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
