Effects of Cannabidiol and Tetrahydrocannabinol on Microbiome and Neuroinflammation in HIV

NCT ID: NCT05514899

Last Updated: 2025-02-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-09-01
• Study Completion Date: 2027-10-31

Brief Summary

This study 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 effects of the study drug.

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. The 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. The investigators 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.

Conditions

HIV; Cannabis; THC; Neuroinflammatory Disease; Neuroinflammatory Response; Microbiome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

THC first, then CBD

THC 10mg daily for 2 weeks, followed by washout for 2 weeks, followed by CBD 600mg daily for 2 weeks

Group Type: EXPERIMENTAL

THC

Intervention Type: DRUG

THC capsule

CBD

Intervention Type: DRUG

oral solution

CBD first, then THC

CBD 600mg daily for 2 weeks, followed by washout for 2 weeks, followed by THC 10mg daily for 2 weeks

Group Type: ACTIVE_COMPARATOR

THC

Intervention Type: DRUG

THC capsule

CBD

Intervention Type: DRUG

oral solution

Interventions

THC

THC capsule

Intervention Type: DRUG

CBD

oral solution

Intervention Type: DRUG

Other Intervention Names

Delta-9 tetrahydrocannabinol; Tetrahydrocannabinol; Delta9-THC; Cannabidiol

Eligibility Criteria

Exclusion Criteria

2. Significant cognitive impairment such as Dementia, including Alzheimer's disease

3. Pregnancy or lactation, or unwillingness to prevent pregnancy during the trial; refusal to maintain highly effective contraceptive methods (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner) during the study for persons of child-bearing potential or those with partners of child-bearing potential

4. Evidence of moderately or worse compromised liver or kidney function, including moderate (Child-Hugh B) or severe (Child-Hugh C) hepatic impairment and AST and ALT above ULN and total bilirubin above ULN;

5. Evidence of significant cardiovascular risk, resting heart rate <50 or >110 beats per minute, uncontrolled hypertension (systolic blood pressure <80 or >140 mmHg; diastolic blood pressure <50 or >90 mmHg), history of myocardial infarction, congestive heart failure, or arrhythmia);

6. Evidence of chronic pulmonary disease requiring supplemental oxygen;

7. Active, recent, or remote medical history of hepatobiliary-related illness, including elevated transaminase levels above 3 times the upper limit of normal accompanied by elevations in total bilirubin above 2 times the upper limit of normal at screening;

8. Insulin dependent diabetics

9. Allergy to the study drugs or any of their constituents including sesame

10. Use of medications with absolute contraindicated or potential significant interactions

11. Use of sedating medications

12. Weighing less than 60 kg at screening to minimize the risk of elevated transaminases as a result of exposure to cannabidiol;

13. Active, uncontrolled psychiatric disorder with psychotic features, severe depression, or suicidality; Participants will be excluded if they have had a history of suicide attempt, recent suicidal ideation or behavior as indexed by their Beck Depression Inventory-II (BDI-II) score is greater than or equal to 29 (severe depression).

14. Neurologic disorder that could compromise interpretation of study findings, including uncontrolled seizure disorder (active seizures within the past 3 months), multiple sclerosis, Parkinson's disease, Alzheimer's disease, and recent (past 3 months) cerebral infarction or hemorrhage with neurological sequelae.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Ronald Ellis

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ronald J Ellis, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UC San Diego

Locations

HIV Neurobehavioral Research Program (HNRP)

San Diego, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Roberto Gallardo

Role: CONTACT

hnrprecruitment@ucsd.edu

619-543-5000

Facility Contacts

Roberto Gallardo

Role: primary

hnrprecruitment@ucsd.edu

(619) 543-5000

Other Identifiers

802514

Identifier Type: -

Identifier Source: org_study_id