Safety and Efficacy of Cannabidiol (CBD) for Symptoms of PTSD in Adults

Double-blind placebo controlled study of Cannabidiol (CBD) for symptoms of PTSD in adults using liquid structure(TM) Formulation (Nantheia ATL5(TM)). Subjects complete 3 weeks of baseline data collection including assessments of activity and sleep. Intervention is Nantheia ATL5 or placebo. Dose is initiated at 400mg BID and maintained over 8 weeks. Standardized symptom profile measurements, clinician assessments, laboratory testing, collection of inflammatory biomarkers, and suicide screening is completed throughout. Age- and gender-matched healthy population subjects are enrolled and complete baseline data collection only. All subjects may complete optional procedures of driving assessments and functional MRI (fMRI).

This study is a single-site phase II, double-blind, placebo-controlled study of Nantheia ATL5 for symptoms of Post-Traumatic Stress Disorder (PTSD) in adults. Subjects will meet criteria for PTSD using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) of ≥ 27. Suicidality is assessed using the Columbia Suicide Severity Rating Scale-Revised (CSSRS-R) at all study visits. Baseline psychopharmacotherapy and/or psychotherapy must be stable (unchanged) for 4 weeks prior to enrollment, and should remain unchanged during study treatment. Effects of Nantheia ATL5 on self-reported quality of life (overall and health-related); functional status measurements of personal and driving (optional) mobility and risk, and sleep dysfunction; neurobiological biomarkers of threat response (optional functional magnetic resonance imaging: fMRI), and serum inflammatory biomarkers (CRP) implicated in PTSD pathophysiology will be assessed. Efficacy and tolerability will be assessed throughout intervention. Serum pregnancy (for subjects of child bearing potential), urine drug screening, CBC, and Comprehensive Metabolic Panel are completed at every on-site visit. Optional consent will be sought from all PTSD and healthy population subjects who agree to complete the fMRI procedures, the driving measures, and providing an additional sample of blood to store for future unspecified research. Baseline characteristics of subjects with PTSD will be evaluated overall and relative to subjects without PTSD (healthy population) during a 3-week baseline period prior to randomization (Nantheia ATL5 or placebo \[PBO\]). Healthy population subjects will complete the study at end of baseline and subjects with PTSD will be randomized 1:1 to Nantheia ATL5 or placebo (PBO). Study drug dose is initiated at 400mg BID and maintained for 8 weeks. Study drug is then withdrawn, and one week later safety measures including laboratory testing, assessment of AE's and CSSRS-R are repeated.

Eligibility Criteria:
Inclusion Criteria:

All Subjects:

1. Ability and willingness to provide informed consent
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged 21-65
4. Able to read and communicate in English.
5. THC use must be less than 3 days per week

Subjects who consent to driving procedures:

1. Legally licensed and experienced drivers (\>3 years driving experience), including a corrected or uncorrected visual acuity of \<20/50 OU (to meet state driving requirements for vision).
2. Active drivers (≥1hr or 25 miles driving per week). Driving a single car at least 90% of driving time (to permit installation of study driving equipment) and have car insurance for the vehicle used in the study.

PTSD Subjects

1. Meets DSM-5 diagnostic criteria for a current diagnosis of Post-Traumatic Stress Disorder on the MINI, with symptoms present for at least 1 month.
2. Clinician administered CAPS-5 score ≥27 at study induction and start of CBD observation.
3. Stable psychopharmacologic and/or psychotherapeutic intervention for 4 weeks prior to enrollment.

Exclusion Criteria:

All Subjects:

1. Current use of prescribed or commercially available CBD products, including Epidiolex®.
2. Suicidal ideation (as defined by answer of "yes" to item 4 or 5 on the baseline Columbia Suicide Severity Rating Scale (C-SSRS) or attempt in the 6 months prior to enrollment.
3. Cognitive impairment in the clinical judgment of the investigator that would impact ability to complete study assessments or confound study results (e.g., neurodegenerative condition or other).
4. Meets criteria for substance or alcohol use disorder of moderate or greater severity in the 6 months prior to study entry based on the MINI. Nicotine dependence is permitted.
5. Self-reported cannabis use on \> 3 days/week starting 4 weeks prior to enrollment.
6. Positive urine drug screen for illicit substances other than cannabis.
7. Pregnant, measured by serum hCG test, or breastfeeding.
8. Co-morbid medical conditions or concomitant treatments that may adversely impact ability to participate in the trial in the clinical judgment of the investigator. E.g., significant immunosuppression due to active chemotherapy, recent organ transplant, uncontrolled diabetes, glomerular filtration rate (GFR) \< 25ml/min or on dialysis, recent acute myocardial infarction (MI), Class IV heart failure, or taking any high-risk drugs for drug-drug interactions (see Appendix A).
9. Treatment with another investigational drug or other intervention within the 3 months prior to enrollment.
10. History of psychosis (schizophrenia, schizophreniform disorder, schizoaffective disorder, or substance induced psychosis), active bipolar disorder, or borderline personality disorder diagnosed by a mental health professional.
11. History of open head injury
12. Self-report of exposure to trauma in the 30 days prior to enrollment.
13. Active military service in the 30 days prior to enrollment.
14. Inpatient psychiatric hospitalization within 6 months prior to enrollment.
15. Seizure in the last 6 months.
16. Use of concomitant anti-viral HIV medications (PrEP is permitted).

Control Subjects:

1. No history of diagnosed PTSD.
2. Pregnant, measured by self-report, or breastfeeding

Subjects who consent to fMRI procedures:

1. Claustrophobia, pregnancy, or any condition (e.g., significant hearing difficulties) that would preclude MRI scanning in the clinical judgment of the investigator.
2. Presence of metal objects in or on the body such as pacemakers, aneurysm clips, metallic prostheses, bone plates, braces, orthodontic devices, cochlear implants/hearing aids, non-removable piercings/implants or metallic-ink tattoos, or shrapnel fragments.
3. Other confounding medical conditions (e.g., Tourette's or Tic Disorder) that would preclude MRI scanning in the clinical judgement of the investigator.

   PTSD Subjects:

17. Index trauma before age 18 and no other traumatic experiences which could relate/identify as part of PTSD.

18. Any history of allergic reaction or significant AEs related to cannabis, CBD, or THC.

19. Currently involved in events giving rise to the disease. 20. Alanine transaminase (ALT)/Aspartate transaminase (AST)/Bilirubin \> 2 x upper limit of normal (ULN) at screening. Abnormalities on the comprehensive metabolic panel or complete blood count which are deemed to be of clinical significance in the judgement of the investigator and clinical team will be evaluated in the clinical context of the subject's history and physical examination to determine eligibility. Testing may be repeated if clinically appropriate at the discretion of the investigator.

21. For subjects of who can become pregnant, refusal to use at least one form of birth control throughout study participation. Forms of birth control may include, but are not limited to, condoms (male or female) with or without spermicide, diaphragm, or cervical cap with or without spermicide, abstinence, or hormonal or implanted birth control (e.g., pill, injection, intra-uterine device \[IUD\], implant).