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Alcohol and Cannabis Co-Use and the Gut-Brain Axis (FRACTAL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04998006
Recruitment Status : Recruiting
First Posted : August 10, 2021
Last Update Posted : July 13, 2022
Sponsor:
Collaborator:
University of Colorado, Boulder
Information provided by (Responsible Party):
Hollis Karoly, Colorado State University

Brief Summary:
This observational study aims to improve our understanding of how legal market cannabis use impacts acute and long-term alcohol use, the microbiota-gut-brain-axis (MGBA), and neurobehavioral alcohol use phenotypes such as impulsivity, impaired cognitive functioning, and craving, among individuals who regularly use both alcohol and cannabis. Over a period of one month, subjects will participate in this three-visit study. Blood samples will be collected to allow for the assessment of inflammatory markers and cannabinoids, a fecal sample will be collected to allow for the analysis of the gut microbiome, and participants will complete cognitive and impulsivity tasks and provide craving ratings during the course of an alcohol self-administration procedure. Subjects will also participate in two 14-day daily diary data collection periods between lab sessions. Daily diary data collection will be used to assess the effects of cannabis use on alcohol use and craving longitudinally.

Condition or disease Intervention/treatment
Cannabis Use Alcohol Use Inflammation Drug: Alcohol and Cannabis vs. Alcohol only

Detailed Description:

At present, the consumption of alcohol and alcohol use disorder (AUD) constitute a public health crisis. Due to the neurobiological complexity of AUD, the development of new treatments requires a deeper understanding of the molecular mechanisms underlying etiology and course of AUD. This includes the degree to which cannabis use may reduce or enhance harms of alcohol consumption through cannabinoid influence on gut and immune functions. One potential mechanism through which cannabinoids may exert beneficial effects in heavy drinkers is through their role in modulating the gut microbiome and immune system, which have been found to be disrupted by alcohol. However, it is also possible that cannabinoids, specifically delta-9-Tetrahydrocannabinol (THC), may confer harms in heavy drinkers by enhancing the intoxicating effects of alcohol. The current study will be the first to explore the acute and long-term effects of cannabis on alcohol use and neurobehavioral phenotypes, including alcohol craving, impulsivity, and impaired cognition, as well as the impact of cannabinoids on the microbiota-gut-brain-axis (MGBA) in human non-treatment-seeking, regular-cannabis-using heavy drinkers.

This study examines the effects of legal market cannabis on acute and long-term alcohol use, (specifically the effects of alcohol and cannabis use on gut microbiome and inflammatory markers in the blood) in a 4-week, observational design using both traditional and mobile lab settings, as well as self-report, daily diary methodology. Participants will complete two Phases (A and B) following by two visits to our mobile laboratory (Visits A and B), the order of which will be counterbalanced across participants so that half of participants will complete phase A/visit A first, and the other half will complete Phase B/Visit B first. Phase A involves 2 weeks of no cannabis use followed by a mobile lab session (Visit A), involving biological sample collection, neurobehavioral testing and an alcohol self-administration task. Phase B involves 2 weeks of ad lib use of participant preferred cannabis product, followed by a session in the mobile lab session (Visit B) in which participants will complete the same neurobehavioral tasks, biological sample collection, and alcohol self-administration task immediately following acute ingestion of preferred cannabis strain in participant homes.

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Study Type : Observational
Estimated Enrollment : 61 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Exploring the Effects of Cannabinoids on Alcohol Consumption and the Microbiota-Gut-Brain Axis
Actual Study Start Date : February 25, 2022
Estimated Primary Completion Date : January 31, 2025
Estimated Study Completion Date : January 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Alcohol Marijuana
Drug Information available for: Ethanol


Intervention Details:
  • Drug: Alcohol and Cannabis vs. Alcohol only
    Self-directed (ad-libitum) cannabis and alcohol vs. self-direct (ad-libitum) alcohol


Primary Outcome Measures :
  1. Change in Acute alcohol consumption [ Time Frame: Change over two time points: Session A (alcohol administration only) and Session B (alcohol administration + ad-libitum cannabis administration). Sessions A and B are 2 weeks apart. ]
    Total number of drinks consumed (out of 4) in a one-hour period.

  2. Change in daily alcohol consumption [ Time Frame: Change over two consecutive 14-day daily time periods. ]
    Two 14-day daily data collection periods using self-report of alcohol craving and amount of alcohol consumed.

  3. Change in Alcohol Craving (Visual-Analog Scale) [ Time Frame: Change over two time points: Session A (alcohol administration only) and Session B (alcohol administration + ad-libitum cannabis administration). Sessions A and B are 2 weeks apart. ]
    Test differences in alcohol craving using Visual Analog Scale in laboratory sessions in which only alcohol is consumed (Session A) and in which cannabis is self-administered prior to alcohol administration (Session B). Possible values range from 0-10, with higher scores indicating greater alcohol craving.

  4. Change in Alcohol Craving (Alcohol Urge Questionnaire) [ Time Frame: Change over two time points: Session A (alcohol administration only) and Session B (alcohol administration + ad-libitum cannabis administration). Sessions A and B are 2 weeks apart. ]
    Test differences in alcohol craving using Alcohol Urge Questionnaire in laboratory sessions in which only alcohol is consumed (Session A) and in which cannabis is self-administered prior to alcohol administration (Session B). Possible values range from 1-7, with higher scores indicating greater alcohol craving.

  5. Change in NIH Toolbox Flanker Test (accuracy) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    This task requires participants to sustain attention on a stimulus while inhibiting attention to stimuli flanking it.

  6. Change in NIH Toolbox Flanker Test (response time) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    This task requires participants to sustain attention on a stimulus while inhibiting attention to stimuli flanking it.

  7. Change in Stop Signal Task (errors) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    This task requires responding quickly to "go" signals, and occasionally inhibiting those responses when a "stop" signal is displayed.

  8. Change in Stop Signal Task (proportion of successful stops) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    This task requires responding quickly to "go" signals, and occasionally inhibiting those responses when a "stop" signal is displayed.

  9. Change in Stop Signal Task (reaction time on Go trials) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    This task requires responding quickly to "go" signals, and occasionally inhibiting those responses when a "stop" signal is displayed.

  10. Change in Stop Signal Task (Stop signal reaction time) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    This task requires responding quickly to "go" signals, and occasionally inhibiting those responses when a "stop" signal is displayed.

  11. Change in Rey Auditory Verbal Learning Test (RAVLT) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart: Pre-alcohol/cannabis consumption, Post-alcohol/cannabis consumption ]
    The RAVLT is a neuropsychological assessment designed to evaluate verbal memory in adult patients. The RAVLT can be used to evaluate the nature and severity of memory dysfunction and to track changes in memory function over time.

  12. Change in circulating levels of pro-inflammatory cytokines [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart ]
    Test levels of inflammation (panel of inflammatory cytokines) at Session A (following 2 weeks of no cannabis use) and Session B (following 2 weeks of ad lib cannabis use).

  13. Circulating levels of pro-inflammatory cytokines [ Time Frame: Through study completion, an average of 4 weeks ]
    Cytokine data from Session B will be compared to an existing sample collected at University of Colorado Boulder (CU) (R01AA024632) of matched non-cannabis using individuals who report heavy drinking.

  14. Change in intestinal permeability [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart ]
    Test levels of recent intestinal permeability measured in blood at Session A (following 2 weeks of no cannabis use) and Session B (following 2 weeks of ad lib cannabis use).

  15. Intestinal permeability [ Time Frame: Through study completion, an average of 4 weeks ]
    Intestinal permeability data from Session B will also be compared to an existing sample collected at CU Boulder (R01AA024632) of matched non-cannabis using individuals who report heavy drinking.

  16. Change in Plasma Gamma-Glutamyl Transferase (GGT) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart ]
    Test levels of recent liver inflammation (GGT) at Session A (following 2 weeks of no cannabis use) and Session B (following 2 weeks of ad lib cannabis use).

  17. Plasma Gamma-Glutamyl Transferase (GGT) [ Time Frame: Through study completion, an average of 4 weeks ]
    Liver inflammation data from Session B will also be compared to an existing sample collected at CU Boulder (R01AA024632) of matched non-cannabis using individuals who report heavy drinking.

  18. Gut microbiota (presence or absence of bacteria) [ Time Frame: Through study completion, an average of 4 weeks ]
    Outcomes of interest include presence or absence of individual bacteria of interest. Gut microbiome data from Session B will be compared to an existing sample collected at CU Boulder (R01AA024632) of matched non-cannabis using individuals who report heavy drinking.

  19. Change in gut microbiota (presence or absence of bacteria) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart ]
    Outcomes of interest include presence or absence of individual bacteria of interest. Gut microbiome data from Session A will be compared to microbiome data from Session B.

  20. Change in gut microbiota (bacterial diversity) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart ]
    Outcomes of interest include gut bacterial diversity. Gut microbiome data from Session A will be compared with gut microbiome data from Session B.

  21. Gut microbiota (bacterial diversity) [ Time Frame: Through study completion, an average of 4 weeks ]
    Outcomes of interest include gut bacterial diversity. Gut microbiome data from Session B will be compared to an existing sample collected at CU Boulder (R01AA024632) of matched non-cannabis using individuals who report heavy drinking.


Secondary Outcome Measures :
  1. Pennsylvania Alcohol Craving Scale (PACS) [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart. Session A craving assessed throughout session. Session B craving assessed throughout session. ]
    Penn Alcohol Craving Scale assessing self-reported alcohol craving used throughout lab Sessions A and B. Possible values range from 0-30, with higher scores indicating greater alcohol craving.

  2. Breath alcohol level during lab sessions [ Time Frame: Change over two time points (Session A [alcohol administration only] and Session B [alcohol administration + ad-libitum cannabis administration]) 2 weeks apart. Session A (throughout session) and Session B (throughout session). ]
    Breath alcohol level will be assessed in each experimental session after a priming drink and every 10 minutes during alcohol self-administration via breathalyzer.

  3. Change in composite measure of inflammatory and gut biomarkers [ Time Frame: Change in inflammatory and gut biomarkers during session A compared with session B (2 weeks apart). Samples will be compared at Sessions A and B. ]
    The investigators will combine the biomarkers listed above (cytokines, intestinal permeability markers, gut microbiota and liver GGT) using averaged z-scores to create a composite measure of gut and immune function.

  4. Change in cannabinoid content in blood [ Time Frame: Change in cannabinoid content during session A compared with session B (2 weeks apart). Samples will be compared at Sessions A (beginning of session) and B (beginning of session and post ad libitum cannabis use). ]
    Cannabinoids including THC, THC metabolites, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), and others assessed using blood draws to quantify cannabinoid levels during Sessions A and B.

  5. Change in endocannabinoid content in blood [ Time Frame: Change in endocannabinoid content during session A compared with session B (2 weeks apart). Samples will be compared at Sessions A (beginning of session) and B (beginning of session and post ad libitum cannabis use). ]
    Endocannabinoids (AEA and 2-AG) assessed using blood draws to quantify endocannabinoid levels during Sessions A and B.

  6. Self-report measures of stress [ Time Frame: Self-report measures administered one time at baseline. Differences in alcohol and cannabis use throughout study procedures will be measured as predictors of these self-report scores. ]
    Depression Anxiety Stress Scale (21-item measure) assessed at baseline. Possible values range from 0-63, with higher scores indicating greater depression, anxiety, and stress.

  7. Self-report measures of depression [ Time Frame: Self-report measures administered one time at baseline. Differences in alcohol and cannabis use throughout study procedures will be measured as predictors of these self-report scores. ]
    Beck Depression Inventory (21-item measure) assessed at baseline. Possible values range from 0-63, with higher scores indicating higher levels of depression.

  8. Self-report measures of anxiety [ Time Frame: Self-report measures administered one time at baseline. Differences in alcohol and cannabis use throughout study procedures will be measured as predictors of these self-report scores. ]
    Beck Anxiety Inventory (21-item measure) assessed at baseline. Possible values ranging from 0-63, with higher scores indicating higher levels of anxiety.

  9. Daily diary survey: cannabis consumption [ Time Frame: Change between cannabis consumption during session A compared with session B (2 weeks apart). ]
    Two 14-day daily data collection periods using self-report of amount of cannabis consumed.

  10. The Alcohol Purchase Task (APT) [ Time Frame: Change between reward value of alcohol when cannabis is on board (session B) compared to when it is not (session A). This task will also be administered at baseline (when not intoxicated) to compare sober state-level alcohol reward. ]
    The APT is a is a well-validated, easy-to-administer measure that will be given at baseline and multiple times during session A and B. This task measures the reinforcing value of alcohol using simulated marketplace survey techniques (i.e. - how many drinks would you purchase if they cost 50 cents?)


Biospecimen Retention:   Samples With DNA
Biospecimen description: whole blood will be collected, plasma will be retained, fecal samples


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Community Sample
Criteria

Inclusion Criteria:

  1. 21-60 years of age
  2. Able to provide consent
  3. Heavy drinker, defined as: for men, consuming more than 4 drinks on any day or more than 14 drinks per week OR, for women, consuming more than 3 drinks on any day or more than 7 drinks per week over the last 3 months.
  4. Regular legal-market cannabis smoker, defined as using smoked flower cannabis obtained from a dispensary at least 3 days per/week over the past 3 months
  5. Willing to abstain from cannabis use for 14 days
  6. We are prioritizing the recruitment of participants in the Fort Collins/Loveland area
  7. Vaccinated and boosted against Covid-19
  8. Willing to wear a mask throughout the duration of all their study sessions, in the lab on campus and the mobile laboratory.

Exclusion Criteria:

  1. Daily tobacco use*** (Vape and Hooka included)
  2. Actively seeking treatment for alcohol use disorder or other substance use disorder
  3. Females cannot be pregnant, breastfeeding or trying to become pregnant
  4. Meet criteria for psychotic, bipolar or major depressive disorder with suicidal ideation, or history of these disorders
  5. Immune-relevant disease (e.g., osteoarthritis, HIV, cancer, recent infection, other autoimmune disorder) or currently taking an immune-modulating medication***
  6. Current use of psychotropic medications (except anti-depressants )
  7. Report illicit drug use in past 60-days or fail drug screen
  8. Major medical condition that contraindicates the consumption of alcohol or cannabis.
  9. Use of an antibiotic medication in the past 3 months
  10. Current GI disorder including: inflammatory bowel disease, irritable bowel disease, diverticular disease, peptic ulcer/gastritis and gastroesophageal reflux disease.
  11. Use of probiotic or supplement drinks at least once per week over the last 3 months
  12. Unvaccinated against COVID-19

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04998006


Contacts
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Contact: Hollis C. Karoly, PhD 970-491-3677 hollis.karoly@colostate.edu

Locations
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United States, Colorado
Colorado State University Recruiting
Fort Collins, Colorado, United States, 80523
Contact: Hollis C. Karoly, PhD         
Principal Investigator: Hollis C. Karoly, PhD         
Sponsors and Collaborators
Colorado State University
University of Colorado, Boulder
Investigators
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Principal Investigator: Hollis C. Karoly, PhD Colorado State University
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Responsible Party: Hollis Karoly, Assistant Professor, Colorado State University
ClinicalTrials.gov Identifier: NCT04998006    
Other Study ID Numbers: K23AA028238-01A1 ( U.S. NIH Grant/Contract )
First Posted: August 10, 2021    Key Record Dates
Last Update Posted: July 13, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The investigators will submit all de-identified individual level phenotypic human subjects data from this project to the NIAAA data archive. The project also involves collection of human specimens (fecal samples) which will generate non-human genomic data. Specifically, the investigators plan to generate 122 (61 subjects x 2 timepoints) human gut microbiota metagenomes (i.e., gut microbiome). Deidentified genomic data from microbiome assays (and relevant phenotypic data) will be submitted to the database of Genotypes and Phenotypes (dbGaP).
Time Frame: Human phenotypic data will be uploaded at least twice a year. Non-human genomes from fecal samples will be shared within 3 months of processing and genotyping all meta-genomes
Access Criteria: Data access through the National Institute of Mental Health Data Archive (NIAAA) and dbGaP.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hollis Karoly, Colorado State University:
Alcohol
Cannabis
Microbiome
Marijuana
Additional relevant MeSH terms:
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Inflammation
Marijuana Abuse
Pathologic Processes
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Ethanol
Anti-Infective Agents, Local
Anti-Infective Agents
Central Nervous System Depressants
Physiological Effects of Drugs