Anxiety, Inflammation, Stress, and Cannabinoids

Novel Approaches to Understanding the Role of Cannabinoids and Inflammation in Anxiety

This study investigates whether the anxiolytic effects and anti-inflammatory properties of cannabis vary as a function of the ratio of CBD to THC, with the goal that these effects may shed light on the mixed data linking cannabis use and anxiety. Individuals with mild to moderate anxiety who elect to use cannabis (smoked flower or edible) will complete four weeks of observation. Participants complete cognitive tasks, a substance use history, health questionnaires concerning sleep and physical activity, and a blood draw at four different time points (Baseline, after 2 weeks of cannabis use, and immediately before and after self-administration after 4 weeks of use) with the use of a mobile pharmacology laboratory, which goes to a convenient location for each participant to self-administer their cannabis. Participants are then followed for five months to self-report on cannabis use, anxiety, subjective cognitive functioning, sleep quality, and other mental health symptoms.

Study Overview

• Status: Completed
• Conditions: Inflammation; Anxiety Disorders; Anxiety; Inflammatory Response; Anxiety Generalized; Anxiety Chronic
• Intervention / Treatment: Drug: Cannabis (smoked flower, ingested edible)

Detailed Description

Marijuana use is on the rise with the number of adults reporting medical and recreational use doubling in the past decade. Among adult medical marijuana users, 39% report using marijuana for the purposes of self-treating or coping with anxiety. Marijuana is approved for medical use in over half the states and is gaining traction for use as an "off-label" add-on therapy for treatment-resistant anxiety and stress-related disorders. Paradoxically, however, while data suggest that marijuana, in particular ∆9-tetrahydrocannabinol (THC), increases anxiety acutely, cross sectional and longitudinal data suggest associations between marijuana use and lower risk for anxiety disorders.

There is some evidence demonstrating that marijuana use is associated with increases in acute anxiety and anxiety disorders. However, other data suggests that marijuana use may be protective for adolescents at-risk for anxiety and decrease the chances of developing an anxiety disorder during college. This finding is consistent with a growing body of evidence from animal models suggesting that marijuana has anxiolytic and anti-inflammatory properties. Clarifying the anxiolytic effects of specific strains that differ in their cannabinoid composition may explain these discrepant findings. Thus, regardless of whether results support or refute the anxiolytic properties of marijuana, findings from this study fill a critical void and can inform public perception.

The study goal is to understand the anxiolytic effects of cannabinoids, in particular the effects of THC-based strains vs. CBD-based strains vs strains containing both THC and CBD in different ratios (1:0, 1:1, or 0:1) on inflammation, cognitive functioning, and anxiety/negative affect. This design will capitalize on the novel opportunity to examine the effects of real world marijuana strains on key outcomes.

• Study Type: Observational
• Enrollment (Actual): 361

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Center for Innovation and Creativity

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Community Sample

Description

Inclusion Criteria:

• Non-users of cannabis must have been a non-user of cannabis for at least six months
• If a user of cannabis, at least one episode of lifetime cannabis use and a desire to use cannabis to cope with anxiety.
• Reports at least mild to moderate anxiety (≥5 on GAD-7)

Exclusion Criteria:

• Seeking treatment for a substance use disorder
• Current use of other drugs (e.g., cocaine, methamphetamine)
• Current use psychotropic or steroid-based medications
• Has an immune-relevant disease (e.g. HIV)
• Daily tobacco user
• Currently pregnant or trying to become pregnant
• In treatment for psychotic disorder, bipolar disorder or major depression disorder with suicidal ideation; or a history with these disorders.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Anxiety: Depression Anxiety Stress Scale (DASS21).	The DASS21 is a 21-item scale that measures self-reported change in anxiety, depression, and stress symptoms. Participants are asked to use 4-point severity/frequency scales (higher values indicate greater severity) to rate the extent to which they have experienced each state. Scores for Depression, Anxiety and Stress are calculated by summing the scores for the relevant items. Changes in DASS subscale self-report will be tested in relation to THC and CBD blood levels. For this aim, only the Anxiety subscale was used. Anxiety subscale score range 0-42 Normal 0-6; Mild 7-9; Moderate 10-14; Severe 15-19; Extremely severe 20-42	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)
Change in Inflammation: Circulating Levels of Cytokines (Panel of Inflammatory Markers).	Change in inflammation from before to after cannabis use will be tested in relation to THC and CBD blood levels. The sum concentration of the cytokines IL-1a, IL-1b, IL-6, IL-8, IL-12, and TNFα, which are generally regarded as pro-inflammatory, will be utilized. The range for these values can be from 0 to infinity. Higher values indicate higher (worse) levels of inflammation.	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)
Patient Global Impression of Change: Global Impression of Change Scale (PGIC).	Patient Global Impression of Change Scale (PGIC) measures self-reported change on a 1-7 scale (i.e. from 1 (very much worse) to 7 (very much improved) in anxiety. Changes in this measure will be tested in relation to THC and CBD blood levels. Scale possible score range 0-7, with higher scores indicating the largest amount of possible change.	This was administered only once, at the 4 week timepoint, asking participants to reflect on how much change they had experienced over the past 4 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Impairment: NIH Toolbox Cognitive Battery, Flanker Inhibitory Control Attention Task (FICA) and International Shopping List Test (ISLT).	Co-outcomes testing multiple domains of thinking, memory, and perception (NIH Toolbox), cognitive impairment in the domains of immediate and delayed recall (ISLT), attention and inhibitory control (FICA). Cognitive outcomes are measured in standard scores (e.g. Range of >70 to >140 (Mean of 100 and SD of 15) with higher scores indicating better performance) and can be averaged to reflect a Standard score of overall cognitive function.	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)
Self-Reported Affect in the Context of Negative Affect Induction Task	Participants reported levels of negative affect on a novel scale from -50 (worst) to +50 (best) while undergoing a guided rumination to induce negative affect.	Acute change in affect from before the negative affect induction task to post-breathing
Change in Depression: Depression Anxiety Stress Scale (DASS21).	The DASS21 is a 21-item scale that measures self-reported change in anxiety, depression, and stress symptoms. Participants are asked to use 4-point severity/frequency scales (higher values indicate greater severity) to rate the extent to which they have experienced each state. For this aim, only the Depression subscale was used. Depression subscale score range 0-21 Normal (0 to 4), Mild (5 to 6), Moderate, (7 to 10), Severe (11 to 13), Extremely Severe (14 and above)	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)
Health and Wellbeing	Self-report measure across primary domains of diet, assessment of sleep quality, and health-related well-being. Each domain was assessed with the following single items: Diet: "In general, how healthy is your overall diet? Would you say" (response options 0- excellent; 1- very good; 2- good; 3- fair; 4- poor) Sleep Quality: "During the past 2 weeks, how would you rate your sleep quality overall?" (response options 0- very good; 1- fairly good; 2- fairly bad; 3- very bad") Health Related Wellbeing: "In general, how would you describe your health?" (response options 0- excellent; 1- very good; 2- good; 3- fair; 4- poor)	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)
Motor Battery: Balance and Motor Function	Motor control assessed via dynamic sway, proprioception, and finger tapping rate. Motor outcomes can be aggregated via Z-score to reflect a Z-score of overall motor function. We calculated the sum of Motor Battery Balance (Eyes Open, Eyes Closed, and Head Back) z-scores. A score of 0 means a participant's balance is at the mean for the sample. Higher scores (scores greater than 0) correspond to worse balance compared to the sample. Scores lower than 0 indicate better balance compared to the sample.	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)
Objective Physical Activity/Exercise	Physical activity via objective daily data on wearable watch as measured by average minutes of moderate to vigorous physical activity (MVPA).	4 weeks
Physical Activity/Exercise	Physical activity via subjective self-report data using the Stanford Leisure-Time Activity Categorical item with 6 item responses (L-CAT; 1-6). Scores are reported as a mean between 1 and 6, larger numbers correspond to higher levels of activity.	4 weeks
Change in Stress: Depression Anxiety Stress Scale (DASS21).	The DASS21 is a 21-item scale that measures self-reported change in anxiety, depression, and stress symptoms. Participants are asked to use 4-point severity/frequency scales (higher values indicate greater severity) to rate the extent to which they have experienced each state. For this aim, only the Stress subscale was used. Stress subscale score range 0-33 Normal (0 to 14), Mild (15 to 18), Moderate, (19 to 25), Severe (26 to 33)	Change from baseline to 4 weeks: Baseline (before 4 weeks of cannabis use) and Post-Administration (after 4 weeks of use and after acute self-administration)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Daily Follow-Up Messages	Brief self-report from participants on anxiety and sleep in the past 24 hours. These are all 1-item novel questions in a daily, text based survey. Anxiety and sleep are on a scale of 1-10, with higher numbers being more anxiety or better sleep. Score is an average rating over 30 days.	One survey per day for 30 days (at the start of the 4 week study)
Exploratory: Monthly Follow-Up Surveys	Self-report from participants on anxiety (DASS anxiety subscale), sleep (novel sleep quality question ranging from 1-10 and 10 being best sleep), subjective cognitive functioning (perceived cognitive ability from the Functional Assessment of Cancer Therapy-Cognitive Function scale as was already reported in secondary measures- see for full description), and general health health (novel health question as was also reported in secondary measures- see for full description).	5 months (post-study completion)

Collaborators and Investigators

• Sponsor: University of Colorado, Boulder
• Collaborators: University of Colorado, Denver
• Investigators: Principal Investigator: Cinnamon Bidwell, PhD, University of Colorado, Boulder

Publications and helpful links

General Publications

• Skrzynski CJ, Rosa L, Drake A, Bryan AD, Bidwell LC. Experimental study on cannabis use and affect: Effects on reactivity to and recovery from negative stimuli. J Psychopathol Clin Sci. 2025 Aug;134(6):639-650. doi: 10.1037/abn0001023. Epub 2025 Jun 16.
• Bidwell LC, Martin-Willett R, Skrzynski C, Lisano J, Ortiz Torres M, Giordano G, Hutchison KE, Bryan AD. Acute and Extended Anxiolytic Effects of Cannabidiol in Cannabis Flower: A Quasi-Experimental ad libitum Use Study. Cannabis Cannabinoid Res. 2024 Aug;9(4):1015-1027. doi: 10.1089/can.2023.0187. Epub 2024 Jan 22.

Helpful Links

• OASIS Website, CU Change Lab, University of Colorado-Boulder

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2018
• Primary Completion (Actual): December 30, 2022
• Study Completion (Actual): May 17, 2023

Study Registration Dates

• First Submitted: February 28, 2018
• First Submitted That Met QC Criteria: April 5, 2018
• First Posted (Actual): April 9, 2018

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 25, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: anxiety; stress; cannabis; inflammation; marijuana
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Substance-Related Disorders; Chemically-Induced Disorders; Pathological Conditions, Signs and Symptoms; Anxiety Disorders; Inflammation; Marijuana Abuse; Generalized Anxiety Disorder; nabiximols
• Other Study ID Numbers: R01DA04413

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No