Lastly, future studies examining the effect of marijuana legalization on adolescent marijuana use should assess mediation by marijuana availability as a potentially important locus of intervention, particularly as more governments are likely to adopt liberalized marijuana policies. Researchers should seek to better understand this association and its environmental determinants, including in South America with additional years of data, in other legalization contexts, and where perceived availability and marijuana use have not increased, such as the US.The present study has several strengths. We used 1) a large, representative sample, 2) novel methods to analyze time-varying associations, and 3) comparable surveys among secondary school students across multiple years and countries. This is the first study to our knowledge to examine time-varying associations between adolescent risk factors for marijuana use and use of marijuana amid changing marijuana policies in the Southern Cone. This study should also be considered in light of its limitations. First, cross-sectional data preclude assuming temporal relationships between risk factors and marijuana use. Although this was not a study of causal effects, potentially important confounders were not considered. Because of finite sample limitations, our ability to examine covariates was restricted, flood tray particularly in Uruguay where the sample size was smallest.
Relatedly, we were not able to model perceived risk and perceived availability together in Argentina, or include all countries in a single model because this would have restricted the analysis to only four years , resulting in insufficient coverage of the time axis for TVEM models . In light of these limitations, we modeled the relationships separately per country, utilizing all years of available data, and note that the strength of associations across countries and within Argentina and Uruguay should be compared with caution. Additionally, these data are self-report, which may contribute to misclassification, for example by social desirability bias. However, methods of data collection and validation used aimed to minimize these biases . While these data are designed to be representative of secondary school students in urban areas, they are not generalizable to other populations. Lastly, although a strength of our study is that it compares secondary school-attending adolescents across countries, slight differences in student populations between Argentina , Uruguay , and Chile may have limited comparability.People living with HIV infection often search for ways to manage symptoms to improve their quality of life. Cannabis is an effective strategy for alleviating symptoms associated with HIV disease and with other conditions such as cancer . Indeed, several meta-analyses of clinical trials have established the effectiveness of cannabis for HIV-related neuropathic pain and nausea, although dosing and administration routes have varied widely.
Some studies suggest that titrating dosing to effectiveness and side effects is a useful strategy for dose selection. PWH disclose, to their health care providers and in unpublished qualitative interviews , using community-acquired cannabis to self-manage symptoms such as poor appetite, gastrointestinal and sleep disorders, pain, or to improve adherence to antiretroviral therapy food intake requirements by increasing appetite . However, some medical providers feel ill-informed to engage the patient in evidence-based conversations regarding cannabis selection, beneficial effects, adverse effects, and harm reduction. Yet, due to federal restrictions, it is difficult to run clinical trials to address better informed evidence-based conversations. Medicinal cannabis is rapidly becoming an acceptable and state-level authorized form of symptom and disease management. Health care providers understand the potential benefits of cannabis for symptom management. However, clinicians feel hindered by a lack of information to make recommendations and have an informed discussion of risk reduction, potential dependence, or possible adverse effects with their patients currently using or desiring to use cannabis. Among 71 clinicians that had authorized medicinal cannabis for their patients in Washington State, 56.4% had limited knowledge of available products and where to get them, and 70% were uncertain of dosing.
An improved understanding of the strategic use of cannabis would support clinicians in their discussions with patients. Compounding this, research on the effects of cannabis in PWH are generally lacking and as such fail to provide clinicians with reliable data for cannabis use recommendations. Cells throughout the human body express a network of receptors and enzymes referred to as the endocannabinoid system for the synthesis and sensing of endogenous lipid ligands. The overarching function of the endocannabinoid system is to mediate regulation of energy utilization and substrate metabolism to maintain a relative state of equilibrium or balance in the body’s physiological and interdependent processes, for example, homeostasis. Endocannabinoid system signaling pathways have been pursued as a target for future pharmacotherapy to reduce inflammation and provide therapy in pathological conditions. Components of cannabis bind to endocannabinoid receptors, modulating the function of the endocannabinoid system. The endocannabinoid system is particularly important in HIV infection for a number of reasons. For example, cannabis use is associated with a reduction in systemic inflammation and immune activation, and there is a more rapid decline of HIV DNA among cannabis users taking ART than with those not using cannabis. Reductions in inflammation and more rapid declines in HIV DNA might contribute to lower viral loads and higher CD4 T cells in PWH cannabis users. We recently reported that more recent use was associated with significantly lower Interleukin -16 levels in cerebrospinal fluid and lower soluble tumor necrosis factor receptor type-II and inducible protein -10 levels in plasma. This review will outline the endocannabinoid system and phytocannabinoids and their effect on the gut–brain axis in the context of HIV infection.HIV infection is associated with systemic CD4 + T cell depletion, gut dysbiosis, gut epithelial barrier dysfunction, chronic inflammation, and consequential poor health outcomes, even when well controlled by antiretroviral therapy. Gut barrier dysfunction permits the translocation of inflammatory microbial products such as a lipopolysaccharide . In particular, following viral control with ART, CD4 + T cells do not return to normal levels in the gut, and gut epithelium deffects are highly correlated with this persistent gut CD4 + cell depletion. Increased apoptosis, chronic inflammatory signals, and reduced proliferation and repair of epithelial cells all contribute to compromised gut barrier function. Altered tryptophan metabolism and deficits in butyrate producing microbes in PWH have been reported and likely also contribute to increased gut permeability. Barrier deffects render HIV+ individuals susceptible to increased local and systemic exposure to pro-inflammatory ligands produced by gut microbiota. Together these alterations lead to poor HIV disease outcomes, including HIV-associated neurocognitive disorders . In this article, we present possible physiologic influence of cannabis on gut barrier integrity in PWH .The gut microbiota regulates and maintains functional activities of the gut mucosal barrier integrity, the gut associated lymphoid Thissue ,4×8 grow table with wheels immunomodulation, and protection against pathogenic organisms. The diverse bacterial community comprising the gut microbiota contains both beneficial and detrimental microorganisms. Beneficial species interact with the host immune system in a mutualistic manner. One of the main functions of the gut microbiota is to communicate with and regulate immune functions that impact immune cells in close proximity, for example, GALT, residing basolaterally to the monolayer of gut epithelium, as well as distal immune responses. The GALT represents 70–80% of the cellular immune compartment and is the largest immune reservoir in the human body. Early in infection, HIV establishes a high titer in the GALT. Ongoing HIV replication is responsible for the depletion of GALT CD4 + T cells and subsequent alterations of the gut microbiota.
Even in the context of antiretroviral treatment and virologic suppression, patients continue to show increased in- flammation and immune cell activation, as well as elevated gut permeability and dysbiotic microbiota. While normal commensal flora contribute to tolerance and balance between T helper subset pattern recognition receptor signaling, loss or replacement of these beneficial flora leads to loss of T-helper cell type 1 function, amplifying GALT dysfunction in HIV infection. Depletion of Th17 cells in the GALT leads to reduced IL-22 production diminishing epithelium repair processes and maintenance of tight gap junctions. Such barrier deffects create a pathway for microbial products to escape the gut lumen and enter the systemic circulation. The entry of microbial products into the blood triggers the innate immune response and release of pro-inflammatory cytokines, such as IL-1b, TNF-a, and others.Microbial dysbiosis is associated with numerous adverse effects, including impaired function of the gut barrier and translocation of microbial products into the bloodstream causing systemic inflammation. PWH develop a dysbiotic gut microbiota—that is, the gut microbiota displays alterations in the diversity, types, and relative proportions of bacteria that normally inhabit the GI tract. Furthermore, dysbiosis creates a vicious cycle with chronic inflammation promoting an environment abundant in pro-inflammatory species. Changes include a greater proportion of gram-negative bacterial family, Enterobacteriaceae, increased abundances of Prevotella particularly, Prevotella copri, and Erysipelotrichaceae, and depletion of Bifidobacterium and Bacteroides. Intriguingly, numerous taxa considered aerotolerant and generally part ofthe oral microbiota, not normally present in the gut, are elevated in PWH . Chronic oxidative stress in the gut may increase O2 levels in the gut enabling aerobic species to flourish in a normally strictly anaerobic environment. The shift in gut microbiota to a Prevotella enriched composition is consistent with reports that a complex carbohydrate dominant diet also enriches for Prevotella. The extent to which Prevotella spp. versus P. copri, in particular, contribute to HIV-associated comorbidities remains unclear. The relative abundance of Prevotella is positively correlated with CXCL10/IP-10, a proinflammatory and antiangiogenic chemokine, levels and anti-correlated with CD4 + T cells. Another study demonstrated that P. copri levels were positively associated with colonic CD1c + myeloid dendritic cells. Increased Prevotella has been implicated as a potential initiator to disturbance of GBA signaling. This change has significant consequences to cognitive function and neurological outcomes. The abundance of P. copri and Prevotella stercorea in PWH has been evaluated in numerous studies and found to be associated with sexual behavior rather than solely HIV status. A few studies examining HIV microbial dysbiosis have been conducted with a majority of men who have sex with men . In these studies, there has been an association with sexual orientation and an abundance of Prevotella enterotype in contrast to men who have sex with women who are rich in Bacteroides. However, this is independent of HIV status and more likely due to sexual behavior of anal intercourse and somewhat is ameliorated with ART initiation. Nevertheless, sexual behavior of anal intercourse has been shown to be a confounder in the link of HIV-related gut dysbiosis; studies involving microbiota in HIV should control for sex behavior with MSM status. This dysbiosis has been suggested to play a role in driving immune activation as opposed to previously suspected microbial translocation alone. However, a more recent study demonstrated that treatment with ART will have an effect on the microbiome that pervades sexual behavior but is correlated with. The impact of cannabis on gut microbiota has not been significantly reported in human populations to date or PWH. One study assessed sexual practice and drug use in PWH, including cannabis on gut microbiota composition noting normalization of taxa commonly observed as dysbiotic in PWH. A decline in Prevotella abundance was associated with cannabis use. A limited number of taxa were quantified by quantitative polymerase chain reaction, and changes in some taxa were observed; however, interpretation of these results should be taken with caution as cannabis administration induced increased short-term hyperphagia. It is hypothesized that the effect of cannabis on gut microbiota is likely to occur in an indirect manner as the result of altered gut inflammation and homeostasis. Gut bacteria control the differentiation and function of immune cells in the intestine, periphery, and brain. There is increasing evidence that gut microbiota and the immune system are critical factors in the pathogenesis of neurodevelopmental, psychiatric, and neurodegenerative disease as microbiota immunomodulation orchestrates communication between the gut and brain. Some of the cognitive domains are subject to immune-mediated central nervous system injury from HIV induced microglial activation and contributing to HIV-related cognitive dysfunction. Furthermore, microglia is exquisitely responsive to the gut microbiome and commensal bacteria support the maintenance of microglia in normal homeostasis conditions. When microbiota is absent, microglia loses the ability to mature, becoming deffected in differentiation, and function. In a study with germfree mice, severely-deffected microglia led to impaired innate immune responses. Recolonization with a complex microbiota environment resulted in partial restoration of normal microglial features. LPS activates microglial cells leading to neuroinflammation and, when chronic, is a likely contributor to CNS pathologies, through a leaky gut–brain barrier .