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

NCT07820033 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: PEARL RCT
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Phase II randomized controlled trial, followed by an open-label extension phase. In the main study, 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 the low dose will be offered to receive a single high-dose of psilocybin (25 mg) in the context of PEARL therapy (Open label extension study).

Conditions

Stage IV Lymphoma; Stage IV Melanoma; Endocrine Cancer; Advanced Cancer; Stage IV Solid Tumor Cancer; Stage IV Sarcoma of Bone

Outcome Measures

Primary Outcomes (1)

• Change in mean severity of depressive symptoms as assessed by the Montgomery-Asperg Depression Rating Scale (MADRS) score from baseline to 2 weeks after completion of PEARL therapy, comparing the 25mg psilocybin group with the 1mg psilocybin group.

  The MADRS is a 10-item rater-administered scale measuring depressive symptoms. Total score range is 0 to 60, with higher scores indicating greater severity of depressive symptoms.

  At T2 (2 weeks after the last follow up)

Secondary Outcomes (10)

• Number of participants with treatment-related adverse events after PEARL as assessed by the Swiss Psychedelic Side Effects Inventory (SPSI).

  T3 (6 weeks after last follow up)

• Change in mean anxiety symptoms from baseline to T3 as assessed by the Generalized Anxiety Disorder (GAD-7) scale.

  T3 (6 weeks after last follow up)

• Change in death-related distress from baseline to T3 as assessed by the Death and Dying Distress Scale (DADDS).

  T3 (6 weeks after last follow up)

• Change in demoralization symptoms from baseline to T3 as assessed by the Demoralization Scale (DS).

  T3 (6 weeks after last follow up)

• Change in spiritual well-being from baseline to T3 as assessed by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp).

  T3 (6 weeks after last follow up)

Other Outcomes (8)

• Quality of Acute Drug Experience in response to PEARL as assessed with Mystical Experiences Questionnaire (MEQ30) and the Persisting Effects Questionnaire (PEQ).

  T1 (day after dosing visit)

• Assess the nature of the PEARL therapy experience and what factors are associated with positive or negative outcomes via qualitative study of participants

  T3 (6 weeks after last follow up)

• Integrity of masking of PEARL.

  T1 (day after dosing visit)

Study Arms (2)

high-dose group

EXPERIMENTAL

Single high-dose (25mg) capsule of psilocybin taken orally in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy.

Drug: Psilocybin (25mg); Other: PEARL Therapy

low-dose group

PLACEBO COMPARATOR

Single low-dose (1mg) capsule of psilocybin taken orally in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy.

Drug: Psilocybin (1mg); Other: PEARL Therapy

Interventions

Psilocybin (25mg) DRUG

Single high-dose (25mg) capsule of psilocybin taken orally in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy

high-dose group

Psilocybin (1mg) DRUG

Single low-dose (1mg) capsule of psilocybin taken orally in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy

low-dose group

PEARL Therapy OTHER

Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy

high-dose group; low-dose group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \>/= 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

University Health Network

Toronto, Ontario, Canada

Location

Related Publications (58)

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• Lo C, Hales S, Zimmermann C, Gagliese L, Rydall A, Rodin G. Measuring death-related anxiety in advanced cancer: preliminary psychometrics of the Death and Dying Distress Scale. J Pediatr Hematol Oncol. 2011 Oct;33 Suppl 2:S140-5. doi: 10.1097/MPH.0b013e318230e1fd.

  PMID: 21952572 BACKGROUND

Related Links

• Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) Therapy for Patients With Advanced Cancer (NCT06416085)

MeSH Terms

Conditions

Osteosarcoma; Lymphoma; Melanoma; Endocrine Gland Neoplasms

Interventions

Psilocybin

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Central Study Contacts

Sarah Hales, MD

CONTACT

416-340-4800; UHNPPRG@uhn.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single high-dose (25mg) capsule of psilocybin or low-dose comparator (1mg capsule of psilocybin- control arm) taken orally in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy.

Study Record Dates

• First Submitted: August 17, 2026
• First Posted: September 15, 2026
• Study Start: September 14, 2026
• Primary Completion (Estimated): December 30, 2028
• Study Completion (Estimated): July 30, 2029
• Last Updated: September 15, 2026

Record last verified: 2026-09

Locations

CA (1)