Clinical TrialPalliative & End-of-Life DistressPsilocybinPsilocybinNot yet recruiting

Psilocybin Therapy for Psychological Distress in Palliative Patients (PsyPal)

Quadruple-blind, randomised, low-dose controlled Phase II trial (n=108) comparing two escalating psilocybin doses (15 mg then 25 mg) versus two low doses (1 mg) in palliative patients with COPD, ALS, MS, or APD and co-morbid depression.

Target Enrollment
108 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

PsyPal is a randomized, double-blind, low-dose controlled Phase II trial evaluating psilocybin therapy for depressive symptoms and psychological distress in patients with COPD, ALS, MS, or atypical Parkinsonian disorders with at least six months life expectancy.

Participants receive three preparation psychotherapy sessions, two supervised oral psilocybin dosing sessions (experimental: 15 mg then 25 mg; control: 1 mg twice), and five integration sessions; outcomes assessed at 6 weeks, 3 months and 6 months.

Primary endpoint is change in depression severity at 6 weeks after the second dose; secondary and exploratory measures include anxiety, demoralization, quality of life, biomarkers (EEG, blood), health-economic outcomes, and qualitative interviews.

Study Protocol

Preparation

3 sessions
90 min each

Dosing

2 sessions
420 min each

Integration

5 sessions
90 min each

Therapeutic Protocol

support

Study Arms & Interventions

High-dose psilocybin

experimental

Three preparation sessions, two supervised dosing sessions (15mg then 25mg) with integration sessions.

Interventions

  • Psilocybin15 - 25 mg
    via Oral• two sessions• 2 doses total

    Escalating: 15 mg first session, 25 mg second session

Low-dose psilocybin

inactive

Low-dose control receiving two 1 mg psilocybin sessions; optional open-label high-dose after primary endpoint.

Interventions

  • Psilocybin1 mg
    via Oral• two sessions• 2 doses total

    Low-dose control (1 mg)

Participants

Ages
18 – 99
Sexes
Male & Female

Inclusion 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 completion of the mood section of the MINI by a screening 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.
  • 7. Patient is able to read and understand the informed consent and all scales used in a local language; competency procedures for ALS/MS/APD described.
  • 8. Patient is able to and willing to adhere to study requirements, including attending all visits and sessions.
  • 9. Patient is able to ingest capsules.

Exclusion Criteria

  • 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 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, or bipolar I/II disorder.
  • 4. 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.
  • 6. Pre-existing psychiatric conditions judged incompatible with safe exposure to psilocybin therapy.
  • 7. Significant suicide risk defined as (1) suicidal ideation with intent to act (MADRS item 10 ≥ 5), (2) suicide attempts within past year, or (3) clinical assessment of significant suicidal risk during interview.
  • 8. Active/current alcohol or drug use disorder.
  • 9. Ongoing treatment with antipsychotic drugs; prohibited agents must be stopped for at least 5x elimination half-life prior to baseline.
  • 10. Unwillingness or inability to pause formal psychotherapy (days 0-42).
  • 11. Neurological conditions expected to conflict with treatment (e.g., intracranial tumour, epilepsy, brain injury).
  • 12. Disease-specific exclusions (unresolved COPD exacerbation, significant cognitive deficits for ALS/MS/APD, dementia for APD, specific functional thresholds).
  • 13. Cardiovascular conditions: recent stroke or MI (<1 year), uncontrolled hypertension (>140/90 mmHg), clinically significant arrhythmia within 1 year, or QTc prolongation exceeding 450 ms (males)/470 ms (females).
  • 14. Moderate to severe hepatic impairment (Child-Pugh ≥ 7).
  • 15. Insulin-dependent diabetes or oral hypoglycaemic agents with current hypoglycaemia risk requiring intervention.
  • 16. Any physical/psychological/medication/lab finding at screening or baseline making patient unsuitable for study.
  • 17. Allergy or intolerance to materials in either drug product.
  • 18. Cognitive/neuropsychological exclusion if MoCA score < mean -1.5 SD adjusted for age/education.
  • 19. Recent (2 weeks) change or planned change in antidepressant medication during intervention.
  • 20. Women who are pregnant, intend to become pregnant during the study, are nursing, or unwilling to use highly effective contraception.

Study Details

Locations

Netherlands

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