Cannabinoids and Traumatic Brain Injury: A Randomized, Placebo Controlled Trial

To better understand the effects of hemp-derived CBD with and without a small amount of THC, we propose a Phase II randomized clinical trial (RCT) to examine the safety, tolerability, and clinical effects of Full Spectrum CBD (fsCBD, contains less than 0.3% THC) vs. Broad Spectrum CBD (bsCBD, does not contain THC), vs. a matching placebo in a population of patients with traumatic brain injury.

This is a double-blind, placebo-controlled, parallel group study designed to assess the tolerability and efficacy of fsCBD and bsCBD, compared to a placebo control, to improve cognition and TBI-related symptoms such as anxiety, pain, depression, and sleep. If eligible for the study, subjects will be randomized to receive one of the conditions for 12 weeks.

The initial Week 0 / Baseline visit will take place at the University of Colorado Anschutz Medical Campus. There will be in-person visits at Weeks 1, 6, and 12. Participants will be contacted remotely each remaining week during the 12-week period.

Inclusion criteria

• Ability to provide valid informed consent
• 18-60 years old
• Current or history of TBI as identified by the Ohio Identification Method
• TBI severity is mild or moderate based on the VA/DoD Classification of TBI Severity
• TBI event must have resulted in hospital evaluation (emergency department or other hospital-based assessment) or evaluation within a clinical setting, except in cases in which the TBI was acquired in a military deployment context in which medical services were not immediately available
• Ongoing neuropsychiatric symptoms (i.e., depressive, anxiety, pain, cognitive complaints, or sleep complaints) that are plausibly associated with TBI and not better accounted for by co-occurring medical or psychological health conditions
• Not currently in another treatment study for TBI-related symptoms or co-occurring medical or psychological health conditions
• Co-occurring treatments must be stable in type, dose, and frequency for the four weeks preceding study enrollment and participants must commit to making no changes in these co-occurring treatments during the study

Exclusion criteria

• Currently incarcerated, paroled, or on probation
• Participant has retained an attorney in relation to the TBI
• Pregnant at the time of study enrollment or unwilling to commit to the use of two forms of contraception throughout the duration of the study
• Vision, hearing, or communication impairments that preclude valid completion of study assessments
• History of autism spectrum disorders, intellectual disability, and/or serious neurological or central nervous system disease that would be expected to affect cognition (e.g., epilepsy, tumors, multiple sclerosis)
• Evidence of poor effort (TOMMe < 8) on neuropsychological testing at baseline/Week 0
• Current or lifetime diagnosis of a schizophrenia spectrum disorder, psychotic disorder, bipolar disorder type I & II, cluster B personality disorders (antisocial, borderline, narcissistic, histrionic), eating disorders, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022)
• Meets criteria for major depressive episode as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022) and with a Beck Depression Inventory-2 score > 24;
• Current suicidal ideation, as indicated by Beck Depression Inventory-2 item #9 score > 0, or C-SSRS endorsement of item #2, or verbal or written report of current suicidal ideation by the participant to any study team member
• History of significant systemic illness or unstable medical condition
• Alcohol use disorder score of 5 or greater, or substance use disorder, based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022), in the six months preceding study enrollment
• Reported use of other drugs (cocaine, opiates, methamphetamine, MDMA) in the past 60 days or test positive on a urine test for those drugs of abuse at baseline;
• Currently taking medications known to be contraindicated with Epidiolex (buprenorphine, leflunomide, levomethadyl acetate, lomitapide, mipomersen, pexidartinib, propoxyphene, sodium oxybate, teriflunomide, clobazam, lamotrigine, valproate).
• Current diagnosis of a seizure disorder or epilepsy
• Report using cannabis once daily or more than once daily over the last 12 months
• Report current use of CBD for medical reasons or TBI symptoms
• Liver function enzymes (AST, ALT) that are greater than 2x normal