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

Safety and Efficacy of Cannabidiol (CBD) for Symptoms of Post-Traumatic Stress Disorder (PTSD) in Adults Using Liquid StructureTM Formulation (NantheiaTM ATL5).

Post-traumatic stress disorder (PTSD) is a psychiatric disorder than may develop following a traumatic event including serious incidents, natural or human-caused disasters, violence, death of a loved one, receipt of traumatic news, or serious illness/hospitalization. While half of US adults experience trauma in their lifetime, most do not develop PTSD. However, those who do develop the disorder may have significant impairments and risk for functional dysfunction across multiple domains. While short term symptoms are the most common, some individuals develop chronic PTSD. These individuals may experience frightening and intrusive thoughts and memories of the event (flashbacks), have sleep disturbances, feel numb or detached, and be easily startled (hypervigilance).

This trial is a double-blind placebo controlled study of cannabidiol (CBD) for symptoms of PTSD in adults using liquid structure Formulation (Nantheia ATL5). Participants complete three 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 participants are enrolled and complete baseline data collection only. All participants may complete optional functional magnetic resonance imaging (fMRI).

Post-traumatic stress disorder (PTSD) is a psychiatric disorder than may develop following a traumatic event including serious incidents, natural or human-caused disasters, violence, death of a loved one, receipt of traumatic news, or serious illness/hospitalization. While half of US adults experience trauma in their lifetime, most do not develop PTSD. However, those who do develop the disorder may have significant impairments and risk for functional dysfunction across multiple domains. While short term symptoms are the most common, some individuals develop chronic PTSD. These individuals may experience frightening and intrusive thoughts and memories of the event (flashbacks), have sleep disturbances, feel numb or detached, and be easily startled (hypervigilance).

This trial is a single-site phase II, double-blind, placebo-controlled study of Nantheia ATL5 to study symptoms of Post-Traumatic Stress Disorder (PTSD) in adults. Participants will meet criteria for PTSD using the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Assessment of Pragmatics (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 mobility and risk, and sleep dysfunction; neurobiological biomarkers of threat response (optional functional magnetic resonance imaging: fMRI), and serum inflammatory biomarkers (hs-CRP) implicated in PTSD pathophysiology will be assessed. Efficacy and tolerability will be assessed throughout intervention. Serum pregnancy (for participants of child bearing potential), urine drug screening, complete blood count (CBC), and Comprehensive Metabolic Panel are completed at every on-site visit. Optional consent will be sought from all PTSD and healthy population participants who agree to complete the functional magnetic resonance imaging (fMRI) procedures and providing an additional sample of blood to store for future unspecified research. Baseline characteristics of participants with PTSD will be evaluated overall and relative to participants without PTSD (healthy population) during a 3-week baseline period prior to randomization [Nantheia ATL5 or placebo (PBO)]. Healthy population participants will complete the study at end of baseline and participants 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.

Inclusion Criteria All Participants

• Ability and willingness to provide informed consent
• Stated willingness to comply with all study procedures and availability for duration of the study
• Aged 21-65 years
• Able to read and communicate in English
• Tetrahydrocannabinol (THC) use less than 3 days per week

PTSD Participants

• Meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for a current diagnosis of Post-Traumatic Stress Disorder (PTSD) on the Mini-Mental State examination (MMS), with symptoms present for at least 1 month
• Clinician administered Clinical Assessment of Pragmatics (CAPs) score ≥27 at study enrollment and start of Cannabidiol (CBD) observation
• Stable psychopharmacologic and/or psychotherapeutic intervention for 4 weeks prior to enrollment

Exclusion Criteria All Participants

• Current use of prescribed or commercially available CBD products, including Epidiolex®
• 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 within 6 months prior to enrollment)
• 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)
• Meets criteria for substance or alcohol use disorder of moderate or greater severity within 6 months prior to study enrollment based on the Mini-Mental State examination (MMS); nicotine dependence permitted
• Self-reported cannabis use on > 3 days/week starting 4 weeks prior to enrollment
• Positive urine drug screen for illicit substances other than cannabis
• Pregnant [confirmed by serum human chorionic gonadotropin (hCG) test], or breastfeeding
• 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]
• Treatment with another investigational drug or other intervention within 3 months prior to enrollment
• 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
• History of open head injury
• Self-report of exposure to trauma within 30 days prior to enrollment
• Active military service in the 30 days prior to enrollment
• Inpatient psychiatric hospitalization within 6 months prior to enrollment
• Seizure in the last 6 months
• Use of concomitant anti-viral human immunodeficiency virus (HIV) medications (PrEP permitted)

Control Participants

• History of diagnosed PTSD
• Pregnant (self-reported) or breastfeeding

Participants who consent to functional magnetic resonance imaging (fMRI) procedures

• Claustrophobia, pregnancy, or any condition (e.g., significant hearing difficulties) that would preclude MRI scanning, in the clinical judgment of the investigator
• Presence of metal objects in or on the body (e.g., 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)
• Other confounding medical conditions (e.g., Tourette's or Tic Disorder) that would preclude MRI scanning, in the clinical judgement of the investigator

PTSD Participants

• Index trauma before age 18 and no other traumatic experiences which could relate/identify as part of PTSD
• History of allergic reaction or significant adverse events (AE) related to cannabis, CBD, or THC
• Currently involved in events giving rise to PTSD
• 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 deemed to be of clinical significance in the judgement of the investigator and clinical team will be evaluated in the clinical context of the participant's history and physical examination to determine eligibility and testing may be repeated if clinically appropriate at the discretion of the investigator)
• Refusal to use at least one form of birth control throughout study participation [including, but are not limited to, male or female condoms, diaphragm, or cervical cap (all with or without spermicide) abstinence, or hormonal/implanted birth control, e.g., pill, injection, intra-uterine device (IUD), implant] by participants who can become pregnant