Depression, AnxietyPhase 1/2NCT04754061
PSilocybin for psYCHological and Existential Distress in PALliative Care (PSYCHED-PAL)
A Phase 1/2 study testing Psilocybin in people with Depression, Anxiety and Distress, Emotional, run by Ottawa Hospital Research Institute at 2 sites in Canada.
Trial summary
The goal of this multi-centre phase I/II open-label, single-arm study is to determine the safety, feasibility, therapeutic dose, and preliminary efficacy of psilocybin microdosing to treat psychological distress among patients with advanced illness. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Depression, Anxiety, Distress, Emotional
- What is being tested?
- Psilocybin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 2 sitesCanada
- Study dates
- 8 Jan 2024to 1 Jan 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients >/=18 years of age
- Advanced illness under palliative care management, defined as having 1 to <12 months life expectancy (in the judgment of the palliative care provider)
- Experiencing psychological distress, defined as a score of 7 or greater on the Depression, Anxiety or Well-being item of the Edmonton Symptom Assessment System
- Ability to understand and communicate in English or French
Who cannot join
- Current or previously diagnosed, or first-degree relative, with psychotic or bipolar disorder
- Previously deemed eligible for MAiD with intention to proceed with MAiD regardless of study intervention effectiveness (this criteria is meant to exclude patients who would be unlikely to complete follow-up - those considering or being assessed for MAiD will still be eligible)
- Documented or suspected delirium in the past 3 months without a clearly defined reversible cause (e.g. opioid toxicity, infection) and resolution
- Documented moderate or severe dementia diagnosis
- Inability to provide first-person informed consent
- Severe or unstable physical symptoms based on the judgment of the palliative care provider
Show all 17Show fewer
- Palliative Performance Scale <30%
- Cancer with known central nervous system (CNS) involvement or other CNS disease
- Use of high-dose psychedelic substances in the past year
- Taking lithium at any dose
- Taking tramadol at any dose
- Taking any monoamine oxidase inhibitor at any dose [American Hospital Formulary Service (AFHS) group 28:16.04.12 or 28:36.32, including, but not limited to, moclobemide, tranylcypromine, phenelzine, selegiline, rasagiline]
- Taking any atypical antipsychotic (aripiprazole, asenapine, brexpiprazole, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone) (patients can be included if their atypical antipsychotic is either stopped, or if appropriate, substituted with haloperidol 48 hours prior to the start and for the duration of the intervention period and follow-up)
- Inability to ingest oral capsule
- Pregnancy or lactation
- For participants taking either an SSRI or an antipsychotic medication, there are several conditions for participation: (1) the PC provider must approve their participation in the study; (2) the SSRI/anti-psychotic medication dose cannot change for the duration of the intervention trial and follow-up, and; (3) the patient must not be taking more than the maximum allowable trial dose for each SSRI.
- All trial participants must agree to not take any other psychedelic substance for the duration of the clinical trial and follow-up, and to notify the investigative team of any medication changes during intervention or follow-up. Participants must also agree not to take their benzodiazepine or antipsychotic medication, if applicable, within 12 hours (6 hours pre and 6 hours post) of taking their psilocybin dose (participants will be given detailed instructions about this in their Instruction Leaflet). Participants must also agree not to drive or operate any heavy machinery on any treatment day for the duration of the 4-week intervention.
Trial locations and contacts
2 sites in 1 country.
Canada2 sites
The Ottawa Hospital
Ottawa, Ontario, K1H 8L6
Bruyere Continuing Care
Ottawa, Ontario, K1R 6K9
About this study
Official title: PSilocybin for psYCHological and Existential Distress in PALliative Care (PSYCHED-PAL): A Multi-site, Open-label, Single Arm Phase I/II Proof-of-concept, Dose-finding, and Feasibility Clinical Trial
The goal of this multi-centre phase I/II open-label, single-arm study is to determine the safety, feasibility, therapeutic dose, and preliminary efficacy of psilocybin microdosing to treat psychological distress among patients with advanced illness. Forty patients will receive psilocybin drug product (1-3mg per day, Mon-Fri) for 4 weeks to be administered via oral capsules by the participant. Feasibility (recruitment rate, rate of intervention and follow-up completion), safety (rate of adverse events), dosing, and preliminary efficacy (depression, anxiety, overall well-being, and global impression of change) will be measured.
Read the detailed description
Patients with advanced illness report feeling a sense of hopelessness, loss of autonomy and relationships, and a lack of purpose in life. These feelings of psychological suffering have been described as "existential distress" and are associated with poor outcomes, including decreased medication adherence and quality of life, increased desire for hastened death and rates of suicide, and has been identified as a primary reason why individuals pursue medical assistance in dying (MAiD).
Current treatments for psychological and existential suffering have low efficacy and are challenging to use in a palliative context. Pharmacological approaches for treating psychological suffering may reduce symptoms of depression and anxiety, but evidence to support their efficacy in palliative care (PC) is underwhelming. Antidepressant and anxiolytic medications also take time to work and can cause serious side effects such as falls and confusion, which can be substantial deterrents for patients. Similarly, results from randomized controlled trials (RCTs) and meta-analyses have demonstrated psychotherapeutic interventions show limited benefit in a PC population. Further, psychotherapy can be time consuming and slow to work, which is not ideal for patients with limited life expectancy. Given the burden of psychological and existential distress among patients followed by PC providers, there is a need to develop scalable, brief, and rapidly effective therapeutic approaches to reduce this distress.
Psychedelic medications offer an innovative, safe, complementary approach to address psychological and existential suffering in patients receiving PC. Studies from the 1950's showed serotonergic hallucinogens ("psychedelics") improved depression and anxiety symptoms in cancer patients. However, legislative changes restricted the use of these medications in clinical care and research. Interest in psychedelic medications has been rekindled by two recently published RCTs that studied the use of psilocybin (a mushroom-derived 5HT2A agonist) during a single psychotherapeutic session in cancer patients with anxiety and/or depression. These trials demonstrated rapid, clinically meaningful, and long-lasting reductions in depressed mood and/or anxiety symptoms and improvements in quality of life and death acceptance. There is also evidence suggesting psilocybin microdosing - taking sub-hallucinogenic doses continuously over longer time periods, rather than a one-time hallucinogenic dose - can improve mood and anxiety. The effects of microdosing, however, have not been rigorously evaluated, particularly in patients with life limiting illness.
Results from recent trials are encouraging but knowledge gaps remain. First, studies to date primarily enrolled patients with localized disease who experience different distress than that of patients with advanced disease who are near the end of life. Second, it is unclear if Canadians would find psilocybin an attractive option in the context of MAiD legalization, which provides an alternative option for patients with severe psychological suffering. Third, there is no empirical research on the therapeutic effects of psilocybin microdosing, as most studies have followed macrodosing protocols. While preliminary efficacy of macrodosing has been demonstrated, there are important barriers to administering this therapy in a PC context. Previous trials had slow recruitment rates, suggesting there may be barriers related to the acceptability of psilocybin macrodosing from the perspectives of patients and families. Macrodosing requires the patient to dedicate an entire day to participating in a guided hallucinogenic experience and remain in an acute care setting where they can be closely monitored. It also requires patients to engage in preparatory sessions with monitors and a post-therapy session. In a PC context, this time commitment may not be acceptable or feasible for patients who are nearing the end of life. Additionally, macrodosing requires at least two trained moderators to guide the patient through their psychedelic experience and facilitate the pre- and post-dosing sessions. In most PC settings, it is not feasible to have clinicians dedicate two days to a single patient, thus limiting the scalability of this intervention.
Psilocybin microdosing has the potential to overcome barriers to the feasibility and acceptability of macrodosing. By removing the requirement for trained moderators, minimizing the time commitment required of patients, eliminating the hallucinogenic effects of the therapy, and allowing patients to receive treatment either as an inpatient or in the community, microdosing may be a more acceptable option to patients and families and allow psychedelic therapy to be scalable across various PC settings. Psilocybin microdosing is a novel, complementary therapy that, while still unproven for patients near the end of life, has the potential to fundamentally change the way psychological and existential distress is responded to in PC, improving the lives of the 30% of patients who experience this suffering at the end of life.
Objective
To determine if psilocybin microdosing is a safe and feasible treatment for psychological distress among patients nearing the end of life followed by palliative care providers. All participants will receive a 4-week psilocybin microdosing intervention. The secondary objective is to examine the preliminary efficacy of psilocybin microdosing.
Sample Size
As this is a feasibility study, no formal sample size calculation was performed to determine the number of patients required to reach a level of precision on any study endpoint. Rather, the goal of this study is to provide estimates, along with their margins of error, of the recruitment rate and efficacy outcomes which will inform a subsequent two-arm randomized controlled trial. Participating sites see approximately 5,300 patients per year. It is anticipated that 30% will have psychological distress. Assuming a minimum of 1 in 6 patients are eligible and 15% of eligible patients will enroll, the goal is to enroll a sample of 20 participants in up to 1-year period.
Statistical Analysis
Analyses will adopt an intent-to-treat approach. Because the goal of this trial is to demonstrate feasibility and preliminary measures of efficacy, the main analyses will include calculation of feasibility outcomes using descriptive statistics and 95% confidence intervals (CIs), as well as effect sizes with 95% CIs for primary and secondary efficacy measures, comparing patients' 4-week follow-up assessments to baseline assessments. Participants will also be stratified based on demographic and clinical characteristics to assess trends in outcomes. Notably, there is some evidence that selective serotonin reuptake inhibitors (SSRIs) in particular may attenuate the effects of psilocybin. As such, sub-analyses will evaluate outcomes in participants taking an SSRI medication versus those who are not. A sub-group analysis by setting of care (inpatient vs outpatient/community) will also be conducted.
Analyses of safety data will include the mean and standard deviation of the peak effect observed (i.e. highest observed blood pressure, heart rate) and proportion of participants experiencing adverse mood and behaviour events. The incidence of delirium and serotonin syndrome will also be recorded.
Details of Eligibility, Intervention Protocol, and Outcome Measures are provided elsewhere.
- Conditions
- Depression, Anxiety, Distress, Emotional
- Being tested
- Psilocybin
- Keywords
- existential distress, psychological distress, psilocybin, microdosing
- Medical subject headings
- Depression, Anxiety Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PsilocybinDrug
Phase 1 (week 1): all enrolled participants will take a single 1mg oral dose of psilocybin once per day on Monday and Thursday. If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 2 for week 2.
Phase 2: The participant will take a single 1mg oral dose of psilocybin once per day for 5 consecutive days (Monday to Friday). If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 3 for week 3.
Phase 3: The participant will take two 1mg oral doses (2mg total) of psilocybin once per day for 5 consecutive days (Monday to Friday). If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 4 for week 4.
Phase 4 (maximum allowable dose): The participant will take three 1mg oral doses (3mg total) of psilocybin once per day for 5 consecutive days (Monday to Friday).
| Study group | Role | What they receive |
|---|---|---|
| Psilocybin Microdosing | Experimental | Participants will receive a 4-week psilocybin microdosing intervention (1-3mg/day, Monday-Friday for up to 4 weeks; start at 1mg with opportunity to increase dose each week) Receives: Drug: Psilocybin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recruitment Rate
Number of patients enrolled divided by number of patients approached
Measured: Through study completion, up to 1 year
Intervention Completion Rate
Number of participants who complete the intervention divided by number of participants enrolled
Measured: Through study completion, up to 13 months
Follow-up Completion Rate
Number of participants who complete follow-up divided by number of participants enrolled
Measured: Through study completion, up to 18 months
Number of Participants With Adverse Events - Change in Blood Pressure
Proportion of participants with systolic blood pressure of >180mmHg or an increase in 40% from baseline measurements
Measured: Measured at baseline and daily (Mon-Fri) from enrolment to intervention completion (up to 4 weeks)
Number of Participants With Adverse Events - Change in Heart Rate
Proportion of participants with resting heart rate >100bpm or an increase in 40% from baseline
Measured: Measured at baseline and daily (Mon-Fri) from enrolment to intervention completion (up to 4 weeks)
Number of Participants With Adverse Events - Delirium
Proportion of participants who develop delirium, measured by the Confusion Assessment Method or the Family Confusion Assessment Method
Measured: Through intervention completion, up to 4 weeks
Number of Participants With Adverse Events - Serotonin Syndrome
Proportion of participants who develop serotonin syndrome, diagnosed by Study Doctor
Measured: Through intervention completion, up to 4 weeks
Number of Participants With Adverse Events - Adverse Mood or Behaviour Change
Proportion of participants who report adverse mood or behaviour changes (recorded daily in a participant diary)
Measured: Measured at baseline and from enrolment to intervention completion (up to 4 weeks); 2-week and 4-week follow-up
Psychological Distress - Anxiety and Depression
Measured using the Hospital Anxiety and Depression Scale (higher score indicate worse anxiety/depression)
Measured: Baseline
Change in Psychological Distress - Anxiety and Depression
Measured using the Hospital Anxiety and Depression Scale (higher score indicate worse anxiety/depression)
Measured: Weekly (every Friday) during intervention (4 weeks)
Change in Psychological Distress - Anxiety and Depression
Measured using the Hospital Anxiety and Depression Scale (higher score indicate worse anxiety/depression)
Measured: Follow-up (1 day, 2 weeks, 4 weeks, 12 weeks, 24 weeks)
Psychological Distress - Anxiety, Depression, and Well-being
Measured using the Edmonton Symptom Assessment System anxiety, depression, and well-being item scores (score 0-10 for each item - higher scores indicate worse symptoms)
Measured: Baseline
Change in Psychological Distress - Anxiety, Depression, and Well-being
Measured using the Edmonton Symptom Assessment System anxiety, depression, and well-being item scores (score 0-10 for each item - higher scores indicate worse symptoms)
Measured: Weekly (every Friday) during intervention (4 weeks)
Change in Psychological Distress - Anxiety, Depression, and Well-being
Measured using the Edmonton Symptom Assessment System anxiety, depression, and well-being item scores (score 0-10 for each item - higher scores indicate worse symptoms)
Measured: Follow-up (1 day, 2 weeks, 4 weeks, 12 weeks, 24 weeks)
Psychological Distress - Global Impression of Change
Measured using the Patient Global Impression of Change scale (higher scores indicate greater positive change)
Measured: Weekly (every Friday) during intervention (4 weeks); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Dosing
Dose at which therapeutic benefit, if any, is achieved assessed by change in Hospital Anxiety and Depression Scale score (score reduction of 50% indicates therapeutic benefit)
Measured: Weekly (each Friday) for intervention period (4 weeks)
Dosing
Dose at which therapeutic benefit, if any, is achieved assessed by Edmonton Symptom Assessment Scale score (two-point score reduction or absolute score less than 3 indicate therapeutic benefit)
Measured: Weekly (each Friday) for intervention period (4 weeks)
Dosing
Dose at which therapeutic benefit, if any, is achieved assessed by Global Impression fo Change score (score of 5 or above indicate therapeutic benefit)
Measured: Weekly (each Friday) for intervention period (4 weeks)
Secondary outcomes (5)
Existential Distress
Measured using the Demoralization scale II (DS-II), a 16-item questionnaire that measures loss of meaning and purpose, distress, and coping abilities. Each item is rated as a 0 (Never), 1 (Sometimes), or 2 (Often). The 16 items are then summed to create a total score. The highest total score that can be obtained is 32. Higher total scores indicate higher levels of demoralization.
Measured: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Psychological distress
Measured by the Hamilton Depression Rating Scale (HDRS), a 17-item questionnaire. We will consider a 50% reduction in score from baseline as achieving clinically meaningful improvement. Each item varies in the maximum value it can be rated at (an item can be rated from 0-2, 0-3, or 0-4). The highest total score that can be obtained is 53. All scores from the 17-items are summed for a total score. Higher total scores indicate increased severity of depression.
Measured: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Participant Quality of Life
Measured using the World Health Organization Quality of Life, Brief Version (higher scores indicate higher quality of life)
Measured: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Wish to Die
Measured using the Categories of Attitudes Towards Death Occurrence (scored 1-6 with scores 4-6 indicating a wish to die)
Measured: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Global Distress
Measured using the Distress Thermometer
Measured: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2021
- Study start8 Jan 2024
- Primary completion1 Oct 2026 (estimated)
- Study completion1 Jan 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for Depression, AnxietyStudies of the same condition, open and under way.
- More trials run by Ottawa Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The study is a multi-site, open-label, single-arm phase 1/2 proof-of-concept dose-finding, feasibility and preliminary efficacy clinical trial.
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ottawa Hospital Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Bruyère Health Research Institute., The Ottawa Hospital, St. Joseph's Healthcare Hamilton, CHU de Quebec-Universite Laval, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Jewish General Hospital, William Osler Health System, Kingston Health Sciences Centre
- Responsible party
- Principal investigator, James Downar, University of Ottawa
- Investigators
- James Downar, MDCM, MSc, Principal investigator, Ottawa Hospital Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04754061
- Sponsor's protocol ID
- 7745629246
- Status last verified
- Jul 2026
- First submitted
- 11 Nov 2020
- Last updated
- 10 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Steis MR, Evans L, Hirschman KB, Hanlon A, Fick DM, Flanagan N, Inouye SK. Screening for delirium using family caregivers: convergent validity of the Family Confusion Assessment Method and interviewer-rated Confusion Assessment Method. J Am Geriatr Soc. 2012 Nov;60(11):2121-6. doi: 10.1111/j.1532-5415.2012.04200.x. Epub 2012 Oct 5.
PubMed 23039310Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x.
PubMed 6880820Mitchell AJ, Meader N, Symonds P. Diagnostic validity of the Hospital Anxiety and Depression Scale (HADS) in cancer and palliative settings: a meta-analysis. J Affect Disord. 2010 Nov;126(3):335-48. doi: 10.1016/j.jad.2010.01.067. Epub 2010 Mar 5.
PubMed 20207007Kamper SJ, Maher CG, Mackay G. Global rating of change scales: a review of strengths and weaknesses and considerations for design. J Man Manip Ther. 2009;17(3):163-70. doi: 10.1179/jmt.2009.17.3.163.
PubMed 20046623Watanabe SM, Nekolaichuk C, Beaumont C, Johnson L, Myers J, Strasser F. A multicenter study comparing two numerical versions of the Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom Manage. 2011 Feb;41(2):456-68. doi: 10.1016/j.jpainsymman.2010.04.020. Epub 2010 Sep 15.
PubMed 20832987Galiana L, Rudilla D, Oliver A, Barreto P. The Short Demoralization Scale (SDS): A new tool to appraise demoralization in palliative care patients. Palliat Support Care. 2017 Oct;15(5):516-523. doi: 10.1017/S1478951516000973. Epub 2017 Jan 9.
PubMed 28065203Templer DI. The construction and validation of a Death Anxiety Scale. J Gen Psychol. 1970 Apr;82(2d Half):165-77. doi: 10.1080/00221309.1970.9920634. No abstract available.
PubMed 4394812Skevington SM, Lotfy M, O'Connell KA; WHOQOL Group. The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res. 2004 Mar;13(2):299-310. doi: 10.1023/B:QURE.0000018486.91360.00.
PubMed 15085902World Health Organization Division of Mental Health. WHOQOL-BREF : introduction, administration, scoring and generic version of the assessment : field trial version, December 1996. Geneva: World Health Organization; 1996
Durst AV, Spencer B, Bula C, Fustinoni S, Mazzocato C, Rochat E, Rubli Truchard E, Monod S, Jox RJ. Wish to Die in Older Patients: Development and Validation of Two Assessment Instruments. J Am Geriatr Soc. 2020 Jun;68(6):1202-1209. doi: 10.1111/jgs.16392. Epub 2020 Feb 29.
PubMed 32112569National Comprehensive Cancer Network. NCCN Distress Thermometer and Problem List for Patients. Version 2, dated March 11th, 2020. https://www.nccn.org/about/permissions/thermometer.aspx
Anderson F, Downing GM, Hill J, Casorso L, Lerch N. Palliative performance scale (PPS): a new tool. J Palliat Care. 1996 Spring;12(1):5-11.
PubMed 8857241Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990 Dec 15;113(12):941-8. doi: 10.7326/0003-4819-113-12-941.
PubMed 2240918Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.
PubMed 27909165Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016 Dec;30(12):1165-1180. doi: 10.1177/0269881116675512.
PubMed 27909164
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PSilocybin for psYCHological and Existential Distress in PALliative Care (PSYCHED-PAL): A Multi-site, Open-label, Single Arm Phase I/II Proof-of-concept, Dose-finding, and Feasibility Clinical Trial
- ClinicalTrials.gov ID
- NCT04754061
- Acronym / sponsor ID
- 7745629246
- Conditions
- Depression, Anxiety, Distress, Emotional
- Keywords
- existential distress, psychological distress, psilocybin, microdosing
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Ottawa Hospital Research InstituteUniversity, hospital or other
- Collaborators
- Bruyère Health Research Institute., The Ottawa Hospital, St. Joseph's Healthcare Hamilton, CHU de Quebec-Universite Laval, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Jewish General Hospital, William Osler Health System, Kingston Health Sciences Centre
- Study start
- 8 Jan 2024 (actual)
- Primary completion
- 1 Oct 2026 (estimated)
- Study completion
- 1 Jan 2027 (estimated)
- First posted
- 15 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this multi-centre phase I/II open-label, single-arm study is to determine the safety, feasibility, therapeutic dose, and preliminary efficacy of psilocybin microdosing to treat psychological distress among patients with advanced illness. Forty patients will receive psilocybin drug product (1-3mg per day, Mon-Fri) for 4 weeks to be administered via oral capsules by the participant. Feasibility (recruitment rate, rate of intervention and follow-up completion), safety (rate of adverse events), dosing, and preliminary efficacy (depression, anxiety, overall well-being, and global impression of change) will be measured.
Detailed description
Patients with advanced illness report feeling a sense of hopelessness, loss of autonomy and relationships, and a lack of purpose in life. These feelings of psychological suffering have been described as "existential distress" and are associated with poor outcomes, including decreased medication adherence and quality of life, increased desire for hastened death and rates of suicide, and has been identified as a primary reason why individuals pursue medical assistance in dying (MAiD).
Current treatments for psychological and existential suffering have low efficacy and are challenging to use in a palliative context. Pharmacological approaches for treating psychological suffering may reduce symptoms of depression and anxiety, but evidence to support their efficacy in palliative care (PC) is underwhelming. Antidepressant and anxiolytic medications also take time to work and can cause serious side effects such as falls and confusion, which can be substantial deterrents for patients. Similarly, results from randomized controlled trials (RCTs) and meta-analyses have demonstrated psychotherapeutic interventions show limited benefit in a PC population. Further, psychotherapy can be time consuming and slow to work, which is not ideal for patients with limited life expectancy. Given the burden of psychological and existential distress among patients followed by PC providers, there is a need to develop scalable, brief, and rapidly effective therapeutic approaches to reduce this distress.
Psychedelic medications offer an innovative, safe, complementary approach to address psychological and existential suffering in patients receiving PC. Studies from the 1950's showed serotonergic hallucinogens ("psychedelics") improved depression and anxiety symptoms in cancer patients. However, legislative changes restricted the use of these medications in clinical care and research. Interest in psychedelic medications has been rekindled by two recently published RCTs that studied the use of psilocybin (a mushroom-derived 5HT2A agonist) during a single psychotherapeutic session in cancer patients with anxiety and/or depression. These trials demonstrated rapid, clinically meaningful, and long-lasting reductions in depressed mood and/or anxiety symptoms and improvements in quality of life and death acceptance. There is also evidence suggesting psilocybin microdosing - taking sub-hallucinogenic doses continuously over longer time periods, rather than a one-time hallucinogenic dose - can improve mood and anxiety. The effects of microdosing, however, have not been rigorously evaluated, particularly in patients with life limiting illness.
Results from recent trials are encouraging but knowledge gaps remain. First, studies to date primarily enrolled patients with localized disease who experience different distress than that of patients with advanced disease who are near the end of life. Second, it is unclear if Canadians would find psilocybin an attractive option in the context of MAiD legalization, which provides an alternative option for patients with severe psychological suffering. Third, there is no empirical research on the therapeutic effects of psilocybin microdosing, as most studies have followed macrodosing protocols. While preliminary efficacy of macrodosing has been demonstrated, there are important barriers to administering this therapy in a PC context. Previous trials had slow recruitment rates, suggesting there may be barriers related to the acceptability of psilocybin macrodosing from the perspectives of patients and families. Macrodosing requires the patient to dedicate an entire day to participating in a guided hallucinogenic experience and remain in an acute care setting where they can be closely monitored. It also requires patients to engage in preparatory sessions with monitors and a post-therapy session. In a PC context, this time commitment may not be acceptable or feasible for patients who are nearing the end of life. Additionally, macrodosing requires at least two trained moderators to guide the patient through their psychedelic experience and facilitate the pre- and post-dosing sessions. In most PC settings, it is not feasible to have clinicians dedicate two days to a single patient, thus limiting the scalability of this intervention.
Psilocybin microdosing has the potential to overcome barriers to the feasibility and acceptability of macrodosing. By removing the requirement for trained moderators, minimizing the time commitment required of patients, eliminating the hallucinogenic effects of the therapy, and allowing patients to receive treatment either as an inpatient or in the community, microdosing may be a more acceptable option to patients and families and allow psychedelic therapy to be scalable across various PC settings. Psilocybin microdosing is a novel, complementary therapy that, while still unproven for patients near the end of life, has the potential to fundamentally change the way psychological and existential distress is responded to in PC, improving the lives of the 30% of patients who experience this suffering at the end of life.
Objective
To determine if psilocybin microdosing is a safe and feasible treatment for psychological distress among patients nearing the end of life followed by palliative care providers. All participants will receive a 4-week psilocybin microdosing intervention. The secondary objective is to examine the preliminary efficacy of psilocybin microdosing.
Sample Size
As this is a feasibility study, no formal sample size calculation was performed to determine the number of patients required to reach a level of precision on any study endpoint. Rather, the goal of this study is to provide estimates, along with their margins of error, of the recruitment rate and efficacy outcomes which will inform a subsequent two-arm randomized controlled trial. Participating sites see approximately 5,300 patients per year. It is anticipated that 30% will have psychological distress. Assuming a minimum of 1 in 6 patients are eligible and 15% of eligible patients will enroll, the goal is to enroll a sample of 20 participants in up to 1-year period.
Statistical Analysis
Analyses will adopt an intent-to-treat approach. Because the goal of this trial is to demonstrate feasibility and preliminary measures of efficacy, the main analyses will include calculation of feasibility outcomes using descriptive statistics and 95% confidence intervals (CIs), as well as effect sizes with 95% CIs for primary and secondary efficacy measures, comparing patients' 4-week follow-up assessments to baseline assessments. Participants will also be stratified based on demographic and clinical characteristics to assess trends in outcomes. Notably, there is some evidence that selective serotonin reuptake inhibitors (SSRIs) in particular may attenuate the effects of psilocybin. As such, sub-analyses will evaluate outcomes in participants taking an SSRI medication versus those who are not. A sub-group analysis by setting of care (inpatient vs outpatient/community) will also be conducted.
Analyses of safety data will include the mean and standard deviation of the peak effect observed (i.e. highest observed blood pressure, heart rate) and proportion of participants experiencing adverse mood and behaviour events. The incidence of delirium and serotonin syndrome will also be recorded.
Details of Eligibility, Intervention Protocol, and Outcome Measures are provided elsewhere.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The study is a multi-site, open-label, single-arm phase 1/2 proof-of-concept dose-finding, feasibility and preliminary efficacy clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Psilocybin Microdosing | Experimental | Drug: PsilocybinParticipants will receive a 4-week psilocybin microdosing intervention (1-3mg/day, Monday-Friday for up to 4 weeks; start at 1mg with opportunity to increase dose each week) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Patients >/=18 years of age
- Advanced illness under palliative care management, defined as having 1 to <12 months life expectancy (in the judgment of the palliative care provider)
- Experiencing psychological distress, defined as a score of 7 or greater on the Depression, Anxiety or Well-being item of the Edmonton Symptom Assessment System
- Ability to understand and communicate in English or French
Key exclusion criteria (17 listed)
- Current or previously diagnosed, or first-degree relative, with psychotic or bipolar disorder
- Previously deemed eligible for MAiD with intention to proceed with MAiD regardless of study intervention effectiveness (this criteria is meant to exclude patients who would be unlikely to complete follow-up - those considering or being assessed for MAiD will still be eligible)
- Documented or suspected delirium in the past 3 months without a clearly defined reversible cause (e.g. opioid toxicity, infection) and resolution
- Documented moderate or severe dementia diagnosis
- Inability to provide first-person informed consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PsilocybinPhase 1 (week 1): all enrolled participants will take a single 1mg oral dose of psilocybin once per day on Monday and Thursday. If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 2 for week 2. Phase 2: The participant will take a single 1mg oral dose of psilocybin once per day for 5 consecutive days (Monday to Friday). If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 3 for week 3. Phase 3: The participant will take two 1mg oral doses (2mg total) of psilocybin once per day for 5 consecutive days (Monday to Friday). If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 4 for week 4. Phase 4 (maximum allowable dose): The participant will take three 1mg oral doses (3mg total) of psilocybin once per day for 5 consecutive days (Monday to Friday). | Drug | Psilocybin Microdosing |
Primary outcome
Recruitment Rate
Time frame: Through study completion, up to 1 year
Number of patients enrolled divided by number of patients approached
Intervention Completion Rate
Time frame: Through study completion, up to 13 months
Number of participants who complete the intervention divided by number of participants enrolled
Follow-up Completion Rate
Time frame: Through study completion, up to 18 months
Number of participants who complete follow-up divided by number of participants enrolled
Number of Participants With Adverse Events - Change in Blood Pressure
Time frame: Measured at baseline and daily (Mon-Fri) from enrolment to intervention completion (up to 4 weeks)
Proportion of participants with systolic blood pressure of >180mmHg or an increase in 40% from baseline measurements
Number of Participants With Adverse Events - Change in Heart Rate
Time frame: Measured at baseline and daily (Mon-Fri) from enrolment to intervention completion (up to 4 weeks)
Proportion of participants with resting heart rate >100bpm or an increase in 40% from baseline
Number of Participants With Adverse Events - Delirium
Time frame: Through intervention completion, up to 4 weeks
Proportion of participants who develop delirium, measured by the Confusion Assessment Method or the Family Confusion Assessment Method
Number of Participants With Adverse Events - Serotonin Syndrome
Time frame: Through intervention completion, up to 4 weeks
Proportion of participants who develop serotonin syndrome, diagnosed by Study Doctor
Number of Participants With Adverse Events - Adverse Mood or Behaviour Change
Time frame: Measured at baseline and from enrolment to intervention completion (up to 4 weeks); 2-week and 4-week follow-up
Proportion of participants who report adverse mood or behaviour changes (recorded daily in a participant diary)
Psychological Distress - Anxiety and Depression
Time frame: Baseline
Measured using the Hospital Anxiety and Depression Scale (higher score indicate worse anxiety/depression)
Change in Psychological Distress - Anxiety and Depression
Time frame: Weekly (every Friday) during intervention (4 weeks)
Measured using the Hospital Anxiety and Depression Scale (higher score indicate worse anxiety/depression)
Change in Psychological Distress - Anxiety and Depression
Time frame: Follow-up (1 day, 2 weeks, 4 weeks, 12 weeks, 24 weeks)
Measured using the Hospital Anxiety and Depression Scale (higher score indicate worse anxiety/depression)
Psychological Distress - Anxiety, Depression, and Well-being
Time frame: Baseline
Measured using the Edmonton Symptom Assessment System anxiety, depression, and well-being item scores (score 0-10 for each item - higher scores indicate worse symptoms)
Change in Psychological Distress - Anxiety, Depression, and Well-being
Time frame: Weekly (every Friday) during intervention (4 weeks)
Measured using the Edmonton Symptom Assessment System anxiety, depression, and well-being item scores (score 0-10 for each item - higher scores indicate worse symptoms)
Change in Psychological Distress - Anxiety, Depression, and Well-being
Time frame: Follow-up (1 day, 2 weeks, 4 weeks, 12 weeks, 24 weeks)
Measured using the Edmonton Symptom Assessment System anxiety, depression, and well-being item scores (score 0-10 for each item - higher scores indicate worse symptoms)
Psychological Distress - Global Impression of Change
Time frame: Weekly (every Friday) during intervention (4 weeks); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Measured using the Patient Global Impression of Change scale (higher scores indicate greater positive change)
Dosing
Time frame: Weekly (each Friday) for intervention period (4 weeks)
Dose at which therapeutic benefit, if any, is achieved assessed by change in Hospital Anxiety and Depression Scale score (score reduction of 50% indicates therapeutic benefit)
Dosing
Time frame: Weekly (each Friday) for intervention period (4 weeks)
Dose at which therapeutic benefit, if any, is achieved assessed by Edmonton Symptom Assessment Scale score (two-point score reduction or absolute score less than 3 indicate therapeutic benefit)
Dosing
Time frame: Weekly (each Friday) for intervention period (4 weeks)
Dose at which therapeutic benefit, if any, is achieved assessed by Global Impression fo Change score (score of 5 or above indicate therapeutic benefit)
5 secondary outcomes
Existential Distress
Time frame: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Psychological distress
Time frame: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Participant Quality of Life
Time frame: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Wish to Die
Time frame: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Global Distress
Time frame: Baseline (Friday prior to first dose administered on a Monday); 1 day, 2 week, 4 week, 12 week, 24 week follow-up
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2026.
- Background: PubMed 23039310Steis MR, Evans L, Hirschman KB, Hanlon A, Fick DM, Flanagan N, Inouye SK. Screening for delirium using family caregivers: convergent validity of the Family Confusion Assessment Method and interviewer-rated Confusion Assessment Method. J Am Geriatr Soc. 2012 Nov;60(11):2121-6. doi: 10.1111/j.1532-5415.2012.04200.x. Epub 2012 Oct 5.
- Background: PubMed 6880820Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x.
- Background: PubMed 20207007Mitchell AJ, Meader N, Symonds P. Diagnostic validity of the Hospital Anxiety and Depression Scale (HADS) in cancer and palliative settings: a meta-analysis. J Affect Disord. 2010 Nov;126(3):335-48. doi: 10.1016/j.jad.2010.01.067. Epub 2010 Mar 5.
- Background: PubMed 20046623Kamper SJ, Maher CG, Mackay G. Global rating of change scales: a review of strengths and weaknesses and considerations for design. J Man Manip Ther. 2009;17(3):163-70. doi: 10.1179/jmt.2009.17.3.163.
- Background: PubMed 20832987Watanabe SM, Nekolaichuk C, Beaumont C, Johnson L, Myers J, Strasser F. A multicenter study comparing two numerical versions of the Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom Manage. 2011 Feb;41(2):456-68. doi: 10.1016/j.jpainsymman.2010.04.020. Epub 2010 Sep 15.
- Background: PubMed 28065203Galiana L, Rudilla D, Oliver A, Barreto P. The Short Demoralization Scale (SDS): A new tool to appraise demoralization in palliative care patients. Palliat Support Care. 2017 Oct;15(5):516-523. doi: 10.1017/S1478951516000973. Epub 2017 Jan 9.
- Background: PubMed 4394812Templer DI. The construction and validation of a Death Anxiety Scale. J Gen Psychol. 1970 Apr;82(2d Half):165-77. doi: 10.1080/00221309.1970.9920634. No abstract available.
- Background: PubMed 15085902Skevington SM, Lotfy M, O'Connell KA; WHOQOL Group. The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res. 2004 Mar;13(2):299-310. doi: 10.1023/B:QURE.0000018486.91360.00.
- BackgroundWorld Health Organization Division of Mental Health. WHOQOL-BREF : introduction, administration, scoring and generic version of the assessment : field trial version, December 1996. Geneva: World Health Organization; 1996
- Background: PubMed 32112569Durst AV, Spencer B, Bula C, Fustinoni S, Mazzocato C, Rochat E, Rubli Truchard E, Monod S, Jox RJ. Wish to Die in Older Patients: Development and Validation of Two Assessment Instruments. J Am Geriatr Soc. 2020 Jun;68(6):1202-1209. doi: 10.1111/jgs.16392. Epub 2020 Feb 29.
- BackgroundNational Comprehensive Cancer Network. NCCN Distress Thermometer and Problem List for Patients. Version 2, dated March 11th, 2020. https://www.nccn.org/about/permissions/thermometer.aspx
- Background: PubMed 8857241Anderson F, Downing GM, Hill J, Casorso L, Lerch N. Palliative performance scale (PPS): a new tool. J Palliat Care. 1996 Spring;12(1):5-11.
- Individual participant dataSharing planned: No
Related trials for Depression, Anxiety
Recruiting
Unified Protocol in Penitentiary Facilities
Depression Disorders, Anxiety
Not yet recruiting
Preventive and Personalized Digital Emotion Regulation Skills Intervention to Reduce Depression and Anxiety in Youths With Adverse Childhood Experiences
Adverse Childhood Experience, Depression / Major Depressive Disorder
Not yet recruitingObservational study
Functional Impact of Psychological Symptoms in Patients With Superior Semicircular Canal Dehiscence Syndrome (SSCD): a National Cross-sectional Study
Superior Semicircular Canal Dehiscence
Recruiting
Trial Phase: Syndemic Adapted Medly Uganda
Mental Health
Recruiting
Cultural Adaptation of an Online Parenting Intervention to Reduce the Risk of Depression and Anxiety in Adolescents
Risk of Depression and Anxiety
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James Downar, MDCM, MSc principal investigator
Ottawa Hospital Research Institute
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Psilocybin in people with Depression, Anxiety and Distress, Emotional, run by Ottawa Hospital Research Institute at 2 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 10 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recruitment Rate (time frame: Through study completion, up to 1 year). The study lists 18 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04754061, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2026.