This randomized, double-blind, placebo-controlled clinical trial investigates the use of Food and Drug Administration (FDA)-approved cannabidiol (EPIDIOLEX®) as an adjunct to cognitive behavioral therapy (CBT) in adults with generalized anxiety disorder (GAD). The study aims to evaluate whether cannabidiol-assisted CBT enhances emotion regulation via dorsomedial prefrontal cortex (dmPFC) activation and improves anxiety symptom outcomes compared to CBT with placebo.

The study is a randomized, double-blind, placebo-controlled clinical trial evaluating cannabidiol (CBD) as an adjunct to cognitive behavioral therapy (CBT) for treating generalized anxiety disorder (GAD) in adults aged 18-45. Participants will be randomly assigned to one of four arms: (1) Brief CBT with moderate-dose EPIDIOLEX® (10 milligrams(mg)/kilograms(kg)/day), (2) Brief CBT with low-dose EPIDIOLEX® (5 mg/kg/day), (3) Brief CBT with matched placebo with dosing matched to the moderate-dose EPIDIOLEX®, or 4) Brief CBT with matched placebo with dosing matched to the low-dose EPIDIOLEX®. The trial uses a neurobiologically informed experimental medicine approach to evaluate target engagement in the dorsomedial prefrontal cortex (dmPFC) during an emotion regulation functional magnetic resonance imaging (fMRI) task before and after treatment. Primary outcomes include change in dmPFC activation, while secondary outcomes include anxiety symptom severity, treatment tolerability, and plasma concentrations of cannabidiol and related biomarkers.

Inclusion Criteria:

• Right-handed
• Age 18-45 years at enrollment
• Able to consent to the study
• Agree to adhere to lifestyle considerations throughout study duration
• Generally medically and neurologically healthy, including no evidence of intellectual disability or serious cognitive impairment
• Have a current generalized anxiety disorder (GAD) diagnosis according to the The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and/or total scores ≥ 8 on the 7-Item Generalized Anxiety Disorders Scale (GAD-7)

Exclusion Criteria:

• Clinically significant medical or neurologic condition or neurocognitive dysfunction that would affect function and/or task performance and/or interfere with the study protocol
• Any current (or within past 2 months) medical condition requiring medication that would interact with cannabidiol or interfere with the study protocol
• Risk of harm to self or others that requires immediate intervention
• Presence of contraindications, current or past allergic or adverse reaction, or known sensitivity to cannabinoid-like substances or components of EPIDIOLEX®
• Positive drug screen or alcohol breathalyzer
• Unwilling/unable to sign informed consent document
• Currently pregnant (positive pregnancy test), planning pregnancy, or lactating (women),
• Under 18 or over 45 years of age
• Traumatic brain injury, as defined by The American Congress of Rehabilitation as a person who has had a traumatically induced physiological disruption of brain function (i.e., the head being struck, the head striking an object, and/or the brain undergoing an acceleration/deceleration movement [i.e., whiplash] without direct external trauma to the head), as manifested by at least one of the following: any loss of consciousness; any loss of memory for events immediately before or after the injury; any alteration in mental status at the time of the incident; or focal neurological deficits that may or may not be transient)
• Inability to tolerate small, enclosed spaces without anxiety (e.g. claustrophobia), as determined by self-report and/or a preliminary session in a mock scanner
• Presence of ferrous-containing metals within the body (e.g., aneurysm clips, shrapnel/retained particles)
• Receiving concurrent psychotherapy or have received psychotherapy, including for research purposes, within the past year
• Current moderate or severe alcohol/drug use disorder or in the past 8 weeks
• Current or past diagnosis of bipolar and other related disorders, schizophrenia spectrum, or other psychotic disorders;
• GAD-7 score < 8
• Use of medications known to have severe drug interactions with cannabidiol or that are strong inducers of cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (CYP2C19)
• Visual impairment
• Baseline labs 3 times outside of normal range
• Use of as needed anti-anxiety medications (e.g., benzodiazepines), unstable dose of other psychoactive drug (i.e., < 4 weeks), or intention to start new treatment during this trial
• Current or past-month use of cannabis, or a tetrahydrocannabinol (THC) or cannabidiol-containing product (self-report and urine drug screen)
• Current or past-month coronavirus disease 2019 (COVID-19) diagnosis or febrile illness
• Treatment with another investigational drug or intervention within the past month
• Difficulty with or inability to comply with the complete clinical trial.

De-identified individual participant data (IPD) supporting the primary and secondary outcomes - including symptom measures, functional magnetic resonance imaging activation and connectivity metrics, and plasma concentrations of cannabidiol and metabolites - will be shared.

Individual participant data (IPD) will be shared beginning 12 months after publication of the primary study results and will remain available for at least 5 years thereafter.

Data will be made available to qualified researchers via the National Institute of Mental Health Data Archive (NDA). Access will be granted to investigators with an approved research proposal and appropriate data use agreement.

All participants, therapists, study staff, and outcomes assessors will be blinded to treatment assignment. Only the principal investigators hold the randomization and blinding key. Placebo is a matched oral solution designed to mimic EPIDIOLEX® in appearance, taste, and smell to maintain effective blinding.