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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.
Locally preserved from ClinicalTrials.govOpen ClinicalTrials.govlast source update 2026-03-09
What this record can show
This locally preserved record separates the registered protocol from source-reported registry results. Neither is a treatment recommendation.
Registry facts
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.
Linked local records
Local links use governed condition terms or exact source-reported intervention names. They are navigation candidates, not efficacy claims.
Interventions
Oral cannabidiol solution (EPIDIOLEX®) administered as an adjunct to cognitive behavioral therapy. Low-dose participants receive 5 milligram/kilogram/day throughout. The intervention targets emotion regulation circuitry and symptom improvement.
EPIDIOLEX®The placebo mimics the appearance, smell, and taste of EPIDIOLEX®. For blinding the moderate-dose cannabidiol arm, dosing starts at 5 mg/kg/day and titrates to 10 milligram/kilogram/day (divided twice a day) after 6 days.
Oral cannabidiol solution (EPIDIOLEX®) administered as an adjunct to cognitive behavioral therapy. Moderate-dose participants receive 5 milligram/kilogram/day for 6 days, then titrate to 10 milligram/kilogram/day. The intervention targets emotion regulation circuitry and symptom improvement.
EPIDIOLEX®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.
Eligibility
primary outcomes
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in dorsomedial prefrontal cortex (dmPFC) activation will be calculated as post-treatment minus baseline values during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
secondary outcomes
Time frame: Post-treatment (~Week 5)
Post-treatment dorsomedial prefrontal cortex (dmPFC) activation during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Post-treatment (~Week 5)
Post-treatment amygdala activation during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in amygdala activation will be calculated as post-treatment minus baseline values during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Post-treatment (~Week 5)
Post-treatment hippocampal activation during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in hippocampal activation will be calculated as post-treatment minus baseline values during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Post-treatment (~Week 5)
Post-treatment inferior frontal gyrus activation during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Publications
No exact PMID-linked public article is currently readable locally.
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in inferior frontal gyrus activation will be calculated as post-treatment minus baseline values during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Post-treatment (~Week 5)
Post-treatment anterior insula activation during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in anterior insula activation will be calculated as post-treatment minus baseline values during an explicit emotion regulation task (Reappraise \> Maintain contrast). Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline and post-treatment (~Week 5)
Plasma anandamide levels will be measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and post-treatment. Change will be calculated as post-treatment minus baseline values (nanogram per milliliter).
Time frame: Baseline and post-treatment (~Week 5)
Plasma 2-arachidonoylglycerol (2-AG) levels will be measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and post-treatment. Change will be calculated as post-treatment minus baseline values (nanogram per milliliter).
Time frame: Baseline and post-treatment (~Week 5)
Plasma cannabidiol levels will be measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and post-treatment. Change will be calculated as post-treatment minus baseline values (nanogram per milliliter).
Time frame: Baseline and post-treatment (~Week 5)
7-hydroxy-cannabidiol (7-OH-CBD; active metabolite) levels will be measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and post-treatment. Change will be calculated as post-treatment minus baseline values (nanogram per milliliter).
Time frame: Post-treatment (~Week 5)
Post-treatment dorsomedial prefrontal cortex (dmPFC) activation during an implicit emotion regulation task. Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in dorsomedial prefrontal cortex (dmPFC) activation will be calculated as post-treatment minus baseline values during an implicit emotion regulation task. Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Post-treatment (~Week 5)
Post-treatment ventromedial prefrontal cortex (vmPFC) activation during implicit emotion regulation. Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline to post-treatment (~Week 5)
Within-participant change in ventromedial prefrontal cortex (vmPFC) activation will be calculated as post-treatment minus baseline values during an implicit emotion regulation task. Measured using blood-oxygen-level-dependent (BOLD) signal from multi-echo functional magnetic resonance imaging (fMRI).
Time frame: Baseline and post-treatment (~Week 5)
Change in depressive symptom severity will be assessed using the 9-item Patient Health Questionnaire (PHQ-9), a validated self-report instrument that measures symptoms of depression over the past two weeks. Each item is rated on a 0-3 scale, producing a total score ranging from 0 to 27, with higher scores indicating greater severity. Scores will be collected at baseline and post-treatment. Change will be calculated as post-treatment minus baseline score.