The goal of this clinical trial is to evaluate whether a single dose of psilocybin is feasible and safe for adults with opioid use disorder (OUD) who are recovering from trauma surgery. The main questions it aims to answer are:

1. Is a single psilocybin dose feasible to administer during postoperative hospitalization?
2. Is psilocybin safe in this patient population?
3. How does psilocybin affect postoperative pain, opioid use, anxiety, and depression after hospital discharge?

Participants will:

Receive one oral dose of psilocybin during their postoperative inpatient stay Complete assessments of pain, mood, and opioid use during recovery

This is an open-label pilot feasibility trial conducted at a single academic medical center. Fourteen participants receive a single oral dose of psilocybin during inpatient hospitalization following trauma surgery. Outcomes in the psilocybin group are compared with a retrospectively identified standard-of-care cohort of 56 trauma surgery patients with opioid use disorder, identified through electronic medical record review.

The standard-of-care cohort is selected using propensity score methods based on baseline characteristics, including age, sex, trauma diagnosis, psychiatric comorbidities, baseline medications, comorbid conditions, type of surgery, and baseline opioid consumption measured in morphine milligram equivalents.

No interim efficacy analyses are planned. After the first three participants have received psilocybin and completed the one-week follow-up assessments, the Data and Safety Monitoring Board reviews safety data to assess ongoing risk and determine whether study procedures should continue unchanged.

Inclusion Criteria:

1. ≥ 25 years old and ≤65 years old
2. Inpatient
3. English-speaking
4. History of opioid use disorder as diagnosed by DSM-V
5. Able to swallow capsules.
6. Patients are able to be enrolled and receive psilocybin within 3 days (72 hours) of surgery (time point 0 for this three-day window begins after patient arrival in the ICU) after a trauma surgery. Psilocybin will be administered in the morning to allow for the 8-hour monitoring period.

Exclusion Criteria:

1. Pregnancy. Women of child-bearing potential need to have a negative pregnancy test result at screening and baseline.
2. Sexually active male participants and/or their female partners and female participants of child-bearing potential need to be on adequate and effective method of contraception (diaphragm, male condom, combined pill, copper IUD, levonorgestrel IUS, etonogestrel implant).for one week following study drug administration.
3. Breastfeeding
4. Patients receiving concurrent ketamine therapy or who have received ketamine therapy during the trauma admission.
5. UDS screen on admission (if obtained) positive for alcohol, opioids other than prescribed for pain or maintenance opioids for OUD, or other substances of abuse
6. History of psychedelic substance use in the preceding 5 years
7. History (or active) cardiovascular disease (non-optimized coronary vascular disease, stable or unstable angina, new onset EKG abnormalities, congenital long QT syndrome, cardiac trauma involving surgical repair or CABG within 1 year)
8. Screening blood pressure SBP >140 mmHg or DBP > 90 mmHg on three separate occasions
9. Head trauma, traumatic brain injury, or concussion.
10. Tachycardia defined as HR > 100, averaged over the previous 12 hours, excluding intra-operative care)
11. History of dementia
12. History of pre-existing neurological conditions (including TIA, stroke, epilepsy, MS, ALS, Guillain-Barre, Parkinson's)
13. Patients on SSRIs, TCAs, MAO-Is, lithium, or other serotonergic medications, antipsychotics. Prohibited medications need to be discontinued at least 30 days prior to psilocybin dosing.
14. Patients that received intra-operative intravenous methadone dosing > 20 mg.
15. On vasopressors
16. Hepatic impairment, mild to moderate, with Child-Pugh score ≥ 7
17. Nicotine dependence, which would prevent the patient from staying in their room for the duration of the 8-hour psilocybin study period.
18. On sedating IV infusions (propofol, ketamine, fentanyl, benzodiazepine, dexmedetomidine)
19. History of suicidal or homicidal ideations within the last year
20. History of seizure disorder
21. Requiring restraints or active sitter
22. Patients with a history of poorly controlled anxiety (GAD7 score of 10 or more), poorly controlled depression (PHQ9 score of 15 or more), panic disorder, paranoia, PTSD, bipolar disorder, any primary psychotic disorder like schizophrenia, schizoaffective disorder, or antisocial personality disorder; personal or first- or second-degree relative history of psychotic or bipolar I or II disorder
23. History of Hallucinogen Use Disorder or Hallucinogen Persisting Perception Disorder (per DSM-V)
24. Unable to consent (intubated/sedated)
25. Intellectual disability
26. Additional or anticipated surgeries within 7248 hrs of psilocybin administration
27. Discharge from hospital pending within 24 hrs of psilocybin administration
28. Any allergy to psilocybin or other inert substances in the product