constituents of Psilocybe cubensis including protein, fats, carbohydrates, ergosterols, beta-glucan, and polyphenols * Hydroxypropyl methylcellulose (HPMC) capsules * Participants who are taking medications with significant potential to interact with study medications will be exclusionary if they cannot be tapered. The taper interval will be at least five times the half-life. These medications include the following: * Selective serotonin reuptake inhibitors (SSRIs) * Serotonin and norepinephrine reuptake inhibitors (SNRIs) * Tricyclic antidepressants (TCAs) * Efavirenz * Serotonin-acting dietary supplements (i.e., 5-hydroxy-tryptophan or St. John's wort) * Centrally acting serotonergic agents (e.g., monoamine oxidase \[MAO\] inhibitors) * Antipsychotics for a psychiatric disorder (e.g., first and second generation) * Antipsychotics that are utilized for nausea, insomnia, or other non-psychiatric condition will be permitted, but patients will be asked to refrain from use 8 hours prior to dosing sessions * Mood stabilizers (e.g., lithium, valproic acid) * Aldehyde dehydrogenase inhibitors (e.g., disulfiram) * Significant inhibitors of UGT 1A9 or UGT 1A10 * Use of serotonergic hallucinogens (e.g., psilocybin, lysergic acid diethylamine \[LSD\]) within the past 12 months or significant lifetime use (\> 25 uses) * Those with a history of prior violent and/or drug-related felonies * Those currently incarcerated will be excluded * Unwilling or unable to follow protocol requirements * Any social circumstance which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug