Psilocybin for Opioid Use Disorder (OUD)

Inclusion Criteria: 1. Are able to provide voluntary informed consent. 2. Have a breath alcohol concentration ≤ 0.01% at Screening Part 2, as determined by a breath alcohol reading from a calibrated breath alcohol sensor. (Note: this criterion may be re-evaluated within the 30-day screening period. This criterion will also be reassessed at Baseline and on Day 0 (prior to IP administration). Those not meeting the criterion may be rescheduled once within 14 days if the criterion is likely to resolve within 14 days in the judgement of the Investigator). 3. Are able to read, speak, and understand English, as documented during the informed consent process. a. Non-English speaking subjects will be excluded because the study is using only validated English-language versions of of assessment instruments. 4. Are 18 to 65 years old, inclusive, at Screening Part 2. 5. Have Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM 5) diagnosis of OUD, based on an evaluation performed by trained study staff using the Mini-International Neuropsychiatric Interview (MINI). 6. Want to stop their use of illicit opioids. 7. Are in treatment at one of participating Opioid Treatment Programs (OTPs) for at least 6 months at the time of Screening Part 2. 8. Are currently prescribed a methadone dose of at least 60 mg per day. 9. Methadone dosage has changed by no more than 20 mg in the past month 10. Have taken methadone at least 25 out of the last 30 days 11. Have had at least one urine drug screen positive for non-prescribed opioids in the past 30 days at the time of Screening Part 2 12. Report using opioids by insufflation, injection, or smoking 13. Are able and willing to adhere to all study requirements, including attending all study visits and treatment sessions, and completing all assessments. 14. Are able to provide at least one drug screen negative for illicit opioids, cocaine, and amphetamine-type stimulants during the screening period. (Note: this criterion may be re-evaluated within the 30-day screening period. This criterion will be reassessed at Day 0 \[prior to IP administration\]. Those not meeting the criterion on Day 0 may be rescheduled within 14 days if the criterion is likely to resolve in the judgement of the Investigator.) 15. Agree to refrain from any non-prescribed psychotropic substance or illicit drug use for at least 72 hours prior to IP administration, with the exceptions of alcohol, cannabis, nicotine, and caffeine. Regarding alcohol and cannabis, subjects must agree to attempt to abstain at least 24 hours before the IP administration session. Regarding nicotine, they must agree not to use nicotine for at least 1 hour before and 6 hours following IP administration. Regarding caffeine, they must agree to consume approximately their usual amount of caffeine on the morning of Day 0 (prior to IP administration). 16. Agree to refrain from taking all non-prescription medications and supplements (nutritional and herbal) for at least 1 week prior to the IP administration session unless approved by the Investigator. 17. Are able to swallow capsules. 18. Agree to practice effective contraception as described below. 1. Subjects are considered able to become pregnant unless they: * Do not have a uterus * Are postmenopausal (has had 12 months of natural amenorrhea with a matching clinical profile \[age, history of vasomotor symptoms\]) prior to Screening Part 2, or * Are surgically sterile (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 2. Subjects who are able to become pregnant must: * Have a negative pregnancy test at Screening Part 2 (Reassessed at Day 0 (pre-IP administration); * Not be currently breastfeeding; * Not intend to become pregnant during participation in this study; * Agree to use a highly effective form of contraception from the time of the Screening Part 2 until 7 days after the IP Administration Session. Highly effective forms of contraception include: 1) Consistent and correct usage of established oral contraception; 2) Injected or implanted hormonal methods of contraception; 3) Established intrauterine device or intrauterine system; 4) Bilateral tubal ligation; 5) Intercourse with a partner who has undergone effective surgical sterilization, provided that partner is the sole sexual partner of the study subject; 6) Abstinence from penile/vaginal intercourse, if the Investigator determines that the subject can reliably adhere to the plan, based on evaluation of the social circumstances of the subject. 3. Agree not to donate or bank eggs from the time of Screening Part 2 until 7 days after the IP Administration Session. 4. Subjects who can emit sperm are defined as those who: * Have one or more testes and * Have not had a documented effective surgical sterilization procedure (e.g., vasectomy, radical prostatectomy). 5. Subjects who can emit sperm must: * Practice effective contraception from Screening Part 2 until 7 days after the IP Administration Session. Effective means forms of contraception include: * use condoms with spermicide if engaging in penile/vaginal intercourse; * abstain from penile/vaginal intercourse, if the Investigator determines that the subject can reliably adhere to the plan, based on evaluation of the social circumstances of the subject * Agree not to donate or bank sperm from the time of the Screening Part 2 until 7 days after the IP Administration Session 19. Have a family member or friend who can assist with transportation and activities of daily living after the IP Administration Session, as determined by self-report at Screening Part 2 and confirmed by direct communication between a member of the clinical support team and the support person prior to randomization. (Note: this criterion will be reassessed on Day 0. 20. Are able to provide adequate locator information. 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