Methamphetamine and Cannabis: A Tale of Two Drugs and their Effects on HIV, Brain, and Behavior

Abstract

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders.

Keywords: Blood-brain-barrier; Cannabis; Gut-brain-axis; HIV-associated neurocognitive disorders; Inflammation; Methamphetamine.

Fig. 1

Caudate putamen dopamine receptors expression and IBA-1 expression in METH-exposed Tat-transgenic mice. Immunohistochemistry on paraffin embedded sections was utilized to examine the protein distribution and levels of dopamine receptor D1, dopamine receptor D2, as well as of IBA-1 in TAT− and TAT+ mice treated with either saline (SAL) or methamphetamine (METH+). Normalized intensity density data are expressed as mean ± standard error of the mean (n=5). *p< 0.05, **p< 0.01, ***p< 0.001. Adapted with permission from Kesby et al. (2017, Brain Behavior and Immunity)

Fig. 2

Cannabis use is associated with less neurocognitive dysfunction in HIV. Substantial past use with recent exposure cannabis exposure (CAN+) was defined as meeting criteria for a lifetime history of cannabis use disorder with self-reported use in the past year. The CAN− group did not have a history of substantial use (i.e., no lifetime cannabis use disorder and estimated lifetime average grams per day of use<1 gram) nor did they report use in the past year. Deficit scores (higher = worse) for global and domain-specific neurocognition were significantly higher in the HIV+/CAN− group compared to HIV+/CAN+ individuals (p range: .001 to .016). Clinically-relevant impairment is defined at a 0.5 deficit score cut-point. Data are expressed as mean ± standard error of the mean. *p< 0.05, **p< 0.01, ***p< 0.001. Data reanalyzed with permission from Watson et al. (2020)

Fig. 3

Preliminary data from the Translational Methamphetamine AIDS Research Cohort (Iudicello et al., unpublished data). Regression analyses examining main and interactive effects of HIV and METH as predictors of plasma vascular cellular adhesion molecule-1 (VCAM-1) levels revealed significant independent main effects of HIV (p=0.006) and METH (p=0.026). Plasma VCAM-1 levels were highest in the dual-risk group (HIV+ METH+), followed by single-risk groups (HIV− METH+ and HIV+ METH+), and lowest in the control group (HIV− METH−). Data are expressed as mean ± standard error of the mean. ^#p< 0.10 *p< 0.05, ***p< 0.001

Fig. 4

Cannabinoid (CB) receptor agonism blocks inflammation-induced toxicity in neuronal mitochondria. Similar to the effects of METH, conditioned media from immune-activated (IL-1b) astrocytes is toxic and reduces mitochondria biogenesis in neurons. In the left panels (a), the top row shows in red the mitochondrial transcription factor, TFAM (red). The middle row shows MAP2 (green) and the bottom row combines TFAM and MAP2. The panels on the right show TFAM (b) and MAP2 (c) are both decreased in cells treated with conditioned media from reactive astrocytes. However, a CB agonist blocks toxicity as TFAM and MAP2 levels are normalized in neurons that were exposed to conditioned media from astrocytes that were treated with a CB agonist. Hence, CB agonists may protect neurons from mitochondrial damage caused by HIV and METH induced inflammation in the brain. Adapted with permission from Swinton et al. (2019), Neurobiology of Disease

Fig. 5

This diagram represents a translational approach to evaluating the effects of cannabis and HIV on the gut-brain-axis in five model systems: people with HIV (PWH) and HIV− humans, HIV-infected humanized mice, gp120 transgenic mice and in vitro fecal cultures. Cannabinoid treatment may normalize HIV-related gut dysbiosis and gut barrier permeability, which in turn may reduce systemic and CNS inflammation, restore blood-brain-barrier integrity, and improve neurocognition. Diagram provided courtesy of Ronald J. Ellis, M.D., Ph.D.

Fig. 6

Translational evidence of executive dysfunction in HIV and METH. Perseveration was assessed using the Wisconsin Card Sorting Task (WCST) in humans and using a visual discrimination protocol with reversal learning in mice. (a) In the Translational Methamphetamine AIDS Research Center human cohort, demographically adjusted T-scores for perseverative responses on the WCST were significantly lower (signifying more perseveration) in METH-dependent participants within both HIV-serostatus groups. METH+ participants living with HIV (HIV+ METH+) also differed significantly from controls (HIV− METH−). (b) In mice, perseverative errors at the initial reversal of reward contingencies was significantly higher in TAT-transgenic mice exposed to METH (TAT+ METH+) compared to the control group (TAT− METH−). Data are expressed as mean ± standard error of the mean. *p<0.05, **p<.005, ***p<.001. Mice data (b) adapted with permission from Kesby et al. (2018, Behavioural Brain Research)

Fig. 7

HIV and a lifetime history of METH use disorder relate to older biological age. The influence of HIV and lifetime METH use disorder on estimated biological age, based on frailty index scores, was calculated relative to the reference group (HIV−METH−). First, linear regression was employed to estimate the effect of age on frailty index values in the HIV−METH− reference group. Next, biological age was estimated by inserting frailty index scores from the HIV+/METH− and HIV+/METH+ groups into the regression equation for the reference group (HIV−METH−) and solving the equation for age. The resulting estimated biological age was subtracted from chronological age to yield the data in Figure 6. Despite comparable chronological age across groups (mean age: HIV−/METH− = 51.2 years, HIV+/METH− = 50.8 years, HIV+/METH+ = 50.0 years; p = .74), HIV and METH produced incremental increases in estimated biological age, with a median increase in biological age of 45.9 years in the HIV+METH+ group. Data reanalyzed with permission from Paolillo et al. (2019)

Fig. 8

Hypothesized HIV group differences in the risk and benefit of cannabis exposure. The risk-benefit ratio of cannabis may differ between PWH (HIV+) and healthy adults (HIV−). In each instance, the risk-benefit ratio is conditioned on cannabis exposure, and in the case of PWH, severity of HIV disease. For HIV− adults, low cannabis exposure may confer little risk and little benefit (since there is no underlying disease process). As use in HIV− increases, risk increases (e.g., neurocognitive impairment [NCI]), which then flattens as tolerance develops. At high exposure, the tolerance is eclipsed by mounting toxicity. For PWH, cannabis’s anti-inflammatory effects may dominate with moderate “steady state” exposure [mid-curve] and this may reduce the risk of NCI. This “benefit” would be most pronounced in those who acquire tolerance and maintain moderate use. Infrequent users, in whom the anti-inflammatory effects are intermittent, would experience more risk, because of greater vulnerability to the repeated, acute impairing effects of cannabis. At progressively higher cannabis exposure, mounting toxicity dominates the putative beneficial effects