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 abreath alcohol reading from a calibrated breath alcohol sensor. (Note: thiscriterion may be re-evaluated within the 30-day screening period. This criterionwill also be reassessed at Baseline and on Day 0 (prior to IP administration). Thosenot meeting the criterion may be rescheduled once within 14 days if the criterion islikely to resolve within 14 days in the judgement of the Investigator).

3. Are able to read, speak, and understand English, as documented during the informedconsent process. a. Non-English speaking subjects will be excluded because the study is using onlyvalidated 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 theMini-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 atleast 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 thepast 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 allstudy 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 criterionmay be re-evaluated within the 30-day screening period. This criterion will bereassessed at Day 0 [prior to IP administration]. Those not meeting the criterion onDay 0 may be rescheduled within 14 days if the criterion is likely to resolve in thejudgement of the Investigator.)

15. Agree to refrain from any non-prescribed psychotropic substance or illicit drug usefor at least 72 hours prior to IP administration, with the exceptions of alcohol,cannabis, nicotine, and caffeine. Regarding alcohol and cannabis, subjects mustagree 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 beforeand 6 hours following IP administration. Regarding caffeine, they must agree toconsume approximately their usual amount of caffeine on the morning of Day 0 (priorto 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 sessionunless approved by the Investigator.

17. Are able to swallow capsules.

18. Agree to practice effective contraception as described below.

19. Subjects are considered able to become pregnant unless they:

• Do not have a uterus
• Are postmenopausal (has had 12 months of natural amenorrhea with amatching clinical profile [age, history of vasomotor symptoms]) prior toScreening 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 theScreening Part 2 until 7 days after the IP Administration Session. Highlyeffective forms of contraception include: 1) Consistent and correct usageof established oral contraception; 2) Injected or implanted hormonalmethods of contraception; 3) Established intrauterine device orintrauterine system; 4) Bilateral tubal ligation; 5) Intercourse with apartner who has undergone effective surgical sterilization, provided thatpartner is the sole sexual partner of the study subject; 6) Abstinencefrom penile/vaginal intercourse, if the Investigator determines that thesubject can reliably adhere to the plan, based on evaluation of the socialcircumstances of the subject.

3. Agree not to donate or bank eggs from the time of Screening Part 2 until 7 daysafter 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 afterthe IP Administration Session. Effective means forms of contraceptioninclude:
• use condoms with spermicide if engaging in penile/vaginal intercourse;
• abstain from penile/vaginal intercourse, if the Investigator determinesthat the subject can reliably adhere to the plan, based on evaluation ofthe social circumstances of the subject
• Agree not to donate or bank sperm from the time of the Screening Part 2until 7 days after the IP Administration Session

19. Have a family member or friend who can assist with transportation and activities ofdaily living after the IP Administration Session, as determined by self-report atScreening Part 2 and confirmed by direct communication between a member of theclinical support team and the support person prior to randomization. (Note: thiscriterion will be reassessed on Day 0.

20. Are able to provide adequate locator information. This criterion may be re-evaluatedwithin the 30-day screening period.

Exclusion Criteria:

1. Have any medical condition that would preclude safe participation in the study,including the following, as determined by medical history review, physicalexamination, electrocardiogram (ECG), and clinical laboratory tests:

2. Seizure disorder

3. Significantly impaired liver function, defined as 1) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN); 2) ALT or AST > 3 × ULN with concomitant total bilirubin > 2.0 × ULN; or

3. ALT or AST ≥ 3 × ULN with the appearance of fatigue, nausea, vomiting, rightupper quadrant pain or tenderness, fever, rash, and/or eosinophilia.

3. Cardiovascular disease including coronary artery disease, angina, history ofarrhythmia (unless a successful ablation has been performed), heart failure,history of heart valve replacement, and history of cerebrovascular accident ortransient ischemic attack.

4. Uncontrolled hypertension with systolic blood pressure > 140 mmHg or diastolicblood pressure > 90 mmHg. (Note: subjects who otherwise qualify at ScreeningPart 2 will have 3 opportunities to produce 1 blood pressure reading ≤ 140/90mmHg (each reading will be collected at least 15 minutes apart). If bloodpressure is consistently elevated > 140/90 mmHg across all 3 attempts, subjectsmay be referred to their primary care provider for management of hypertension.Upon management of blood pressure, subjects will have an opportunity to returnonce within the 30 day screening window to make 3 additional attempts at ablood pressure reading ≤ 140/90 mmHg. Subjects will be considered eligible uponregistering 1 blood pressure reading ≤ 140/90 mmHg during the screening period.Blood pressure will be reassessed on Day 0 prior to dosing, and must be lessthan or equal to 140 systolic, 90 diastolic, with resting pulse ≤ 100 (ascertained within 20 minutes of drug administration in order for theparticipant to receive study medication.)

5. Serious ECG abnormalities present on the ECG obtained on Day -65 (e.g.,evidence of ischemia, myocardial infarction, QT interval corrected for heartrate [QTc] prolongation (QTc > 0.45 seconds), arrhythmia, or conductionabnormalities that increase the risk of arrhythmia.

6. Hyperthyroidism

7. Insulin-dependent diabetes

8. Any other medical condition which precludes safe participation in the study inthe medical opinion of the Investigator.

(Note: medical history will be updated and ECG will be repeated on Day 0, prior todosing. Those not meeting the criterion will not be randomized but may berescheduled once within 14 days if the criterion is likely to resolve within 14 daysin the judgement of the Investigator.)

2. Have any of the following DSM-5 psychiatric disorders, as determined by the MINI,Psychiatric History and Psychosis Screening Questionnaire at Screening Part 2: (Note: psychiatric history will be re-evaluated on Day 0, but the MINI will not bere-administered on Day 0)

3. Lifetime history of schizophrenia spectrum or other psychotic disorder.

4. Lifetime history of bipolar disorder.

5. Current severe major depression (based on a MINI diagnosis of major depression,current, and a MADRS score >34 at Screening)

6. Alcohol use disorder including alcohol withdrawal.

7. More than mild opioid withdrawal (COWS score >12). (This criterion may bere-evaluated within the 30-day screening period. This criterion will bereassessed on Day 0. Those not meeting the criterion may be rescheduled oncewithin 14 days if the criterion is likely to resolve within 14 days in thejudgement of the Investigator.)

8. Have active suicidal ideation with intent, based on Columbia - Suicide SeverityRating Scale (C-SSRS) assessment (severity score >3) at Screening Part 2, confirmedby the Investigator. (Note: this criterion will be reassessed at each visit thatoccurs prior to Day 0, and on Day 0 prior to IP administration. Subjects will bedischarged if actively suicidal, and appropriate follow-up will bearranged.arranged.

9. Have made a suicide attempt within the past 12 months, based on C-SSRS assessment atScreening Part 2 and confirmation by the Investigator. (Note: this criterion will bereassessed at each visit that occurs prior to Day 0, and on Day 0 prior to IPadministration. Subjects will be discharged if actively suicidal, and appropriatefollow-up will be arranged.

10. Have a family history (first degree relatives) of schizophrenia, schizoaffectivedisorder, or bipolar disorder type 1.

11. Have a history of hallucinogen use disorder or hallucinogen persisting perceptiondisorder (HPPD).

12. Have any hallucinogen use in the past 1 year.

13. Have > 25 lifetime uses of classic psychedelics.

14. Are currently in jail, prison, or other overnight facility as required by court oflaw or have pending legal action that could prevent participation in studyactivities.

15. Are taking any protocol-prohibited medications and supplements (See Section 6.5.3).Any prohibited medications and supplements must have been stopped for at least 5elimination half-lives or 14 days, whichever is longer, prior to Day 0. Prescribedpsychotropic medications and any other medically necessary medications must not bestopped in order to qualify for the study. (Note: concomitant medications will bereassessed on Day 0.)

16. Have a known allergy or hypersensitivity to psilocybin or any of the materialscontained in the IP used in the study.

17. Have an allergy, hypersensitivity, or other contraindication that would precludesafe treatment of acute hypertension, anxiety, or psychotic symptoms if necessaryduring or immediately after the IP Administration Session, using the adjunctivemedications used in this study to treat these symptoms (i.e., unable to takecaptopril and unable to take clonidine; unable to take diazepam and unable to takelorazepam; or unable to take olanzapine).

18. Have any other medical, psychiatric, or psychosocial disorder, symptom, condition,or situation that is likely to interfere with the establishment of rapport,adherence to study requirements, or safe administration of psilocybin, based on thejudgement of the Investigator. (Note: This criterion will be reassessed on Day 0.Those not meeting the criterion will not be randomized but may be rescheduled oncewithin 14 days if the criterion is likely to resolve within 14 days in the judgementof the Investigator.)