Cannabidiol-Assisted Learning for Managing Generalized Anxiety Disorder

NCT07123467 | Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: IRB-24-11-7333R61MH137105
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Generalized Anxiety Disorder (GAD); Anxiety Disorders

Keywords

Cannabidiol; EPIDIOLEX; Cognitive Behavioral Therapy; Generalized Anxiety Disorder; functional magnetic resonance imaging

Outcome Measures

Primary Outcomes (1)

• 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).

  Baseline to post-treatment (~Week 5)

Secondary Outcomes (18)

• Post-treatment dorsomedial prefrontal cortex activation when reappraising negative images

  Post-treatment (~Week 5)

• Post-treatment amygdala activation when reappraising negative images

  Post-treatment (~Week 5)

• Change in amygdala activation when reappraising negative images

  Baseline to post-treatment (~Week 5)

• Post-treatment hippocampal activation when reappraising negative images

  Post-treatment (~Week 5)

• Change in hippocampal activation when reappraising negative images

  Baseline to post-treatment (~Week 5)

Study Arms (4)

Brief Cognitive Behavioral Therapy + Moderate-Dose Cannabidiol

EXPERIMENTAL

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.

Drug: Moderate-Dose Cannabidiol

Brief Cognitive Behavioral Therapy + Low-Dose Cannabidiol

EXPERIMENTAL

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.

Drug: Low-Dose Cannabidiol

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

PLACEBO COMPARATOR

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.

Drug: Placebo Matched to Moderate-Dose Cannabidiol

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

PLACEBO COMPARATOR

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.

Drug: Placebo Matched to Low-Dose Cannabidiol

Interventions

Low-Dose Cannabidiol DRUG

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.

Also known as: EPIDIOLEX®

Brief Cognitive Behavioral Therapy + Low-Dose Cannabidiol

Placebo Matched to Moderate-Dose Cannabidiol DRUG

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.

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

Moderate-Dose Cannabidiol DRUG

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.

Also known as: EPIDIOLEX®

Brief Cognitive Behavioral Therapy + Moderate-Dose Cannabidiol

Placebo Matched to Low-Dose Cannabidiol DRUG

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.

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

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Wayne State University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Wayne State University School of Medicine, Tolan Park Medical Building

Detroit, Michigan, 48201, United States

RECRUITING

Related Publications (6)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Generalized Anxiety Disorder; Anxiety Disorders

Interventions

Cannabidiol

Condition Hierarchy (Ancestors)

Mental Disorders

Intervention Hierarchy (Ancestors)

Cannabinoids; Terpenes; Hydrocarbons; Organic Chemicals

Study Officials

• Hilary Marusak, PhD

  Wayne State University

  PRINCIPAL INVESTIGATOR

• Christine Rabinak, PhD, MBA

  Wayne State Universty

  PRINCIPAL INVESTIGATOR

• Leslie Lundahl, PhD

  Wayne State University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hilary Marusak, PhD

CONTACT

(313) 577-1278; hmarusak@med.wayne.edu

Christine Rabinak, PhD, MBA

CONTACT

(313) 577-9875; rabinak@wayne.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Department of Psychiatry and Behavioral Neuroscience

Study Record Dates

• First Submitted: August 2, 2025
• First Posted: August 14, 2025
• Study Start: November 3, 2025
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027
• Last Updated: March 9, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: 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.
• Access Criteria: 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.

Locations

US (1)