key: cord-1016734-jyazds3h
authors: Anil, Seegehalli M.; Peeri, Hadar; Koltai, Hinanit
title: Medical Cannabis Activity Against Inflammation: Active Compounds and Modes of Action
date: 2022-05-09
journal: Front Pharmacol
DOI: 10.3389/fphar.2022.908198
sha: f462e9f9b405412c31c76c3be0c95ccc0e81961b
doc_id: 1016734
cord_uid: jyazds3h

Inflammation often develops from acute, chronic, or auto-inflammatory disorders that can lead to compromised organ function. Cannabis (Cannabis sativa) has been used to treat inflammation for millennia, but its use in modern medicine is hampered by a lack of scientific knowledge. Previous studies report that cannabis extracts and inflorescence inhibit inflammatory responses in vitro and in pre-clinical and clinical trials. The endocannabinoid system (ECS) is a modulator of immune system activity, and dysregulation of this system is involved in various chronic inflammations. This system includes cannabinoid receptor types 1 and 2 (CB1 and CB2), arachidonic acid-derived endocannabinoids, and enzymes involved in endocannabinoid metabolism. Cannabis produces a large number of phytocannabinoids and numerous other biomolecules such as terpenes and flavonoids. In multiple experimental models, both in vitro and in vivo, several phytocannabinoids, including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabigerol (CBG), exhibit activity against inflammation. These phytocannabinoids may bind to ECS and/or other receptors and ameliorate various inflammatory-related diseases by activating several signaling pathways. Synergy between phytocannabinoids, as well as between phytocannabinoids and terpenes, has been demonstrated. Cannabis activity can be improved by selecting the most active plant ingredients (API) while eliminating parts of the whole extract. Moreover, in the future cannabis components might be combined with pharmaceutical drugs to reduce inflammation.

The immune system consists of both adaptive and innate immunity. Innate immunity is the rapid and non-specific response to pathogens mediated by myeloid cells and natural killer (NK) cells. On the other hand, adaptive immunity is a slower but specific response that generates immunological memory, involving the activation of B and T lymphocytes (Netea et al., 2019) . During normal inflammation, innate immunity is activated within minutes to hours as a first line of defense against pathogen infection, followed by the elimination of the threats carried out by both the innate and the adaptive immune responses (Netea et al., 2019) . Ending inflammation and returning to homeostasis is a process known as resolution. However, failure to remove the inciting stimulus efficiently can lead to the development of chronic inflammation and progression of tissue damage (Feehan and Gilroy, 2019) . This kind of chronic, unresolved inflammation contributes significantly to various pathogeneses, including that of asthma (Pothen et al., 2015) , COVID-19 (Effenberger et al., 2021) , atherosclerosis (Galkina and Ley, 2009) , chronic obstructive pulmonary disease (Sevenoaks and Stockley, 2006) , inflammatory bowel disease (Actis et al., 2019) , neurodegenerative disease (Perry, 2004) , multiple sclerosis (Sá, 2012) and rheumatoid arthritis (Masoumi et al., 2021) .

Cannabis (Cannabis sativa) has been used as medicine for the treatment of inflammation for millennia, but its use in modern medicine has been hampered by a lack of scientific knowledge (Ryz et al., 2017) . Previous studies reported that cannabis extracts and inflorescence inhibited inflammatory responses in vitro and in pre-clinical and clinical studies. For example, a high-CBD cannabis ethanolic extract reduced the release of skin inflammation mediators in keratinocytes (Sangiovanni et al., 2019) . Similarly, a study on a mouse model of colitis showed that oral or intraperitoneally treatment with high-CBD cannabis extract led to a reduction in intestinal inflammation and hypermotility, in contrast to pure CBD treatment at matched doses (Pagano et al., 2016) . Moreover, two clinical trials on patients with Crohn's disease reported that daily treatment with THC-rich cannabis inflorescence had beneficial effects against the disease symptoms with no significant side effects and reduced the need for other medications (Naftali et al., 2011; Naftali et al., 2013) . In another clinical trial, daily cannabis treatment was associated with lower levels of pro-inflammatory biomarkers in cerebral fluid (CSF) of HIV patients (Watson et al., 2021) .

Great efforts have been made to suppress chronic inflammation. Cannabis and its compounds were shown to have anti-inflammatory activity (see Appendix A for methodology), but to exploit the full potential of cannabis it is important to define the active molecules and understand the cellular and molecular mechanisms that underlie its anti-inflammatory activity.

Monocytes are the major starting entities of inflammation. Once released from bone marrow, monocytes migrate through the blood into various tissues and undergo the tissue-specific maturation required to become inflammatory macrophages that respond to infection, injury, or damage. The various subpopulations of activated macrophages may differ in morphology, release of inflammatory mediators and functional properties, but in inflammation they have three major functions: phagocytosis, antigen presentation and immunomodulation (Fujiwara and Kobayashi, 2005) . The process of inflammation is orchestrated via inflammatory mediators. Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β are released from activated macrophages in response to infection ( Figure 1 ; Abdulkhaleq et al., 2018) . TNF-α and IL-1β act through specific cell membrane-bound receptors and participate in the recruitment of polymorphonuclear neutrophils (PMNs) into the site of infection and their activation (Hackel et al., 2021) .

TNF-α facilitates the release of other pro-inflammatory cytokines from immune effector cells, including interferon alpha (IFN-α), interferon gamma (IFN-γ), IL-1β, IL-6, IL-8, Transforming growth factor beta (TGF-β) and chemokines (Silva et al., 2019) . Further, in cases of enhanced inflammation, when the cell is stimulated, typically by bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines, there is induction of inducible nitric oxide synthase (iNOS). An increase in iNOS levels generates significant amounts of nitric oxide (NO) radicals or cyclooxygenase 2 (COX2); COX2 catalyzes the conversion of arachidonic acid to prostaglandins (PGs), prostacyclin and thromboxane A 2 (Salvemini et al., 2013; Cinelli et al., 2020) .

The signal transduction of inflammatory responses involves several signaling pathways including mitogen-activated protein kinase (MAPK), toll-like receptor (TLR), Janus kinase/signal transducers and activators of transcription (JAK-STAT), and nuclear factor kappa B (NFκB) pathways ( Figure 1 ; Zhao et al., 2021) . The activation of these pathways involves a series of phosphorylation events leading to the induction of various anti-apoptotic target genes and the expression of cytokines, chemokines, and adhesion molecules (Taniguchi and Karin, 2018; Fitzgerald and Kagan, 2020) . Moreover, during inflammatory processes, reactive oxygen species (ROS) are commonly multiplied and can contribute to host cell and organ damage. Further, intracellular redox changes induced by ROS augment NF-κB activation through the phosphorylation and degradation of IκB by increasing IkB kinase ß (IKK) or Akt kinase activity (Haddad, 2002) .

Resolution of inflammation may involve increased production of IL-10, among others. IL-10 is an anti-inflammatory cytokine, which inhibits the release of lipid mediators and proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α; Figure 1 ; Panigrahy et al., 2021) .

The endocannabinoid system (ECS) is a modulator of multiple physiological activities, including in the nervous, endocrine, immune, blood circulation, gastrointestinal tract and reproductive systems (Di Marzo et al., 1998) . Accordingly, dysregulation of the ECS is involved with various pathological conditions, including inflammation among others (Di Marzo and Piscitelli, 2015; Hillard, 2018) , whereas therapeutic modulation of ECS activity has beneficial effects on various medical conditions, including those associated with inflammation (Ambrose and Simmons, 2019; Giacobbe et al., 2021) . ECS is involved in both innate and adaptive immunity and in several chronic inflammatory diseases . ECS includes cannabinoid receptors types 1 and 2 (CB1 and CB2, respectively) and multiple other receptors such as the peroxisome proliferator-activated receptors (PPARs) and ion channels (e.g., the transient receptor potential ankyrin [TRPA] family and the transient receptor potential vanilloid [TRPV] family) (Biringer, 2021) . Also included in the ECS are the receptors' ligand, arachidonic acid derived endocannabinoids, and enzymes for endocannabinoid metabolism (Di Marzo et al., 1998) .

Most immune cells express endocannabinoids, the enzymes regulating their biosynthesis and degradation, and endocannabinoid receptors . Both CB1 and CB2 are expressed in immune cells, with CB2 being expressed 10-100 times higher than CB1 in these cells (Jean-Gilles et al., 2010; Rahaman and Ganguly, 2021) . Moreover, CB receptor activation regulates anti-inflammatory responses. For example, activation of CB2 receptors by its agonist inhibited the release of the pro-inflammatory cytokine IL-12 and IL-23 and enhanced the release of the anti-inflammatory cytokine IL-10 from cultured activated macrophages. This study suggested that the inhibitory effect of CB2 on IL-12 production was mediated by ERK1/2-MAPK (Correa et al., 2009) .

In another example, a CB2 receptor agonist reduced in human peripheral blood mononuclear cells LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and release of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-8 (Capozzi et al., 2021) . A selective/inverse agonist of CB2 induced the differentiation of Th0 cells into regulatory T cells (Treg) cell phenotypes in a naïve CD4 + T lymphocyte population isolated from a mouse spleen. The Treg phenotype is important for suppressing immune response by inhibiting T cell proliferation and cytokine production. The Treg phenotype was induced via P38 phosphorylation and STAT5A activation and was characterized by the expression of FoxP3, TGF-β and IL-10. Accordingly, treatment with this CB2 selective/inverse agonist reduced colitis severity in vivo (Gentili et al., 2019) . 

Cannabis produces a large number of phytocannabinoids (Hanuš et al., 2016) . Phytocannabinoids are aromatic oxygenated hydrocarbons, derived from meroterpenoids with a resorcinyl core structure with isoprenyl, alkyl or aralkyl substitutions. The characteristic alkyl side chain typically contains an odd number of carbon atoms (Hanuš et al., 2016; Gülck and Møller, 2020) . They are produced in the plant in their acid form and are decarboxylated to the active form (Gülck and Møller, 2020) . Among the phytocannabinoids, Δ 9 -trans-tetrahydrocannabinols (Δ 9 -THCs) and cannabidiols (CBDs) are the most abundant (Table 1) . Cannabigerol (CBG) in its acid form (CBGA) serves as a core intermediate that diverges to provide the phytocannabinolic acids ( Table 1 ; Hanuš et al., 2016; Tahir et al., 2021) . In addition to phytocannabinoids, cannabis produces a plethora of non-cannabinoid constituents including a vast array of terpenes as the second-largest class of cannabis constituents (El Sohly et al., 2017) . Cannabis biosynthesizes flavonoids as well, among them cannflavins, which are prenylated (C5) and geranylated (C10) flavones (Bautista et al., 2021) .

Cannabidiol CBD was demonstrated in multiple experimental models, in vitro and in vivo, to exert anti-inflammatory activities and ameliorate various inflammatory-related degenerative diseases. The mechanism of this anti-inflammatory activity is, however, not completely understood. CBD treatment of hypoxic-ischemic (HI) immature brains of newborn mice was shown to significantly reduce IL-6, TNF-α, COX-2 and iNOS expression in brain slices. This activity was suggested to be mediated via CB2 and adenosine A 2A receptors (Figure 1 ; Castillo et al., 2010) . Likewise, treatments of lipopolysaccharide-treated mice with a low dose of CBD decreased TNF-α production; this effect was abolished in A 2A receptor knockout mice and reversed with an A 2A adenosine receptor antagonist, supporting the notion that CBD may enhance adenosine signaling (Carrier et al., 2006) . Further, in a murine model of acute lung injury, CBD, via the A 2A adenosine receptor, significantly reduced leukocyte migration into the lungs and reduced the levels of albumin, TNF-α, IL-6 and other chemokines in bronchoalveolar lavage fluid (Figure 1 ; Ribeiro et al., 2012) . CBD also reduced the activity of myeloperoxidase (MOP, an index of neutrophil infiltration) in lung tissue (Ribeiro et al., 2012) .

In newborn pigs with HI brain injury, CBD administration reduced inflammation and prevented the increase in brain IL-1 levels. It also prevented the decrease in the number of viable neurons and the increase of excitotoxicity and oxidative stress. This activity was suggested to be mediated via CB2 and 5HT1A receptors (Figure 1 ; Pazos et al., 2013) . In liver filtrate from mice with acute hepatitis, CBD was shown to trigger Myeloid-derived suppressor cells (MDSCs); these cells are regulators of the immune system that suppress T cell functions. MDSCs induction by CBD was mediated through activation of TRPV1 ( Figure 1 ). CBD also significantly reduced blood levels of IL-2, TNF-α, IFN-γ, IL-6, IL-12, IL-17, MCP-1 and C-C motif chemokine (CCL)-11 in this model (Hegde et al., 2011) .

CBD is also a selective antagonist of GPR55, another G protein-coupled receptor present in human macrophages (Figure 1) . Pharmacological activation of GPR55 by its selective agonist O-1602 enhanced pro-inflammatory responses in macrophages-derived foam cells associated with a reduction in IL-10 levels and induction in TNF-α levels .

CBD treatment completely inhibited TNF-α production via p38 MAPK pathway (Figure 1 ) in microglial cells isolated from the retinas of newborn rats treated with endotoxin or LPS for acute ocular inflammation. In addition, LPS-treated rat retinas accumulated macrophages and activated microglia, increased levels of ROS and nitrotyrosine, and activated p38 MAPK and neuronal apoptosis. Treatment with CBD blocked all these effects (El-Remessy et al., 2008) .

CBD decreases the production and release of IL-1β, IL-6 and IFN-β from LPS-activated microglial cells of BV-2 mice. CBD reduced the activity of the NF-κB pathway and the levels of IL-1β and IL-6. CBD also decreased Socs3 gene expression; Socs3 is a main negative regulator of STATs. In accordance, CBD treatment up-regulated the STAT3 transcription factor phosphorylation, needed for its activation (Figure 1 ; Kozela et al., 2010) . However, NF-κB and STAT3 are likely to play important and in some cases, overlapping roles in pro-inflammatory and cancer processes (He & Karin, 2011) . In contrast, CBD decreased the phosphorylation of the LPS-induced STAT1 transcription factor, a key player in pro-inflammatory processes that are IFN-β-dependent (Kozela et al., 2010) .

The anti-inflammatory activity of CBG is less studied than that of CBD. Yet, several studies demonstrated significant antiinflammatory activity of CBG. For example, CBG treatment was shown to reduce nitric oxide production in macrophages via the CB2 receptor and reduce ROS formation in intestinal epithelial cells and iNOS expression (Figure 1 ) in the inflamed colons. Treatment with CBG also reduced oedema in colon submucosa. This treatment also reduced the colon weight/ length ratio; this ratio is a reliable marker of intestinal inflammation in a murine model of colitis glands (Borrelli et al., 2013) . In addition, CBG decreased dinitrobenzene sulfonic acid (DNBS)-induced neutrophil infiltration, as evaluated by MOP activity (Borrelli et al., 2013) .

In a study that characterized the anti-inflammatory properties of CBG on human skin cells in vitro, it was demonstrated that CBG treatment reduced ROS levels in human dermal fibroblasts, better than vitamin C. CBG also protected human epidermal keratinocytes by inhibiting proinflammatory cytokines that were released following induction using UVA, UVB or Cutibacterium acnes exposure, including TNF-α, IL-1β, IL-6 and IL-8 (Figure 1 ; Perez et al., 2022) . Furthermore, the researchers performed a single-blind clinical study on 20 healthy volunteers with sodium lauryl sulfate (SLS)induced contact dermatitis and found that topical application of 0.1% CBG serum showed significantly lower trans-epidermal Frontiers in Pharmacology | www.frontiersin.org May 2022 | Volume 13 | Article 908198 water loss (TEWL) values compared to placebo and untreated sites. Moreover, the CBG serum reduced redness and inflammation following 48 h treatment, and after 2 weeks of application, the skin condition almost returned to baseline levels of visual grade (Perez et al., 2022) . Several studies have described the neuroprotective properties of CBG against inflammation. It was demonstrated that CBG pretreatment of cultured motor neurons not only reduced the levels of pro-inflammatory cytokines, including IL-1β, TNF-α and IFN-γ (Figure 1) , but also inhibited apoptosis in LPS-stimulated macrophages, via suppression of caspase-3 and Bax expression and induction of Bcl-2 levels (Gugliandolo et al., 2018) . In addition, in a study that examined the effects of CBG on Huntington's disease pathology in 3-nitropropionate model in vivo, it was found that treatment with the phytocannabinoid reduced neuronal death by half and significantly attenuated the upregulation of expression of COX-2, iNOS and pro-inflammatory cytokines such as TNF-α and IL-6 ( Figure 1 ; Valdeolivas et al., 2015) .

Several experiments suggest that THC has anti-inflammatory effects. For example, topical treatment of THC on DNFBmediated allergic contact dermatitis in mice revealed that THC effectively decreased myeloid immune cell infiltration and contact allergic ear swelling (Gaffal et al., 2013) . These anti-inflammatory effects were evident in both wild-type and CB1/2 receptordeficient mice suggesting that these activities of THC were not mediated via CB1 or CB2 receptors. In addition, THC reduced the production by epidermal keratinocytes of CCL8 and CCL2 induced by IFNγ and the production of IFNγ by T cells (Figure 1) . As a result, in a CB1/2 receptor-independent way, THC limited the recruitment of myeloid immune cells in vitro (Gaffal et al., 2013) .

Interestingly, in LPS-induced macrophages, THC (and CBD) attenuated TLR3/4 signaling in a MyD88-independent manner (Fitzpatrick et al., 2020) . TLR3 signaling is mediated via a tollinterleukin-1 receptor (TIR)-domain-containing adaptorinducing interferon-β (TRIF). TLR4-induced expression of regulatory factor 3 (IRF3) activation, and CXCL10 and IFN-β were repressed by the THC and/or CBD (alone or in combination) treatments. However, these phytocannabinoid treatments did not impact TNF-α/CXCL8 expression and TLR4-induced IκB-α degradation. These activities of THC and CBD were independent of the cannabinoid receptors or PPARγ (Figure 1 ; Fitzpatrick et al., 2020) . Finally, THC, dosedependently, protected against diclofenac-induced gastric inflammation, hemorrhagic streaks and gastric ulcers in male mice, and protected against tissue damage at doses insufficient to cause common cannabinoid side effects (Kinsey and Cole, 2013) .

The synergy between phytocannabinoids (Mazuz et al., 2020; Anis et al., 2021) as well as between phytocannabinoids and terpenes has been demonstrated. Preclinical evidence suggests an 'entourage effect' might be inferred from the superior medical activities of full-spectrum cannabis extracts versus single molecules (Koltai et al., 2019) . Furthermore, in some cases a "parasitage effect" might be detected, as there might also be negative molecular interactions in vitro .

Indeed, as detailed above, phytocannabinoids are potent antiinflammatory and immunomodulatory agents and in some cases they act via different signaling pathways. For example, although both THC and CBD decreased inflammation in LPS-activated microglial cells of a BV-2 mouse, they acted through different, although partially overlapping, mechanisms. CBD but not THC inhibited the NF-κB-dependent pathway, yet both CBD and THC regulated the IFNβ pathway activity (Kozela et al., 2010) .

In order to take advantage of the synergy and to diminish negative interactions between phytomolecules, activity might be improved by selecting the most active phytomolecules while eliminating parts of the whole extract. This approach was demonstrated in the reduction of inflammation in colon cells and tissues. A THCA-rich fraction from the cannabis strain was shown to have superior activity against inflammation over the crude extract (Nallathambi et al., 2017) suggesting that the selection of active compounds may reduce the presence of inactive compounds or even those that have pro-inflammatory effects.

Moreover, in some cases, the activity of a combination of phytomolecules was found to be superior over that of a single molecule. This was demonstrated in an in vivo study on inflammation, where treatment with CBD combined with cannabis extract overcame the bell-shaped dose-response of purified CBD, suggesting that components found in the extract synergize with CBD to achieve the desired anti-inflammatory action (Gallily et al., 2015) . In addition, a phytocannabinoid formulation showed superior activity reducing lung inflammation over the cannabis-derived fraction in vitro. Moreover, this particular phytocannabinoid and CBD formulation had superior activity over CBD alone .

Cannabis compounds, in some cases via the endocannabinoids system, were shown to affect some of the cornerstones of chronic inflammation. However, in light of the large number of active molecules produced by cannabis and their sometimes-synergistic interactions, there is a need to better specify cannabis-based treatments and the active compounds, while utilizing the synergy identified between cannabis phytomolecules. Thus, even if CBD or THC are considered potentially leading molecules, additional cannabis-derived compounds may be selected for improved activity.

Future approaches for improved usage of cannabis demand the development, transformation and formulation of fullspectrum cannabis extracts into active plant ingredients (APIs) to achieve higher effectivity. This might be done via careful selection of phytomolecules composition (Koltai et al., 2019; Koltai and Namdar, 2020) . Notably, selecting only a few compounds for drug formulation may be compatible with modern medicine due to the potential for standardization, and careful dosing of API-based products. Importantly, once the mode of action of phytocannabinoids and that of their combination is known, APIs might be targeted towards specific mechanisms involved with inflammation.

Moreover, it might be that cannabis components can be combined with other pharmaceutical drugs to reduce inflammation. On the one hand, complementary effects might be identified due to different and perhaps complementary modes of action of cannabis compounds and pharmaceutical drugs. For example, THC was shown to reduce gastric inflammation caused by diclofenac, which may facilitate diclofenac's effective usage against inflammation (Kinsey and Cole, 2013) . On the other, CBD and THC were shown to have metabolism-dependent inhibition for Cytochrome P450 (CYP) enzymes. CYPs are responsible for drug metabolism, including detoxication and metabolic activation of xenobiotics (Yamaori et al., 2011) . Hence, combined treatment with cannabis and antiinflammatory drugs should be carefully considered.

SA composed the first draft of the manuscript, HP improved the draft and HK composed the final draft of the manuscript.

SA and HP are research scholars of ARO and HK is an employee of ARO. No external funding supported this manuscript.

The Crucial Roles of Inflammatory Mediators in Inflammation: A

History of Inflammatory Bowel Diseases

Cannabis, Cannabinoids, and the Endocannabinoid System-is There Therapeutic Potential for Inflammatory Bowel Disease?

Cannabis Compounds Exhibit Anti-inflammatory Activity In Vitro in COVID-19-Related Inflammation in Lung Epithelial Cells and Proinflammatory

Cannabis-Derived Compounds Cannabichromene and Δ9-Tetrahydrocannabinol Interact and Exhibit Cytotoxic Activity against Urothelial Cell Carcinoma Correlated with Inhibition of Cell Migration and Cytoskeleton Organization

Flavonoids in Cannabis Sativa: Biosynthesis, Bioactivities, and Biotechnology

Endocannabinoid Signaling Pathways: beyond CB1R and CB2R

Beneficial Effect of the Non-psychotropic Plant Cannabinoid Cannabigerol on Experimental Inflammatory Bowel Disease

Anti-inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells

Inhibition of an Equilibrative Nucleoside Transporter by Cannabidiol: a Mechanism of Cannabinoid Immunosuppression

The Neuroprotective Effect of Cannabidiol in an In Vitro Model of Newborn Hypoxic-Ischemic Brain Damage in Mice Is Mediated by CB(2) and Adenosine Receptors

The Differential Characterization of GPR55 Receptor in Human Peripheral Blood Reveals a Distinctive Expression in Monocytes and NK Cells and a Proinflammatory Role in These Innate Cells

Inducible Nitric Oxide Synthase: Regulation, Structure, and Inhibition

A Role for CB2 Receptors in Anandamide Signalling Pathways Involved in the Regulation of IL-12 and IL-23 in Microglial Cells

The Endocannabinoid System and its Modulation by

Endocannabinoids: Endogenous Cannabinoid Receptor Ligands with Neuromodulatory Action

Systemic Inflammation as Fuel for Acute Liver Injury in COVID-19

Phytochemistry of Cannabis Sativa L," in Phytocannabinoids: Unraveling the Complex Chemistry and Pharmacology of Cannabis Sativa

Neuroprotective Effects of Cannabidiol in Endotoxin-Induced Uveitis: Critical Role of P38 MAPK Activation

Is Resolution the End of Inflammation?

Toll-like Receptors and the Control of Immunity

MyD88-dependent and -independent Signalling via TLR3 and TLR4 Are Differentially Modulated by Δ9-tetrahydrocannabinol and Cannabidiol in Frontiers in Pharmacology | www

Macrophages in Inflammation

Anti-inflammatory Activity of Topical THC in DNFB-Mediated Mouse Allergic Contact Dermatitis Independent of CB1 and CB2 Receptors

Immune and Inflammatory Mechanisms of Atherosclerosis

Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

Selective CB2 Inverse Agonist JTE907 Drives T Cell Differentiation towards a Treg Cell Phenotype and Ameliorates Inflammation in a Mouse Model of Inflammatory Bowel Disease

A Systematic, Integrative Review of the Effects of the Endocannabinoid System on Inflammation and Neurogenesis in Animal Models of Affective Disorders

Phytocannabinoids: Origins and Biosynthesis

In Vitro model of Neuroinflammation: Efficacy of Cannabigerol, a Nonpsychoactive Cannabinoid

TNF-α and IL-1β Sensitize Human MSC for IFN-γ Signaling and Enhance Neutrophil Recruitment

Redox Regulation of Pro-inflammatory Cytokines and IκB-α/ NF-κB Nuclear Translocation and Activation

Phytocannabinoids: a Unified Critical Inventory

NF-κB and STAT3 -Key Players in Liver Inflammation and Cancer

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

Circulating Endocannabinoids: from Whence Do They Come and where Are They Going?

Interaction between Cytokines, Cannabinoids and the Nervous System

Acute Δ(9)-tetrahydrocannabinol Blocks Gastric Hemorrhages Induced by the Nonsteroidal Anti-inflammatory Drug Diclofenac Sodium in Mice

Cannabis Phytomolecule 'Entourage': From Domestication to Medical Use

Promoting Cannabis Products to Pharmaceutical Drugs

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-Activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells

Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses, while Reducing Cholesterol Efflux from Human Macrophages

Destructive Roles of Fibroblast-like Synoviocytes in Chronic Inflammation and Joint Damage in Rheumatoid Arthritis

Synergistic Cytotoxic Activity of Cannabinoids from Cannabis Sativa against Cutaneous T-Cell Lymphoma (CTCL) In-Vitro and Ex-Vivo

Treatment of Crohn's Disease with Cannabis: an Observational Study

Cannabis Induces a Clinical Response in Patients with Crohn's Disease: a Prospective Placebo-Controlled Study

Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid that Interacts with Additional Compounds in Cannabis Extracts

Terpenoids and Phytocannabinoids Co-produced in Cannabis Sativa Strains Show Specific Interaction for

Chronological Review and Rational and Future Prospects of Cannabis-Based Drug Development

Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host's Response to Pathogens

An Orally Active Cannabis Extract with High Content in Cannabidiol Attenuates Chemically-Induced Intestinal Inflammation and Hypermotility in the Mouse

Resolution of Inflammation: An Organizing Principle in Biology and Medicine

Mechanisms of Cannabidiol Neuroprotection in Hypoxic-Ischemic Newborn Pigs: Role of 5HT(1A) and CB2 Receptors

In Vitro and Clinical Evaluation of Cannabigerol (CBG) Produced via Yeast Biosynthesis: a Cannabinoid with a Broad Range of Anti-inflammatory and Skin Health-Boosting Properties

The Influence of Systemic Inflammation on Inflammation in the Brain: Implications for Chronic Neurodegenerative Disease

A Computational Model of Unresolved Allergic Inflammation in Chronic Asthma

Endocannabinoids in Immune Regulation and Immunopathologies

Cannabidiol, a Non-psychotropic Plant-Derived Cannabinoid, Decreases Inflammation in a Murine Model of Acute Lung Injury: Role for the Adenosine A(2A) Receptor

Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain

Physiopathology of Symptoms and Signs in Multiple Sclerosis

Frontiers in Pharmacology | www.frontiersin.org

Reciprocal Regulation of the Nitric Oxide and Cyclooxygenase Pathway in Pathophysiology: Relevance and Clinical Implications

Cannabis Sativa L. Extract and Cannabidiol Inhibit In Vitro Mediators of Skin Inflammation and Wound Injury

Chronic Obstructive Pulmonary Disease, Inflammation and Co-morbidity--a Common Inflammatory Phenotype?

The Role of TNF-α as a Proinflammatory Cytokine in Pathological Processes

The Biosynthesis of the Cannabinoids

NF-κB, Inflammation, Immunity and Cancer: Coming of Age

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-Lesioned Mice

Daily Cannabis Use Is Associated with Lower CNS Inflammation in People with HIV

Differential Inhibition of Human Cytochrome P450 2A6 and 2B6 by Major Phytocannabinoids

Inflammation and Tumor Progression: Signaling Pathways and Targeted Intervention

We thank Zach Dunseth for English editing.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Methodology: To reflect on the effect of cannabis and its derived compounds on acute or chronic inflammation and the accumulating knowledge regarding cannabis active compounds and their mode of action, we have conducted a literature review using the following terms: "inflammation ", "acute inflammation", "chronic inflammation", "medical use of cannabis", "therapy" "Cannabis sativa", "C. sativa", "cannabis", "cannabinoids", "terpenes", "cannabis oil", "adverse effects", "endocannabinoid", "phytocannabinoid" and "entourage effect". The search was conducted on general and multidisciplinary research databases for peer-reviewed scientific manuscripts, including PubMed, Google Scholar, Scopus, and Web of Science.