The Acute and Long-term Impact of Support in Psilocybin Therapy for Depression: The Psilocybin Setting Trial (PSISET)

Prior treatment

• Concomitant treatment with medication that modulates uridine diphosphate (UDP) or glucuronosyltransferase (UGT).
• Use of any serotonergic psychedelic drug within the past 10 years or > 25 lifetime uses.
• Concomitant treatment against depressive disorder including pharmacotherapies, electroconvulsive therapy, deep brain stimulation, and vagus nerve stimulation. Benzodiazepines and sleep medicine is allowed, except on the day of dosing.
• Ongoing tapering off antidepressant or any other serotonergic medication. Prescribed medication must have been stopped at least 5 x elimination half-life. Study personnel will not encourage any tapering off.

Other illness

• Meeting ICD-10 diagnostic criteria for mental retardation, schizophrenia spectrum, or other psychotic disorders, and bipolar disorders.
• Uncontrolled hypertension (systolic blood pressure >150mm Hg, diastolic blood pressure >90 mm Hg*).
• Hypersensitivity to the active substance or any of the excipients
• Any condition that the investigator feels would interfere with trial participation.
• Immediate family history of psychotic disorders or bipolar disorders, including parents and siblings, but not offspring.
• Any co-morbid psychiatric condition deemed to be incompatible with the safe administration of psilocybin, e.g., inability to establish rapport.
• Meeting ICD-10 diagnostic criteria for substance use disorder and/or alcohol use disorders.
• History of suicide attempt or: 1) active suicidal ideation with some intent to act without specific plan (C-SSRS item 4), 2) active suicidal ideation with specific plan and intent (C-SSRS item 5), 3) have a score of ≥ 5 on Item 10 (suicidal thoughts) on MADRS at screening, 4) have any suicidal ideation or thoughts, in the opinion of the study personnel, PI, the support person or close relatives, that present a serious risk of suicidal or self-injurious behavior at any time.
• Present or former severe neurological disease, including epilepsy and head trauma with loss of consciousness > 30 min.

Lab values

• Cardiovascular disease, including a history of myocardial infarction, angina pectoris, heart failure (NYHA class ≥ III), prolonged QTc interval (>450 ms/470 ms men/women)
• Pregnancy (serum human chorionic gonadotropin (hCG) > 3 U/L at inclusion).

Other

• Females of childbearing potential who are pregnant, breastfeeding or have the intention of becoming pregnant within the next 12 weeks, or are not using contraceptives (during the whole study period) considered as highly effective (combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) intrauterine device – IUD, IUS, bilateral tubal occlusion, vasectomised partner, sexual abstinence)
• Unable to speak and/or understand Danish
• No psychotic symptoms of depression or the like.

• Informed oral and written consent.
• Meeting diagnostic criteria for moderate-severe MDD according to the International Classification of Diseases 10 (ICD-10) and The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
• A MADRS total score between 20-60 (both included).
• Aged 18 years or above
• Being willing to abstain from other psychotherapeutic or antidepressant treatments until at least the 6-week primary endpoint.
• Have an identified support person.