PROJECT SUMMARY
Understanding how co-morbidities in persons with HIV (PWH) such as substance use affect risk-taking, decision-
making, and other cognitive behaviors is important given implications for everyday functioning and transmission
risk. The high prevalence of cannabis use in PWH, medicinally and recreationally, may indicate disease severity,
impart therapeutic benefits, or adverse consequences. In fact, cannabis is recommended to those with HIV to
alleviate nausea, improve appetite, relieve pain, and lift mood. To-date, the consequences of cannabis use in
PWH remain unclear as do potential interactions with HIV treatments. In healthy participants, heavy cannabis
use is associated with cognitive deficits e.g., risky decision-making, response disinhibition and inattention, but
pro-cognitive effects in PWH may exist at mild use levels due to its anti-inflammatory and anti-excitotoxic
properties. Furthermore, little has been done to determine the effects of cannabis use on the endocannabinoid
(EC) system in general or in PWH. This area of study is especially germane to cognition since the virus affects
brain regions rich in ECs. CNS relevance is of particular importance given that the EC system exerts regulatory
effects over the dopaminergic system, critical for these cognitive processes. This application will utilize a cross-
species approach to delineate the effects EC system activation has on HIV-relevant cognitive and motivational
domains. Animal studies enable mechanistic insights on chronic and withdrawal effects in this system. Both
behavioral and mechanistic overlap will occur between the human and animal studies. Specific Aim 1 will
determine the effects of the two primary cannabis constituents (¿9-tetrahydrocannabinol [THC], cannabidiol
[CBD]) vs. placebo on risky decision-making, response inhibition, reward learning, temporal perception, and
motivation, plus EC and homovanillic acid (HVA; a surrogate for dopamine activity) levels in HIV+ and HIV-
subjects. Participants with infrequent cannabis use will undergo baseline cognitive testing and biomarker assays
with antiretrovirals (ART) use quantified. They will be randomized to a 5-day course of either THC, CBD, or
placebo and return for follow-up testing and re-assaying of ECs and HVA levels. Specific Aim 2 will conduct
parallel experiments in a rodent model of HIV on acute, chronic, and withdrawal effects of 2 doses of THC vs. 2
doses of CBD, plus combined THC/CBD/ART (dolutegravir) on the same cognitive and motivational tests, plus
EC and HVA levels to provide directionality and potential interaction of drug effects. Each experiment will train
and test HIV-1 transgenic and wildtype littermate rats on cross-species versions of tasks used in Aim 1. Rats will
be tested at baseline, immediately after acute, then chronic treatment, then during withdrawal. The brains of rats
will be harvested and assessed for EC and dopamine receptor levels to determine potential mechanisms of the
beneficial/negative effects of cannabinoid treatments on symptoms related to HIV. Disentangling the cognitive
and biological effects of THC and CBD and their relation with ART is a much-needed advance in the HIV field
and will inform development of therapeutics and policy advice for co-morbid substance use.
Project Summary/Abstract Page 6