Alcohol and Cannabis Co-Use and the Gut-Brain Axis

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.

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.

Eligibility 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

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