Research: Cannabis and Immune Health — The Many Layers of Interaction

When we talk about the immune system, we often focus on one thing—not getting sick. The immune system is our frontline defense against pathogens; we want it to be strong, but how strong? As with most things in our bodies, it’s about balance. The COVID-19 pandemic demonstrated what an exaggerated immune response can do. We also need to consider what our immune systems are defending us from. Anyone with an autoimmune condition knows the pain of a misdirected immune response. As research explores the effect of cannabis on immune health, all these factors must be considered, as well as the different components, forms, and dosages of cannabis—a plant with more than 120 different cannabinoids.1 Finally, like any organic compound, its effects will depend how much, in what form, and by whom.

The Endocannabinoid and Immune Systems
These are two complex systems, and one was only recently discovered. While all the mechanisms aren’t understood, research has shown there’s a relationship between the endocannabinoid system and the immune system.

At the most basic level, the immune system is composed of organs, cells, and chemicals (white blood cells, antibodies, the complement system, the lymphatic system, spleen, bone marrow, and thymus). White blood cells, which include T-cells, B-cells, and natural killer cells, among others, form the infantry of the immune system. When the body transcribes DNA, these cells are produced in different measures. When they’re balanced, they work to fight pathogens. But sometimes there’s an imbalance of these cells, and other times they overreact to foreign invaders. The former can result in autoimmune conditions such as rheumatoid arthritis and lupus; the latter can cause a cytokine storm—an extreme inflammatory response. For example, a lessened transcription of regulatory T-cells or an overproduction of CD8+ T-cells and CD4+ T-cells can increase risk of developing an autoimmune disease.1,2

At the most foundational level, the endocannabinoid system comprises CB1, CB2, and peroxisome proliferation activated receptors (PPARs), and transient receptor potential channels. These receptors are activated by endogenous cannabinoids; the most predominantly studied are anandamide and 2-arachidonoyl glycerol. The receptors can also be activated by exogenous cannabinoids, the most widely studied of which are CBD and THC.

What does this have to do with the immune system? CB2 receptors are heavily expressed in the thymus and spleen—key organs for T-cell maturation and differentiation. CB2 messenger RNA is also expressed in white blood cells, such as B-cells, CD8+ T-cells, monocytes, and CD4+ T-cells.3 Activation of CB1 and CB2 receptors activates mitogen-activated protein kinase, which plays a key role in the innate immune system (the body’s first line of defense).4

Decreased inflammation is attributed to PPAR activation, particularly in connection to metabolic diseases and neurodegenerative diseases.4 Transient receptor potential channels are involved in T- and B-cell receptor signaling and activation, antigen presentation, neutrophil and macrophage bactericidal activity, and mast cell degranulation.5 They also play a key role in retaining a functional neuronal expression in immune and epithelial cells. Recent research has tied the endocannabinoid system to the gut-microbiome axis, which plays a role in healthy immune functioning.

Exogenous cannabinoid use—smoking or the use of edibles and tinctures—activates cannabinoid receptors and influence the immune system. It’s not known exactly how cannabis affects the immune system, but research is beginning to provide interesting (and sometimes promising) insights.

Cannabis and Cancer
Recent research from a prospective observational study in Israel shows how using cannabis can dampen the effects of immunotherapy.6 Specifically, the study focused on patients with advanced malignancies who were being treated with immune checkpoint inhibitors. The small study looked at 102 cancer patients during a two-year period from 2016 to 2018. Of the patients in the study, 34 used cannabis and more than 50% had non–small cell lung cancer. Cannabis users who consumed an average of 20 g of cannabis per month had a decreased response to immunotherapy and an increase in progressive disease symptoms. Additionally, cannabis users had a faster time to tumor progression than did nonusers (3.4 months vs 13.1 months) and a decreased overall survival (64 months vs 28.5 months).

At the same time, cannabis users had significantly fewer adverse events (commonly reported with immunotherapy). The study also indicated that immunotherapy affected endogenous cannabinoids—even without cannabis use. The study had several limitations, including the use of various strains and intake methods of cannabis, as patients were permitted to change products on a monthly basis. No attention was given to CBD vs THC levels, and types of cancer weren’t uniform.

The Israeli study specifically focused on the effects of cannabis on immunotherapy and provided insight into potential warning signs in these patients. Regarding practical implications of the study, Eloise Theisen, AGPCNP-BC, a board-certified adult geriatric nurse practitioner and past president of the American Cannabis Nurses Association, says, “The dosages coming out of the Israel study were anywhere from 200 to 250 mg daily of THC. I can safely put patients on 50 mg or less a day and monitor them. Additionally, there are other cannabinoids that you can consider for nausea; there is good research on delta-8-THC and on CBDA [cannabidiolic acid], although we’re not sure how those affect the immune system.”

On the other hand, recent research into CBD suggests a positive effect on the immune response to cancer. A 2020 review highlighted ways in which CBD can augment the host immune response to cancer and limit the growth and spread of cancer cells.7

The Immune System — Too Much of a Good Thing
For the growing number of people with autoimmune conditions, suppressing an overactive immune system is a common treatment goal. Cannabis consumption could be a welcome alternative to steroids, which uniformly suppress the immune system; cannabis, on the other hand, has the potential to modulate and balance T-cells. THC has been shown to decrease CD8+ T-cells and cytotoxic lymphocytes.6 “THC, when it suppresses the immune system, can be beneficial in some autoimmune disease. You look at rheumatoid arthritis and lupus—those conditions often respond well to THC. We’ve even seen some disease-modifying effects,” Theisen says.

Often, the many compounds in cannabis work in tandem to induce an anti-inflammatory effect, while also tamping an overactive immune system.8 The main immunoregulatory effects of CB receptor binding include decreased immune system activation and immune cell migration, which are induced by apoptosis and the suppression of transcription factors and cytokine release. CBD is often credited with a greater anti-inflammatory effect than THC, but THC can play an important role in immune modulation.

Although more high-quality clinical trials are needed, a combination of animal models, cell line studies, and small clinical studies suggests that cannabis may be particularly useful in certain autoimmune disorders. In the case of rheumatoid arthritis, there’s evidence that nonsynthetic cannabinoids reduce the production of interleukin-6 and -8 by fibroblast-like synovial cells. One preliminary randomized, placebo-controlled study assessed five weeks’ treatment with a synthetic THC analog in 58 patients with rheumatoid arthritis and found that pain was significantly reduced and disease activity significantly suppressed.9

In patients with multiple sclerosis, cannabis is used to reduce spasticity and is being considered for its potential to inhibit glial response and slow neurodegeneration. Concerning irritable bowel disease, preclinical studies have shown the role of the endocannabinoid system in regulating intestinal inflammation.8

Cannabis and COVID-19
There are three concerns about the use of cannabis and COVID-19: vulnerability to the virus, immune response once one is infected, and response to the vaccine. As with any virus, suppression of the immune system and increased vulnerability to infection depend on the amount of cannabis used and its composition. Regarding the immune response, research suggests that cannabis could quell the cytokine storm that leads to many of the severe effects of COVID-19 in infected individuals.10

Regarding vaccination, there’s concern about whether cannabis might decrease the vaccine’s effectiveness. According to Theisen, “There was discussion around whether using CBD and THC would blunt your COVID vaccine response. There were many cannabis clinicians who erred on the side of caution and said, ‘Don’t use cannabis after you get your vaccine.’” The results of a study published in 2018 reviewing whether cannabis would blunt the effects of hepatitis B vaccination suggested that cannabis use had no effect.11

Is it safe for individuals to use cannabis while they have COVID-19? “I think it’s definitely worth considering the risk vs benefit. I think you could use it safely. Some of the research is really focused on CBD, CBDA, and CBGA. So far, we think it can lessen the severity and the duration of the virus,” Theisen says.

Does Cannabis Interfere With the Immune Response?
It’s unclear whether cannabis consumption can detrimentally suppress a healthy immune system. The question goes back to dosage, route of administration, cannabis composition, and the individual. According to the National Academies of Sciences, Engineering, and Medicine, there’s insufficient evidence to draw overarching conclusions about the effects of cannabis on a healthy immune system. The National Academies point out that most studies focus on only a few immunological endpoints but note a decrease in inflammatory cytokines with cannabis use in both animal and human models. The organization concluded that there was insufficient evidence of any other cannabis-related immune changes in healthy individuals.12

Guidance for Clinicians
Any person undergoing medical care should consult with their provider before using cannabis as a therapy. Providers with patients interested in medicinal cannabis should recommend them to cannabis specialists and incorporate those specialists into the patient’s care team. “At the end of the day, everything has side effects, and it’s often a matter of risk vs reward,” Theisen says.

People with a personal or family history of psychosis should avoid cannabis, and those who have suffered from cannabis dependence should use medicinal cannabis only under the care of a cannabis specialist.

Patients actively undergoing immunotherapy should be closely monitored when using cannabis to alleviate their symptoms.

The Path Forward
As more people turn to medicinal cannabis, research is needed to better understand its many effects on human health. Beyond research, it’s also necessary to consider equity and availability. “The challenge is that someone can get steroids for maybe $5 a month with a prescription, whereas cannabis, if you needed a high dose of CBD, could be hundreds of dollars a month, so it becomes a luxury item to use it,” Theisen says. There’s growing evidence that cannabis could be a beneficial therapeutic, but until the market supports it, cannabis straddles a quasi-legal line. The result is a dearth of research and a gap in equitable access.

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.

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