By Yoel. H. Sitbon, PhD
The immune system is comprised of a variety of organs, cells, and chemicals that defend the body against pathogens (e.g., bacteria, viruses, toxins) by recognizing and neutralizing harmful substances one may encounter in the environment via a variety of complex interactions. While these processes are needed to prevent or destroy pathogenic invasion, dysregulation of the immune system can lead to a poor immune response that increases one’s susceptibility to infections (immunodeficiency) or a situation in which one’s own immune system mistakenly attacks one’s body (autoimmune diseases). Although treatments are currently available to help manage these conditions, novel approaches are being investigated with the goal of reducing significant side effects. One exciting area of research is focused on the potential of medical cannabis to treat some diseases of the immune system, based on its intersection with the endocannabinoid system.
The immune system is comprised of a variety of organs, cells and chemicals that defend the body against pathogens (e.g., bacteria, viruses, toxins) by recognizing and neutralizing harmful substances one may encounter in the environment, as well as to detect and fight disease-causing changes in the body (i.e., mutations leading to cancer).1 There are two types of immune responses that ensure appropriate activation of the immune response to provide protection against infection: innate and adaptive. The innate immune response refers to defense mechanisms including physical barriers (e.g., skin), physiologic components (e.g., temperature, low pH), and specialized cells (e.g., macrophages, neutrophils) which results in a fast response that is non-specific to the type of pathogen.2 By contrast, the adaptive immune response is a slow response that is specific to the types of antigens (recognizable peptide components) produced by a particular pathogen, and is activated if the innate immune system is not successful.3 The latter type of immunity also includes an immunologic memory component if a later infection by the same pathogen takes place; this is mediated via lymphocytes (B and T cells), which produce proteins created to fight germs and foreign substances, called antibodies.4 While these processes are needed to prevent or destroy pathogenic invasion, dysregulation of the immune system can lead to immunodeficiency (i.e., a poor immune response that increases one’s susceptibility to infections) or autoimmune diseases (i.e., one’s own immune system mistakenly attacks one’s body). Examples of immunodeficiency diseases include severe combined immune deficiency (SCID), common variable immune deficiency (CVID), or human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS); some autoimmune disorders include rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD). While treatment options are available for immunodeficiency (e.g., immunoglobin, interferon-gamma therapy, stem cell transplantation) and autoimmune diseases (e.g., anti-inflammatory, corticosteroids, immunosuppressant drugs), novel therapies with fewer side effects are being investigated to improve patients’ everyday quality-of-life.5-8
One exciting area of research is focused on the potential of medical cannabis to treat inflammatory diseases, due to the presence of endocannabinoid receptors on various types of immune cells. The endocannabinoid system (ECS) which includes these receptors is primarily located in the central and peripheral nervous system (CNS, PNS) where it helps maintain body homeostasis, but it also plays a role in the immune system.9-11 Phytocannabinoids isolated from the cannabis plant also interact with the ECS, with THC (tetrahydrocannabinol, the primary psychoactive molecule) acting as a partial activator of both cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) while CBD (cannabidiol, the non-psychoactive analog) has little binding affinity to either but can inhibit them in the presence of THC.12,13 Because of the growing body of research into the ECS and the immune system, there are an increasing number of investigational studies attempting to understand how phytocannabinoids can be used to treat immune diseases.14-16 In this article, we will focus on and summarize the relevant findings on the potential role of phytocannabinoids in two types of autoimmune diseases: RA and MS.
Autoimmune diseases are conditions in which the immune system cannot distinguish between healthy and harmful cells and as a result, attacks its own body.17 One example is RA, a chronic, symmetrical, inflammatory autoimmune disease that most notably affects the joints. This disease eventually can lead to bone erosion, joint deformity, and pain; eventually this process also can impact the skin, eyes, heart, kidneys, and lungs.18 RA is characterized by infiltration of inflammatory cells and the subsequent production of proinflammatory cytokines (small proteins important in cell signaling) resulting in the above-described phenotypes.19 While there are treatments available (e.g., non-steroidal anti-inflammatory drugs, or disease-modifying antirheumatic drugs), these are often associated with side effects. However, increasing evidence suggests that medical cannabis can modulate the immune system response and may be a promising agent for these patients. Recent studies have shown that modulating the ECS, in particular through administration of CBD, was able to slow or stop arthritic progression in animal models.20-22 In human subjects, a double-blind, randomized study showed that the use of the oromucosal spray Sativex (1:1 ratio of THC to CBD, manufactured by GW Pharmaceuticals) was able to reduce pain levels, improved sleep quality and suppress inflammatory activity in patients with RA treated.23 A subsequent clinical trial in Denmark was designed to determine the efficacy and safety of CBD alone or in combination with THC for the treatment of pain in patients with RA; results are yet unpublished.24 Overall, the use of medical cannabis may be a promising alternative strategy for the treatment of RA, but more clinical studies are needed to fully understand the effects.
MS is also a chronic autoimmune, inflammatory disease, but which targets the neurological tissue of the CNS. In this disease, the immune system mistakenly attacks the protective layer around nerve fibers, leading to the release of proinflammatory cytokines and lesions that disturb nerve signals between the brain and other parts of the body.25 Symptoms include pain, spasticity, fatigue or tremors which may cause physical and cognitive disability for these patients.26 While current treatments are available to slow disease progression and relieve symptoms, they are often associated with a higher risk of serious adverse reactions and may not be completely effective.27 As such, alternative pharmacological treatments are currently being investigated. Several lines of evidence suggest that activation of cannabinoid receptors by exogenous cannabinoids may have immunomodulatory and immunosuppressive effects and as such may be good agents to treat autoimmune diseases.28 Preclinical research using animal models of MS showed that treatment with CBD led to an amelioration of clinical and histological scores, reduced demyelination, and axonal loss while administration of THC by itself and in combination with CBD suppressed neuroinflammation.29-34 Some clinical studies attempting to use medical cannabis to relieve some of the symptoms associated with MS have also been conducted. These have shown the administration of Sativex in double-blind, randomized, placebo-controlled trials results in a significant improvement in self-reported spasticity and in sleep disturbance in patients with MS.35-37 A recent investigational study from Europe showed that administration of Cannador (2:1 ratio of THC and CBD, manufactured by IKF-Berlin) led to an improvement in spasms, pain levels, and sleep.38 A currently-ongoing phase 3 clinical trial is investigating the potential role of Dronabinol (THC-derived compound approved to treat severe nausea and vomiting caused by cancer chemotherapy, manufactured by Benuvia Therapeutics Inc) in treating patients with MS.39 Additionally, another currently-ongoing phase 3 placebo-controlled clinical trial is currently being conducted to demonstrate the effect of Sativex in the treatment of patients who suffer from muscle spasms associated with MS.40
Overall, the immune system is beautifully orchestrated to protect the body using specialized cells and chemicals to contend with pathogenic infections. While necessary for healthy homeostasis, dysregulation of this system can lead to autoimmune and immunodeficiency diseases. Despite currently available pharmacological approaches, there remains a need to investigate other more effective therapies with less severe side effects. Medical cannabis is already known to help regulate the immune system and appears to be a promising strategy for these diseases. While clinical studies have demonstrated clinical potential for medical cannabis products in this area, additional work is necessary. This includes testing different doses of phytocannabinoids and terpenes, understanding the mechanisms of action of cannabis products on receptor activation and downstream effects, and the potential adverse outcomes associated with their use. As of 2010, the United Kingdom (UK) has licensed Sativex as the first medical cannabis product available with a prescription for the treatment of patients with MS; however, no medical cannabis products are currently approved by the FDA for the treatment of immunological diseases.41
- InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); How does the immune system work? (Available fromhttps://www.ncbi.nlm.nih.gov/books/NBK279364/).
- Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 2018;14(Suppl 2):49. DOI: 10.1186/s13223-018-0278-1.
- Chaplin DD. Overview of the immune response. J Allergy Clin Immunol 2010;125(2 Suppl 2):S3-23. DOI: 10.1016/j.jaci.2009.12.980.
- Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010;125(2 Suppl 2):S33-40. DOI: 10.1016/j.jaci.2009.09.017.
- Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol 2011;164 Suppl 2:2-5. DOI: 10.1111/j.1365-2249.2011.04387.x.
- Choubey D, Moudgil KD. Interferons in autoimmune and inflammatory diseases: regulation and roles. J Interferon Cytokine Res 2011;31(12):857-65. DOI: 10.1089/jir.2011.0101.
- Li P, Zheng Y, Chen X. Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics. Front Pharmacol 2017;8:460. DOI: 10.3389/fphar.2017.00460.
- Richard-Eaglin A, Smallheer BA. Immunosuppressive/Autoimmune Disorders. Nurs Clin North Am 2018;53(3):319-334. DOI: 10.1016/j.cnur.2018.04.002.
- Joshi N, Onaivi ES. Endocannabinoid System Components: Overview and Tissue Distribution. Adv Exp Med Biol 2019;1162:1-12. DOI: 10.1007/978-3-030-21737-2_1.
- Battista N, Di Tommaso M, Bari M, Maccarrone M. The endocannabinoid system: an overview. Front Behav Neurosci 2012;6:9. DOI: 10.3389/fnbeh.2012.00009.
- Osei-Hyiaman D, Harvey-White J, Batkai S, Kunos G. The role of the endocannabinoid system in the control of energy homeostasis. Int J Obes (Lond) 2006;30 Suppl 1:S33-8. DOI: 10.1038/sj.ijo.0803276.
- Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008;153(2):199-215. DOI: 10.1038/sj.bjp.0707442.
- Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 2007;150(5):613-23. DOI: 10.1038/sj.bjp.0707133.
- Hoggatt J, Pelus LM. Eicosanoid regulation of hematopoiesis and hematopoietic stem and progenitor trafficking. Leukemia 2010;24(12):1993-2002. DOI: 10.1038/leu.2010.216.
- Acharya N, Penukonda S, Shcheglova T, Hagymasi AT, Basu S, Srivastava PK. Endocannabinoid system acts as a regulator of immune homeostasis in the gut. Proc Natl Acad Sci U S A 2017;114(19):5005-5010. DOI: 10.1073/pnas.1612177114.
- Xiang W, Shi R, Kang X, et al. Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression. Nat Commun 2018;9(1):2574. DOI: 10.1038/s41467-018-04999-8.
- Angum F, Khan T, Kaler J, Siddiqui L, Hussain A. The Prevalence of Autoimmune Disorders in Women: A Narrative Review. Cureus 2020;12(5):e8094. DOI: 10.7759/cureus.8094.
- Lee JE, Kim IJ, Cho MS, Lee J. A Case of Rheumatoid Vasculitis Involving Hepatic Artery in Early Rheumatoid Arthritis. J Korean Med Sci 2017;32(7):1207-1210. DOI: 10.3346/jkms.2017.32.7.1207.
- Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010;376(9746):1094-108. DOI: 10.1016/S0140-6736(10)60826-4.
- Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 2000;97(17):9561-6. DOI: 10.1073/pnas.160105897.
- Gui H, Liu X, Liu LR, Su DF, Dai SM. Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis. Immunobiology 2015;220(6):817-22. DOI: 10.1016/j.imbio.2014.12.012.
- McDougall JJ, Muley MM, Philpott HT, Reid A, Krustev E. Early blockade of joint inflammation with a fatty acid amide hydrolase inhibitor decreases end-stage osteoarthritis pain and peripheral neuropathy in mice. Arthritis Res Ther 2017;19(1):106. DOI: 10.1186/s13075-017-1313-1.
- Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 2006;45(1):50-2. DOI: 10.1093/rheumatology/kei183.
- Hendricks O, Andersen TE, Christiansen AA, et al. Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for amulticentre, randomised, placebo-controlled study. BMJ Open 2019;9(6):e028197. DOI: 10.1136/bmjopen-2018-028197.
- Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician 2004;70(10):1935-44. (https://www.ncbi.nlm.nih.gov/pubmed/15571060).
- Kister I, Bacon TE, Chamot E, et al. Natural history of multiple sclerosis symptoms. Int J MS Care 2013;15(3):146-58. DOI: 10.7224/1537-2073.2012-053.
- Gholamzad M, Ebtekar M, Ardestani MS, et al. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res 2019;68(1):25-38. DOI: 10.1007/s00011-018-1185-0.
- Goncalves ED, Dutra RC. Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand? Drug Discov Today 2019;24(9):1845-1853. DOI: 10.1016/j.drudis.2019.05.023.
- Elliott DM, Singh N, Nagarkatti M, Nagarkatti PS. Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells. Front Immunol 2018;9:1782. DOI: 10.3389/fimmu.2018.01782.
- Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB. Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 1989;23(1):73-81. DOI: 10.1016/0165-5728(89)90075-1.
- Kozela E, Lev N, Kaushansky N, et al. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol 2011;163(7):1507-19. DOI: 10.1111/j.1476-5381.2011.01379.x.
- Al-Ghezi ZZ, Miranda K, Nagarkatti M, Nagarkatti PS. Combination of Cannabinoids, Delta9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways. Front Immunol 2019;10:1921. DOI: 10.3389/fimmu.2019.01921.
- Giacoppo S, Galuppo M, Pollastro F, Grassi G, Bramanti P, Mazzon E. A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis. Daru 2015;23:48. DOI: 10.1186/s40199-015-0131-8.
- Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia 2017;116:77-84. DOI: 10.1016/j.fitote.2016.11.010.
- Collin C, Davies P, Mutiboko IK, Ratcliffe S, Sativex Spasticity in MSSG. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007;14(3):290-6. DOI: 10.1111/j.1468-1331.2006.01639.x.
- Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 2010;32(5):451-9. DOI: 10.1179/016164109X12590518685660.
- Novotna A, Mares J, Ratcliffe S, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R)) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 2011;18(9):1122-31. DOI: 10.1111/j.1468-1331.2010.03328.x.
- Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG, Group MR. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry 2012;83(11):1125-32. DOI: 10.1136/jnnp-2012-302468.
- BX-1 in Spasticity Due to Multiple Sclerosis. (Assessed April 28th 2021https://clinicaltrials.gov/ct2/show/NCT03756974cond=Multiple+Sclerosis+THC&draw=2&rank=6).
- Safety and Effectiveness of Nabiximols Oromucosal Spray as Add-on Therapy in Participants With Spasticity Due to Multiple Sclerosis (RELEASE MSS3). (Assessed April 28th, 2021https://clinicaltrials.gov/ct2/show/NCT04203498).
- Sativex Oromucosal Spray (GW Pharma, Ltd). (https://www.medicines.org.uk/emc/product/602/smpc).