Generalized Anxiety Disorder (GAD)Phase 3CALMNCT07123467
Cannabidiol-Assisted Learning for Managing Generalized Anxiety Disorder
A Phase 3 study testing Low-Dose Cannabidiol and Moderate-Dose Cannabidiol in people with Generalized Anxiety Disorder (GAD) and Anxiety Disorders, run by Wayne State University at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Generalized Anxiety Disorder (GAD), Anxiety Disorders
- What is being tested?
- Low-Dose Cannabidiol and Moderate-Dose Cannabidiol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 90 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Nov 2025to 31 Aug 2027
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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)
Who cannot join
- 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
Show all 23Show fewer
- 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 locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Wayne State University School of Medicine, Tolan Park Medical Building
Detroit, Michigan, 48201
Hilary Marusak, PhD, (313) 577-1278, hmarusak@med.wayne.edu
Leslie Lundahl, PhD, (313) 993-1374, llundahl@med.wayne.edu
About this study
Official title: Cannabidiol-Enhanced Cognitive Behavioral Therapy for Generalized Anxiety Disorder
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.
Read the 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.
- Being tested
- Low-Dose Cannabidiol, Placebo Matched to Moderate-Dose Cannabidiol, Moderate-Dose Cannabidiol, Placebo Matched to Low-Dose Cannabidiol
- Keywords
- Cannabidiol, EPIDIOLEX, Cognitive Behavioral Therapy, Generalized Anxiety Disorder, functional magnetic resonance imaging
- Medical subject headings
- Generalized Anxiety Disorder, Anxiety Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low-Dose CannabidiolDrug
Also called EPIDIOLEX®
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.
Placebo Matched to Moderate-Dose CannabidiolDrug
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.
Moderate-Dose CannabidiolDrug
Also called EPIDIOLEX®
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.
Placebo Matched to Low-Dose CannabidiolDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Placebo Matched to Low-Dose Cannabidiol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline to post-treatment (~Week 5)
Secondary outcomes (18)
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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: Baseline and post-treatment (~Week 5)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2025
- Study start3 Nov 2025
- Primary completion31 Aug 2027 (estimated)
- Study completion31 Aug 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Generalized Anxiety Disorder (GAD)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Wayne State University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Hilary Marusak, Wayne State University
- Investigators
- Hilary Marusak, PhD, Principal investigator, Wayne State UniversityChristine Rabinak, PhD, MBA, Principal investigator, Wayne State UniverstyLeslie Lundahl, PhD, Principal investigator, Wayne State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07123467
- Sponsor's protocol ID
- IRB-24-11-7333
- Other IDs
- R61MH137105
- Acronym
- CALM
- Status last verified
- Oct 2026
- First submitted
- 2 Aug 2025
- Last updated
- 21 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual participant data (IPD) supporting the primary and secondary outcomes - including symptom measures, functional magnetic resonance imaging activation and connectivity metrics, and plasma concentrations of cannabidiol and metabolites - will be shared.
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.
PubMed 39412674Zabik 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.
PubMed 37088409Pacitto 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.
PubMed 35981598Mayo 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.
PubMed 34598785Gorka 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.
PubMed 26647971Gowatch 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.
PubMed 38683635
Study at a glance
From the registry record, last updated by the sponsor on 21 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cannabidiol-Enhanced Cognitive Behavioral Therapy for Generalized Anxiety Disorder
- ClinicalTrials.gov ID
- NCT07123467
- Acronym / sponsor ID
- CALM / IRB-24-11-7333
- Keywords
- Cannabidiol, EPIDIOLEX, Cognitive Behavioral Therapy, Generalized Anxiety Disorder, functional magnetic resonance imaging
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- Wayne State UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 3 Nov 2025 (actual)
- Primary completion
- 31 Aug 2027 (estimated)
- Study completion
- 31 Aug 2027 (estimated)
- First posted
- 14 Aug 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Brief Cognitive Behavioral Therapy + Moderate-Dose Cannabidiol | Experimental | Drug: Moderate-Dose CannabidiolParticipants 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. |
| Brief Cognitive Behavioral Therapy + Low-Dose Cannabidiol | Experimental | Drug: Low-Dose CannabidiolParticipants 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. |
| Brief Cognitive Behavioral Therapy + Placebo Titrated to Match Moderate-Dose Cannabidiol | Placebo comparator | Drug: Placebo Matched to Moderate-Dose CannabidiolParticipants 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. |
| Brief Cognitive Behavioral Therapy + Placebo Titrated to Match Low-Dose Cannabidiol | Placebo comparator | Drug: Placebo Matched to Low-Dose CannabidiolParticipants 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. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (23 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low-Dose CannabidiolAlso: EPIDIOLEX®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 | Brief Cognitive Behavioral Therapy + Low-Dose Cannabidiol |
| Placebo Matched to Moderate-Dose CannabidiolThe 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 | Brief Cognitive Behavioral Therapy + Placebo Titrated to Match Moderate-Dose Cannabidiol |
| Moderate-Dose CannabidiolAlso: EPIDIOLEX®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 | Brief Cognitive Behavioral Therapy + Moderate-Dose Cannabidiol |
| Placebo Matched to Low-Dose CannabidiolThe 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 | Brief Cognitive Behavioral Therapy + Placebo Titrated to Match Low-Dose Cannabidiol |
Primary outcome
Change in dorsomedial prefrontal cortex activation when reappraising negative images
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).
18 secondary outcomes
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)
Change in plasma concentration of 7-hydroxy-cannabidiol (7-OH-CBD) from baseline to post-treatment
Time frame: Baseline and post-treatment (~Week 5)
Post-treatment dorsomedial prefrontal cortex activation during implicit emotion regulation
Time frame: Post-treatment (~Week 5)
Change in dorsomedial prefrontal cortex activation during implicit emotion regulation
Time frame: Baseline to post-treatment (~Week 5)
Post-treatment ventromedial prefrontal cortex activation during implicit emotion regulation
Time frame: Post-treatment (~Week 5)
Change in ventromedial prefrontal cortex activation during implicit emotion regulation
Time frame: Baseline to post-treatment (~Week 5)
Change in depressive symptom severity
Time frame: Baseline and post-treatment (~Week 5)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Oct 2026.
- Background: PubMed 39412674Zabik 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.
- Background: PubMed 37088409Zabik 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.
- Background: PubMed 35981598Pacitto 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.
- Background: PubMed 34598785Mayo 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.
- Background: PubMed 26647971Gorka 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.
- Background: PubMed 38683635Gowatch 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.
- Individual participant dataSharing planned: Yes. De-identified individual participant data (IPD) supporting the primary and secondary outcomes - including symptom measures, functional magnetic resonance imaging activation and connectivity metrics, and plasma concentrations of cannabidiol and metabolites - will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Hilary Marusak, PhD principal investigator
Wayne State University
Christine Rabinak, PhD, MBA principal investigator
Wayne State Universty
Leslie Lundahl, PhD principal investigator
Wayne State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Low-Dose Cannabidiol and Moderate-Dose Cannabidiol in people with Generalized Anxiety Disorder (GAD) and Anxiety Disorders, run by Wayne State University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 21 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Hilary Marusak, PhD ((313) 577-1278, hmarusak@med.wayne.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in dorsomedial prefrontal cortex activation when reappraising negative images (time frame: Baseline to post-treatment (~Week 5)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07123467, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Oct 2026.