Clinical trial NCT06782724: Psilocybin Therapy for Psychological Distress in Palliative Patients
Official title: The Safety and Efficacy of Psilocybin Therapy Compared to Low-dose Control in Reducing Depressive Symptoms in Patients with COPD, ALS, MS, or APD.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: COPD (Chronic Obstructive Pulmonary Disease)
ALS (Amyotrophic Lateral Sclerosis)
MS (Multiple Sclerosis)
Major Depressive Disorder (MDD)
Atypical Parkinson Disease
Keywords: psilocybin
therapy
palliative
care
palliative care
end-of-life distress
depression
psychological distress
psypal
copd
als
ms
apd
chronic obstructive pulmonary disorder
amyotrophic lateral sclerosis
multiple sclerosis
major depressive disorder
atypical parkinson disease
existential distress
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: HumanKindLabs
name: University of Copenhagen
name: CTC Clinical Trial Consultants AB
name: OPEN Foundation
name: IESE Business School
name: Uppsala University
name: The Champalimaud Centre, Lisbon, Portugal
name: Stockholm University
name: University of Groningen, The Netherlands
name: National Institute of Mental Health (NIMH), Prague, Czech Republic
name: European Association for Palliative Care (EAPC)
name: Madopa
name: Bispebjerg Hospital, Copenhagen, Denmark
name: European Association of Neurological Associations (EFNA)
name: 29k International AB
name: Lung Alliance Netherlands
name: European Psychiatric Association
name: Norrsken Mind
First posted: 2025-01-20
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized double-blind low-dose controlled clinical trial
Primary purpose: SUPPORTIVE_CARE

Brief summary: The goal of this clinical trial is to evaluate whether psilocybin therapy can effectively treat depression and psychological distress in adult patients with COPD, ALS, MS, or APD who have at least 6 months life expectancy. The main questions it aims to answer are:

* Can psilocybin therapy safely reduce depressive symptoms compared to low-dose control?
* Will the therapeutic effects be rapid and sustained over a 6-month period?

Researchers will compare patients receiving two escalating doses of psilocybin (15mg followed by 25mg) against those receiving two low doses (1mg) to see if the higher doses lead to greater improvements in depression, anxiety, demoralization, and quality of life.

Participants will:

* Attend three preparation sessions with psychotherapists (1-2 hours each)
* Undergo two supervised psilocybin dosing sessions (6-8 hours each)
* Complete five integration therapy sessions following the dosing sessions
* Participate in follow-up assessments at 6 weeks, 3 months, and 6 months
* Have access to a digital care platform and peer support groups during the 6-month follow-up period
* Optional: Control group participants may receive one high-dose psilocybin session (25mg) after the initial study period

Detailed description: Rationale Patients with chronic obstructive pulmonary disorder (COPD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or atypical and advanced Parkinsonian disorder (APD) often suffer from severe psychological distress with demoralization and death anxiety, which may culminate in to depressive disorder. Treatments of depression in palliative care currently involves psychotherapy and/or the use of antidepressants. However, these treatments have shown limited efficacy which urgently calls for new and innovative approaches. In recent years, a number of studies have shown very promising results of psilocybin therapy in alleviating psychological distress in patients with advanced cancer. The current study (PsyPal) aims to evaluate whether psilocybin therapy can also lead to rapid and sustained decreases in depressive symptoms, demoralization and other facets of psychological distress in patients who suffer from COPD, ALS, MS and APD.

Objective The primary objective of the PsyPal study is to assess the safety and efficacy of psilocybin therapy compared to low-dose control in reducing depressive symptoms in patients with COPD, ALS, MS, or APD. Secondary objectives of PsyPal are to assess change in clinical functioning, end-of-life anxiety, psychological/existential distress, health-related quality of life, and how it impacts caregiver 's health- and economic burden. The safety objective of PsyPal is to evaluate the difference in adverse events between high and low dose groups before, during and after the dosing session. Exploratory objectives include the investigation of psychological mechanism, subjective effects, biomarkers (EEG and blood-based), cost-effectiveness, and the usefulness of a digital care platform, with a mixed methods approach.

Main trial endpoints The main trial endpoint for PsyPal is the change in depression severity from baseline to 6 weeks after the second dose of psilocybin (high dose session). Adverse events and change in depression symptoms will also be assessed at 3- and 6-month follow-up to determine the safety and sustained effects of psilocybin therapy.

Secondary trial endpoints Secondary trial endpoints will be assessed at baseline and 6 weeks after the second dose of psilocybin. These include response rate, anxiety, demoralization, health-related quality of life, experiential avoidance, coping with illness, death anxiety, the wish to hasten death, self-compassion, spirituality, attachment, pain, healthcare resource use, blood-based biomarkers, and functional brain changes. Some secondary endpoints will also be assessed at the 3- and 6-month follow-up, including anxiety, demoralization, health-related quality of life, experiential avoidance, and coping with illness. These endpoints aim to improve our understanding of the effects of psilocybin therapy, how psilocybin therapy works, and to see which patients show the best response. Finally, changes in (religious/spiritual) beliefs/understandings and the experience(s) with psilocybin therapy will be assessed through in-depth qualitative interviews with patients that are conducted 6 weeks after the second dose of psilocybin.

Trial design PsyPal trial consists of a double-blind randomized low-dose controlled clinical trial with long term follow-up. Patients who are enrolled in the trial will be actively participating for ten weeks. After the primary endpoint, patients who received a low dose of psilocybin (1 mg) will be offered an optional single open label high-dose of psilocybin (25mg) together with three integration sessions. During long-term follow-up, patients will have access to a digital care platform and peer support groups.

Trial population The trial population in PsyPal consists of patients with COPD, ALS, MS, or APD and co-morbid depression. The main further inclusion criteria for participation are an age of 18 or higher, having an identified caregiver or support person, and a life expectancy of at least 6 months. The main exclusion criteria are current use of antipsychotic drugs, suicidal ideations, schizophrenia or other psychotic disorders, bipolar I/II disorder, other major neurological conditions, cardiovascular conditions, diabetes, and/or moderate to severe hepatic impairment (i.e., liver failure). Other exclusion criteria are a first-degree relative on the schizophrenia spectrum, other psychotic disorders, or bipolar I disorder.

Interventions

Patients will receive psilocybin therapy consisting of three phases; 1) preparation, 2) dosing, and 3) integration:

Preparation - The preparation phase consists of three psychotherapy sessions of 1-2 hours each. The purpose of these sessions is threefold: to build a therapeutic alliance between the patient and the therapist, to make a psychotherapeutic treatment plan for the patient using a process-based approach, and to educate patients about psilocybin's acute effects and how patients and therapists together can handle difficult experiences during the dosing sessions.

Dosing - The dosing phase of PsyPal starts 1-3 days after the last preparation session. It consists of two escalating dosing sessions of 6-8 hours each. The patient first receives a moderate dose of psilocybin (15mg). Two weeks later, the patient receives a high dose of psilocybin (25mg). Patients in the control group will receive two doses of psilocybin (1mg). All dosing sessions take place under supervision of two trained therapists within a treatment room specifically designed for psilocybin therapy and with a medical doctor on call.

Integration - The integration phase consists of five psychotherapeutic sessions of 1-2 hours each. There are two integration sessions following the first dosing session and three integration sessions following the second dosing session. The integration sessions are intended for further psychotherapeutic work, including working with the experience(s) that may have emerged during dosing sessions, and clinical assessment of the patient. Central topics may include the relationship with their life-limiting illness, death, meaning, sense of purpose, personal (religious/spiritual) beliefs, (social) relationships, and conflict resolution. The patient can also share thoughts and feelings about the PsyPal trial.

Long-term follow-up After the intervention, patients will be returned to regular care and followed for a period of 6 months, tracking usage of healthcare resources, the digital care platform, and peer support groups. Qualitative aspects of the intervention will be evaluated for patients, caregivers and therapists. Long-term safety data of psilocybin therapy will be collected for the four patient populations.

Eligibility criteria: Inclusion Criteria:

1. Patient has to be diagnosed with one of the following four conditions, defined as:

   COPD i) Diagnosis by medical specialist ii) Postbronchodilator FEV1/FVC \< 0,7 and FEV1 \<80% pred iii) ≥ 40 years old iv) ≥ 10 years smoking

   ALS i) ALS according to Goldcoast criteria (Shefner et al, Clin Neurophysiol, 2020) ii) ALS-FRS-R subscores of minimum 1 in item 2, 3 and 8, subscore of minimum 2 in item 1, 4 and 10 and a subscore of minimum 3 in item 11 and 12

   MS i) Fulfilled diagnostic revised McDonald criteria for MS from 2017 (Thompson et al., 2018) ii) EDSS ≥ 1,0

   APD i) Advanced to Late-Stage Parkinson's Disease - patients with a diagnosis of Parkinson's Disease per the MDS clinical diagnosis criteria with evidence of motor and non-motor fluctuations ii) Diseases in the spectrum of Progressive supranuclear palsy (PSP), fulfilling possible and probable criteria, according to the MDS diagnostic criteria iii) Clinically Established and Clinically Probable Multiple System Atrophy (MSA) according to the MDS diagnostic criteria
2. Patient meets ICD-10 criteria for major depressive disorder documented through the com-pletion of the mood section of the Mini International Neuropsychiatric Interview by a screen-ing psychologist or physician.
3. Patient has a MADRS score of \> 19.
4. Patient should have a life expectancy of at least 6 months (assessed by study physician).
5. Patient is at least 18 years of age.
6. Patient has an identified caregiver/support person. See specific conditions for Czechia in Appendix 5.
7. Patient is able to read and understand the informed consent and all scales used in a local language. For those with ALS, MS, or APD, competency is ensured via neurologist assessment, cognitive screening, caregiver support during screening and interactive approaches where the screening clinician ask the patient to explain their understanding of consent elements, re-explaining potentially misunderstood information.
8. Patient is able to and willing to adhere to study requirements, including attending all study visits, preparatory and follow-up sessions, and completing all study evaluations.
9. Patient is able to ingest capsules.

Exclusion Criteria:

1. Patient has used a psychedelic substance in the past 6 months (e.g., psilocybin, LSD, 5-MeO-DMT, DMT, ayahuasca or mescaline).
2. Patient is in active treatments for other psychiatric disorders, judged by the screening clinician to be a more significant clinical problem than depression / distress.
3. Patient meets ICD-10 criteria for schizophrenia spectrum or other psychotic disorders, including major depressive disorder with psychotic features (except substance/medication-induced or due to another medical condition) or bipolar I/II disorder.
4. Patients with any lifetime diagnosis of schizophrenia spectrum or other psychotic disorders.
5. Patient has a first-degree relative with schizophrenia spectrum, bipolar I disorder or other psychotic disorders (expect substance/medication-induced or due to another medical condition).
6. Patients with a pre-existing psychiatric condition judged to be incompatible with safe exposure to psilocybin therapy.
7. Significant suicide risk as defined by (1) suicidal ideation with intent to act (defined as ≥ 5 on MADRS item 10), (2) suicidal attempts within the past year, or (3) clinical assessment of significant suicidal risk during patient interview.
8. Patient meets ICD-10 criteria for active/current alcohol or drug use disorder.
9. Patient has ongoing treatment with antipsychotic drugs. Any prohibited agents must have been stopped at least 5x the elimination half-life of the specific drug at the time of baseline (see Appendix 1a for Prohibited medications).
10. Patient is unwilling or unable to pause formal psychotherapy (days 0-42).
11. Patient has neurological conditions (e.g., intracranial tumour, epilepsy, brain injuries, or other neurological disorders) expected by the PIs to conflict with the treatment / study protocol.
12. Disease-specific exclusion criteria:

    COPD: Unresolved exacerbation or pulmonary infection within last 4 weeks. ALS: Significant cognitive deficits (MoCa, see below). MS: Significant cognitive deficits (MoCa, see below), epilepsy or radiologically isolated syndrome.

    APD: Dementia (MoCa, see below), or Schwab and England ADL scale with scores \> 80% in the best functional state.
13. Cardiovascular conditions: recent stroke (\< 1 year from signing of ICF), recent myocardial infarction (\< 1 year from signing of ICF), uncontrolled hypertension (blood pressure \> 140/90 mmHg), clinically significant arrhythmia within 1 year of signing the ICF, or QTc prolongation exceeding 450ms (males) / 470ms (females).
14. Patient has moderate to severe hepatic impairment (Child-Pugh score ≥ 7).
15. Patient has insulin-dependent diabetes or who are taking oral hypoglycaemic agents and have a current risk of hypoglycaemia that would require medical intervention.
16. Patient has any physical or psychological symptoms, medications, blood test results or clinically significant findings at Screening or Baseline (based on the clinical judgement of clinical/medical study personnel) that would make a patient unsuitable for the study.
17. Patient has an allergy or intolerance to any of the materials contained in either drug product.
18. Cognitive and Neuropsychological assessment: Patients will be excluded if they score below mean minus 1.5 Standard Deviation according to normative age and scholarity adjusted data on the Montreal Cognitive Assessment (MoCA) assessment.
19. Recent (2 weeks) change or planned change in antidepressant medication during the intervention.
20. Women who are pregnant, intend to become pregnant during the study or who are currently nursing, or are unwilling to use Highly Effective Contraceptive Methods

Primary outcomes:
measure: Depressive symptoms (MADRS)
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
Secondary outcomes:
measure: Response rate
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: End-of-life anxiety
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Anxiety and depression (symptoms)
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Demoralization
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Impact on Quality of life
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Caregiver burden
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Daily functioning in COPD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Health-related quality of life in COPD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Health-related quality of life in ALS
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Functional status in ALS
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Health-related quality of life in MS
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Health-related quality of life in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Motor and non-motor symptoms in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Functional magnetic resonance imaging (fMRI) in APD
timeFrame: Baseline (Day -14) to one week after Dose 2 (Day 21)
measure: Incidence, severity, and frequency of (serious) adverse events following psilocybin therapy
timeFrame: Baseline (Day -14), Dose 1 (Day 0), Integration 1 (Day 1), Integration 2 (Day 7), Dose 2 (Day 14), Integration 3 (Day 15), Integration 4 (Day 21), Integration 5 (Day 28), Primary endpoint (Day 56), Open label dose (Day 62), 3- and 6-month follow-up
Other outcomes:
measure: Experiential avoidance
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: Coping
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: The wish to hasten death
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: Self-compassion
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: Attachment
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: Pain perception
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: Spiritual well-being
timeFrame: Baseline to Primary Endpoint (Day 56)
measure: Mystical experience
timeFrame: Dosing session 1 (Day 0) and Dosing session 2 (Day 14)
measure: Emotional breakthrough
timeFrame: Dosing session 1 (Day 0) and Dosing session 2 (Day 14)
measure: Challenging experiences
timeFrame: Dosing session 1 (Day 0) and Dosing session 2 (Day 14)
measure: Experience of music during dosing sessions
timeFrame: Dose 1 (Day 0) and Dose 2 (Day 14)
measure: Brain function
timeFrame: Baseline (Day -14), one day after Dose 1 (Day 1), and one day after Dose 2 (Day 15)
measure: Blood-based biomarkers
timeFrame: Baseline (Day -14) to Dose 2 (Day 14) and primary endpoint (Day 56)
measure: Cost-effectiveness
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Long-term positive and negative effects
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56) and 3-month (Day 104) and 6-month follow-up (Day 194)
measure: Verbal learning and memory in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Working memory and attention in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Cognitive flexibility in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Executive function, lexical retrieval, and processing speed in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Sustained attention and working memory in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Processing speed, working memory, sustained attention, visual-motor coordination, and executive function in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Reading skills in APD
timeFrame: Baseline (Day -14) to Primary Endpoint (Day 56)
measure: Optional: qualitative interviews (patients)
timeFrame: After Primary Endpoint (Day 56)
measure: Optional: focus group (patients)
timeFrame: At the end of Long-Term Follow-Up (Day 194)
measure: Optional: journaling (patients)
timeFrame: Continuous during clinical trial
measure: Optional: focus groups (therapists)
timeFrame: At the end of Long-Term Follow-Up (Day 194)
measure: Optional: journaling (therapists)
timeFrame: Baseline to 3-month and 6-month follow-up
measure: Optional: focus group (caregivers)
timeFrame: After Primary Endpoint (Day 56) and at the end of Long-Term Follow-Up (Day 194)
Locations:
Study officials:
References: