This is a feasibility study to examine the use of use of Psilocybin (magic mushrooms) to alleviate pain in chronic neuropathic pain.

While theoretical mechanisms demonstrate promise, there is no clinical evidence. This vacuum of clinical evidence has been occupied by a "psychedelic hype bubble" with media communications touting psychedelics as a 'miracle cures'. The mismatch between evidence and perception creates an urgent need for RCT to fill this significant gap. This trial aims to address this gap by conducting a pilot trial assessing the feasibility, tolerability, and preliminary efficacy of psilocybin for chronic neuropathic pain to inform a future larger, multi-centre study.

The purpose is to conduct a randomized control double-blinded trial of psilocybin and active placebo (dextromethorphan).

At this time, the aim of the trial is to recruit 30 participants from St. Michael's Hospital, to learn whether it will be feasible to plan a larger study in the future.

Brief title PEACE-PAIN Trial Indication Adult patients suffering from chronic neuropathic pain Condition(s) of focus of study Moderate-to-severe chronic neuropathic pain Number of participants 30 Primary outcome Feasibility (recruitment success, consent rate, adherence, patient withdrawal, missing data, adverse outcomes) Secondary outcome Change in pain intensity and pain interference Study design Study type: An intervention trial Allocation: Randomized Intervention model: 2-Arm Parallel Group Primary purpose: Feasibility Phase: Phase II Masking Participants, all study team including outcome assessors

Test Products, Dose, and Mode of Administration Treatment arm: Psilocybin 25mg + placebo PO single dose plus psychological support Placebo arm: Dextromethorphan 400mg PO single dose plus psychological support

Follow-Up Days: 1, 7, 14, 30, and 90

Inclusion Criteria:

• 18-65 years of age
• Diagnosis of chronic neuropathic pain as determined by a pain specialist
• Moderate-to-severe neuropathic pain determined by Patient Reported Outcomes Measurement Information System (PROMIS)
• Previous trials of at least two medications recommended in the Canadian consensus guidelines on the management of neuropathic pain with no self-reported meaningful improvement in symptoms
• Sufficient command of English to participate in psychotherapy
• For participants of childbearing potential, use of a highly effective or double-barrier methods of contraception.

Exclusion Criteria:

• History of Dextromethorphan addiction or abuse.
• Enzyme CYP2D6 deficient as shown on the pharmacogenetic test.
• Underlying psychiatric conditions: lifetime or family history of a primary psychotic disorder, bipolar disorder, borderline personality disorder, paranoid personality disorder, current suicidal ideation, and substance use disorder within the past 12 months as assessed by history and confirmed by the Mini International Neuropsychiatric Interview (MINI)
• Medications that interact with study drugs
• Medical condition that is unstable or inadequately controlled, including cardiovascular disease, liver disease, or end-stage renal disease
• Previous lifetime use of a serotonergic psychedelic drug
• Nursing or pregnant women.
• Any other clinically significant medical illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study

No individual participant data has been planned to be shared with other researchers at this point, since this is a feasibility study with only 30 participants