While CB1 receptors are primarily located in the central nervous system, CB2 receptors are located in your peripheral organs. In light of recent research, studies are now further investigating the critical role of CB2 receptors in the immune system.
Both endocannabinoids and phytocannabinoids influence your immune functioning. Endocannabinoids are those produced endogenously; i.e., they’re cannabinoids naturally produced by your body. On the other hand, phytocannabinoids are produced by cannabis and hemp plants.
The knowledge of endocannabinoid-immune cell crosstalk will pave the way to therapeutic implications of modulators of this pathway in autoimmune and chronic inflammatory disorders.” —
O. Rahaman & D. Ganguly (2021)
Harnessing the natural benefits offered by the endocannabinoid system bears promise for developing therapeutic interventions for autoimmune diseases, which are often difficult and costly to treat. This area of research is also important for medical cannabis patients with conditions that leave them immunocompromised.
How Cannabinoids Influence Your Immune System
The endocannabinoid system regulates various critical functions throughout the body, including pain perception, fear response, energy metabolism, inflammation, and immune functioning. Certain cannabinoids bind to ECS receptors and influence these processes.
Endocannabinoids are produced in the outermost layer of cells in response to stimuli. N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) are the most recognizable endocannabinoids with the most research behind them.
Although many phytocannabinoids exist in cannabis and hemp, THC is the only one that consistently binds to CB1 and CB2 receptors. Non-psychoactive cannabinoids have a very low affinity for binding to ECS receptors, suggesting that their effects result from binding elsewhere in the body.
CB2 receptors are predominantly expressed in immune cells. CB1 receptors do exist in immune cells, too, but CB2 is expressed at rates 10 to 100 times higher than CB1 receptors.
Endocannabinoids & the Immune System
Anandamide affects the chemokines and cytokines in T cells. Chemokines and cytokines are small proteins that facilitate communication between cells. In the immune system, chemokines and cytokines are necessary for nearly every part of an immune response.
2-AG also affects certain aspects of T cells and NK cells, giving both endocannabinoids immunosuppressive properties across different routes.
Now, you may be thinking, “Immunosuppression? Don’t I want my immune system to be on high guard? Why would I want to ‘suppress’ it?”
Some conditions cause your immune system to go into overdrive. In the case of autoimmune diseases, your immune cells start attacking different parts of your body because it mistakenly perceives a threat that isn’t really there.
Immunosuppressants are often used to treat autoimmune conditions, such as lupus, psoriasis, and arthritis. They’re also prescribed to those who receive an organ transplant to prevent their body from rejecting the new organ.
However, there are cases in which immunosuppression isn’t helpful. Immunosuppression could exacerbate the immune system’s vulnerability in conditions that leave an individual immunocompromised — such as cancer or HIV.
Considering that patients with cancer and HIV both use cannabis to alleviate their symptoms, it’s essential to further investigate the immunosuppressive properties of cannabinoids to ensure it doesn’t further compromise their immune systems.
When functioning correctly, though, your endocannabinoids are natural immunosuppressants that keep your immune system balanced.
Endocannabinoids in the immune system are viable targets for treating inflammatory diseases, the Immunology Journal review says. Multiple pharmaceutical drugs that target CB2 receptors are currently in development for treating inflammatory disorders and cancers.
Lastly, endocannabinoids and immune homeostasis are a two-way street. Endocannabinoids affect immune homeostasis and vice versa. When a disease or illness triggers your immune system, it affects the levels of endocannabinoids present in your immune system.
While this variability could make it challenging to study endocannabinoids in the role of disease pathology, it does present the opportunity to use endocannabinoids as “biomarkers” to track the progression of diseases.
Phytocannabinoids & the Immune System
Phytocannabinoids have similar immunosuppressant properties to endocannabinoids. There are many signaling pathways in the immune system that phytocannabinoids act on. Most of which, affect cytokine and chemokine production.
As mentioned above, endocannabinoid levels are affected in the presence of disease. But it appears immune-mediated diseases also impact them.
The immunosuppressive properties of cannabinoids have prompted multiple studies on the efficacy of treating immune-mediated diseases through endocannabinoids and phytocannabinoids.
According to the Advances in Pharmacology chapter, there have been extensive studies on the relationship between the following immune-mediated diseases and cannabinoids.
Systemic Lupus Erythematosus (SLE)
α/β-hydrolase domain-containing 6 (ABHD6), a specific gene linked to SLE, causes individuals to have less of the endocannabinoid 2-AG. This disrupts the natural immunosuppressive effects of 2-AG.
These findings suggest that ABHD6 is pro-inflammatory and negatively affects immune homeostasis.
Multiple Sclerosis (MS)
In preclinical studies, THC was the first cannabinoid to significantly decrease inflammation in animal models of MS. Since then, many other cannabinoids (including synthetic, pharmaceutical cannabinoids) have significantly reduced MS in animal studies.
Cannabinoids also decrease MS-induced neuroinflammation and reduce spasticity.
Inflammatory Bowel Disease (IBD)
IBD is an umbrella term for conditions related to gut inflammation, such as Crohn’s Disease, Ulcerative Colitis, and Celiac’s Disease. Clinical data on treating IBD with cannabinoids is limited.
However, cannabinoids have anti-inflammatory properties, increase gut motility, and reduce leaky gut. It’s possible that cannabinoids could serve as an adjunct therapy to IBD.
Type 1 Diabetes
Type 1 diabetes is classified as an autoimmune disease because immune cells begin destroying insulin-producing cells in the pancreas. In animal models of type 1 diabetes, THC reduced blood sugar, increased insulin levels, and suppressed pancreatic expression of cytokines.
In similar studies, CBD reduced diabetes-induced eye inflammation and inflammatory signaling in the heart, but didn’t reduce blood sugar. Oral administration of anandamide reduced diabetes incidents among mice, as well.
However, there have also been reports of cannabis use increasing the risk of developing diabetic ketoacidosis and adverse cardiovascular effects. As such, more clinical studies are needed to evaluate the safety of cannabis as a therapy for diabetes.
Inflammatory Liver Diseases
In animal models, cannabinoids have reduced liver steatosis (fatty liver disease), as well as alcohol and diet-induced liver inflammation. In one human study, cannabis use was associated with significantly lower incidences of steatosis, hepatitis, cirrhosis, and cancer among participants with alcoholic liver disease.
Arthritis
The first studies that assessed the efficacy of cannabinoids for treating arthritis found anandamide and THC reduced pain associated with polyarthritis caused by Complete Freund’s Adjuvant. Studies on dogs with osteoarthritis have also found that THC, CBD, CBC, and CBG reduce pain among the pups.
Although more human trials are needed, many patients have self-reported that cannabis reduces pain and sleep disturbances related to arthritis.
Pulmonary Inflammatory Diseases
Most animal studies thus far demonstrate that cannabinoids suppress asthma-induced immune responses. CBD, CBN, and THC, in particular, reduce pro-inflammatory cytokines in the lungs.
Some studies have reported that THC possesses short-term bronchodilator effects. Yet, further studies haven’t found data to support THC as a long-term bronchodilator in humans.
Human Immunodeficiency Virus (HIV)
Studies have shown that 25 to 37 percent of individuals with HIV use cannabis to alleviate their symptoms. Cannabinoids help these individuals increase their appetite, relieve anxiety, depression, and pain. More recent research shows cannabinoids may slow the progression of HIV-associated neurocognitive disorder (HAND).
While the anti-inflammatory effects of cannabis can reduce symptoms of HIV, there are concerns about the immunosuppressive properties of cannabis reducing the body’s ability to fight off HIV.
More studies are needed to determine whether the immunosuppressive properties could be doing more harm than good. But overall, cannabis use is associated with a decrease in HIV symptoms and HIV-induced neurocognitive decline.
Can CBD Enhance Immunity?
Although THC is the only phytocannabinoid that truly binds to CB1 and CB2 receptors, non-psychoactive cannabinoids such as CBN and CBD can also modulate the immune system. Consistently, CBD has exhibited widespread anti-inflammatory effects both internally and externally (via topicals).
Thus far, research suggests that CBD interacts with the immune system and may alleviate symptoms associated with immune-related disorders.
However, CBD appears to have more immunosuppressive properties rather than immune-boosting effects.
Key Takeaways: CB2 Receptors and Cannabinoids Help Regulate Immunity
CB2 receptors are expressed abundantly throughout the immune system, making the ECS a viable target for treating immune-mediated diseases.
Both endocannabinoids and phytocannabinoids have immunosuppressive and anti-inflammatory properties, which could be useful for reducing symptoms of various autoimmune conditions.
However, there are cases in which immunosuppression could be harmful to the individual, especially if their pre-existing condition already leaves them immunocompromised.
As research progresses in the fields of cannabis and immunology, it provides an opportunity to create effective treatments for autoimmune conditions and other immune-mediated disorders. Endocannabinoids could also become important “biomarkers” for tracking the progression of certain diseases.
Lastly, further research will establish a better understanding of the safety and potential risks associated with cannabis use among individuals who are immunocompromised.
References
- Rahaman, O., & Ganguly, D. (2021). Endocannabinoids in immune regulation and immunopathologies. Immunology, 164(2), 242–252. https://doi.org/10.1111/imm.13378
- Sinobiological. (n.d.). What are Chemokines. https://www.sinobiological.com/resource/cytokines/what-is-chemokine
- Zhang, J. M., & An, J. (2007). Cytokines, Inflammation, and Pain. International Anesthesiology Clinics, 45(2), 27–37. https://doi.org/10.1097/aia.0b013e318034194e
- Kaminski, N. E., & Kaplan, B. L. (2021). Immunomodulation by cannabinoids: Current uses, mechanisms, and identification of data gaps to be addressed for additional therapeutic application. Advances in Immunopharmacology, 1–59. https://doi.org/10.1016/bs.apha.2021.01.001