Inclusion Criteria: A participant must meet all the following criteria to be eligible to participate in this study:
1. Is willing and able to provide written informed consent.
2. ≥18 and \<65 years of age at Screening.
3. Meets Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5) criteria for PTSD according to CAPS-5-R, Past Month assessment at Screening and Baseline.
4. The index trauma must have occurred more than 3 months prior to screening.
5. Has a CAPS-5-R, Past Month total score of ≥26 at Screening and Baseline. Note: The CAPS-5 scoring grid will be used to score answers and to calculate the total score to determine eligibility.
6. Is currently serving, or has previously served, in a branch of the US military service (ie, Air Force, Army, Navy, Marine Corps, and Coast Guard including Reserves and National Guard).
7. Agrees to consistently use an acceptable method of birth control as defined in Section 7.4.2 (required for both males and females who are of reproductive potential and sexually active with partners of the opposite sex) throughout the duration of participants' involvement in the study and for a minimum of 30 days after the last dose of study intervention or longer, as specified in the assigned cohort-specific appendices.
1. For females of reproductive potential, acceptable birth control methods are defined as: hormonal contraceptives, intrauterine device, or double barrier contraception (ie, male condom and diaphragm, male condom or diaphragm with spermicidal gel or foam). Hormonal contraceptives must have been started at least 2 months prior to the Baseline visit. In addition, agrees to no egg donation or harvesting for the duration of the study and for at least 30 days after the last dose of study treatment or as specified in the assigned cohort-specific appendices.
2. Non-reproductive potential for females is defined by a post-menopausal (12 consecutive months without menses or surgically sterile). If in question, an Follicle-stimulating hormone (FSH) of \>40 U/mL, per central laboratory testing must be documented. Surgical sterility (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) must be documented.
3. Females of reproductive potential must have a negative pregnancy test at the screening (serum) and baseline (urine) visits.
4. For males, adequate birth control methods will be defined as the use of double barrier contraception (eg, male condom and diaphragm, male condom or diaphragm with spermicidal gel or foam). In addition, male participants must agree not to donate sperm for the duration of the study and for at least 30 days after the last dose of study treatment or as specified in the assigned cohort-specific appendices.
5. Non-reproductive potential for males is defined as surgical sterility (ie, vasectomy) at least 3 months prior to baseline.
8. Is able and willing to participate in study assessments and undergo blood draws.
9. Is willing to undergo magnetic resonance imaging (MRI) eg, is not claustrophobic, has no contraindications to MRI.
Exclusion Criteria: A participant who meets any of the following criteria will not be eligible to participate in this trial:
1. Is pregnant or breastfeeding at the Screening or Baseline visits, or planning pregnancy during the study.
2. Is at risk for suicide based on any of the following:
1. Had any suicidal ideation or behavior (including preparatory behavior) that required psychiatric hospitalization in the 3 months prior to screening.
2. Had more than 2 actual suicide attempts within the last 3 years, not including interrupted or aborted attempts, preparatory acts or behaviors, or non-suicidal self-injurious behavior (as per C-SSRS response).
3. Has any history of suicidal ideation and/or intent following initiation of a medication used for psychiatric symptoms or disorders.
4. Has any history of suicide-related hospitalization following initiation of a medication used for psychiatric symptoms or disorders.
3. Is taking any prohibited medication per Section 8.5.1 or cohort-specific restrictions (see cohort-specific appendices), is unable/unwilling to discontinue medications, or in the PI's judgement, cannot discontinue medications. Subjects must agree to a washout period of at least 14 days or 5 half-lives, whichever is longer, prior to the first dose of study intervention. Note, the half-life of the parent drug (not metabolites) should be used in this calculation.
4. In the 3 months prior to the Baseline visit, has initiated or terminated individual or group PTSD specific psychotherapy (eg, Eye Movement Desensitization \& Reprocessing, Prolonged Exposure, Cognitive Processing Therapy, Stress Inoculation Training, Present Centered Therapy), or therapy is anticipated to conclude during the study. Completion of ≤2 sessions in the prior 3 months with no plans to continue is not exclusionary. Participants in stable trauma-focused or non-trauma focused therapy must agree to continue treatment for the duration of participation in the study.
5. Has undergone or plans to undergo gender reassignment surgery. Note: participants who are currently undergoing stable hormone replacement therapy are eligible for inclusion in the study.
6. Meets DSM-5 (American Psychiatric Association 2013) criteria for moderate or severe alcohol use disorder (AUD) or other substance use disorders (SUDs), including cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, or stimulants within 3 months of screening. Nicotine use disorder is allowed.
7. Has a positive screen for illicit drugs (excluding cannabis) or recent heavy alcohol consumption (as possibly indicated by an elevated gamma-glutamyl transferase (GGT) or an elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio - to be interpreted in the context of other clinical information) at the Baseline visit.
8. Has a lifetime history or current symptoms of psychotic features, as determined by the Mini International Neuropsychiatric Interview (MINI) Psychotic Disorders and Mood Disorders with Psychotic Features screening questions.
9. Has a current diagnosis of obstructive sleep apnea (OSA) considered not well-managed (AHI ≥5) with C-, Bi-, or V PAP. Participants who have AHI ≥5 at Screening with the OSA screening device may repeat the OSA assessment prior to the Baseline visit or provide documentation from a physician stating that their C-, Bi-, or V-PAP machine AHI readings are \<5.
10. Has a history of neoplastic disease or completion of treatment in the last 5 years, except for treated basal cell or squamous cell carcinoma of the skin.
11. Has any clinically significant abnormal findings on the 12-lead electrocardiogram (ECG) at the Screening or Baseline visits, such as:.
1. Abnormal heart rhythm (such as atrial fibrillation, ventricular fibrillation, or torsade de pointes)
2. ECG with a QTc interval \>450 msec for males or \>470 msec for females (QT interval corrected with Fridericia correction \[QTcF\]).At Screening, eligibility will be based on the central ECG reading. At baseline, eligibility will be based on the local ECG reading by a qualified site investigator.
12. Has abnormal laboratory results at the Screening visit:
1. serum creatinine \>1.5 mg/dL OR
2. estimated creatinine clearance of \<50 mL/min calculated by the Cockcroft and Gault formula).
13. Has clinically significant abnormal laboratory results at the Screening visit that indicate impaired liver function:
1. ALT or AST \>2 × ULN
2. total bilirubin level \>1.5 × ULN (unless previously known Gilbert syndrome)
3. prolonged prothrombin time \>1.5 × ULN
14. Has a prior history of drug induced liver injury characterized by ALT or AST \>3 × upper limit of normal (ULN) AND total bilirubin level \>2 × ULN without cholestasis (ie, Alkaline Phosphatase \<2 × ULN).
15. Has any other clinically significant laboratory result at Screening that could impact the participant's safety or participation in the study, as determined by the Site PI.
16. Has any other concurrent psychiatric or medical condition that would impact the participant's safety, ability to appropriately complete evaluations, or participation in the study, as determined by the Site PI.
17. Does not have a stable method of contact over the duration of the study.
18. Is currently involved in litigation, medical evaluation for disability benefits or damages, or benefit examination related to the PTSD diagnosis.
19. Has participated in any interventional clinical trial or treatment with any investigational drug or other investigational intervention within 3 months or 5 half-lives, whichever is longer, of screening.
Note: Previous participation in an observational study is permitted.
Note: Subjects who are enrolled in the M-PACT, and who are eligible for re randomization, are permitted to remain in the study and receive alternative cohort intervention following a 14 day or 5 half-lives washout period, whichever is longer. The half-life of the parent drug (not metabolites) should be used in this calculation.
20. Is unavailable for the duration of the trial, unlikely to be compliant with the protocol, or deemed by the Site PI to be unsuitable for participation in the trial for any reason.
21. Systolic blood pressure \>140 mm Hg and/or diastolic blood pressure \>90 mm Hg or Systolic blood pressure \<90 mm Hg and/or diastolic blood pressure \<50 mm Hg.
