Low dose psilocybin as a treatment for moderate depression

INTERVENTION: The MicroDep trial will investigate a course of low dose psilocybin as a treatment for major depressive disorder of moderate severity. The experimental drug is 4mg WP001 (psilocybin) capsules, taken orally. Participants will complete a screening and baseline visit, followed by a si Xweek intervention. The intervention will consist of 11 doses, administered every 3‐4 days. Doses will be taken on site and adherence will be confirmed by trial staff. Following the intervention participants will complete study endpoint, 1‐week and 1‐month followup visits. Participants will attend the trial site for all study visits. Participants will be monitored by a psychiatrist throughout the trial and may be titrated down to 2mg if they show any signs of impairment. There will also be a neuroimaging substudy, which will recruit a maximum of 80 participants. Participants in this substudy will complete an magnetoencephalography (MEG) scan at baseline and during the first dosing visit. MEG scans are non‐invasive. Participants will be asked to lie the scanner while responding to audio and visual cues via a response button. Every third participant will be invited to take part in the neuroimaging study. If a participant declines to take part, the subsequent participant will be invited to the substudy. Any deviation from protocol will be documented. CONDITION: Major Depressive Disorder of moderate severity; ; Major Depressive Disorder of moderate severity Mental Health ‐ Depression PRIMARY OUTCOME: Change in the Hamilton Rating Scale for Depression (GRID‐HAMD) from baseline[ Baseline and 6 weeks from baseline] SECONDARY OUTCOME: 1. Change in GRID‐HAMD from baseline to week 10[ Baseline and 1‐month followup visit (week 10)] 10. Change in cognitive function, assessed using the trailmaking test, from baseline to visits 1B, 2B, 3B, 4B, and 5B[ Baseline, visit 1B (week 1 post‐baseline), 2B (week 2 post‐baseline), 3B (week 3 post‐baseline), 4B (week 4 post‐baseline), and 5B (week 5 post‐baseline)] 11. Change in wellbeing, assessed with the EQ‐5D, from baseline to week 6 and week 10[ Baseline and study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline) ; ] 12. Change in anxiety, assessed with the Depression, Anxiety, Stress Scale from baseline to week 6 and week 10[ Baseline and study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline)] 13. Change in alcohol misuse, assessed with the Alcohol, Smoking and Substance Involvement Test, from baseline to week 6 and week 10 ; [ Baseline and study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline)] 14. Change in drug misuse, assessed with the Alcohol, Smoking and Substance Involvement Test, from baseline to week 6 and week 10[ Baseline and study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline) ; ] 15. Change in tobacco misuse, assessed with the Alcohol, Smoking and Substance Involvement Test, from baseline to week 6 and week 10[ Baseline and study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline) ; ] 16. Ratings of the Acceptability of Intervention Measure (AIM) at week 6 ; [ Study endpoint (week 6 post‐baseline) ; ] 17. Ratings of the Intervention Appropriateness Measure (IAM) at week 6 ; [ Study endpoint (week 6 post‐baseline) ; ] 18. Ratings of the Feasibility of Intervention Measure (FIM) at week 6 ; [ Study endpoint (week 6 post‐baseline) ; ] 19. Change in blood‐based biomarker battery (includine tryptophan metabolites, multiple Xcytokine array, and enzyme‐linked immunosorbent array) from baseline to week 1 and week 3 (acute biomarkers) ; [ Baseline, visit 1A (week 1 post‐baseline), and 3B (week 3 post‐baseline) ; ] 2. Rates of clinical response (50% reduction on GRID‐HAMD from baseline score) at week 6 (study endpoint) and week 10 (1M FollowUp)[ Study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline)] 20. Change in blood‐based biomarker battery (includine tryptophan metabolites, multiple Xcytokine array, and enzyme‐linked immunosorbent array) from baseline to week 6, week 7 and week 10 (sustained biomarkers) ; [ Baseline, study endpoint (week 6 post‐baseline), 1‐week followup (week 7 post‐baseline), and 1‐month followup (week 10 post‐baseline) ; ] 21. Changes in visual long term potentitation, measured with magnetoencephlatography (MEG) from baseline to first dosing day. ; [ Baseline and visit 1A (week 1 post‐baseline) ; ] 22. Changes in resting state, measured with MEG from baseline to first dosing day. ; [ Baseline and visit 1A (week 1 post‐baseline) ; ] 23. Changes in auditory oddball performance, measured with MEG from baseline to first dosing day ; [ Baseline and visit 1A (week 1 post‐baseline) ; ] 3. Rates of remission (score <8 on GRID‐HAMD) at week 6 (primary endpoint) and week 10 (1M FollowUp) [ Study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline)] 4. Proportion of participants with Severe Adverse Events or Adverse Events (e.g., headache, nausea, dizziness) associated with participation in the trial from week 1 through to week 6. Adverse events will be assessed using a study specific questionnaire.[ At conclusion of study.] 5. Proportion of participants with suicidality (Columbia Suicide Severity Rating Scale [CSSRS] ‐ Brief Form scores >1) during the study [ At conclusion of study] 6. Proportion of participants who down‐titrate dose (determined by audit of study records)[ At conclusion of study] 7. Proportion of participants who remain in study until study week 6 (study endpoint) and week 10 (1M FollowUp). This will be determined by audit of study records.[ At conclusion of study] 8. Change in Sheehan Disability Scale (SDS) from baseline to week 6 and week 10[ Baseline and study endpoint (week 6 post‐baseline) & 1‐month followup visit (week 10 post‐baseline)] 9. Change in driving simulator performance from baseline to week 1 and week 5[ Baseline, visit 1B (week 1 post‐baseline) and 5B (week 5 post‐baseline)] INCLUSION CRITERIA: Participants may be included in the study if they meet all of the following inclusion criteria. 1. Age greater than or equal to 18 years at the time of screening 2. Self‐reported fluency in English 3. Meets the definition of moderate depression, defined as a score of between 15 and 23 on the Hamilton Rating Scale for Depression 4. Diagnosis of major depressive disorder, as assessed by the Mini International Neuropsychiatric Interview (MINI) 5. Able to swallow WP001 or Caffeine capsules 6. Has a body weight between 50kg and 120kg, and BMI above 16. 7. Refrains from the use of any psychoactive medication not approved by the research team from baseline through Study Termination. 8. Agrees to abstain from herbal, complementary or over the counter medications with serotonergic effects including, but not limited to, St John’s Wort, S‐adenosyl methionine (SAM‐e), 5‐hydroxytryptophan (5‐HTP) and L‐tryptophan. 9. Agrees to comply with cont