Psilocybin-assisted therapy for PTSD in veterans

Eligible participants must be over the age of 18. They must self-identify as military veterans, reservists, National Guard members, or active-duty servicemembers. Additionally, they must be seeking treatment for PTSD, which will be confirmed by a CAPS-5-R assessment. The criteria below will be applicable to all participants, regardless of study treatment arm.

Inclusion Criteria

1. Meet criteria for PTSD due to trauma occurring at least 3 months prior based on CAPS-5-R diagnostic scoring rules.
2. Able to speak and read English (due to standardization of outcome measures).
3. Willingness of participant to sign a release for the investigators to communicate with their primary care or mental health providers, if indicated
4. Are 18 years and older.
5. Are able to swallow pills.
6. Agree to have study visits video and/or audio recorded, including Medicine Session, Independent Rater assessments, and non-drug psychotherapy sessions.
7. Must provide a contact (relative, spouse, close friend, or other support person) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable.
8. Must agree to inform the investigators within 48 hours of any medical conditions and procedures.
9. If able to become pregnant, participants must have a negative pregnancy test prior to study entry, at study entry, and prior to each Medicine Session. They must agree to use highly effective birth control for a month prior to the Medicine session and through 10 days after the Medicine session.
10. Agree to the following lifestyle modifications: comply with requirements for fasting and refraining from certain medications prior to Medicine Session, not participate in any other interventional clinical trials during the duration of the treatment, and agree not to operate their vehicles (or heavy machinery) up to 24 hours after Medicine Session, and commit to medication dosing, therapy, and study procedures.

Exclusion Criteria

1. Are not able to give adequate informed consent.
2. Have a family history bipolar disorder type 1 or a psychotic disorder in first degree relatives.
3. Have any current problem which, in the opinion of the investigator or Medical Monitor, might interfere with participation.
4. Have hypersensitivity to any ingredient of the IMP (Investigational Medicinal Product).
5. Have a history of or current bipolar type 1 disorder, primary psychotic disorder (e.g., schizophrenia), or secondary psychotic features (i.e., Major Depressive disorder with psychotic features.
6. Have met criteria at any time during their life for amphetamine or cocaine substance use disorder or any drug of abuse the study physician determines to be unfit for the study.
7. Meet criteria for current (past 3 months) moderate or severe substance use disorder, as defined by 4 or more DSM SUD criteria symptoms.
8. Have a positive screen for any drug of abuse (amphetamines, etc.) on drug test administered in local community or on site unless being taken as prescribed by a physician.
9. Any participant presenting current serious suicide risk, as determined through psychiatric interview and clinical judgment of the investigator will be excluded;

   1. Suicidal ideation score of 4 or greater within the last 6 months.
   2. Any suicidal behavior, including suicide attempts or preparatory acts, within the last 6 months of the assessment
   3. However, history of suicide attempts is not an exclusion.
10. Require ongoing concomitant therapy with a psychiatric medication with exceptions described in protocol section on Concomitant Medications.

    Medical History
11. Have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure and heart rate, or any medical condition the study physician believes would pose a safety risk or interfere with the effects of the treatment.

    1. This includes, but is not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm.
    2. Participants with other stable chronic medical problems may be enrolled if the site physician believes would not significantly increase the risk of Psilocybin administration or be likely to produce significant symptoms during the study that could interfere with study participation or be confused with side effects of the IMP.
12. Have any unstable medical or central nervous system-related illness that would interfere with participation.
13. Systolic blood pressure \>= 140 mmHg or diastolic blood pressure \>= 90 mmHg, measured in the supine position after at least five minutes at rest. If the initial blood pressure is \>= 140/90 mmHg, up to three additional attempts before dosing visit are permitted. The study physician will manage blood pressure monitoring from baseline through 10 days after drug administration.
14. Have a history of clinically significant arrhythmia, other than premature atrial contractions (PACs) or occasional PVCs in the absence of ischemic heart disease, within 12 months of screening.

    a. Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular tachycardia or any other arrhythmia associated with a bypass tract may be enrolled only if they have been successfully treated with ablation and have not had recurrent arrhythmia for at least one year off all antiarrhythmic drugs and confirmed by a cardiologist.
15. Have a marked Baseline prolongation of QT/QTc interval e.g., repeated demonstration of a QTc interval \> 450 milliseconds (ms) in males and \>470 ms in females. For transgender or non-binary participants, QTc interval will be evaluated based on sex assigned at birth.
16. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, family history of Long QT Syndrome).
17. Have significant liver enzyme elevations as evidenced by total bilirubin \>1.5mg/dL and/or ALT and AST (\>two times upper limit of normal \[ULN\]) per baseline laboratory test.
18. Creatinine clearance: \<30 mL/min)
19. Non-ambulatory or require two-person assistance with transfers (Fall risk)
20. Body Mass Index (BMI) \<18
21. Are pregnant or nursing
22. fMRI Scan Exclusions Only: History of cranial surgery, metallic particles in the eye or head (exclusive of mouth), implanted cardiac pacemaker or any intra-cardiac lines, implanted neurostimulators, intra-cranial implants (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or implanted medical pumps.

    1. NOTE: these ineligibility criteria preclude participants from undergoing a fmri scan but does not exclude them from the primary study participant and they may proceed without fMRI.