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Cannabidiol to Reduce Anxiety Reactivity

Primary Purpose

Social Anxiety, Social Anxiety Disorder

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cannabidiol
Placebo
Sponsored by
University of California, San Diego
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Social Anxiety focused on measuring Cannabidiol (CBD), Social Anxiety

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria: (1) Principal diagnosis of social anxiety disorder (SAD) according to the Mini-International Neuropsychiatric Interview for DSM-5 (MINI Version 7.0.2; Sheehan, 2016); (2) clinician-administered LSAS score ≥ 60 and score ≥ 2 on Question 6 (public speaking fear/anxiety sub-scale; Mennin et al., 2002); (3) ages 18-70; (4) able to provide informed, written consent; (5) English proficiency. Exclusion criteria are included to ensure that participation does not place subjects at undue risk, and to minimize confounding interpretation of our findings: Current or imminent risk of suicide assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) Bipolar or psychotic disorders History of major neurological disorder or moderate to severe traumatic brain injury or severe or unstable medical conditions that might be compromised by participation in the study. Past 6-month substance use disorder (any severity, with the exception of mild alcohol use disorder) Prior history of cannabis use disorder, or allergy or intolerance to cannabinoids Current (within past 7 days) cannabinoid use (medicinal or recreational; assessed using patient report and a urine sample). Concurrent cannabinoid use is prohibited during the study. Positive urinalysis screen for psychoactive drug use (that is not physician prescribed) Abnormal and clinically relevant blood count, liver, renal or EKG findings as determined by physician Currently prescribed medications with known CBD-interactions (e.g., amiodarone, fluconazole, metronidazole, miconazole, sulfamethoxazole, clarithromycin, erythromycin, cyclosporine, verapamil, itraconazole, voriconazole, boceprevir, St. John's Wart, and carbamazepine) People who are pregnant, breastfeeding, or planning to become pregnant within the next 6 months. People who are able to get pregnant who do not meet those exclusions must agree to use an acceptable method of contraception from at least 21 days prior to the first dose of study drug and for 3 months after the last dose of study drug for study entry. Concurrent empirically supported psychosocial treatments for anxiety or mood disorders (e.g., cognitive behavioral therapy) Use of any psychotropic medication (e.g. SSRIs, benzodiazepines) within 14 days before study entry [except for fluoxetine within 30 days]. Concurrent use is prohibited during the study. Use of beta-adrenergic blocking agents ("beta blockers") within 14 days before study entry. Concurrent use is prohibited during the study. Use of any over-the-counter, prescription, or herbal product for treating symptoms of anxiety or social anxiety within 14 days before study entry. Concurrent use is prohibited during the study. Inability to complete the assessments or test sessions. Clinical conditions assessed by the interviewer that necessitate more imminent clinical care. These criteria are in place so participants with these other, more several symptoms can be referred for appropriate services. Prior participation in a clinical trial involving cannabinoids. Non-correctable vision or hearing problems, as some tests require intact sensory functioning. No telephone or easy access to telephone. Severe depression symptoms (PHQ-9 >= 20)

Sites / Locations

  • University of California, San DeigoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Cannabidiol 900 mg/d

Cannabidiol 300 mg/d

Placebo

Arm Description

Participants will receive CBD (900 mg/d). Evenly split doses of 450 mg will be taken at morning and evening meals for 3 days, and a 450 mg dose will be taken in the morning of day 4 (before the post-test).

Participants will receive CBD (300 mg/d). Evenly split doses of 150 mg will be taken at morning and evening meals for 3 days, and a 150 mg dose will be taken in the morning of day 4 (before the post-test).

Participants will receive a CBD matching placebo. Evenly split doses will be taken at morning and evening meals for 3 days, and a dose will be taken in the morning of day 4 (before the post-test).

Outcomes

Primary Outcome Measures

Anandamide
Change in blood plasma levels of anandamide collected pre-stress task. A standardized mean difference (SMD) increase of 0.5 or greater in favor of CBD (either 300 mg/d or 900 mg/d) vs. placebo is defined as the primary biological target.
Change in state anxiety (SUDs) during stress task anticipation phase
Self-reported current feelings of anxiety using a 0 to 100 subjective units of distress scale. Higher scores reflect greater levels of anxiety. A standardized mean difference (SMD) decrease of 0.3 or greater in favor of CBD (either 300 mg/d or 900 mg/d) vs. placebo during the anticipation phase of the stress task is defined as one of two primary biobehavioral targets.
Change in state anxiety (SUDs) during stress task performance phase
Self-reported current feelings of anxiety using a 0 to 100 subjective units of distress scale. Higher scores reflect greater levels of anxiety. A standardized mean difference (SMD) decrease of 0.3 or greater in favor of CBD (either 300 mg/d or 900 mg/d) vs. placebo during the performance phase of the stress task is defined as one of two primary biobehavioral targets.

Secondary Outcome Measures

Change in state anxiety (STAI) during stress task anticipation phase
The Spielberger State-Trait Anxiety Inventory-State subscale (STAI-State) is a 20-item measure that uses a 4-point (1 to 4) Likert scale to assess current anxiety-related affect. Higher scores indicate greater current anxiety.
Change in state anxiety (STAI) following the stress task
The Spielberger State-Trait Anxiety Inventory-State subscale (STAI-State) is a 20-item measure that uses a 4-point (1 to 4) Likert scale to assess current anxiety-related affect. Higher scores indicate greater current anxiety.
Change in negative self-statements during the stress task
The Self-Statements during Public Speaking - Negative Self-Perception Scale (SSPS-N) is a 5-item scale that measures negative self-evaluations of one's performance on a 0 to 5 Likert scale. Higher scores reflect greater negative self-evaluations.

Full Information

First Posted
April 10, 2023
Last Updated
April 28, 2023
Sponsor
University of California, San Diego
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1. Study Identification

Unique Protocol Identification Number
NCT05823753
Brief Title
Cannabidiol to Reduce Anxiety Reactivity
Official Title
Endocannabinoid System Engagement to Reduce Anxiety Reactivity With Cannabidiol in Social Anxiety Disorder (R61 Project)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 19, 2023 (Actual)
Primary Completion Date
April 2025 (Anticipated)
Study Completion Date
April 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study seeks to understand how cannabidiol (CBD) - a non-intoxicating chemical compound obtained from the Cannabis sativa plant - affects biological and stress-related responses that are believed to underlie anxiety disorders. This study will evaluate the effects of different doses of CBD on blood plasma levels of anandamide (a molecule in the brain that has been shown to help regulate stress responses; primary biological signature) and anxiety reactivity to a standardized stress task (secondary target) in an acute (4-day) dosing study (i.e., when steady state CBD levels have been reached). Approximately 60 subjects with social anxiety disorder (SAD), ages 18-70, will participate in this study. They will be assigned by chance to receive one of two doses of CBD (150 mg BID or 450 mg BID administered in two divided doses daily) or placebo (which resembles the study drug but has no active ingredients) BID for 3 days and on the morning of day 4. Knowledge gained from this study will help determine the therapeutic potential of CBD for anxiety.
Detailed Description
Background and aims: The proposed two-phase, milestone driven project seeks to understand how cannabidiol (CBD) effects biological and stress-related responses that are believed to underlie anxiety disorders. This knowledge will help advance the therapeutic potential of CBD for anxiety. The R61 phase project will evaluate the dose-dependent effects of CBD on blood plasma levels of anandamide (a molecule in the brain that has been shown to help regulate stress responses; primary biological signature) and anxiety reactivity to a standardized stress task (secondary target) in an acute (4-day) dosing study (i.e., when steady state CBD levels have been reached). Aim 1 will test the hypothesis that CBD increases anandamide levels and decreases anxiety reactivity compared to placebo. Aim 2 will determine which dose (150 mg BID or 450 mg BID) of CBD produces a greater effect on anandamide and anxiety reactivity. To achieve these aims, 60 participants meeting diagnostic criteria for social anxiety disorder (SAD) will be randomized 1:1:1 to one of two doses of CBD (300 mg/day or 900 mg/day) or placebo. They will complete standardized paradigms assessing anxiety reactivity and blood draws for determination of CBD and anandamide levels at baseline and day 4. Research design and procedures: This phase II clinical trial will randomize 60 subjects using a double-blind, parallel group design, 1:1:1 to CBD (300 mg/day or 900 mg/day) or placebo. Randomization will be stratified by sex assigned at birth. Study personnel and subjects will be blinded throughout. Only the study biostatistician and pharmacist will be unblinded. Session 1 (intake session) will involve explanation of study procedures, informed written consent, a clinical evaluation, a series of questionnaires, medical exam and history including current treatments, and urine and blood test. This session will determine eligibility to take part in the study. Session 2 (baseline assessment session) will include vital signs, urine test, blood draw (to assess plasma CBD and endocannabinoid metabolites), state mood assessments, computerized tasks assessing responses to emotional faces, and reactivity to a standardized stress task. At the end of this session, subjects will receive their CBD/placebo dispensation kit and instructions for taking CBD/placebo from the study physician. The CBD product to be used in this study is Epidiolex® (Jazz Pharmaceuticals/Greenwich), a plant-derived, highly purified CBD oral solution that is FDA approved for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. Participants will receive CBD or placebo oral solution twice daily (evenly split doses at morning and evening meals) for three days (to achieve steady state) following the baseline assessment (day 0). Session 3 (post-test session) will occur on the morning of day 4 (time of day matched to baseline ±1h). Participants will be instructed to take their morning dose with a meal as done in previous days. Post-test assessments will be the same as those taken at baseline, including blood draw, urine test, state mood assessments, computerized tasks assessing responses to emotional faces, and reactivity to a standardized stress task. Frequency of adverse and serious adverse events (AE/SAEs) and medication adherence will be assessed by the study physician. At the end of this session, subjects will be debriefed and referred for additional care as appropriate.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Social Anxiety, Social Anxiety Disorder
Keywords
Cannabidiol (CBD), Social Anxiety

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
A phase II, 3-arm, sub-acute (4-day) steady state dosing clinical trial.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Identical taste, smell, color and viscosity of liquid provided in identical bottles. Each participant will receive two bottles, with instructions of how many ml to take BID from each of Bottle #1 and Bottle #2. The research pharmacy will label the bottles for each randomized participant so they take the dose to which they were randomized.
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cannabidiol 900 mg/d
Arm Type
Active Comparator
Arm Description
Participants will receive CBD (900 mg/d). Evenly split doses of 450 mg will be taken at morning and evening meals for 3 days, and a 450 mg dose will be taken in the morning of day 4 (before the post-test).
Arm Title
Cannabidiol 300 mg/d
Arm Type
Active Comparator
Arm Description
Participants will receive CBD (300 mg/d). Evenly split doses of 150 mg will be taken at morning and evening meals for 3 days, and a 150 mg dose will be taken in the morning of day 4 (before the post-test).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will receive a CBD matching placebo. Evenly split doses will be taken at morning and evening meals for 3 days, and a dose will be taken in the morning of day 4 (before the post-test).
Intervention Type
Drug
Intervention Name(s)
Cannabidiol
Other Intervention Name(s)
Epidiolex
Intervention Description
The CBD product to be used in this study is Epidiolex (Jazz Pharmaceuticals/Greenwich), a plant-derived, highly purified CBD oral solution that is FDA approved for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. Doses will be 300 mg/d or 900 mg/d according to participants' assigned condition. Participants will receive CBD or placebo oral solution twice daily (evenly split doses at morning and evening meals) for three days (to achieve steady state) following the baseline assessment (day 0), and in the morning of day 4 (before the post-test).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo solution (excipients only, also by Jazz Pharmaceuticals/Greenwich).
Primary Outcome Measure Information:
Title
Anandamide
Description
Change in blood plasma levels of anandamide collected pre-stress task. A standardized mean difference (SMD) increase of 0.5 or greater in favor of CBD (either 300 mg/d or 900 mg/d) vs. placebo is defined as the primary biological target.
Time Frame
Baseline, day 4
Title
Change in state anxiety (SUDs) during stress task anticipation phase
Description
Self-reported current feelings of anxiety using a 0 to 100 subjective units of distress scale. Higher scores reflect greater levels of anxiety. A standardized mean difference (SMD) decrease of 0.3 or greater in favor of CBD (either 300 mg/d or 900 mg/d) vs. placebo during the anticipation phase of the stress task is defined as one of two primary biobehavioral targets.
Time Frame
Baseline, day 4
Title
Change in state anxiety (SUDs) during stress task performance phase
Description
Self-reported current feelings of anxiety using a 0 to 100 subjective units of distress scale. Higher scores reflect greater levels of anxiety. A standardized mean difference (SMD) decrease of 0.3 or greater in favor of CBD (either 300 mg/d or 900 mg/d) vs. placebo during the performance phase of the stress task is defined as one of two primary biobehavioral targets.
Time Frame
Baseline, day 4
Secondary Outcome Measure Information:
Title
Change in state anxiety (STAI) during stress task anticipation phase
Description
The Spielberger State-Trait Anxiety Inventory-State subscale (STAI-State) is a 20-item measure that uses a 4-point (1 to 4) Likert scale to assess current anxiety-related affect. Higher scores indicate greater current anxiety.
Time Frame
Baseline, day 4
Title
Change in state anxiety (STAI) following the stress task
Description
The Spielberger State-Trait Anxiety Inventory-State subscale (STAI-State) is a 20-item measure that uses a 4-point (1 to 4) Likert scale to assess current anxiety-related affect. Higher scores indicate greater current anxiety.
Time Frame
Baseline, day 4
Title
Change in negative self-statements during the stress task
Description
The Self-Statements during Public Speaking - Negative Self-Perception Scale (SSPS-N) is a 5-item scale that measures negative self-evaluations of one's performance on a 0 to 5 Likert scale. Higher scores reflect greater negative self-evaluations.
Time Frame
Baseline, day 4
Other Pre-specified Outcome Measures:
Title
Change in anxiety-related behavior during stress task
Description
Observer-rated participant behavior during the stress task using 6 items reflecting the anxiety-related behaviors commonly displayed during social-evaluative stress (e.g., fidget, appear tense or rigid). Items are rated on a 7-point scale (1 to 7) from not at all to very much. Higher scores reflect greater anxious behavior.
Time Frame
Baseline, day 4
Title
Change in Emotional Attention Bias
Description
Attentional bias (AB) for positive (happy) and negative (disapproving) faces will be measured by computing response latency differences to identify a visual probe that replaces the emotional stimulus compared to a neutral stimulus. Higher scores reflect greater AB for the emotional stimuli.
Time Frame
Baseline, day 4
Title
Change in Emotion Recognition
Description
A discriminability (d') index based on signal detection theory will be computed to measure subjects' ability to detect subtle emotion displays across varying intensities of six basic emotions (happiness, surprise, sadness, fear, anger and disgust), which are morphed between each prototype and a neutral face.
Time Frame
Baseline, day 4
Title
Change in behavior on a Driving task
Description
A simulated 1-dimensional driving task. The position of a virtual car is controlled with a gaming joystick. In each trial, subjects are instructed to drive the car as quickly as possible and stop as close as possible to a stop sign without crossing the stop-line. Behavior on this task can be modelled according to continuous adjustments in response to both current error and predicted future error, and has been shown to be predictive of self-reported fear. There are two computed parameters for the driving task, Kp (a driving parameter) and Kd (a damping parameter).
Time Frame
Baseline, day 4
Title
Change in approach-avoidance motivations - Social Approach-Avoidance Paradigm (SAAP)
Description
The SAAP measures the degree to which morphed facial expressions elicit motivation to approach and avoid another individual. On each trial in the SAAP, participants are presented with a single facial expression and asked to self-report the degree to which they would like to approach and avoid.
Time Frame
Baseline, day 4
Title
Change in safety behaviors during the stress task
Description
Safety behavior change will be assessed using the Safety Behavior Questionnaire. Items are rated on a 9-point scale ranging from 0 (not at all) to 8 (all the time). Higher scores indicate greater use of safety behaviors during the stress task.
Time Frame
Baseline, day 4
Title
Change in cannabinoid metabolites collected pre-stress task
Description
Blood plasma levels of 6-OH-CBD (6-hydroxy-cannabidiol), 7-OH-CBD (7-hydroxycannabidiol) and 7-COOH-CBD (7-carboxy-cannabidiol).
Time Frame
Baseline, day 4
Title
Change in 2-arachidonoylglycerol (2-AG) collected pre-stress task
Description
Blood plasma levels of 2-arachidonoylglycerol (2-AG).
Time Frame
Baseline, day 4
Title
Change in N palmitoylethanolamide (PEA) collected pre-stress task
Description
Blood plasma levels of N palmitoylethanolamide (PEA).
Time Frame
Baseline, day 4
Title
Change in N oleoylethanolamide (OEA) collected pre-stress task
Description
Blood plasma levels of N oleoylethanolamide (OEA).
Time Frame
Baseline, day 4
Title
Change in blood plasma levels of cannabidiol collected pre-stress task
Description
Blood plasma levels of cannabidiol (CBD).
Time Frame
Baseline, day 4
Title
Change in threat-related predictions collected before the stress task
Description
Self-ratings of (a) the perceived probability and (b) the perceived cost (consequence) of participants' most feared outcome occurring during the stress task ranging from 0 (not at all likely/bad) to 100 (extremely likely/bad). Higher scores reflect greater threat-related expectancies.
Time Frame
Baseline, day 4
Title
Change in threat-related outcomes collected after the stress task
Description
Self-ratings of (a) the perceived occurrence and (b) the perceived cost (consequence) of participants' most feared outcome occurring during the stress task ranging from 0 (not at all) to 100 (completely/extremely bad). Higher scores reflect greater threat-related outcome perceptions.
Time Frame
Baseline, day 4
Title
Global Rating of Change
Description
Participant reported perceptions of change from baseline (day 0) in response to the stress task. Change is rated on a 7-point scale ranging from 'much worse' to 'much better'
Time Frame
Day 4
Title
Global Satisfaction with Change
Description
Participant reported satisfaction with the amount of perceived change from baseline (day 0) in response to the stress task. Satisfaction is rated on a 7-point scale ranging from 'very dissatisfied' to 'very satisfied'
Time Frame
Day 4

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: (1) Principal diagnosis of social anxiety disorder (SAD) according to the Mini-International Neuropsychiatric Interview for DSM-5 (MINI Version 7.0.2; Sheehan, 2016); (2) clinician-administered LSAS score ≥ 60 and score ≥ 2 on Question 6 (public speaking fear/anxiety sub-scale; Mennin et al., 2002); (3) ages 18-70; (4) able to provide informed, written consent; (5) English proficiency. Exclusion criteria are included to ensure that participation does not place subjects at undue risk, and to minimize confounding interpretation of our findings: Current or imminent risk of suicide assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) Bipolar or psychotic disorders History of major neurological disorder or moderate to severe traumatic brain injury or severe or unstable medical conditions that might be compromised by participation in the study. Past 6-month substance use disorder (any severity, with the exception of mild alcohol use disorder) Prior history of cannabis use disorder, or allergy or intolerance to cannabinoids Current (within past 7 days) cannabinoid use (medicinal or recreational; assessed using patient report and a urine sample). Concurrent cannabinoid use is prohibited during the study. Positive urinalysis screen for psychoactive drug use (that is not physician prescribed) Abnormal and clinically relevant blood count, liver, renal or EKG findings as determined by physician Currently prescribed medications with known CBD-interactions (e.g., amiodarone, fluconazole, metronidazole, miconazole, sulfamethoxazole, clarithromycin, erythromycin, cyclosporine, verapamil, itraconazole, voriconazole, boceprevir, St. John's Wart, and carbamazepine) People who are pregnant, breastfeeding, or planning to become pregnant within the next 6 months. People who are able to get pregnant who do not meet those exclusions must agree to use an acceptable method of contraception from at least 21 days prior to the first dose of study drug and for 3 months after the last dose of study drug for study entry. Concurrent empirically supported psychosocial treatments for anxiety or mood disorders (e.g., cognitive behavioral therapy) Use of any psychotropic medication (e.g. SSRIs, benzodiazepines) within 14 days before study entry [except for fluoxetine within 30 days]. Concurrent use is prohibited during the study. Use of beta-adrenergic blocking agents ("beta blockers") within 14 days before study entry. Concurrent use is prohibited during the study. Use of any over-the-counter, prescription, or herbal product for treating symptoms of anxiety or social anxiety within 14 days before study entry. Concurrent use is prohibited during the study. Inability to complete the assessments or test sessions. Clinical conditions assessed by the interviewer that necessitate more imminent clinical care. These criteria are in place so participants with these other, more several symptoms can be referred for appropriate services. Prior participation in a clinical trial involving cannabinoids. Non-correctable vision or hearing problems, as some tests require intact sensory functioning. No telephone or easy access to telephone. Severe depression symptoms (PHQ-9 >= 20)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Taylor Smith, BS
Phone
858-534-6407
Email
trs004@health.ucsd.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Nuzhat Beg, MBBS, MAS
Email
nbeg@health.ucsd.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Murray B Stein, MD, MPH
Organizational Affiliation
University of California, San Diego
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Charles Taylor, PhD
Organizational Affiliation
University of California, San Diego
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Deigo
City
San Diego
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Taylor Smith, BS
Phone
858-534-6407
Email
trs004@health.ucsd.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Cannabidiol to Reduce Anxiety Reactivity

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