Inclusion Criteria:
* Voluntary, written, informed consent;
* Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations;
* DSM-5 criteria for Opioid Use Disorder;
* Documented evidence (by urine toxicology) of opioid use (upon screening);
* Inpatient verified \> 1 week of abstinence;
* For females, a negative serum pregnancy (beta-HCG) test.
Exclusion Criteria:
* DSM-5 criteria for other substance use disorders (e.g., alcohol, cocaine, sedative hypnotics), except for nicotine (concurrent alcohol or drug use is allowed if it does not meet criteria for a substance use disorder and does not take place during inpatient stay)
* A primary DSM-5 Axis I diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or major depression, as determined by psychiatric history (Mini International Neuropsychiatric Interview, MINI), or another disorder that may interfere with the study's primary outcomes in the view of PI
* Immediate (first-degree relative) family history of formally diagnosed schizophrenia or other psychotic disorders (e.g., delusional disorder, schizoaffective disorder), or bipolar I/II disorder
* A history of significant and/or uncontrolled medical or neurological illness
* Hypertension at screening defined as: systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg;
* History of cardiovascular disease, including but not limited to clinically significant coronary artery disease, cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction, angina pectoris, coronary artery bypass graft or artificial heart valve, stroke, transient ischemic attack, or any clinically significant arrhythmia
* Any clinically significant abnormal electrocardiogram (ECG) finding, such as findings suggestive of ischemia or infarct, complete bundle branch block, atrial fibrillation or other symptomatic arrhythmia, or predominantly non-sinus rhythm, at screening
* Resting QT interval with Fridericia's correction (QTcF) ≥ 450 msec (male) or ≥ 470 msec (female) at Screening, or inability to determine QTcF interval
* Presence of risk factors for torsades de pointes, including: long QT syndrome, uncontrolled hypokalemia or hypomagnesemia, history of cardiac failure, history of clinically significant/symptomatic bradycardia, family history of idiopathic sudden death or congenital long QT syndrome, or concomitant use of a torsadogenic medication
* Current use of psychotropic and/or potentially psychoactive prescription medications considered to the investigators are likely to interfere clinically with human subject's safety (i.e., contraindicated drug-drug interactions with psilocybin) or scientifically (i.e., likely to influence or alter outcomes of the study)
* Medical contraindications to MRI procedures (e.g., ferromagnetic implants/foreign bodies, claustrophobia, etc.)
* Arterial Line Exclusion: Blood donation within eight weeks of the start of the study
* Arterial Line Exclusion: History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto)
* Participation in other research studies involving ionizing radiation within one year of the PET scans that would cause the subject to exceed the yearly dose limits followed by the Yale PET Center (21CFR361.1).
