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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
90
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.
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.
Wayne State University Eugene Applebaum College of Pharmacy & Health Sciences
Detroit, Michigan, United States
Wayne State University School of Medicine, Tolan Park Medical Building
Detroit, Michigan, United States
Change in dorsomedial prefrontal cortex activation when reappraising negative images
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).
Time frame: Baseline to post-treatment (~Week 5)
Post-treatment dorsomedial prefrontal cortex activation when reappraising negative images
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 when reappraising negative images
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: Post-treatment (~Week 5)
Change in amygdala activation when reappraising negative images
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: Baseline to post-treatment (~Week 5)
Post-treatment hippocampal activation when reappraising negative images
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).
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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.
Time frame: Post-treatment (~Week 5)
Change in hippocampal activation when reappraising negative images
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: Baseline to post-treatment (~Week 5)
Post-treatment inferior frontal gyrus activation when reappraising negative stimuli
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).
Time frame: Post-treatment (~Week 5)
Change in inferior frontal gyrus activation when reappraising negative images
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: Baseline to post-treatment (~Week 5)
Post-treatment anterior insula activation when reappraising negatives images
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: Post-treatment (~Week 5)
Change in anterior insula activation when reappraising negative images
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 to post-treatment (~Week 5)
Change in plasma concentration of anandamide from baseline to post-treatment
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)
Change in plasma concentration of 2-arachidonoylglycerol (2-AG) from baseline to post-treatment
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)
Change in plasma concentration of cannabidiol from baseline to post-treatment
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)
Change in plasma concentration of 7-hydroxy-cannabidiol (7-OH-CBD) from baseline to post-treatment
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: Baseline and post-treatment (~Week 5)
Post-treatment dorsomedial prefrontal cortex activation during implicit emotion regulation
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: Post-treatment (~Week 5)
Change in dorsomedial prefrontal cortex activation during implicit emotion regulation
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: Baseline to post-treatment (~Week 5)
Post-treatment ventromedial prefrontal cortex activation during implicit emotion regulation
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: Post-treatment (~Week 5)
Change in ventromedial prefrontal cortex activation during implicit emotion regulation
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 to post-treatment (~Week 5)
Change in depressive symptom severity
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.
Time frame: Baseline and post-treatment (~Week 5)