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.

People with human immunodeficiency virus (HIV) commonly use cannabis but whether cannabis affects the antiretroviral therapy (ART) that treats HIV is not well known. Cannabis can inhibit the activity of enzymes that metabolize and eliminate ART drugs from the body, which could result in higher concentrations of ART drugs in the body. Cannabis may also affect the distribution of ART drugs into the brain, which could have both beneficial (e.g., better HIV control) and detrimental (e.g., toxicity) effects. The effects of cannabis may are likely influenced by factors like how much is used (e.g., light vs. heavy use) and the route of use (e.g., smoked vs. ingested). This study will address whether cannabis affects ART concentrations in blood and cerebrospinal fluid as well as mood, and thinking. The project will have two phases. Phase 1 is an observational study, in which 120 people will be assessed once 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.

Inclusion Criteria for Study Entry:

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

Exclusion Criteria for Study Entry:

1. Traumatic brain injury, including head injury with loss of consciousness for greater than 30 minutes or resulting in neurologic complications;
2. Dementia, including Alzheimer's disease;
3. History of stroke with residual neurologic sequelae;
4. History of seizure disorder with a seizure in the past year;
5. Severe psychiatric disorder (e.g., schizophrenia) that might make the person's participation in the study unsafe;
6. Substance or alcohol use disorder in the past 3 months;
7. Contraindications to lumbar puncture for those consenting to lumbar puncture (e.g., coagulopathy).

Additional Inclusion Criteria for participation in the cannabis administration visits (Phase 2-interventional):

1. Treatment with an integrase inhibitor (i.e. dolutegravir);
2. 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;
3. Willing to refrain from driving or operating heavy machinery after the visit; and
4. Willing to abstain from cannabis for at least 48 hours prior to the cannabis administration visits.
5. Willing to abstain from grapefruit juice consumption for 4 weeks prior to cannabis administration and during the administration visits

Additional Exclusion Criteria for participation in the cannabis administration visits (Phase 2-interventional):

1. Younger than 21 years due to problems with the use of cannabis in children and adolescents;
2. 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;
3. History of cardiovascular disease, including myocardial infarction;
4. 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;
5. Resting pulse greater than 100 beats per minute prior to study product administration;
6. 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;
7. Active opportunistic infection or malignancy requiring treatment;
8. Unintentional loss of 10% or more of body weight during the previous 6 months;
9. CD4+ T-cell count less than 200 cells/µL;
10. Estimated glomerular filtration rate < 30 mL/minute, indicative of renal dysfunction;
11. Hepatic transaminases > 2 times the upper limit of normal;
12. Current severe depressive symptoms (BDI-II score ≥ 31) or suicidal ideation;
13. Known sensitivity to Acetaminophen (the probe for UGT activity);
14. Current use of substances that could have adverse interactions with Acetaminophen or cannabis (e.g., grapefruit juice).

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.