Endocannabinoids & Autoimmunity

JAKE F. FELICE, ND, LMP 

Autoimmune conditions and diseases of the nervous system are typically chronic, often have an early age of onset, and frequently cause significant pain, debility, and suffering. Autoimmunity is an arena of medicine that remains largely misunderstood, given that the immune system and immune regulation are still relatively new areas of medicine, since the late 20th century. The mainstay of conventional therapy for autoimmune diseases is immunosuppressive glucocorticoids despite their well-known adverse long-term effects. 

CB2 Receptors & Immunity   

Plant cannabinoids provide potential benefits for autoimmunity via 3 major avenues: modulation of the immune system, reduction of general inflammation, and digestive system support. Cannabinoid therapies may also treat symptomatic aspects of autoimmune diseases, including pain and muscle spasms. Other modes of influence on immune activity by the ECS include effects on cytokine information networks, induction of apoptosis by immune cells, and downregulation of adaptive and innate immune responses.  

The ECS consists of cannabinoid (CB) receptors CB1 and CB2, endogenous ligands such as the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their transport mechanisms, and endocannabinoid-metabolizing enzymes. CB1 receptors are expressed mainly in neural tissue, while CB2 receptors are expressed largely in immune cells and are the main focus of this paper. In addition to CB1 and CB2 receptors, endocannabinoids modulate several other pathways and receptors, including TRPV1, GPR-55, and others.1-4  

The wide distribution of cannabinoid receptors-2 (CB2) on immune cells makes the endocannabinoid system (ECS) – a highly complex interconnected web of biochemical pathways – a natural candidate for the exploration of new treatment options for autoimmune disease. By affecting a plethora of receptors and biologic networks,2 cannabinoids including CBD expand their influence far beyond “classical” pharmacologic pathways. Current evidence indicates that phytocannabinoids modulate immune activity in a way that balances both overactive and underactive immune responses. They have been shown to act upon B-cells, T-cells, monocytes, and other immune cells, creating an environment that reduces inflammatory cytokines and increases anti-inflammatory cytokines.1 Interestingly, one of the ways that CBD affects the ECS is through via inhibitory actions on the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH).2 Targeting the inactivation of FAAH may be a useful and non-toxic way to modulate the body’s concentrations of cannabinoids and reduce inflammation in autoimmune conditions.5 

Besides plant cannabinoids, the role of terpenes in cannabis deserves mention. The sesquiterpene beta-caryophyllene (BCP), made by cannabis and many other botanicals, also activates CB2 receptors.2 Through this interaction, BCP has been shown to reduce neuroinflammation and improve motor paralysis in a rodent model of multiple sclerosis via actions on multiple immune cell lines.6 Maintenance of homeostasis is considered to be one of the ECS’ major responsibilities. Modulation of ECS signaling cascades and the restoration of homeostatic endocannabinoid tone thus portend a promising future in the treatment and understanding of autoimmunity.   

The ECS responds not only to cannabis and cannabinoids; it is also positively affected by diet, exercise, acupuncture, probiotics, prebiotics, acupuncture, osteopathic manipulation, mind-body medicine, and other non-cannabis botanicals and CAM therapies.7 As such, the body’s own ECS offers potential insights into how various current and future non-cannabinoid-based CAM therapies can potentially provide therapeutic benefit through their actions on the endocannabinoid system.7 The ECS offers 21st-century clinicians an invaluable mechanism to unify our most current biochemical discoveries with traditional naturopathic and CAM modalities. 

The ECS & Immune Modulation 

It goes without saying that in many cases of autoimmunity, the balancing or suppression of an overactive immune response can provide clinical benefit. Although much more research is needed, studies to date indicate that manipulation of the ECS affects autoimmune-related tissue damage and even the course of certain diseases. Endocannabinoids have profound effects on immune cells and immunity, functioning as key regulators, including the modulation of immune cell trafficking and effector cell functions.   

Lymphocytes 

While naïve T-cell and B-cells produce only small amounts of the endocannabinoid 2-AG, the immune activation of these cells was shown in a mouse model to promote an increase in the production of 2-AG, which in turn modulated inflammation by decreasing Th1 and Th17 responses. The findings suggest that 2-AG could confer therapeutic benefit in Th1-driven diseases.8  

In a cell assay, THC and the endocannabinoid AEA were shown to have immunosuppressive effects by directly inhibiting B-cells through the CB2 receptor.9 Additionally, in a mouse model, the CB2 receptor was shown to be involved with the retention of immature B-cells in bone marrow.10  

The effect of the ECS on T-cells is such that both Th1 and Th2 cytokines can be inhibited or upregulated by endocannabinoids.11 The CB2 receptor has been shown in animal and in-vitro studies to suppress T-cell activation.12-15 Interestingly, during vaccination in mouse models, 2-AG levels are upregulated in immune tissues, whereas CB2 blockade reduces vaccination-induced immunity.16  

Neutrophils 

In a cell-line model of intestinal inflammation, ECS activity diminished the mobilization of neutrophils that were contributing to the inflammation.17 Similarly, stimulation of CB2 receptors have been shown in multiple studies to significantly inhibit recruitment of neutrophils.18 Conversely, a deficiency of CB2 receptors in mice was observed to enhance neutrophil recruitment and increase inflammation.19  

Macrophages 

In a mouse study, ECS activity via AEA contributes to how the well the gut tolerates foreign antigens by enhancing the activity of a subtype of anti-inflammatory macrophages (CX3CR1) in the gut.20 Commenting on this immune mediation via the ECS, the authors of this paper stated, “These results uncover a major conversation between the immune and nervous system.”20  

Dendritic Cells 

Migration of dendritic cells is recognized as one of the most important means by which the immune system encounters foreign antigens.21 CB2 receptor activity decreases dendritic cell migration, helping to decrease inflammation and reestablish homeostasis.22 Meanwhile, 2-AG has been shown in mice to chemoattract dendritic cells.23 The authors stated, “As 2‐AG may be induced in tissues by various stimuli at concentrations similar to that used in our study, this evidence might be of a wide‐ranging pathophysiological relevance.”23 

Cannabinoids in Autoimmune Disease  

The effects of ECS-based treatments in immune-related diseases are potentially immense and include areas of transplantation, cancer treatment, infectious disease, and autoimmunity. Because this subject is so vast, this paper will limit its focus on issues of autoimmunity, and limit its discussion to rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease.   

There is a large body of preclinical data on the ECS’ role in autoimmune disease. One particular area of interest involves how cannabinoids affect the dynamic balance between regulatory T-cells and proinflammatory Th17 cells, the latter of which are associated with numerous autoimmune conditions.12 Cannabinoids demonstrate a unique modulation of the cytokine milieu by decreasing the inflammatory Th17 autoimmune phenotype while at the same time increasing the expression of anti-inflammatory IL-10.24 Specifically, CB2 receptor signals drive the immune response away from a proinflammatory cascade and towards a regulatory T-cell phenotype.25 

Rheumatoid Arthritis 

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases and is a well-known major source of pain, disability, and joint malformation.   

Interestingly, analysis of the synovial fluid of healthy volunteers shows undetectable levels of endocannabinoids, while the synovial fluid of RA patients reveals detectable levels of the endocannabinoids 2-AG and AEA.26 

Murine models indicate not only ECS involvement in RA, but also potential therapeutic effects. In a study of both bovine and murine models of arthritis, CBD effectively blocked the progression of disease after the onset of symptoms and protected the joints from severe degradation.27 The CBD-treated mice also showed decreases in proinflammatory tumor necrosis factor-alpha (TNFα) and interferon-gamma (INFγ), as well as decreased lymphocyte proliferation.27  

In a murine model of arthritis with human synovial tissue, CB2 stimulation reduced the production of the proinflammatory cytokines interleukin (IL)-6 and TNFα in a dose-dependent manner.28 The authors stated that activation of CB2 has “therapeutic potential for RA to suppress synovitis and alleviate joint destruction by inhibiting the production of autoantibodies and proinflammatory cytokines.”28   

In a double-blind, randomized, parallel-group study of RA patients who were administered a cannabis-based medicine or placebo for 5 weeks, significant suppression of disease activity occurred in the cannabis group, as well as improvements in quality of sleep, pain at rest, and pain during movement.29 Though animal data consistently show benefits of cannabinoids in RA, more clinical research on disease modification in humans is clearly needed. 

Multiple Sclerosis 

Multiple sclerosis (MS) is a chronic, progressive autoimmune disease that causes demyelination within the CNS. As with joint protection by cannabinoids in RA, animal models of MS demonstrate neuroprotective effects.   

Using an murine model of MS known as experimental autoimmune encephalomyelitis (EAE), CBD treatment led to a dramatic increase in anti-inflammatory myeloid suppressor cells and significantly reduced clinical scores of paralysis.30 In another EAE study, by Lyman et al, 100% of control animals developed severe clinical EAE, and over 98% of them died.31 In contrast, THC-treated animals showed either no clinical manifestations or mild disease with delayed onset, as well as a survival rate of over 95%.31 

A human study by Sexton et al found significantly higher levels of AEA in MS patients compared to normal controls.32 

A cannabinoid-based medicine (1:1 THC:CBD oral-mucosal spray) is sometimes used as an add-on therapy for spasticity in MS patients. A recent systemic literature review of observational studies and treatment registries, from 2011 to 2017, examined various aspects of this treatment.33 Results revealed overall reductions in the spasticity numeric rating scale (NRS), as well as improvements in spasm counts, sleep impairment, and pain.33 The CBD:THC product was well tolerated, and no unknown safety issues emerged.33 The authors concluded, “In therapy-resistant spasticity, that is, in patients not adequately responding to or not tolerating previous anti-spastic drugs, the add-on use of THC:CBD is an effective therapeutic option with a good tolerability and safety profile. No new or unexpected [adverse events] have been reported in clinical practice, and there are no indications of abuse or tolerance development with long-term use.”33   

A separate analysis of the 1:1 CBD:THC oral mucosal spray revealed persistent relief from MS spasticity, and good tolerability.34 The authors stated, “The ability of treatment-resistant patients to respond to THC:CBD oromucosal spray may relate to its novel modes of action which distinguish it from conventional antispasticity medications. Patients with a longer disease history may stand to gain the greatest benefit from treatment with add-on THC:CBD oromucosal spray.”34  

Inflammatory Bowel Disease 

Inflammatory bowel disease (IBD) refers to disorders of autoimmune chronic inflammation in the digestive tract, including ulcerative colitis (UC) and Crohn’s disease (CD). In patients with CD and UC, endocannabinoid levels have been found to be increased in plasma.35 Similarly, in murine colitis models, both endocannabinoids and cannabinoid receptors are upregulated.31,36–38 Other studies show that cannabinoid receptor blockade and in models of cannabinoid receptor deficiency, these anti-inflammatory effects are reversed.31,36–38 Likewise, in mouse models, the inhibition of endocannabinoid hydrolytic enzymes (MAGL and FAAH) raises endocannabinoid levels and concomitantly diminishes disease scores of colitis.39,40   

In a small human study of patients with active CD who failed to respond to corticosteroid treatment, inhaled cannabis produced clinically significant improvements in 10 out of 11 patients, and complete remission in 5 of 11 participants.41 Finally, in a randomized, placebo-controlled, double-blind, parallel-group study examining the use of a CBD-rich botanical extract in UC patients, participants’ global impression of change and quality-of-life outcomes were improved.42 

Conclusion 

The ECS acts as a modulatory network that may be considered a future target of pharmacotherapy for immune-related disorders such as autoimmune disease. Like many exciting new discoveries, the study of this robust system portends opportunities to shed light on previously unknown aspects of the human immune system, paving the way for new classes of pharmacologic as well as CAM and plant-based therapeutic agents. In the meantime, autoimmune patients who use medical cannabis and CBD products for concomitant symptoms of pain, spasm, sleep, or anxiety may experience benefits from the immune modulation provided by cannabinoid-based therapies. 

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Jake F. Felice, ND, LMP is a cannabis author, clinician, educator, and consultant whose vision is to advance the science and practical application of cannabis for medical and recreational markets around the world. Dr Felice provides world-class educational experiences by speaking authentically about hemp and cannabis. He consults with healthcare providers, industry, and the general public. His Category 1 CME courses for doctors, nurses, and pharmacists has been translated into 4 languages. Dr Felice is the founder of Cannabis Matrix Consulting, LLC, and he maintains a regular cannabis blog at drjakefelice.com. 

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