Cannabidiol-Assisted Learning for Managing Generalized Anxiety Disorder (CALM)

Wayne State University

Status and phase: Not yet enrolling; Phase 3

Conditions: Generalized Anxiety Disorder (GAD); Anxiety Disorders

Treatments: Drug: Moderate-Dose Cannabidiol; Drug: Low-Dose Cannabidiol; Drug: Placebo Matched to Low-Dose Cannabidiol; Drug: Placebo Matched to Moderate-Dose Cannabidiol

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07123467

R61MH137105 (U.S. NIH Grant/Contract)

IRB-24-11-7333

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 90 estimated patients

Sex: All

Ages: 18 to 45 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

90 participants in 4 patient groups, including a placebo group

Brief Cognitive Behavioral Therapy + Moderate-Dose Cannabidiol

Experimental group

Description:

Participants will receive a 5-week course of brief cognitive behavioral therapy (CBT) combined with oral cannabidiol (EPIDIOLEX®) at a moderate dose. Dosing starts at 5 milligram/kilogram/day and titrates to 10 milligram/kilogram/day (divided twice a day) after 6 days. Cannabidiol is administered chronically throughout CBT to examine target engagement and symptom outcomes.

Treatment:

Drug: Moderate-Dose Cannabidiol

Brief Cognitive Behavioral Therapy + Low-Dose Cannabidiol

Experimental group

Description:

Participants will receive a 5-week course of brief cognitive behavioral therapy (CBT) combined with a lower dose of oral cannabidiol (EPIDIOLEX®), maintained at 5 milligram/kilogram/day (divided twice a day) throughout the treatment period. No titration is required.

Treatment:

Drug: Low-Dose Cannabidiol

Brief Cognitive Behavioral Therapy + Placebo Titrated to Match Moderate-Dose Cannabidiol

Placebo Comparator group

Description:

Participants will receive a 5-week course of brief cognitive behavioral therapy (CBT) combined with a matched placebo oral solution. The placebo mimics the appearance, smell, and taste of EPIDIOLEX®. For blinding the moderate dose cannabidiol arm, dosing starts at 5 milligram/kilogram/day and titrates to 10 milligram/kilogram/day (divided twice a day) after 6 days.

Treatment:

Drug: Placebo Matched to Moderate-Dose Cannabidiol

Brief Cognitive Behavioral Therapy + Placebo Titrated to Match Low-Dose Cannabidiol

Placebo Comparator group

Description:

Participants will receive a 5-week course of brief cognitive behavioral therapy (CBT) combined with a matched placebo oral solution. The placebo mimics the appearance, smell, and taste of EPIDIOLEX®. For blinding the low-dose cannabidiol arm, dosing is maintained at 5 milligram/kilogram/day (divided twice a day) throughout the treatment period. No titration is required.

Treatment:

Drug: Placebo Matched to Low-Dose Cannabidiol