Beneficial Effects of Cannabis on Blood-Brain Barrier Function in Human Immunodeficiency Virus

Abstract

Background: Human immunodeficiency virus (HIV) infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity.

Methods: We studied persons with HIV (PWH) and HIV-negative (HIV-) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay.

Results: Participants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P < .001). PWH had higher (more abnormal) BBB index values than HIV- individuals (mean ± SD, 0.361 ± 1.20 vs -0.501 ± 1.11; P = .0214). HIV serostatus interacted with cannabis use frequency, such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV- individuals. Worse BBB index values were associated with higher NFL in CSF (r = 0.380, P = .0169).

Conclusions: Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity.

Keywords: HIV; blood-brain barrier; cannabis; cerebrospinal fluid; neuroscience.

Figure 1.

Proposed model of interaction between HIV and cannabis with respect to the blood–brain barrier. In the presence of elevated permeability associated with HIV, cannabis reduces permeability and neuroinflammation but has no effect when the blood–brain barrier is intact in HIV. Abbreviations: CSAR, cerebrospinal fluid-to-serum albumin ratio; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; HIV+, HIV positive; HIV−, HIV negative; suPAR, soluble urokinase plasminogen activator receptor.

Figure 2.

BBB index values were better in those with more frequent cannabis use over the past month for PWH (black) but not for those without HIV (gray). Abbreviations: BBB, blood–brain barrier; HIV, human immunodeficiency virus; PWH, persons living with HIV.

Figure 3.

Worse BBB indices were associated with greater axonal injury as reflected in CSF NFL levels. Black, PWH; gray, individuals without HIV. Abbreviations: BBB, blood–brain barrier; CSAR, cerebrospinal fluid-to-serum albumin ratio; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; NFL, neurofilament light; PWH, persons living with HIV; uPAR, urokinase plasminogen activator receptor.