Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) Therapy for Patients With Advanced Cancer: A Randomized Controlled Trial

Individuals with advanced cancer often experience high levels of distress due to physical suffering, difficult treatment decisions, social isolation, and fear of death. While there are many treatment options for the management of physical symptoms associated with cancer, there are relatively few standard treatment approaches to help patients deal with psychological and existential suffering. Over the past decade, research has shown that psychotherapies incorporating existential, attachment and relational approaches can address the specific needs and challenges of the advanced cancer population and thus help to reduce distress. Simultaneously, recent research has shown that psilocybin-assisted psychotherapy, in which, an individual ingests the psychoactive drug within the carefully monitored therapeutic setting, can reduce end-of-life distress and greatly benefit those with advanced disease. The multidisciplinary team has combined these two evidence-based approaches into what the team calls Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy. PEARL therapy combines elements from psilocybin-assisted psychotherapy, including preparatory therapy sessions, a high-dose drug session, and integration sessions, with important elements from manualized individual psychotherapies designed for patients with advanced cancer. This study will determine if PEARL therapy with 25mg of psilocybin is associated with greater improvement in depressive symptoms when compared to control 2 weeks after treatment completion. Participants will receive either a single high-dose (25 mg) or low-dose (1 mg) of psilocybin in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy. Upon completion of main study, participants who received low-dose will be offered to receive a single high-dose of psilocybin (25 mg) in the context of PEARL therapy (Open label expansion study). This type of therapy has the potential to improve quality of life among those with advanced disease and careful research is needed to build upon previous findings to outline the necessary components of therapy and guide public policy, legislation, and clinical guidelines.

Inclusion criteria

• >/= 18 years of age
• Ability to speak and read English fluently (participant to provide written informed consent and participate in PEARL intervention, as determined by study personnel)
• Resident of Ontario;
• No cognitive impairment indicated in medical record or by attending oncologist or palliative care physician;
• Confirmed diagnosis of stage IV solid tumour cancer, sarcoma, endocrine, melanoma cancers, or stage 4 lymphoma with expected survival of greater than 6 months as determined by their oncologist or palliative care physician
• At least mild depressive symptoms at the time of screening, defined as a score >/= 10 on the Montgomery-Asperg Depression Rating Scale (MADRS) Note: Participants may be asked to retake the MADRS if they initially score under 10.
• Interest in and ability to participate in and complete the PEARL intervention and protocol as outlined
• 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 from the time of informed consent until 28 days after psilocybin administration.
• 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 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 number of caffeine-containing beverages (e.g., coffee, tea) that they consume 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 someone drive them after the session to where they are staying (home, hotel or another location), since 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

Exclusion criteria

• Primary cancer of the brain, or metastasis to the brain associated with clinically-significant symptoms (e.g., affective, cognitive, personality-related, psychotic, or other symptoms, including seizures)
• Symptoms consistent with delirium, psychosis, or other symptoms judged to be incompatible with establishment of rapport or safe exposure to psilocybin;
• A history of past intolerability of psilocybin or other psychedelics;
• Past/present psychiatric diagnoses including bipolar I disorder, psychotic disorders, active substance use disorders, or suicidality (as distinguished from desire for hastened death or readiness for death, per the discretion of the study team);
• If participant is under 30 years of age, has first degree relative with a primary psychotic disorder
• Severe hypertension (defined as systolic blood pressure >150/or diastolic pressure >95), based on two readings on the same day (measured during the screening period); if the second reading remains over 150/95, 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;
• Moderate or severe hepatic impairment, as defined by Child-Pugh class B or C, or elevations in AST or ALT greater than 3 times the upper limit of normal;
• Severe renal impairment (defined as eGFR < 30)
• Known paraneoplastic syndrome or "ectopic" hormone production by the primary tumor if incompatible with psilocybin, as determined in consultation with the study palliative care physician; participants could be enrolled if it is determined that their condition is compatible with psilocybin administration.
• Cardiovascular conditions including uncontrolled hypertension, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation without rate control), transient ischemic attack in the last six months, stroke, peripheral or pulmonary vascular disease (no active claudication)
• Uncontrolled epilepsy or history of seizures in past 6 months
• If participant has diabetes, inability to skip a meal (lunch), or required administration of medication more than twice daily, or symptomatic hypoglycemia within 30 days prior to screening
• Gastrointestinal bleed in the 6 months prior to screening
• Use of other agents that would be inappropriate to take with psilocybin in the judgment of the investigator. These agents may include psychoactive prescription medications (e.g., benzodiazepines, lithium, SSRIs), medications having a primary pharmacological effect on serotonin-2a (5-HT2A) receptors (e.g., olanzapine), 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)
• Any other medication condition or lab abnormality judged to be incompatible with safe exposure to psilocybin.