90. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature (2004) 430(6996):213–8. doi: 10.1038/nature02664
227. Cinar R, Gochuico BR, Iyer MR, Jourdan T, Yokoyama T, Park JK, et al. Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis. JCI Insight (2017) 2(8):e92281. doi: 10.1172/jci.insight.92281
Role of NLRP1
222. Shi CS, Nabar NR, Huang NN, Kehrl JH. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discov (2019) 5:101. doi: 10.1038/s41420-019-0181-7
108. Carvalho ACA, Souza GA, Marqui SV, Guiguer EL, Araujo AC, Rubira CJ, et al. Cannabis and Canabidinoids on the Inflammatory Bowel Diseases: Going Beyond Misuse. Int J Mol Sci (2020) 21(8):2940. doi: 10.3390/ijms21082940
52. Klein TW, Cabral GA. Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J Neuroimmune Pharmacol (2006) 1(1):50–64. doi: 10.1007/s11481-005-9007-x
Among the cannabis extracts, the THC is the main psychoactive component due to the lipophilic structure that allows the molecule to cross the blood-brain barrier . Once in the central nervous system, the THC acts as a cannabinoid agonist, and its modulation of cannabinoid receptor 1 (CB1) is linked to pleasurable sensations. Such sensations are achieved because the CB1 is heterogeneously distributed around the brain, modulating the dopaminergic transmission in the limbic cortex and the association cortices . The most commonly reported pleasure sensations are feeling of well being, calmness, relaxation, and hilarity . Furthermore, according to Carlini et al. , the most common physical symptoms are xerostomia, red eyes, polyphagia, and tachycardia. Medical properties of cannabis extracts, however, are due to the several neurotransmitters involved on CB1 and CB2 (cannabinoid receptor 2) receptors .
In conclusion, the cannabis extracts are recognized by their hallucinogens and therapeutic properties, but the medical literature about their use is inconclusive and even contradictory. We conducted a narrative review approaching the inflammatory markers in individuals who used cannabis aiming at supplying the lack of literature exploring the therapeutics effects of cannabis use and looking at the cannabinoids as a potential anti-inflammatory agent in humans.
Materials and Methods
Reviewed studies categorized by the Oxford Centre for Evidence-Based Medicine – Levels of Evidence in the order from highest to lowest levels A, B, C, and D
The correlation between immune response and cannabis use has been explored, as in the longitudinal study performed by Kagen et al. , which aimed to evaluate the role of cannabis use on inducing sensitization to Aspergillus. It was important to find that cannabis users had a higher risk of fungal exposure and infection, increasing the variety of immunologic lung disorders presented by the subjects. Roth et al.  performed a study aiming to analyze the production of nitric oxide (NO) on cannabis users and the role of NO as an antimicrobial agent. The study provides the role of cannabis use decreasing NO production, which acts as an important mediator of antibacterial effects. So, these studies illustrate direct and indirect impact of cannabis use on the susceptibility to infections.
Within the medical effects of cannabis use, the anti-inflammatory properties can be explored therapeutically. Klein et al.  explored the alteration of immune mediators referring the suppression of tumor necrosis factor alpha (TNF-α) and other cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 6 (IL-6), interferon-gamma (IFN-γ), and interleukin 12 (IL-12) have also been observed following exposure to high affinity and psychoactive ligands such as cannabinoids and THC. MacCallum et al.  portray that cannabis extracts have important pharmacological properties, whereas THC has been noted to produce anti-inflammatory effects by the antagonism of TNF-α  and to be a strong anti-emetic  and was recently demonstrated to be an agonist of the peroxisome proliferator-activated receptor gamma (PPAR-γ) nuclear receptor with neuroprotective effects , as well as anticonvulsant efficacy . CBD is also a powerful anti-emetic  and anti-anxiety agent  in rodents.
By lowering ROS levels, CBD also protects non-enzymatic antioxidants, preventing their oxidation, as in the case of GSH in the myocardial tissue of C57BL/6J mice with diabetic cardiomyopathy  and doxorubicin-treated rats . An increase in GSH levels after CBD treatment was also observed in mouse microglia cells  and in the liver of cadmium poisoned mice . This is of great practical importance because GSH cooperates with other low molecular weight compounds in antioxidant action, mainly with vitamins such as A, E, and C . CBD exhibits much more antioxidant activity (30–50%) than α-tocopherol or vitamin C .
Indirect antioxidant and anti-inflammatory effects of CBD (closed arrows indicate inhibition; opened arrows indicate activation.
Direct antioxidant effects of CBD (closed arrows indicate reducing effects; opened arrows indicate inducing action).
3.1. Direct Antioxidant Effects of CBD
In addition to the direct reduction of oxidant levels, CBD also modifies the redox balance by changing the level and activity of antioxidants [19,26]. CBD antioxidant activity begins at the level of protein transcription by activating the redox-sensitive transcription factor referred to as the nuclear erythroid 2-related factor (Nrf2) , which is responsible for the transcription of cytoprotective genes, including antioxidant genes . CBD was found to increase the mRNA level of superoxide dismutase (SOD) and the enzymatic activity of Cu, Zn- and Mn-SOD, which are responsible for the metabolism of superoxide radicals in the mouse model of diabetic cardiomyopathy type I and in human cardiomyocytes treated with 3-nitropropionic acid or streptozotocin . Repeated doses of CBD in inflammatory conditions were found to increase the activity of glutathione peroxidase and reductase, resulting in a decrease in malonaldehyde (MDA) levels, which were six times higher in untreated controls . Glutathione peroxidase activity (GSHPx) and glutathione level (GSH) were similarly changed after using CBD to treat UVB irradiated human keratinocytes. The high affinity of CBD for the cysteine and selenocysteine residues of these proteins is a possible explanation for this observation . It is known that under oxidative conditions, alterations in enzymatic activity may be caused by oxidative modifications of proteins, mainly aromatic and sulfur amino acids . It has also been suggested that the reactive CBD metabolite cannabidiol hydroxyquinone reacts covalently with cysteine, forming adducts with, for example, glutathione and cytochrome P450 3A11, and thereby inhibiting their biological activity . In addition, CBD has been found to inhibit tryptophan degradation by reducing indoleamine-2,3-dioxygenase activity . CBD also supports the action of antioxidant enzymes by preventing a reduction in the levels of microelements (e.g., Zn or Sn), which are usually lowered in pathological conditions. These elements are necessary for the biological activity of some proteins, especially enzymes such as superoxide dismutase or glutathione peroxidase .
In addition to lipid peroxidation, oxidative conditions also favor the oxidative modification of proteins by ROS. The aromatic and sulfhydryl amino acid residues are particularly susceptible to modifications, and can result in production of levodopa ( l -DOPA) from tyrosine, ortho-tyrosine from phenylalanine, sulfoxides and disulfides from cysteine, and kynurenine from tryptophan, among others . The resulting changes in the protein structures cause disruption of their biological properties and, as in the case of lipid modification, affect cell metabolism, including signal transduction [46,50].
CBD has been shown to affect redox balance by modifying the level and activity of both oxidants and antioxidants ( Figure 2 and Figure 3 ). CBD, like other antioxidants, interrupts free radical chain reactions, capturing free radicals or transforming them into less active forms. The free radicals produced in these reactions are characterized by many resonance structures in which unpaired electrons are mainly found on the phenolic structure, suggesting that the hydroxyl groups of the phenol ring are mainly responsible for CBD antioxidant activity .
CBD is one of the main pharmacologically active phytocannabinoids . It is non-psychoactive, but has many beneficial pharmacological effects, including anti-inflammatory and antioxidant effects. . In addition, it belongs to a group of compounds with anxiolytic, antidepressant, antipsychotic, and anticonvulsant properties, among others . The biological effects of cannabidiol, including the various molecular targets, such as cannabinoid receptors and other components of the endocannabinoid system, with which it interacts, have been extensively studied. The therapeutic potential of CBD has been evaluated in cardiovascular, neurodegenerative, cancer, and metabolic diseases, which are usually accompanied by oxidative stress and inflammation . One of the best studied uses of CBD is for therapeutic effect in diabetes and its complications in animal and human studies . CBD, by activating the cannabinoid receptor, CB2, has been shown to induce vasodilatation in type 2 diabetic rats [8,9], and by activating 5-HT1A receptors, CBD showed a therapeutic effect in diabetic neuropathy . Moreover, this phytocannabinoid accelerated wound healing in a diabetic rat model by protecting the endothelial growth factor (VEGF) . In addition, by preventing the formation of oxidative stress in the retina neurons of diabetic animals, CBD counteracted tyrosine nitration, which can lead to glutamate accumulation and neuronal cell death .