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

Not Applicable

Not yet recruiting

• Conditions: Caregiver Distress
• Interventions: Drug: Psilocybin

• Registration Number: NCT07048743
• Lead Sponsor: University Health Network, Toronto

Brief Summary

The PEARL-C1 trial is a phase II open-label trial. Participants will receive a single high-dose (25 mg) of psilocybin in the context of Psilocybin-assisted Existential, Attachment and RelationaL (PEARL) therapy.

Detailed Description

Caregivers of patients with advanced cancer often experience high levels of distress but there is currently little evidence-based guidance on how to help caregivers who experience depression, anxiety, anticipatory grief, spiritual suffering, caregiving burden and/or impaired quality of life. 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 related distress. Simultaneously, recent research has shown that psilocybin-assisted psychotherapy, in which an individual ingests the psychoactive drug within a carefully monitored therapy, can reduce end-of-life distress and greatly benefit those with advanced disease. The multidisciplinary team has combined these two evidence-based approaches into 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 and their families facing advanced cancer. This study will assess the feasibility, acceptability, and safety of PEARL therapy among caregivers of patients with advanced cancer. This study will contribute to the growing research around the efficacy of psychedelic-assisted therapies for the psychological distress associated with advanced disease and mortality. This type of therapy has the potential to improve quality of life among caregivers of those with advanced disease, to build upon previous findings to help outline the necessary components of therapy, and to inform public policy and clinical guidelines.

Study Timeline

• Study First Submitted: 2025-06-04
• Study First Submitted QC: 2025-06-24
• Status Verified: 2025-07
• Study Start: 2025-07-02
• Study First Posted: 2025-07-02
• Last Update Submitted: 2025-07-08
• Last Update Posted: 2025-07-11
• Primary Completion: 2027-12-02
• Study Completion: 2027-12-02

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 15

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PEARL Therapy	Psilocybin	-

Primary Outcome Measures

Name	Time	Method
Retention feasibility as assessed by the number of caregivers completing primary endpoint measures/number of caregivers consented.	30 months	Used to assess feasibility of PEARL therapy.
Adherence feasibility as assessed by the number of caregivers completing all PEARL sessions/number of caregivers consented.	30 months	Used to assess feasibility of PEARL therapy.
Recruitment feasibility as assessed by the number of caregivers who consent/number of caregivers who meet eligibility criteria.	30 months	Used to assess feasibility of PEARL therapy.
Acceptability of PEARL therapy from the perspective of the caregivers of patients with advanced cancer obtained through qualitative interviews.	30 months	Participants will be interviewed regarding their experiences with PEARL, including acceptability and perceived positive and negative effects of the intervention, with a semi-structured interview guide.
Safety of PEARL therapy.	30 months	Safety will be assessed throughout the trial. Adverse events (AEs) attributed to psilocybin will be monitored for and recorded after the psilocybin session. This study will use CTCAE v5.0 to assess AEs.; Serious adverse events (SAEs) will be tracked until study completion and will be defined as any adverse drug experience that: results in death; that is life-threatening (i.e. any AE that places the participant, in the view of the investigators, at immediate risk of death from the reaction as it occurs); requires hospital admission; results in persistent or significant disability (i.e. a substantial disruption of a person's ability to conduct normal life functions); or may jeopardize the participant or necessitate medical intervention to prevent one of the aforementioned criteria.

Secondary Outcome Measures

Name	Time	Method
Caregiver perspectives on the clinical relevance of potential PEARL therapy outcomes: Anxiety symptoms as assessed with the GAD-7.	30 months	The Generalized Anxiety Disorder-7 (GAD-7) is a 7-item self-report scale used to screen for and measure anxiety symptoms. Total score range is 0 to 21. Higher scores indicate higher levels of anxiety.
Caregiver perspectives on the clinical relevance of potential PEARL therapy outcomes: Depressive symptoms as assessed with the PHQ-9.	30 months	The Patient Health Questionnaire-9 (PHQ-9) is a 9-item self-report scale measuring depressive symptoms. Total score range is 0 to 27. Higher scores indicate greater severity of depression.
Caregiver perspectives on the clinical relevance of potential PEARL therapy outcomes: Subjective burden as assessed with the short version of the BSFC-s.	30 months	The short version of the Burden Scale for Family Caregivers (BSFC-s) is a 10-item self-report scale designed to measure the subjective burden of family caregivers. Total score range is 0 to 30. Higher scores indicate greater caregiver burden.
Caregiver perspectives on the clinical relevance of potential PEARL therapy outcomes: Broad quality of life construct for family members of patients with serious illness as assessed with the QUAL-E (Fam).	30 months	The Quality of Life at the End of Life Measure - Family experience (QUAL-E (Fam)) is a 17-item measure that includes subscales assessing symptom impact, relationship with health care provider, completion, and preparation. For symptom impact, score range is 4 to 20, with higher scores reflecting greater symptom control; for the relationship with healthcare provider, score range is 1 to 5, with lower scores reflecting a better relationship with healthcare providers; for completion, score range is 1 to 5, with lower scores reflecting a greater sense of completion in their relationship with the patient; and for preparation, score range is 4 to 20, with lower scores reflecting greater sense of preparation.
Caregiver perspectives on the clinical relevance of potential PEARL therapy outcomes: Overall measure of spiritual well-being, meaning/peace and faith as assessed with the FACIT-Sp.	30 months	The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp) is a 12-item scale designed to measure important aspects of spirituality including sense of meaning in one's life, harmony, peacefulness and a sense of comfort and strength from one's faith. Total score range is 0 to 48. Higher scores indicate higher spiritual well-being.
Patient perspectives on the clinical relevance of potential PEARL therapy outcomes: Anticipatory grief as assessed with the AGS.	30 months	The Anticipatory Grief Scale (AGS) is a 27-item self-report measure of grief before loss in family caregivers. Total score range is 27 to 135. Higher scores indicate higher levels of anticipatory grief.

Trial Locations

Locations (1)

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada