Psilocybin Therapy for Psychological Distress in Palliative Patients

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.

Inclusion criteria

• 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

• 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.
• Patient has a MADRS score of > 19.
• Patient should have a life expectancy of at least 6 months (assessed by study physician).
• Patient is at least 18 years of age.
• Patient has an identified caregiver/support person. See specific conditions for Czechia in Appendix 5.
• 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.
• 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.
• Patient is able to ingest capsules.

Exclusion criteria

• Patient has used a psychedelic substance in the past 6 months (e.g., psilocybin, LSD, 5-MeO-DMT, DMT, ayahuasca or mescaline).
• Patient is in active treatments for other psychiatric disorders, judged by the screening clinician to be a more significant clinical problem than depression / distress.
• 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.
• Patients with any lifetime diagnosis of schizophrenia spectrum or other psychotic disorders.
• 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).
• Patients with a pre-existing psychiatric condition judged to be incompatible with safe exposure to psilocybin therapy.
• 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.
• Patient meets ICD-10 criteria for active/current alcohol or drug use disorder.
• 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).
• Patient is unwilling or unable to pause formal psychotherapy (days 0-42).
• 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.
• 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.

• 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).
• Patient has moderate to severe hepatic impairment (Child-Pugh score ≥ 7).
• Patient has insulin-dependent diabetes or who are taking oral hypoglycaemic agents and have a current risk of hypoglycaemia that would require medical intervention.
• 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.
• Patient has an allergy or intolerance to any of the materials contained in either drug product.
• 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.
• Recent (2 weeks) change or planned change in antidepressant medication during the intervention.
• 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