Both in vitro studies and animal models show that CB2R mediated anti-inflammatory activity may account for the neuroprotective action of the ECS by decreasing glial reactivity. Both natural and synthetic cannabinoids are neuroprotective after various types of CNS insults, such as stroke. Preclinical models show activation of CBRs can trigger removal of activated immune cells, down regulate pro-inflammatory cytokine and chemokine production, and inhibit HIV-associated synapse loss and neural injury. In vitro, THC treatment suppresses several pro-inflammatory factors, including TNF-α, IL-6, and IL-8, and decreases monocyte-derived interleukin IL-1ß production and astrocyte secretion of MCP-1 and IL-6 from a human coculture system. We recently reported that more recent cannabis use was associated with significantly lower IL-16 levels in cerebrospinal fluid and lower soluble tumor necrosis factor receptor type-II and IP-10 levels in plasma. An additional benefit of cannabis, likely linked to its anti-inflammatory effects, is stabilization of the blood–brain barrier , which we demonstrated in a separate report, showing that more frequent use of cannabis was associated with better markers of BBB integrity in PWH. Recently, studies have determined that cannabis is associated with reduced markers of immune activation and inflammation in CSF. In sum, there is substantial evidence that cannabinoids display beneficial anti-inflammatory effects that are relevant to HIV infection. Anti-inflammatory effects of cannabinoids in the brain may translate to clinical bene- fits, particularly with respect to neurocognition. HIV causes T-cell and monocyte migration to the brain and subsequent interactions with astrocytes and microglia lead to the secretion of neurotoxic cytokines and chemokines. These pro-inflammatory factors are linked to worse neurocognitive performance in PWH , and lowering them might benefit neurocognitive function.
We showed that lower levels of the monocyte activation marker, vertical growing system monocyte chemoattractant protein type 1 related to better performance in tests of learning ability, and that lower IP-10 also related to better learning as well as delayed recall and motor skills. These cognitive domains frequently show deficits in virally suppressed PWH. However, not all studies support neuroprotective effects of cannabis. For example, a brain diffusion tensor imaging study suggested axonal loss in the uncinate fasciculus, which is involved in verbal memory and emotion, in cannabis users. This study also showed greater than normal age-dependent fractional anisotropy declines in white matter tracts and globus pallidus of cannabis users, suggesting reduced neuronal integrity in these regions. For example, a review of 107 case reports over a total of 55 years described strokes associated with intake of both raw and synthetic cannabis. Affected individuals were most frequently young males with chronic tobacco smoking and unusually high levels of cannabis and alcohol consumption just before their stroke. Ischemic strokes and much more common than hemorrhagic strokes with cannabis use. Proposed underlying mechanisms explaining a possible link between stroke and cannabis use, reactive oxygen species generation inducing oxidative stress, cerebral artery luminal stenosis, cerebral auto-dysregulation, cardioembolism, reversible cerebral vasoconstriction syndrome and angiopathy. None of these reports focused on HIV infection, where effects of cannabis on chronic inflammation may counterbalance adverse vascular effects. An additional limitation of the historical literature is the many confounds associated with cannabis consumption that themselves are risk factors for stroke. These include concomitant tobacco smoking and intake of alcohol and synthetic cannabinoids, as well as a variety of other comorbidities. In the case of ROS, similar to tobacco smoke, these could be generated as a byproduct of marijuana combustion rather than a specific effect of cannabinoids.
Smoking involves inhalation of products of combustion that may be the source of adverse vascular effects. Thus, no strong link between cannabis and stroke has been yet established. These effects may be eliminated when using cannabis in oral or vaporized form. Ongoing trials may be found at clinicaltrials.gov. Finally, there is considerable evidence that, rather than being a risk factor for stroke, cannabis may be vasculo- and neuro-protective. Thus, cannabinoids may have significant therapeutic value in stroke, as suggested in a recent systemic review and meta-analysis by England et al. showing that all sub-classes of cannabinoids, cannabis-derived, synthetic, specific CB1R, and CB2R agonists significantly reduced infarct volume in transient and permanent ischemia and improved both early and late functional outcome in experimental stroke when given after stroke onset. In large mammals, cerebral vessels perfused with cannabinoids demonstrated relaxation rather than constriction. Cannabis disturbs cognition acutely, but its longer-term effects on brain function in HIV are not well understood. While there is limited evidence of increased cognitive impairment in some cannabis-using PWH, chronic exposure may also reduce inflammation, possibly resulting in improved CNS outcomes among PWH. Still, thedegree and pattern of cannabis exposure that may be therapeutic, neutral, or harmful is not understood. We hypothesize that an “optimal” level of cannabis exposure will improve some HIV-related outcomes. Studies of human and mouse cannabinoid systems in the context of neuroinflammatory exposures show that CB2Rs are highly upregulated during inflammatory insult and their selective activation reduces vascular inflammation, pathological microglial activation and BBB dysfunction, thus indirectly decreasing oxidative stress and subsequent cell death, and HIV-associated synapse loss. Taken together, this literature cumulatively suggests there may be some therapeutic potential of compounds that target the cannabinoid system through modulation of neurotoxic and inflammatory processes in HIV disease and other neuroinflammatory diseases.
To evaluate the effects of cannabis use in PWH and people without HIV and BBB permeability and soluble urokinase plasminogen activator receptor , a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the basal lamina around cerebral capillaries. We found a statistically significant interaction between HIV serostatus and frequency of cannabis use such that more frequent use was associated with lower concentrations of uPAR in CSF in PWH, but not in PWoH. Within PWH, higher CSF uPAR levels correlated with higher CSAR values and more inflammation . These findings suggest that cannabis may have a beneficial impact on HIV-associated BBB injury and neuroinflammation, and since BBB disruption may permit increased entry of toxins with consequent CNS injury, these results support the potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity. In a recent report, we hypothesized that more recent cannabis use would be associated with reduced biomarkers of immune activation and inflammation in CSF. This hypothesis was based on previous research demonstrating that selective stimulation of CB2R suppressed neuroinflammation and microglial activation. We measured a panel of pro-inflammatory cytokines -16, C-reactive protein , IL- 6, CXCL-10, sCD14 and soluble tumor necrosis factor receptor type II in CSF and blood plasma in PWH and PWoH who did or did not use cannabis at various levels from none too heavy. Participants were 35 PWH and 21 PwoH cannabis ever users, 15 never users. We calculated factor scores of biomarkers using exploratory factor analysis separately for CSF and plasma. We used multiple linear regression to evaluate the association of factor scores with the effects of cannabis use, HIV status and their interaction. Of the three CSF biomarker factors identified, one that loaded on CRP, IL-16 and sTNFRII was associated with more recent cannabis use in both HIV status groups. In plasma, more recent cannabis use was associated with lower values on a biomarker factor loading on sTNFRII and IP-10. Thus, we found recent cannabis use to be associated with lower levels of inflammatory biomarkers, both in CSF and blood plasma, but in different patterns, consistent with compartmentalization of immune effects. Cannabinoids are highly lipid soluble and sequestered in brain tissue, and thus our findings are consistent with specific anti-neuroinflammatory effects that may benefit PWH with or at risk for neurocognitive impairment. However, other studies of cohorts differing in age and HIV disease characteristics have reported conflicting findings. Cannabis as a clinical intervention in HIV disease would be a significant contribution to the field. When ingested, inhaled, or absorbed, THC and CBD, along with other exoge-nous cannabis components, are anti-inflammatory and counter oxidative stress. Patients report that cannabis has less harmful effects than other drugs. However, how to dry cannabis cannabis used improperly can have adverse side effects. People who use cannabis frequently with heavy doses have a higher risk of developing psychiatric symptoms. Long-term users have a reduction in hippocampal volume, affecting memory and verbal learning. In areas with high cannabis use, hospital emergency rooms report increased prevalence of visits due to nausea/vomiting, cardiovascular, psychiatric complaints. Caution is recommended for adolescents using cannabis due to the effect of cannabis on the developing brain. Adolescents who used cannabis regularly developed deficits in executive function involved in planning and decision making, as well as memory loss. Cerebral white matter organization is altered, affecting neural communication, potentially leading to higher impulsivity in adolescents. Further investigations are needed to refine the effects of dose, timing, and cannabis compound on this relationship, which could inform guidelines for safe cannabis use among populations vulnerable to NCI, cognitive decline, and inflammation. Clinical trials are needed to support recommendations to balance the trade-offs between therapeutic benefits and harm.Sixteen states have legalized the medical use of cannabis, and several others may do so by the end of the 2012 election cycle.
Medical cannabis dispensaries —storefronts that dispense the drug to qualified patients—have proliferated in several of these jurisdictions. California was the first state to legalize medical cannabis, and there are now hundreds of dispensaries serving an estimated 300,000 patients throughout the Golden State . In the legal grey area between California law and federal prohibition, a handful of cities have taken it upon themselves to regulate MCDs within their jurisdiction. Unfortunately, the debate surrounding medical cannabis tends to be intensely polarized, heavy on political ideology, and light on empirical evidence. In this paper I aim to contribute knowledge that can be used objectively by researchers and policymakers interested in the effects of locally regulated MCDs on crime. Using spatial data and linear regression models, I explore the relationship between MCDs and crime across 189 census tracts in San Francisco. In framing a land use question, this study strives to analyze dispensaries in the same way that local government officials and staff might analyze bars, retail stores, or any other business in their community. Some constituents may want them, and others may not. From a policy standpoint, I argue that the interesting question is not whether to allow for the distribution of medical cannabis, but how. Every other legal substance—from alcohol to azithromycin—is dispensed by some type of storefront retailer. In California, cannabis is a legal substance within certain medical contexts. In this study I investigate whether, and to what extent, storefronts that provide medical cannabis are associated with higher crime rates.Law enforcement groups have mounted organized resistance against the proliferation of MCDs, focusing their attacks first and foremost on California—the state that opened Pandora’s box, as it were. A 2009 report entitled Marijuana Dispensaries and the Federal Government: Recommendations to the Obama Administration stated that: “In, California, dispensaries have had 13 years to flourish, and it is in California that their abuses have become evident” . In 2009 the California Police Chiefs Association also published its White Paper on Marijuana Dispensaries. It alleges that dispensaries “have been tied to organized criminal gangs” and that murders and armed robberies occur commonly as “ancillary byproducts of their operation” . It goes on to relate a series of sensational anecdotes involving “hooded home invaders”, victims bleeding to death, and even poisonings . In neither report do the authors include statistical analyses indicating that MCDs attract these crimes at rates higher than any other business. Proponents of medical cannabis dispensaries contend that regulated dispensaries actually reduce crime and restrict access to cannabis by minors, and they point to several successful jurisdictions in making the case that regulation is preferable to prohibition. In a report released in early 2011, Americans for Safe Access, a non-profit advocacy organization representing medical cannabis patients and MCDs, cites agreement from local government and law enforcement officials representing municipalities as diverse as Kern County, Oakland, and Sebastopol. In Oakland, a notoriously high-crime jurisdiction, city administrator Barbara Killey was quoted as saying that since enacting its dispensary ordinance, “the areas around the dispensaries may be some of the safest areas of Oakland” . In this paper I aim to test these competing claims empirically using data collected for the year 2010 across 189 census tracts in San Francisco.