Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) Therapy for Caregivers of Patients With Advanced Cancer

Inclusion Criteria: * 18 years of age or older. * Participant must reside in Ontario, Canada. * Ability to speak and read English (participant to provide written informed consent and participate in PEARL intervention, as determined by study personnel). * No cognitive impairment indicated in medical record or by the primary care physician. * Primary or significant caregiver of a patient with advanced cancer enrolled in a companion trial of PEARL for patients with advanced cancer or caregiver of a patient receiving psilocybin-therapy through the Special Access Program (SAP) at University Health Network (UHN); such patients will have been recruited from psychosocial oncology or palliative care clinics at Princess Margaret (study physicians to assess appropriateness of inclusion and whether treatment will support the family system). * At least mild anxiety or depression symptoms, defined as a score of \>5 on the General Anxiety Disorder-7 (GAD-7) or \>8 on the Patient Health Questionnaire-9 (PHQ-9). * Interest in and ability to participate in and complete the PEARL intervention and protocol as outlined. * Normal hepatic functioning as determined by prior medical history or/and screening bloodwork (international normalized ratio \[INR\]\<1.5, aspartate aminotransferase \[AST\]/alanine transaminase \[ALT\] \< 2x upper limit of normal, normal range bilirubin, platelets ≥150). * Normal renal functioning as determined by prior medical history or/and screening bloodwork (estimated glomerular filtration rate \[eGFR\]\>45). * Participants who are sexually active and could become pregnant or inseminate a partner must be using one method of highly effective contraception (hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy or tubal ligation). Alternatively, they may use a combination of two or more effective methods of contraception which include male condom, female condom, cervical cap, diaphragm, or contraceptive sponge. These acceptable methods of contraception must be used prior to study entry, during study participation, and for the duration of the study. * For participants of child-bearing potential, a negative serum pregnancy test result is required at screening. A urine pregnancy test will be administered on the morning of psilocybin administration for applicable participants. Participants cannot be pregnant or nursing through the duration of the study. * If using prescribed medications or other substances, participants must agree to refrain from taking them if instructed by study investigators. These include: * not using any non-prescription medication, nutritional supplement, or herbal supplement except when approved by the treatment team (exceptions will be evaluated by the Sponsor-Investigator and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals). * not using nicotine for at least 2 hours before psilocybin administration, and not again until approximately 7 hours after psilocybin administration. * consuming approximately the same amount of caffeine-containing beverages (e.g., coffee, tea) that they consumes on a usual morning before arriving at the treatment centre for the psilocybin session day. * not taking any as needed medications on the mornings of psilocybin sessions (with the exception of daily and as needed opioid pain medication). * refraining from using any psychoactive drugs, including alcoholic beverages, within 24 hours of the psilocybin administration. * Participants must have a responsible individual to drive them after the dosing session to where they are staying (home, hotel or another location) and to accompany/attend to them because psilocybin may affect their alertness and concentration on the evening of the dosing session. * Participants must agree not to drive or operate machinery for at least 24 hours after dose administration. * The therapist involved in the participant's psilocybin dosing session and/or the principal investigators will provide their phone number, in advance of the session, to the participant, in case the participant needs to reach them for emergency support in the 24 hours following the psilocybin dosing session. Because the therapists will change from participant to participant, the study team cannot provide the same emergency phone number to every study participant. Exclusion Criteria: * A history of past intolerability to psilocybin or other psychedelics. * Past/present psychiatric diagnoses of bipolar disorder, any psychotic disorder, active substance use disorders, or dementia. a. Participants may have current mild alcohol or cannabis use disorder (meets 3 of 11 diagnostic criteria per The Diagnostic and Statistical Manual of Mental Illnesses \[DSM-5\]) or moderate alcohol or cannabis use disorder in early remission for the 3 months prior to enrollment (meets 5 of 11 diagnostic criteria per DSM-5). * Clinically significant suicidal ideation either currently or within the past 6 months, as judged by study clinicians. * Participant under the age of 30 years who has a first degree relative with a primary psychotic disorder. * Other personal circumstances or behaviour judged to be incompatible with establishment of rapport or safe exposure to psilocybin. * Severe hypertension (defined as systolic blood pressure \>140 or diastolic pressure \>90) based on two readings on the same day. If the second reading remains over 140/90 the participant can be brought in for another reading on a different day. Participants can be re-screened for participation once blood pressure is adequately controlled. * Hepatic dysfunction (history of cirrhosis and/or abnormal parameters \[INR\>1.5, elevated AST/ALT 2x upper limit, elevated bilirubin, platelets \< 150\]) or liver failure, defined as clinical diagnosis of liver fibrosis, cirrhosis of the liver, or advanced liver disease. * Cardiovascular conditions including uncontrolled hypertension, heart failure (defined as class IV of the New York Heart Association classification), angina, a clinically significant electrocardiogram \[ECG\] abnormality (e.g., atrial fibrillation without rate control, prolonged Corrected QT Interval (QTc) defined as \> 450ms for males or \> 470ms for females), transient ischemic attack in the last six months, stroke, peripheral or pulmonary vascular disease (no active claudication). * Uncontrolled epilepsy or history of seizures. * Diabetes with inability to skip a meal (lunch), requiring administration of medication more than twice daily, or symptomatic hypoglycemia within the prior 30 days. * GI bleed in last 6 months. * Use of other investigational agents that would be inappropriate to take with psilocybin in the judgement of the investigator, psychoactive prescription medications (e.g., benzodiazepines, lithium, SSRIs), medications having a pharmacological effect on serotonin-2a (5-HT2A) receptors (e.g., olanzapine, mirtazapine, or trazodone), medications that are monoamine oxidase (MAO) inhibitors, any potent metabolic inducers (e.g. rifamycin, rifampin, rifabutin, rifapentine, carbamazepine, phenytoin, phenobarbital, nevirapine, efavirenz, Taxol, dexamethasone, St John's wort) or inhibitors (e.g. HIV protease inhibitors, itraconazole, ketoconazole, erythromycin, clarithromycin, troleandomycin). Note: Inhibitors of UGT1A9 and 1A10 may increase systemic psilocin exposure (i.e., the Cmax and AUC) of psilocin and should be discontinued at least five half-lives prior to the administration of psilocybin. Similarly, aldehyde or alcohol dehydrogenase inhibitors should be discontinued at least 5 half-lives prior to the dose of psilocybin. In suitable participants, contraindicated medications may be tapered by a study physician between study enrolment and the psilocybin session when it is deemed safe to do so and in coordination with the prescribing physician. A safe and appropriate tapering regimen will then be developed based on the particular medication, on a case-by-case basis. If taking an MAO inhibitor, the psilocybin session will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose. Participants prescribed opioids will be allowed to take their usual dose regimen for analgesia, including the use of as needed analgesic medications on psilocybin session days.