Cannabis Effects on Antiretroviral Therapy Pharmacokinetics and Neurotoxicity

NCT04800159 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: DA050491
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study will address whether cannabis affects antiretroviral therapy (ART) drug concentrations, mood, and thinking. The project will have two phases. Phase 1 is an observational study, in which 120 people will be assessed to evaluate the effects of chronic cannabis use on ART drug concentrations, mood, and thinking. In Phase 2, the study will administer cannabis (or placebo) to 40 people to examine its acute effects on ART drug concentrations.

Conditions

HIV; Cannabis Use

Outcome Measures

Primary Outcomes (21)

• 1a i. Antiretroviral therapy (ART) drug concentration in blood

  This will be done separately for participants who use ART drugs that are predominantly metabolized by cytochrome P450 (CYP) or uridine 5'-diphospho-glucuronosyltransferase (UGT) (estimated N=60 in each).

  Cross-sectional; measured before ART ingestion

• 1a ii. Cerebrospinal fluid (CSF)/plasma ratio of ART drug concentrations

  This will be done separately for CYP and UGT groups (estimated N=60 in each).

  Cross-sectional; measured before ART ingestion

• 1a iii. Change in ART drug concentrations in blood

  This will be done separately for CYP and UGT groups (estimated N=60 in each).

  2 hours; measured before ART ingestion and at 2 hours after the ART ingestion

• 1a iv. Change in CSF/plasma ratio of ART drug concentrations

  This will be done separately for CYP and UGT groups (estimated N=60 in each).

  2 hours; measured before ART ingestion and at 2 hours after the ART ingestion

• 1b i. Effects of placebo, THC, and CBD on ART drug concentration

  The investigators will use a mixed effects model to assess effects of acute cannabis treatment (placebo, THC, or CBD: N=40) on the area under the time-drug concentration curve.

  5 hours

• 1b ii. Effects of placebo, THC and CBD on the CSF/plasma ratio of ART drug concentrations

  The investigators will use a mixed effects model to assess effects of acute cannabis treatment (placebo, THC, or CBD: N=40) on CSF/plasma ratio of ART drug concentrations

  5 hours

• 1b iii. Comparison between the effects of placebo and THC on ART pharmacokinetics and between the effects of placebo and CBD on ART pharmacokinetics

  Comparison of the the area under the time-concentration curve of ART pharmacokinetics for placebo and THC and placebo and CBD (n=40). The effect size will be measured as the standardized difference in mean outcomes between any two groups (Cohen's d).

  3 to 30 days

• 1b iv. Comparison between the effects of placebo and CBD on the CSF/plasma ratio of ART drug concentrations and between the effects of placebo and THC on the CSF/plasma ratio of ART drug concentrations

  Comparison of the the CSF/plasma ratio of ART drug concentrations with placebo and CBD and with placebo and THC (n=40). The effect size will be measured as the standardized difference in mean outcomes between any two groups (Cohen's d).

  3 to 30 days

• 2a. Effects of chronic cannabis use on the CSF/serum albumin ratio and P-glycoprotein (P-gp) expression.

  Multivariate linear regression will be used to regress markers of blood-brain barrier integrity and P-gp on cannabis use (n = 120), then ART drug concentrations on blood-brain barrier integrity and P-gp separately for the UGT and CYP groups

  3 to 30 days

• 2b. Examine the correlation between ART concentration in CSF and blood during placebo treatment compared to THC and CBD administration.

  The investigators will use a mixed effects model to evaluate the effects of cannabis on the correlation between ART concentration in CSF and blood (n = 40).

  3 to 30 days

• 2c. Effects of THC or CBD on uridine 5'-diphospho-glucuronosyltransferase (UGT) activity compared to placebo.

  The investigators will use a mixed effects model to examine the effects of drug treatment on UGT metabolism (n = 40).

  3 to 30 days

• 3a. i. Correlation between CD4+ T-cell count and ART drug concentration.

  Multivariable linear regressions will be used for testing correlation between CD4+ T-cell count and ART drug concentration (N=60 in each UGT and CYP groups).

  Up to 5 weeks: baseline to administration visits

• 3a. ii. Correlation between HIV DNA and ART drug concentration.

  Multivariable logistic regressions will be used for testing correlation between HIV DNA and ART drug concentration (N=60 in each UGT and CYP groups).

  Up to 5 weeks: baseline to administration visits

• 3b i. Effects of cannabis use on the correlation between ART and neurocognitive performance.

  The total cognitive outcome from the National Institutes of Health Toolbox will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates. Values range from 0 to 100 with lower values being worse.

  3 to 30 days

• 3b ii. Effects of cannabis use on the correlation between ART and depression.

  Depression (measured with the Beck Depression Inventory-II) will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates.

  3 to 30 days

• 3b iii. Effects of cannabis use on the correlation between ART and emotional health.

  The National Institutes of Health Toolbox-Emotional Battery outcome, Negative Affect, will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates. This measure ranges between 0 and 100 with higher values reflecting more Negative Affect.

  3 to 30 days

• 3b iv. Effects of cannabis use on the correlation between ART and emotional health.

  The National Institutes of Health Toolbox-Emotional Battery outcome, Social Satisfaction, will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates. This measure ranges between 0 and 100 with lower values reflecting worse Social Satisfaction.

  3 to 30 days

• 3b v. Effects of cannabis use on the correlation between ART and emotional health.

  The National Institutes of Health Toolbox-Emotional Battery outcome, Psychological Wellbeing, will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates. This measure ranges between 0 and 100 with lower values reflecting worse Psychological Wellbeing.

  3 to 30 days

• 3b vi. Effects of cannabis use on the correlation between ART and neurotoxicity.

  A measure of neurotoxicity (mitochondrial DNA) will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates.

  3 to 30 days

• 3b vii. Effects of cannabis use on the correlation between ART and neurotoxicity.

  A measure of neurotoxicity (8-hydroxydeoxyguanosine) will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates.

  3 to 30 days

• 3b viii. Effects of cannabis use on the correlation between ART and neurotoxicity.

  A measure of neurotoxicity (F2-isoprostane) will be regressed in multivariable models on ART drug concentration and cannabis use, their interaction, and known confounders and relevant covariates.

  3 to 30 days

Secondary Outcomes (2)

• 1b v. Comparison between the effects of THC and CBD on ART pharmacokinetics.

  3 to 30 days

• 1b vi. Comparison between the effects of THC and CBD on the CSF/plasma ratio of ART drug concentrations.

  3 to 30 days

Study Arms (3)

THC Cannabis

ACTIVE COMPARATOR

11.86% THC/ 1.12% CBD

Drug: THC Cannabis

CBD Cannabis

ACTIVE COMPARATOR

0.35% THC/ 11.27% CBD

Drug: CBD Cannabis

Placebo

PLACEBO COMPARATOR

≤ 0.03% THC/ ≤ 0.05% CBD

Drug: Placebo

Interventions

THC Cannabis DRUG

Vaporization of cannabis

Also known as: Marijuana

THC Cannabis

CBD Cannabis DRUG

Vaporization of cannabis

Also known as: Marijuana

CBD Cannabis

Placebo DRUG

Vaporization of placebo

Also known as: Marijuana with < 0.01% of THC and CBD

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 or older;
• Capacity to provide informed consent;
• Presence of HIV infection by a standard diagnostic test;
• On a stable ART regimen for at least 1 month and with a suppressed viral load by self-report;
• Willing to abstain from cannabis for at least 24 hours prior to the Phase 1 assessment.
• Willing to abstain from grapefruit juice consumption for 4 weeks prior to the Phase 1 assessment.

You may not qualify if:

• Traumatic brain injury, including head injury with loss of consciousness for greater than 30 minutes or resulting in neurologic complications;
• Dementia, including Alzheimer's disease;
• History of stroke with residual neurologic sequelae;
• History of seizure disorder with a seizure in the past year;
• Severe psychiatric disorder (e.g., schizophrenia) that might make the person's participation in the study unsafe;
• Substance or alcohol use disorder in the past 3 months;
• Contraindications to lumbar puncture for those consenting to lumbar puncture (e.g., coagulopathy).
• Treatment with an integrase inhibitor (i.e. dolutegravir);
• Use of cannabis in the past 10 years without a severe adverse reaction (e.g., disorientation, paranoia, or hallucinations). The two-year cutoff is to ensure exposure to modern cannabis, which is more likely to match the drug concentrations administered in this study;
• Willing to refrain from driving or operating heavy machinery after the visit; and
• Willing to abstain from cannabis for at least 48 hours prior to the cannabis administration visits.
• Willing to abstain from grapefruit juice consumption for 4 weeks prior to cannabis administration and during the administration visits
• Younger than 21 years due to problems with the use of cannabis in children and adolescents;
• a respiratory condition that would be exacerbated by inhaling vaporized cannabis (e.g., asthma or chronic obstructive pulmonary disease) or limited lung capacity that would prevent the individual from performing the Foltin puff procedure;
• History of cardiovascular disease, including myocardial infarction;

Sponsors & Collaborators

• University of California, San Diego: lead
• Center for Medicinal Cannabis Research: collaborator

Study Sites (1)

Ucsd Hnrp-Cmcr

San Diego, California, 92103, United States

Location

MeSH Terms

Interventions

nabiximols; Dronabinol

Intervention Hierarchy (Ancestors)

Cannabinoids; Terpenes; Hydrocarbons; Organic Chemicals

Study Officials

• Scott Letendre, MD

  UCSD

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants will randomly receive one of the study products at each visit. All participants will receive all three of the study products. Allocation assignment of visits will be assigned using a randomization string provided by the statistician. The allocation schedule will be kept in the pharmacy and concealed from all other study personnel.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: The interventional component of the project (Phase 2) will have a randomized cross-over design that randomly assigns the order of the administration of the three study products (placebo, cannabis with higher concentration of tetrahydrocannabinol (THC) and lower concentration of cannabidiol (CBD), or cannabis with higher CBD concentration and lower THC concentration). The cannabis administration phase of this study will compare the study products to: 1) ART concentrations in blood and CSF and 2) measures of uridine 5'-diphospho-glucuronosyltransferase (UGT) activity.

Study Record Dates

• First Submitted: February 19, 2021
• First Posted: March 16, 2021
• Study Start: February 19, 2021
• Primary Completion: October 30, 2025
• Study Completion: April 30, 2026
• Last Updated: October 15, 2025

Record last verified: 2025-10

Locations

US (1)