Methods for operationalizing access to cannabis delivery remain undeveloped, but cannabis delivery constitutes a growing portion of the retail market, a pattern accelerated by the COVID-19 pandemic.Given that most jurisdictions banning outlets also ban delivery businesses, the associations we have observed may be relevant to delivery businesses as well, but this should be evaluated empirically in future research. Other limitations include the potential for uncontrolled confounding. We may have also underestimated effect measure modification by controlling for confounders of the policy-outlet relationship that are also on the pathway from median income or racial–ethnic composition to outlet densities. Additionally, illegal outlets may be under counted in our data in 2020, because legal action in the previous year encouraged Weedmaps to purge listings of illegal outlets. We assessed local policies cross-sectionally in 2020 and assumed them to be time-invariant over the study period. Policies may have been adopted several months or years prior to 2020. We could not assess how within-place temporal changes in policies affected outlet densities, either immediately or lagged. We modeled the temporal relationships between outlet densities and time-varying covariates such as sociodemographics, but we could not model other temporal dynamics, including whether a recreational outlet was previously medical-only versus newly opened. Reverse causation, in which local policies are adopted in response to outlet densities, is also possible. However, the cannabis norms and political orientations that determine local policies are unlikely to change substantially and systematically over the 3-year study period. We focused on a subset of California,microgreens shelving which limits generalizability. Nonetheless, our study areas captured the majority of the California population and diverse approaches to cannabis regulation.
Although block groups are very small spatial units, it is possible that analyses at other levels of spatial aggregation could produce different results . Some mismeasurement of spatial effects is possible because block groups at the edge of the study regions lacked measurements for all neighbors, but any bias is likely to be small because this concern applies to only a small minority of study areas. Finally, we define “equity” as the absence of differential associations between policies and outlets by block group median income and racial–ethnic composition, but other measures may also be appropriate. Conclusions As with all policies, cannabis legalization likely involves balancing harms and benefits. For jurisdictions that have chosen to legalize recreational cannabis, the optimal density of outlets is unknown. If lessons from alcohol and tobacco apply to cannabis, limiting outlet densities may protect public health.Alternatively, if cannabis outlets promote substitution of alcohol, tobacco, or opioids for cannabis, and these substances are less harmful than cannabis, then health may be improved.Local control of legal cannabis has resulted in considerable variation in cannabis policies across California with important implications for health equity. This analysis suggests that bans on outlets were disproportionately adopted in jurisdictions with more White residents, higher median income, and less poverty, and this pattern has resulted in the disproportionate placement of cannabis outlets in less advantaged communities. Moreover, although local policies in jurisdictions permitting cannabis outlets have the potential to address inequitable distributions of cannabis outlets, those policies adopted to date do not appear to have achieved this. Findings from this study should be incorporated into broader assessments of the costs and benefits of recreational cannabis legalization considering short-term and long-term public health and social welfare outcomes. Alternative policy and public health approaches that protect vulnerable communities from disproportionate harms related to cannabis should be explored.
Under suppressive antiretroviral therapies , infection with Human Immunod efficiency Virus remains a challenge, both due to the maintenance of cellular reservoirs and to chronic inflammation driven by low viral replication and dys regulated immune mechanisms . In end organs such as the brain, where the majority of the HIV-1 targets and reservoirs are of myeloid origin , the remaining inflammatory environment contributes to co-morbidities , including neurological and cognitive problems , particularly if ART is not introduced sufficiently early . Substance use disorders are frequent among the HIV-infected population, further contributing to cognitive impairment . Nonetheless, the mechanisms by which addictive substances and HIV interact are multi-factorial and poorly understood. Drugs of abuse impact the brain reward system, by modifying levels and balance of neurotransmitters . The HIV target cells, macrophages and microglia, as well as CD4 T cells, express receptors to neurotransmitters, so SUDs are likely to impact mechanisms of immune and inflammatory, and anti-viral responses . Biomarkers that detect the effect of SUDs, and distinguish HIV in that context, may clarify how drugs affect HIV and inflammation. Cannabis is one of the most prevalent substances among HIVþ subjects, compared to the non-infected population , either prescribed for ameliorating symptoms associated with the virus or with ART , or used recreationally, as well as a component of poly substance use , which in itself is a risk factor for HIV infection. The effects of cannabis may drastically differ from the effects of stimulant drugs such as Methamphetamine , particularly in the context of HIV infection . Yet, similar to other drugs of abuse, cannabis may be a confounder shifting the expression of biomarkers of inflammation and cognition, masking our ability to clearly measure the impact of virus, ART or other treatments in the immune status and brain pathogenesis, or may be altogether beneficial. In terms of cognition, cannabis exposure has been linked to lower odds of impairment in people living with HIV. On the other hand, impaired verbal learning and memory, may be negatively impacted by cannabis use . Other studies report no differences, or detrimental effects in HIV-negative populations, suggesting that the observed effects of cannabis, including its benefits, may be largely domain and context-dependent. It has been reported that cannabis use improves biomarkers of inflammation in the CSF and plasma of HIVþ subjects and decreases the number of circulating inflammatory cells . We have tested the value of a large panel of transcripts associated with inflammation and neurological disorders, digitally multiplexed and detectable in peripheral blood cells from HIV-positive and HIV-negative subjects, users of cannabis or not . The differences between groups were analyzed using a systems biology approach that identified associated gene networks based on pathways and molecular interfaces, for identifying and visualizing orchestrated transcriptional patterns consistent with HIV infection, CAN exposure, and their interactions.
Trends in the behaviors of gene clusters and their predicted regulators revealed that effects of cannabis differ between HIVand HIVþ groups. Moreover, mixed statistical models have pinpointed genes that are further influenced by cannabis in the context of poly substance use. These context-dependent effects of cannabis indicate the complexity of its molecular actions and properties, and the challenges of biomarker discovery in the context of SUDs. At the same time, the results suggest that cannabis in the context of HIV infection may drive benefits by promoting a decrease of pro-inflammatory and neurotoxic transcriptional patterns, changes and changes in gene clusters associated with leukocyte transmigration and neurological disorders.The impact of HIV, cannabis and their interaction on peripheral markers of cell subset, cellular function and activation was estimated using a combination of cell surface protein detection by flow cytometry and a targeted digital multiplex transcriptomic analysis. The specimens were from males, with homogeneous age and education, and the same race distribution, as shown in Table 1. The examination of clinical data revealed that in HIVþ individuals, cannabis did not significantly affect CD4 nadir, CD4/CD8 ratio, plasma or CSF viral load. Cannabis users were significantly more likely to engage in poly substance use, or use other drugs, including alcohol, cocaine and METH. HIV status significantly increased the incidence of lifetime major depressive disorders,greenhouse tables which was not affected by cannabis use . Neuropsychological data indicated that cannabis had a marginal effect on Global T scores . By flow cytometry, we verified that the specimen freezing process did not impact subset distribution . For instance, HIVþ subjects had significantly lower percentage of CD11bþCD14þ monocytes compared to HIV- subjects, particularly the ones exhibiting the inflammatory marker CD16þ, regardless of cannabis use . The percentage of CD4þ T cells was also decreased in HIVþ specimens when compared to HIV, with no effect of cannabis . The percentage of CD8þ cells, on the other hand, was significantly increased in HIVþ non-cannabis users, but not in cannabis users, compared to respective controls .Molecular markers of neuroinflammation, activation and leukocyte transmigration were measured in the peripheral blood cells under the hypothesis that cannabis use has an effect by itself and on modulating the effects of HIV. A panel of 784 markers relevant to neurological disorders and inflammation were tested by Nanostring. Of these 381 did not produce any signal in any of the specimens and were excluded from the analysis. The expression of genes with significant signal over noise in more than arbitrarily 10% of the samples was normalized by an average of 8 housekeeping genes. Hierarchical clustering performed using average normalization method applied to digital gene expression data has revealed similarities between HIV-/CANþ, HIVþ/CAN- and HIVþ/ CANþ, but all these groups were distinct from HIV-/CAN-. Clustering also allowed to identify individual specimens that showed patterns distinct from the majority within groups . Systems biology strategies were used to identify defining expression patterns in transcriptional data, and gene clusters exhibiting orchestrated behaviors perturbed by HIV infection, by the use of cannabis, or by their interaction.
We have identified significant trends in a number of gene clusters functionally annotated to biological processes and pathways of relevance to the neuropathogenesis of HIV. Overall, the analysis indicates context-dependent effects of cannabis. The majority of the digitally multiplexed genes exhibited detectable and overlapping interactions based on pathway, as indicated in Fig. 4.In cells from HIVþ/CANþ individuals, a number of genes showed decreased expression compared to HIV-/CAN- . HIV infection in the context of cannabis, revealed by the comparison of HIVþ/CANþ and HIV-/CANþ , was characterized by stronger upregulation of genes, but also several genes with decreased expression. The effects of cannabis in the context of HIV measured by the ratio between HIVþ/CANþ and HIVþ/CAN-, were characterized by a higher number of down regulated genes, and a more modest upregulation, as suggested by overall lighter orange shades. A complete list of the genes in this network and T ratio in indicated comparisons can be found in Supplementary Materials 1. Pathway-based interactions were subdivided for identification of embedded functional annotations impacted by HIV and/or cannabis, identified by DAVID Bio-informatics Resources with a gene list input. Individual functional annotations were then assembled in GeneMania for visualization of effects. A complete list of significant pathways and functional annotations can be found in Supplementary Materials 1. The pathways selected for visualization were curated based on the expression of inflammatory genes, significance to neurological disorders in the context of HIV, viral infection, pathogenesis and networks with interventional value. For instance, a gene network functionally annotated to viral host interactions was identified , where the ratio between HIVþ/CAN- and HIV-/CAN- indicated that HIV increased a number of genes annotated to that function. The ratio between HIV-/ CANþ and HIV-/CAN- , as well as between HIVþ/CANþ subjects were compared to HIV-/CANþ , indicated that both cannabis alone and HIV in the context of cannabis use increased a large number of genes in this cluster, but several genes were also decreased in both conditions, including the Ras homolog gene family GTPase RhoA, the Proteasome 20S Subunit Beta 8 , the intracellular cholesterol transporter , the E1A Binding Protein P300 and the histone deacetylase Sirtuin 1 . The ratio between HIVþ/CANþ and HIVþ/CAN- indicated that cannabis in the context of HIV was associated with a mild increase of genes in viral host interaction function , and a decrease in the general transcription factor IIB and the ubiquitin protein ligase 3A were characteristic of this comparison. Apoptosis was also identified as a relevant functional annotation , showing differential effects of HIV and/or cannabis. HIV alone decreased Caspase 7 CASP7, but increased CASP9 and the apoptosis regulator BCL2 . The effect of cannabis, on the other hand , indicated decrease in BCL2 . Likewise, HIV in the context of cannabis had a decrease in BCL2 . On the other hand, the ratio between HIVþ/CANþ and HIVþ/CAN- indicated that cannabis decreased or had mild effects on the expression of genes associated with apoptotic functions detectable in peripheral leukocytes .