Low-Dose Cannabidiol Treatment does not Alter Cognitive Performance in the HIV-1 Transgenic Rat Model of NeuroHIV

HIV-associated neurocognitive impairment (NCI) remains prevalent among virally suppressed people living with HIV (PLWH) and approved treatments target these symptoms. Cannabidiol (CBD), a non-intoxicating cannabinoid with neuroprotective and anti-inflammatory properties, has been proposed as a potential therapeutic candidate for HIV-associated NCI, yet its cognitive effects in the context of HIV have not been experimentally tested.

Female and male HIV-1 transgenic (HIV-1Tg; n = 57) and Fischer 344 (F344; n = 57) control rats were assessed using a translational cognitive battery measuring risk-based decision-making (Iowa Gambling Task; IGT), learning and cognitive flexibility (Probabilistic Reversal Learning Task; PRLT), and effortful motivation (Progressive Ratio Breakpoint Task; PRBT). Animals were tested at baseline to establish innate cognitive performance, then retested following acute and chronic (16-day) CBD administration (0, 0.3, and 3 mg/kg).

HIV-1Tg rats exhibited subtle IGT deficits and persistent reversal learning deficits in the PRLT, with preserved learning and motivation, modeling key features of HIV-associated NCI. These selective impairments in cognitive flexibility persisted across testing periods, with performance in other domains largely intact. CBD produced modest, dose-specific effects on response latencies and motivation but did not affect cognitive performance.

HIV-1Tg rats exhibited selective cognitive deficits similar to those seen in PLWH, supporting their utility as a preclinical model of HIV-associated NCI. Across multiple translatable cognitive domains CBD did not significantly alter cognitive performance in HIV-1Tg rats at the doses tested. Further research using broader dosing, different administration routes, and co-administration with other cannabinoids is needed to fully explore the therapeutic potential of CBD for targeting HIV-associated NCI.