Cannabis Effects on Antiretroviral Therapy Pharmacokinetics and Neurotoxicity
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ClinicalTrials.gov Identifier: NCT04800159 |
Recruitment Status :
Recruiting
First Posted : March 16, 2021
Last Update Posted : May 16, 2022
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
HIV Cannabis Use | Drug: THC Cannabis Drug: CBD Cannabis Drug: Placebo | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 40 participants |
Allocation: | Randomized |
Intervention Model: | Crossover Assignment |
Intervention Model Description: | 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. |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Masking Description: | 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. |
Primary Purpose: | Basic Science |
Official Title: | Cannabis Effects on Antiretroviral Therapy Pharmacokinetics and Neurotoxicity |
Actual Study Start Date : | February 19, 2021 |
Estimated Primary Completion Date : | January 30, 2025 |
Estimated Study Completion Date : | April 30, 2025 |
Arm | Intervention/treatment |
---|---|
Active Comparator: THC Cannabis
12.13% THC/ 0.09% CBD
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Drug: THC Cannabis
Vaporization of cannabis
Other Name: Marijuana |
Active Comparator: CBD Cannabis
0.35% THC/ 11.27% CBD
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Drug: CBD Cannabis
Vaporization of cannabis
Other Name: Marijuana |
Placebo Comparator: Placebo
≤ 0.01% THC/ ≤ 0.01% CBD
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Drug: Placebo
Vaporization of placebo
Other Name: Marijuana with < 0.01% of THC and CBD |
- 1a i. Antiretroviral therapy (ART) drug concentration in blood [ Time Frame: Cross-sectional; measured before ART ingestion ]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).
- 1a ii. Cerebrospinal fluid (CSF)/plasma ratio of ART drug concentrations [ Time Frame: Cross-sectional; measured before ART ingestion ]This will be done separately for CYP and UGT groups (estimated N=60 in each).
- 1a iii. Change in ART drug concentrations in blood [ Time Frame: 2 hours; measured before ART ingestion and at 2 hours after the ART ingestion ]This will be done separately for CYP and UGT groups (estimated N=60 in each).
- 1a iv. Change in CSF/plasma ratio of ART drug concentrations [ Time Frame: 2 hours; measured before ART ingestion and at 2 hours after the ART ingestion ]This will be done separately for CYP and UGT groups (estimated N=60 in each).
- 1b i. Effects of placebo, THC, and CBD on ART drug concentration [ Time Frame: 5 hours ]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.
- 1b ii. Effects of placebo, THC and CBD on the CSF/plasma ratio of ART drug concentrations [ Time Frame: 5 hours ]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
- 1b iii. Comparison between the effects of placebo and THC on ART pharmacokinetics and between the effects of placebo and CBD on ART pharmacokinetics [ Time Frame: 3 to 11 days ]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).
- 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 [ Time Frame: 3 to 11 days ]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).
- 2a. Effects of chronic cannabis use on the CSF/serum albumin ratio and P-glycoprotein (P-gp) expression. [ Time Frame: 3 to 11 days ]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
- 2b. Examine the correlation between ART concentration in CSF and blood during placebo treatment compared to THC and CBD administration. [ Time Frame: 3 to 11 days ]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).
- 2c. Effects of THC or CBD on uridine 5'-diphospho-glucuronosyltransferase (UGT) activity compared to placebo. [ Time Frame: 3 to 11 days ]The investigators will use a mixed effects model to examine the effects of drug treatment on UGT metabolism (n = 40).
- 3a. i. Correlation between CD4+ T-cell count and ART drug concentration. [ Time Frame: Up to 5 weeks: baseline to administration visits ]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).
- 3a. ii. Correlation between HIV DNA and ART drug concentration. [ Time Frame: Up to 5 weeks: baseline to administration visits ]Multivariable logistic regressions will be used for testing correlation between HIV DNA and ART drug concentration (N=60 in each UGT and CYP groups).
- 3b i. Effects of cannabis use on the correlation between ART and neurocognitive performance. [ Time Frame: 3 to 11 days ]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.
- 3b ii. Effects of cannabis use on the correlation between ART and depression. [ Time Frame: 3 to 11 days ]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.
- 3b iii. Effects of cannabis use on the correlation between ART and emotional health. [ Time Frame: 3 to 11 days ]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.
- 3b iv. Effects of cannabis use on the correlation between ART and emotional health. [ Time Frame: 3 to 11 days ]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.
- 3b v. Effects of cannabis use on the correlation between ART and emotional health. [ Time Frame: 3 to 11 days ]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.
- 3b vi. Effects of cannabis use on the correlation between ART and neurotoxicity. [ Time Frame: 3 to 11 days ]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.
- 3b vii. Effects of cannabis use on the correlation between ART and neurotoxicity. [ Time Frame: 3 to 11 days ]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.
- 3b viii. Effects of cannabis use on the correlation between ART and neurotoxicity. [ Time Frame: 3 to 11 days ]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.
- 1b v. Comparison between the effects of THC and CBD on ART pharmacokinetics. [ Time Frame: 3 to 11 days ]Comparison of the treatment arm to the the area under the time-concentration curve of ART pharmacokinetics (n=40).
- 1b vi. Comparison between the effects of THC and CBD on the CSF/plasma ratio of ART drug concentrations. [ Time Frame: 3 to 11 days ]Comparison of treatment arm to the CSF/plasma ratio of ART drug concentrations.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria for All Visits:
- 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 3 months;
- Taking an ART drug that is metabolized by either cytochrome p450 (CYP) isozymes or by uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes; and
- 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.
Additional Inclusion Criteria for participation in Phase 2 (interventional):
- Treatment with an integrase inhibitor (i.e. dolutegravir);
- Use of cannabis in the past two 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
Exclusion Criteria for All Visits:
- 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 12 months;
- Contraindications to lumbar puncture for those consenting to lumbar puncture (e.g., coagulopathy).
Additional Exclusion Criteria for participation in the cannabis administration visits:
- Younger than 21 years (due to safety of cannabis in children and adolescents);
- 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;
- Uncontrolled hypertension with systolic blood pressure greater than 160 mm Hg or a diastolic blood pressure greater than 100 mm Hg prior to study product administration;
- Resting pulse greater than 100 beats per minute prior to study product administration;
- Pregnancy as determined by a human chorionic gonadotropin urine test, women who are lactating, or unwillingness to prevent pregnancy during the cannabis administration portion of the study (using birth control in women of child-bearing age). Acceptable methods of birth control are: oral contraceptive pills, diaphragm, condom, progestin implant, intrauterine contraceptive device, sterilization, etc;
- Active opportunistic infection or malignancy requiring treatment;
- Unintentional loss of 10% or more of body weight during the previous 6 months;
- CD4+ T-cell count less than 200 cells/µL;
- Estimated glomerular filtration rate < 40 mL/minute, indicative of renal dysfunction;
- Hepatic transaminases > 2 times the upper limit of normal;
- Current severe depressive symptoms (BDI-II score ≥ 31) or suicidal ideation;
- Known sensitivity to acetaminophen (the probe for UGT activity);
- Current use of substances that could have adverse interactions with acetaminophen or cannabis (e.g., grapefruit juice).

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): NCT04800159
Contact: Roberto Gallardo | 619-543-5000 | hnrprecruitment@ucsd.edu |
United States, California | |
Ucsd Hnrp-Cmcr | Recruiting |
San Diego, California, United States, 92103 | |
Contact: Roberto Gallardo 619-543-5000 hnrprecruitment@ucsd.edu |
Principal Investigator: | Scott Letendre, MD | UCSD |
Responsible Party: | Scott Letendre, Professor, University of California, San Diego |
ClinicalTrials.gov Identifier: | NCT04800159 |
Other Study ID Numbers: |
DA050491 |
First Posted: | March 16, 2021 Key Record Dates |
Last Update Posted: | May 16, 2022 |
Last Verified: | May 2022 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Product Manufactured in and Exported from the U.S.: | No |
Neurotoxicity Syndromes Marijuana Abuse Substance-Related Disorders Chemically-Induced Disorders |
Mental Disorders Nervous System Diseases Poisoning |