Cannabidiol-Assisted Learning for Managing Generalized Anxiety Disorder

Official title

Cannabidiol-Enhanced Cognitive Behavioral Therapy for Generalized Anxiety Disorder

Overview

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.

Detailed 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.

Interventions

• Drug Low-Dose Cannabidiol
  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.
• Drug Placebo Matched to Moderate-Dose Cannabidiol
  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.
• Drug Moderate-Dose Cannabidiol
  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.
• Drug Placebo Matched to Low-Dose Cannabidiol
  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.

Primary outcome measures

• Change in dorsomedial prefrontal cortex activation when reappraising negative images [Time frame: Baseline to post-treatment (~Week 5)]

Secondary outcome measures (12)

• Post-treatment dorsomedial prefrontal cortex activation when reappraising negative images [Time frame: Post-treatment (~Week 5)]
• Post-treatment amygdala activation when reappraising negative images [Time frame: Post-treatment (~Week 5)]
• Change in amygdala activation when reappraising negative images [Time frame: Baseline to post-treatment (~Week 5)]
• Post-treatment hippocampal activation when reappraising negative images [Time frame: Post-treatment (~Week 5)]
• Change in hippocampal activation when reappraising negative images [Time frame: Baseline to post-treatment (~Week 5)]
• Post-treatment inferior frontal gyrus activation when reappraising negative stimuli [Time frame: Post-treatment (~Week 5)]
• Change in inferior frontal gyrus activation when reappraising negative images [Time frame: Baseline to post-treatment (~Week 5)]
• Post-treatment anterior insula activation when reappraising negatives images [Time frame: Post-treatment (~Week 5)]
• Change in anterior insula activation when reappraising negative images [Time frame: Baseline to post-treatment (~Week 5)]
• Change in plasma concentration of anandamide from baseline to post-treatment [Time frame: Baseline and post-treatment (~Week 5)]
• Change in plasma concentration of 2-arachidonoylglycerol (2-AG) from baseline to post-treatment [Time frame: Baseline and post-treatment (~Week 5)]
• Change in plasma concentration of cannabidiol from baseline to post-treatment [Time frame: Baseline and post-treatment (~Week 5)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Wayne State University School of Medicine, Tolan Park Medical Building — Detroit

Publications

• Zabik NL, Iadipaolo A, Peters CA, Baglot SL, Hill MN, Rabinak CA. Dose-dependent effect of acute THC on extinction memory recall and fear renewal: a randomized, double-blind, placebo-controlled study. Psychopharmacology (Berl). 2026 Feb;243(2):235-250. doi: 10.1007/s00213-024-06702-w. Epub 2024 Oct 16. PMID 39412674
• Zabik NL, Rabinak CA, Peters CA, Iadipaolo A. Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder. Neurobiol Learn Mem. 2023 May;201:107758. doi: 10.1016/j.nlm.2023.107758. Epub 2023 Apr 22. PMID 37088409
• Pacitto R, Peters C, Iadipaolo A, Rabinak CA. Cannabinoid modulation of brain activation during volitional regulation of negative affect in trauma-exposed adults. Neuropharmacology. 2022 Nov 1;218:109222. doi: 10.1016/j.neuropharm.2022.109222. Epub 2022 Aug 15. PMID 35981598
• Mayo LM, Rabinak CA, Hill MN, Heilig M. Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation? Biol Psychiatry. 2022 Feb 1;91(3):262-272. doi: 10.1016/j.biopsych.2021.07.019. Epub 2021 Jul 24. PMID 34598785
• Gorka SM, Phan KL, Lyons M, Mori S, Angstadt M, Rabinak CA. Cannabinoid Modulation of Frontolimbic Activation and Connectivity During Volitional Regulation of Negative Affect. Neuropsychopharmacology. 2016 Jun;41(7):1888-96. doi: 10.1038/npp.2015.359. Epub 2015 Dec 9. PMID 26647971
• Gowatch LC, Evanski JM, Ely SL, Zundel CG, Bhogal A, Carpenter C, Shampine MM, O'Mara E, Mazurka R, Barcelona J, Mayo LM, Marusak HA. Endocannabinoids and Stress-Related Neurospsychiatric Disorders: A Systematic Review and Meta-Analysis of Basal Concentrations and Response to Acute Psychosocial Stress. Cannabis Cannabinoid Res. 2024 Oct;9(5):1217-1234. doi: 10.1089/can.2023.0246. Epub 2024 Apr 29. PMID 38683635

Identifiers

NCT: NCT07123467 · IRB-24-11-7333 · R61MH137105

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗