Psilocybin in Cancer Pain Study

Inclusion Criteria: * Participants must be 18 year old or older; * Participants must have advanced cancer, defined as a cancer that is unlikely to be cured or controlled with treatment; * Participants must have progressed on or be intolerant to approved therapies with a known clinical benefit (unless it is documented that they have refused such treatments); * Participants must evaluate their average pain on BPI Severity Scale ≥ 4/10 over the past week; * Participants must receive chronic opioid pharmacotherapy for pain with an Oral Morphine Equivalent (OME) ≥ 200mg/day; * Participants must have been seen by a palliative care clinician either at DFCI, MGH or associated satellites in the last three months; * Participants must have an ECOG Performance Status ≤ 2 * Participants must meet the following organ and marrow function on their last available bloodwork as defined below: * Platelets ≥ 50,000/mcL * AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN * Participants must be able to understand and willing to sign a written informed consent document * Participants must be able to swallow pills. * Participants must provide a contact (relative, spouse, close friend or other support person) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable. * Participants must agree to inform the investigators within 48 hours of any new medical conditions and procedures. * Participants must agree to the following lifestyle modifications (described in more detail in Section 3.4 Lifestyle Modifications): * Comply with requirements for diet, * Refrain from certain medications prior to Experimental Sessions, * Be driven home after each Experimental Session, * Commit to medication dosing, therapy, and study procedures. Exclusion Criteria: * Participants who receive concurrent (less than four weeks or planned within 6 weeks) cytotoxic chemotherapy or radiation therapy that may impair general level of physical functioning or affect study outcomes; * Participants with a condition impairing oral intake or digestive absorption; * Participants who are not able to give adequate informed consent; * Participants who have a significant suicide risk as defined by suicidal ideation with intent and with or without a plan as endorsed on items 4 and/or 5 on the C-SSRS within the past 6 months or at V0 * Participants who have a history of, or a current diagnostic of primary psychotic disorder, major depressive disorder with psychotic features, bipolar affective disorder type 1 or history of or current dissociative identity disorder; and 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 based on risk assessment. * Participants for whom there is a 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 * 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. 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 + one week for stabilization). See section 5.3 of the protocol for concomitant medications and tapering instructions. * Participants who have evidence or history of significant (controlled or uncontrolled) hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, renal, gastrointestinal, immunocompromising, or neurological disease, including seizure disorder, or any other medical disorder judged by the investigator to significantly increase the risk of psilocybin administration (participants with hypothyroidism who are on adequate and stable thyroid replacement will not be excluded). * Participants with brain tumors or brain metastases that haven't been successfully treated * Participants with lab abnormalities that may contribute to somnolence, confusion or delayed metabolism of psilocybin and/or with severe lab abnormalities (grade 3 or more per CTCAE scale). * Participants with a diagnosis of cirrhosis or liver failure * Participants who have uncontrolled hypertension using the standard criteria of the American Heart Association (values of 140/90 milligrams of Mercury \[mmHg\] or higher assessed on three separate occasions) * Participants who have a heart rate \> 100 bpm on three separate occasions * Participants who have a history of ventricular arrhythmia at any time, other than occasional premature ventricular contractions (PVCs) in the absence of ischemic heart disease. * Participants who have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation. * Participants who have a history of arrhythmia, other than premature atrial contractions (PACs) or occasional PVCs in the absence of ischemic heart disease, within 12 months of screening. Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular tachycardia or any other arrhythmia associated with a bypass tra