By Rosa Holder, BSc

Reviewed by Liran Baram, PhD

                                                                            

Endocannabinoid system and immunity

The immune system is comprised of immune cells, such as granulocytes, natural killer cells (NKC), mast cells, monocytes and lymphocyte T and B cells, which produce a range of signalling molecules, called cytokines[i]. Cytokines mediate and regulate immune responses, inflammation, and haematopoiesis (the formation of blood cells)[ii]^,[iii].

The endocannabinoids system (ECS) is a regulatory signalling system located throughout the body. The ECS is primarily comprised of cannabinoid type 1 (CB1) and 2 (CB2) receptors, while also recruiting additional receptors, such as transient receptor potential (TRP) channels and Peroxisome proliferator-activated receptors (PPARs)[iv]. The ECS endogenous ligands include anandamide (AEA) and 2-Arachidonoylglycerol (2-AG), along with other mediators recently discovered[v].

While CB1 receptors are expressed by many cell types throughout the body, CB2 receptors are found most commonly in immune cells. There appears a direct relationship between CB receptor activation and immune function[vi]^,[vii].

Throughout the literature the relationship between the immune system and CB2 receptors is activated, leading to theorization that compounds targeting CB2 receptor will aid in regulating immune homeostasis, particularly through inhibiting the inflammatory immune response.

CBD anti-inflammatory effects

Cannabidiol (CBD), the main non-psychoactive component of the Cannabis plant, has been shown to supress production of a range of pro-inflammatory mediators by immune cells. Specifically, CBD inhibits IL-2, IL-6, IFN-γ, TNF-α, COX-2 and cell proliferation, predominantly through the CB2 receptor[viii]. Moreover, CBD promotes production of functional T-regulatory cells and the anti-inflammatory cytokine IL-10[ix]. CBD has shown to reduce acute pulmonary inflammation in animal models[x]^,[xi].

CBD reduces oxidative stress and permanent tissue damage due to chronic inflammation in various   in vitro and in vivo models[xii]. In such models, CBD reportedly reduced oxidative conditions, as seen through the reduction of nitric oxide (NO) and reactive oxygen species (ROS)[xiii]. Modulation of the balance of oxidant and antioxidant activity was attributed to CBD through interruption of the chain reaction forming free radicals.

In a model of multiple sclerosis (MS), an autoimmune neuroinflammatory disease, CBD was shown to significantly reduce specific chemokines, cytokines and ameliorate microglial reactivity[xiv].

CBD anti-viral effects

CBD is shown to interfere specifically with SARS-CoV-2 replication in lung epithelial cells through inhibiting both viral gene expression and host cell gene transcription[xv]. CBD and cannabis use has also been associated with improved disease outcomes of patients with HIV and co-infections[xvi]. Using computational tools and in vitro models CBD was found to have an antiviral effect against SARS-CoV-2 and was more potent compared to available drugs (lopinavir, chloroquine and remdesivir)[xvii]. Furthermore, the reduction in pro-inflammatory cytokines with CBD also has implications in viral disease progression, such as SARS-CoV-2, where overproduction of cytokines, termed ‘cytokine storm’ is associated with disease severity and morbidity. The anti-inflammatory effects of CBD in respiratory airway tissue showed positive clinical outcomes in various mice models, baring similarities to disease progression of SARS-CoV-2, including ‘cytokine storm’s and acute respiratory distress syndrome (ARDS)[xviii]^,[xix].

CBD anti-microbial effects

In vitro models have shown a high anti-bacterial and anti-fungal effects of CBD and its precursor cannabidiolic acid (CBDA), both of which show bactericidal effects against cultivated gram-positive bacteria, S. aureus, S. epidermidis, E. coli and P. aeruginosa [xx].

Moreover, the anti-microbial effects of cannabinoids appear synergistic with antibiotics, even in some cases of antibiotic resistance as evident from in vitro models[xxi].

Additional advantages

CBD is non-toxic and well tolerated at chronic, high doses (up to 1500mg) in humans.

CBD has relatively high oral bioavailability of CBD in water solvent, making it a good therapeutic candidate compound[xxii].

CBD has reported analgesic properties and thus may help alleviate inflammatory-induced pain[xxiii].

Potential adverse effects

There is a large therapeutic window for CBD, meaning a range of doses are effective and safe to use[xxiv].

Findings generally indicated CBD to be well tolerated and show only minor adverse effects in small portions of the patients[xxv]^{,[xxvi],[xxvii]}.

However, more studies assessing CBD side effects following chronic and acute administration are needed, as well as studies researching CBD side effects on other drugs in cases of coadministration. CBD effects should be further studied and may affect fertility, hepatic drug metabolism and drug transporter proteins[xxviii].

Disclaimer

This content is intended only for educational purpose only, and by no means replace for professional medical advice or treatment. Always consult with a medical professional if you are seeking medical advice, diagnosis, or treatment. Particularly if you are taking other drugs to rule out unwanted interactions and side effects.

 

[i] Parkin, J. and Cohen, B., 2001. An overview of the immune system. The Lancet, 357(9270), pp.1777-1789.

[ii] Barrett, K.E., 1996. Cytokines: sources, receptors and signalling. Baillière's clinical gastroenterology, 10(1), pp.1-15.

[iii] Testar, J., 2022. Cytokines: Introduction. British Society for Immunology. (online) Immunology.org.

[iv] Khoury, M., Cohen, I. and Bar-Sela, G., 2022. “The Two Sides of the Same Coin”—Medical Cannabis, Cannabinoids and Immunity: Pros and Cons Explained. Pharmaceutics, 14(2), p.389.

[v] Almogi-Hazan, O. and Or, R., 2020. Cannabis, the Endocannabinoid System and Immunity—the Journey from the Bedside to the Bench and Back. International journal of molecular sciences, 21(12), p.4448.

[vi] Khoury, M., Cohen, I. and Bar-Sela, G., 2022. “The Two Sides of the Same Coin”—Medical Cannabis, Cannabinoids and Immunity: Pros and Cons Explained.

[vii] Almogi-Hazan, O. and Or, R., 2020. Cannabis, the Endocannabinoid System and Immunity—the Journey from the Bedside to the Bench and Back

[viii] Sunda, F. and Arowolo, A., 2020. A molecular basis for the anti‐inflammatory and anti‐fibrosis properties of cannabidiol. 

[ix] Śledziński, P., Nowak-Terpiłowska, A. and Zeyland, J., 2021. Cannabinoids in medicine: cancer, immunity, and microbial diseases. International journal of molecular sciences, 22(1), p.263.

[x] Karmaus, P.W., Wagner, J.G., Harkema, J.R., Kaminski, N.E. and Kaplan, B.L., 2013. Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. Journal of immunotoxicology, 10(3), pp.321-328.

[xi] Vuolo, F., Abreu, S.C., Michels, M., Xisto, D.G., Blanco, N.G., Hallak, J.E., Zuardi, A.W., Crippa, J.A., Reis, C., Bahl, M. and Pizzichinni, E., 2019. Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. European journal of pharmacology, 843, pp.251-259.

[xii] Sunda, F. and Arowolo, A., 2020. A molecular basis for the anti‐inflammatory and anti‐fibrosis properties of cannabidiol. The FASEB Journal, 34(11), pp.14083-14092.

[xiii] Atalay, S., Jarocka-Karpowicz, I. and Skrzydlewska, E., 2020. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants, 9(1), p.21.

[xiv] Mecha, M., Feliú, A., Iñigo, P.M., Mestre, L., Carrillo-Salinas, F.J. and Guaza, C., 2013. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiology of disease, 59, pp.141-150.

[xv] Nguyen, L.C., Yang, D., Nicolaescu, V., Best, T.J., Gula, H., Saxena, D., Gabbard, J.D., Chen, S.N., Ohtsuki, T., Friesen, J.B. and Drayman, N., 2022. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Science advances, p.eabi6110

[xvi] Ellis, R.J., Wilson, N. and Peterson, S., 2021. Cannabis and Inflammation in HIV: A Review of Human and Animal Studies. Viruses, 13(8), p.1521.

[xvii] Raj, V., Park, J.G., Cho, K.H., Choi, P., Kim, T., Ham, J. and Lee, J., 2021. Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches. International journal of biological macromolecules, 168, pp.474-485.

[xviii] Byrareddy, S.N. and Mohan, M., 2020. SARS-CoV2 induced respiratory distress: Can cannabinoids be added to anti-viral therapies to reduce lung inflammation?. Brain, Behavior, and Immunity, 87, p.120.

[xix] Khodadadi, H., Salles, É.L., Jarrahi, A., Chibane, F., Costigliola, V., Yu, J.C., Vaibhav, K., Hess, D.C., Dhandapani, K.M. and Baban, B., 2020. Cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic RNA. Cannabis and cannabinoid research, 5(3), pp.197-201.

[xx] Martinenghi, L.D., Jønsson, R., Lund, T. and Jenssen, H., 2020. Isolation, Purification, and antimicrobial characterization of cannabidiolic acid and cannabidiol from Cannabis sativa L. Biomolecules, 10(6), p.900.

[xxi] Schofs, L., Sparo, M.D. and Sánchez Bruni, S.F., 2021. The antimicrobial effect behind Cannabis sativa. Pharmacology research & perspectives, 9(2), p.e00761

[xxii] Vitetta, L., Butcher, B., Henson, J.D., Rutolo, D. and Hall, S., 2021. A pilot safety, tolerability and pharmacokinetic study of an oro-buccal administered cannabidiol-dominant anti-inflammatory formulation in healthy individuals: A randomized placebo-controlled single-blinded study. Inflammopharmacology, 29(5), pp.1361-1370.

[xxiii] De Gregorio, D., McLaughlin, R.J., Posa, L., Ochoa-Sanchez, R., Enns, J., Lopez-Canul, M., Aboud, M., Maione, S., Comai, S. and Gobbi, G., 2019. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain, 160(1), p.136.

[xxiv] Blessing, E.M., 2015. Cannabidiol as a potential treatment for anxiety disorders. 12(4), pp.825-836.

[xxv] Shannon, S., 2019. Cannabidiol in anxiety and sleep: a large case series. 23.^,

[xxvi] Berger, M., Li, E. and Amminger, G.P., 2020. Treatment of social anxiety disorder and attenuated psychotic symptoms with cannabidiol. BMJ Case Reports CP, 13(10), p.e235307.

[xxvii] Moltke, J. and Hindocha, C., 2021. Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems. Journal of cannabis research, 3(1), pp.1-12.

[xxviii] Machado Bergamaschi, M., Helena Costa Queiroz, R., Waldo Zuardi, A. and Crippa, A.S., 2011. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Current drug safety, 6(4), pp.237-249.