CAMI: Effects of Cannabidiol and Tetrahydrocannabinol on Microbiome and Neuroinflammation in HIV
Study Details
Study Description
Brief Summary
We are conducting this study as it has the potential to contribute to a more complete understanding of the independent and combined effects of cannabis use and HIV on the brain and on inflammation. Such knowledge may inform future strategies for treating brain disease and inflammation. Participants will be randomly assigned to one of two groups, both of which will receive the same treatment in a different order over a period of about 6 weeks. The visits include physical examinations, blood tests, and other procedures designed to monitor subject safety and measure the effect of the study drug.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
This project will characterize the microbiome and endocannabinoid system (ECS) in people with HIV (PWH) and how they relate to neuroinflammation and blood-brain barrier (BBB) function. The study hypothesizes that pathogenic alterations in the gut microbiota (dysbiosis) and impaired gut barrier integrity (leaky gut) are mediators between the ECS, neuroinflammation and BBB dysfunction in HIV. Our major goals are to (1) characterize the gut microbiota and ECS in response to exogenous cannabinoid exposure in both PWH and people without HIV (PWoH); (2) characterize patterns of HIV-associated inflammation (innate, adaptive, T-cell, B-cell) in blood and cerebrospinal fluid (CSF) in response to controlled cannabis exposure; (3) assess effects of cannabinoid exposure on these patterns and how they are mediated through changes in the ECS, gut microbiota and gut barrier function. We will perform a clinical trial of 50 PWH and 50 PWoH exposed in a randomized, cross-over fashion to 14 days each of oral THC and CBD to determine if treatment with either phytocannabinoid reduces inflammation and improves gut function. The experimental approach will use fecal shotgun metagenomic sequencing to characterize the gut microbiome, with particular attention to aerotolerant bacteria, pro-inflammatory species, Prevotella spp., Bifidobacterium and Bacteroides spp. and butyrate-producing bacteria. We will evaluate how the microbiota and leaky gut relate to neuroinflammation and impaired BBB function, the latter potentially leading to increased central nervous system (CNS) exposure to microbially-produced pro-inflammatory ligands. The rationale for the study is that virologic suppression on antiretroviral therapy (ART) does not normalize gut lymphoid tissue cluster of differentiation 4 (CD4)+ T cell depletion, leaky gut, dysbiosis, chronic gut inflammation, and microbial antigen translocation (MAT). These alterations ultimately drive systemic and CNS inflammation. Compromised gut barrier function due to altered tight junctions, apoptosis and reduced epithelial cell proliferation and repair render PWH susceptible to increased tissue exposure to pro-inflammatory ligands produced by gut microbiota and are important in HIV neuropathogenesis. Of particular relevance here are recent findings that the ECS in the large intestine interacts with the gut microbiota to regulate epithelial barrier permeability. Thus, constituents of cannabis, acting through the EC systems in the gut, brain and immune system, may be therapeutic. The existing literature suggests that the two principal constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have differential effects on the ECS.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm 1 Food and Drug Administration (FDA)-approved THC (Dronabinol) + placebo for 2 weeks, washout for 2 weeks, FDA-approved CBD (Epidiolex) + placebo for 2 weeks |
Drug: THC
FDA-approved THC capsule
Other Names:
Drug: CBD
oral solution
Other Names:
|
| Active Comparator: Arm 2 CBD for 2 weeks + placebo, washout for 2 weeks, THC + placebo for 2 weeks. |
Drug: THC
FDA-approved THC capsule
Other Names:
Drug: CBD
oral solution
Other Names:
|
Outcome Measures
Primary Outcome Measures
- PC1 [2 weeks]
first component (PC1) of the principal component analysis (PCA), a composite marker of inflammation
Secondary Outcome Measures
- blood-brain barrier (BBB) [2 weeks]
BBB markers: claudin, suPAR, CSF/serum albumin ratio, MMP-2, occludin
Eligibility Criteria
Criteria
Inclusion Criteria:
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Aged 21 and older
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Possess the capacity to provide informed consent to a set of neuromedical assessment procedures.
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Experience with THC-containing cannabis use at least once in the past 5 years without major adverse effects (e.g., psychosis, syncope)
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No or low cannabis use in the past 6 months, defined as no cannabis exposure or use or use limited to only once per month in the past 6 months.
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Individuals with HIV must be virally suppressed on stable ART for at least 3 months.
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Ability to adhere to the study visit schedule.
Exclusion Criteria:
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any substance use disorder (abuse or dependence) other than cannabis in the last 30 days;
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Pregnancy or lactation, or unwillingness to prevent pregnancy during the trial;
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Evidence of moderately or worse compromised liver or kidney function;
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Evidence of significant cardiovascular risk, uncontrolled hypertension, or chronic pulmonary disease requiring supplemental oxygen;
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Insulin dependent diabetics
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Use of contraindicated medications (e.g., warfarin);
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Active, uncontrolled psychiatric disorder with psychotic features, severe depression, or suicidality;
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Neurologic disorder that could compromise interpretation of study findings.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | HIV Neurobehavioral Research Program (HNRP) | San Diego | California | United States | 92103 |
Sponsors and Collaborators
- University of California, San Diego
Investigators
- Principal Investigator: Ronald J Ellis, MD, PhD, UC San Diego
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 802514