01 Apr Cannabis & The Immune System: A Complex Balancing Act
CANNABIS & THE IMMUNE SYSTEM: A COMPLEX BALANCING ACT
Cannabis sativa has been consumed for health and nutritional purposes for thousands of years. Many ancient civilizations – from the Chinese to the Greeks – included cannabis in their pharmacopoeia. Back then, no one questioned how or why cannabis relieved pain and calmed the spirits. It was a helpful ally – that’s all that mattered.
Fast forward to the 21st century. Scientists are trying to understand not only the molecular makeup of cannabis, but also how it interacts with the complex web of biological systems in our bodies. Yet, despite many exciting discoveries, we still know relatively little, especially when it comes to the interplay between cannabis and the immune system.
Some studies suggest that cannabinoids like THC and CBD are immunosuppressant, which can explain the relief experienced by medical cannabis users with autoimmune diseases and chronic inflammation. Other studies have shown that regular cannabis use can increase white blood cell counts in immunodeficiency disorders such as HIV, suggesting an immune-boosting effect.
It gets even more complicated when we consider that the effects of cannabis are mediated primarily by the endocannabinoid system, which scientists believe interacts with all biological activity, including our immune system.
The bottom line is that much remains to be discovered about how cannabis affects our immune system. Here’s some of what we know so far.
OUR IMMUNE SYSTEM: AN OVERVIEW
We are constantly exposed to infectious diseases, bacteria and viruses (antigens), all intent on running amok and wreaking havoc. Without any inbuilt defences to keep these invaders at bay, we’d all last about five minutes on this planet. Thank goodness we have an immune system: the complex network of cells, tissues and organs, running with military precision to keep us healthy.
A key player in the immune system’s arsenal are white blood cells or leukocytes, which seek out and destroy any unwanted visitors. Leukocytes can be divided into two groups: 1) lymphocytes (B cells and T cells) that destroy antigens and help the body to remember previous attackers; and 2) phagocytes that absorb and neutralize foreign intruders.
Many of us are familiar with T cells because of their relationship with the HIV virus, which wipes them out; this is what makes HIV patients vulnerable to normally harmless infections.
Our immune system also plays a key role in detecting malfunctioning cells inside our bodies, and, through the process of apoptosis or cell death, ensures that these cells do not continue to grow and become tumors.
Killing cells is a crucial element of a healthy functioning immune system, which maintains a delicate balance between growth and death. If, for example, there is too much cell death, autoimmune diseases can result, while too little can create the perfect environment for cancer.
THE ENDOCANNABINOID SYSTEM & THE IMMUNE SYSTEM
Optimum immune function entails a complex balancing act that relies on constant communication between our immune cells, tissues, and organs. With the discovery of the endocannabinoid system (ECS) in the 1990s, scientists have found another key piece of the puzzle.
The endocannabinoid system comprises two main G protein-coupled receptors (CB1 and CB2), endogenous ligands known as endocannabinoids (anandamide and 2-AG), plus the proteins that transport our endocannabinoids and the enzymes that break them down in the body.
Endocannabinoids are produced on demand, travelling backwards across chemical synapses and modulating cell activity. This partly explains why the ECS has been termed a homeostatic regulator – continually working to maintain a state of biological balance.
The ECS is a homeostatic regulator – continually working to maintain a state of biological balance.
CANNABIS & THE IMMUNE SYSTEM
When we talk about cannabis, we’re dealing with upwards of 400 different molecules. These include the more frequently studied cannabinoids like THC and CBD, more than 100 other minor cannabinoids, dozens of terpenes, and a host of flavonoids – the combination of which varies according to the cannabis strain.
While most work has been carried out on individual cannabinoids, in particular THC and CBD, if you’re looking for some solid conclusions about how they affect the immune system, think again.
THC has been the focus of the bulk of research. THC binds to the CB2 receptor and activates it, which has an anti-inflammatory effect. This suggests that THC is immunosuppressant. Accordingly, THC is thought to show promise for autoimmune diseases, such as Crohn’s and multiple sclerosis. CBD, despite little binding affinity with cannabinoid receptors, is also considered to be immunosuppressant, reducing cytokine production3 and inhibiting T-cell function4.
But that’s only part of the story. A new wave of research and mounting anecdotal evidence points towards cannabinoids having an adaptive, immunomodulating effect, rather than just suppressing immune activity.
CANNABIS & HIV
Medical cannabis is a well-established palliative treatment for HIV thanks to the plant’s ability to reduce anxiety, improve appetite, and ease pain. But recent research takes THC’s role even further, suggesting that it can actually upregulate the immune system, potentially improving patient outcomes.
Initially, preclinical research had corroborated the view that THC was immunosuppressant in HIV, increasing viral load and worsening the disease.5 More recent research, however, has suggested immune-stimulating effects.
A 2011 study by Lousiana State University scientists revealed astonishing results when monkeys were given THC over 28 days prior to SIV infection (the simian version of the virus). THC appeared to have some kind of protective effect, lengthening the lives of the monkeys and reducing viral load.6
Scientists discovered that infection-fighting immune cell counts were higher in HIV patients using cannabis.
Additional research by the same team in 2014 took these findings one step further. This time monkeys were given THC for a period of seventeen months before SIV infection. Not only was there an increase in T-cells and a reduction in viral load, but THC appeared to have protected the monkeys against the intestinal damage commonly caused by the virus.7
These exciting results have also been replicated in humans. In a study conducted by researchers at universities in Virginia and Florida, CD4 and CD8 white blood cell counts were compared in a sample of 95 HIV patients, some of whom were chronic cannabis users.8 Scientists discovered that both types of infection-fighting immune counts were higher in patients using cannabis, suggesting their immune systems had been bolstered by the plant.
CANNABIS, CANCER, & THE IMMUNE SYSTEM
Cancer will affect one in two of us at some point in our lifetime. There’s no hard and fast rule why it appears, but most cancers share the same mechanism.
Our immune system is primed to spot rogue cells and, through mechanisms such as apoptosis, eliminate any that might become tumors. Unfortunately, cancer cells can outwit our immune system by getting it to work in their favour.
Esther Martinez, a cannabinoid research scientist at Madrid’s Complutense University, describes a kind of crosstalk between cancer cells and the immune system. “When the tumor talks with immune cells, it reverses the signal,” she told Project CBD. “So, it’s like, ‘I’m here, and now I want you to work for me.’ And instead of attacking the tumor, it gives pro-survival signals, so the immune system around the cancer goes through a change. The tumors have the capacity to shut off the immune system.”
With the immune system unarmed, cancer cells grow uncontrollably. Until recently, the only approved anticancer weapons have been treatments like chemotherapy, which destroy not just the cancer cells, but also fast-growing, healthy cells.
It’s no surprise, then, that tremendous excitement lies around the antitumoral properties of the cannabis plant, in particular THC and CBD. In fact, it was Esther’s colleagues at the Complutense University, Manuel Guzman and Cristina Sanchez, who paved the way in investigating the cancer-killing effects of cannabinoids, primarily, but not exclusively through apoptosis.9
However, very little is known about the relationship between the immune system and cannabinoids in this process. One reason is that in many preclinical trials, human tumors grafted onto immunosuppressed mice are used to avoid rejection by their rodent hosts.
Some studies do exist using immune competent mice, such as Dr Wai Liu’s 2014 report, which examined the effects of THC and CBD on brain tumors when combined with radiotherapy. Not only were the tumors significantly reduced, but little if no immune suppression was witnessed in the study, according to Dr Liu, a London-based Research Fellow and cannabinoid Scientist.10
This is welcome news, as cannabinoids can also cause apoptosis in lymphocyte cells, potentially suppressing the immune system. The ability of cannabinoids to both suppress and bolster immune function lends credence to the idea that the endocannabinoid system is involved in immunomodulation, as Dr. Liu told Project CBD: “I suspect that cannabinoids are having a double-punch effect of 1) direct killing and 2) enhancing immunity by suppressing those immune cells that serve to hold back the immune-based killing cells.”
IMMUNOTHERAPY FOR CANCER
Uncertainty about the interaction between cannabinoids and the immune system raises doubts regarding the use of medical cannabis during immunotherapy. Proclaimed the wonder cancer treatment of the future, immunotherapy retrains white blood cells to detect and kill cancer in the body. Thus far, however, there has only been one study examining how cannabinoids may affect this process – and the results were problematic.
Conducted at the Rambam Medical Centre in Haifa, Israel, patients taking medical cannabis alongside the immunotherapy cancer drug Nivolumab responded 50% less compared to those on immunotherapy alone.11 Curiously, subjects taking medical cannabis high in THC responded better to immunotherapy than those on a low strength THC product. No significant change in overall survival rates for patients was noted.
There are also anecdotal reports from California cancer patients who maintain that they benefited by combining immunotherapy with a low-dose, CBD-rich cannabis oil regimen under a doctor’s supervision. In addition, a small but growing body of preclinical data suggests that combining CBD and THC with conventional chemotherapy and radiation could have a powerful synergistic effect as an anticancer treatment. But these findings have not been replicated in human trials.
Despite a lack of clarity regarding cannabinoids and immunotherapy, the preponderance of scientific data suggests that it’s time to abandon the antiquated and misleading immunosuppressant label and embrace the idea that cannabinoids are bidirectional immunomodulators. This is what Dr. Mariano Garcia de Palau, a Spanish cannabis clinician and member of the Spanish Medical Cannabis Observatory, has seen in his practice.
Cannabis is immunosuppressive when there is hyper-immune response, but otherwise it regulates and corrects the immune system, bringing equilibrium to the organism.
“I believe [cannabis] is immunosuppressive when there is hyper-immune response,” says Dr. Garcia de Palau, “but otherwise it regulates and corrects the immune system. In fact, you could say it functions like the endocannabinoid system, bringing equilibrium to the organism.”
What does this mean in practical terms if you regularly use cannabis, have a compromised immune system or are starting immunotherapy? Where possible consult with your medical practitioner. In the meantime, we can only hope that more research will shed light on the complex relationship between the endocannabinoid system, our immune response, and compounds in the cannabis plant.
Mary Biles is a journalist, blogger and educator with a background in holistic health. Based in the UK, she is committed to accurately reporting advances in medical cannabis research.
Copyright, Project CBD. May not be reprinted without permission.
1. Caroline Turcotte, Marie-Renée Blanchet, Michel Laviolette, and Nicolas Flamand. The CB2 receptor and its role as a regulator of inflammation. Cellular and Molecular Life Sciences. 2016; 73(23): 4449–4470. doi: 10.1007/s00018-016-2300-4
2. Rupal Pandey, Khalida Mousawy, Mitzi Nagarkatti, and Prakash Nagarkatti. Endocannabinoids and immune regulation. Pharmacol Res. 2009 Aug; 60(2): 85–92, doi: 10.1016/j.phrs.2009.03.019
3. Francieli Vuolo, Fabricia Petronilho, Beatriz Sonai, Cristiane Ritter, Jaime E. C. Hallak, Antonio Waldo Zuardi, José A. Crippa, and Felipe Dal-Pizzol. Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. Mediators of Inflammation. 2015; 2015: 538670. doi: 10.1155/2015/538670
4. Barbara L. F. Kaplan, Alison E. B. Springs, and Norbert E. Kaminski. The Profile of Immune Modulation by Cannabidiol (CBD) Involves Deregulation of Nuclear Factor of Activated T Cells (NFAT). Biochem Pharmacol. 2008 Sep 15; 76(6): 726–737. doi: 10.1016/j.bcp.2008.06.022
5. Roth MD, Tashkin DP, Whittaker KM, Choi R, Baldwin GC. Tetrahydrocannabinol suppresses immune function and enhances HIV replication in the huPBL-SCID mouse. Life Sciences. 2005 Aug 19;77(14):1711-22.
6. Patricia E. Molina Peter Winsauer Ping Zhang Edith Walker Leslie Birke Angela Amedee Curtis Vande Stouwe Dana Troxclair Robin McGoey Kurt Varner Lauri Byerley Lynn LaMotte. Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus. AIDS Research and Human Retroviruses Vol. 27, No. 6. https://doi.org/10.1089/aid.2010.0218
7. Patricia E. Molina,Angela M. Amedee, Nicole J. LeCapitaine, Jovanny Zabaleta, Mahesh Mohan, Peter J. Winsauer, Curtis Vande Stouwe, Robin R. McGoey, Matthew W. Auten, Lynn LaMotte, Lawrance C. Chandra, and Leslie L. Birke. Modulation of Gut-Specific Mechanisms by Chronic Δ9-Tetrahydrocannabinol Administration in Male Rhesus Macaques Infected with Simian Immunodeficiency Virus: A Systems Biology Analysis. AIDS Res Hum Retroviruses. 2014 Jun 1; 30(6): 567–578. doi: 10.1089/aid.2013.0182
8. Keen L, Abbate A, Blanden G, Priddie C, Moeller FG, Rathore M. Confirmed marijuana use and lymphocyte count in black people living with HIV. Drug Alcohol Depend. 2017 Nov 1;180:22-25. doi: 10.1016/j.drugalcdep.2017.07.026.
9. Guzmán M. M J Duarte, C Blázquez, J Ravina, M C Rosa, I Galve-Roperh, C Sánchez, G Velasco, and L González-Feria. A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer. 2006 Jul 17; 95(2): 197–203. doi: 10.1038/sj.bjc.6603236
10. Katherine A. Scott, Angus G. Dalgleish and Wai M. Liu. The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Molecular Cancer Therapeutics. MCT-14-0402 doi: 10.1158/1535-7163
11. Taha T, Meiri D, Talhamy S, Wollner M, Peer A, Bar-Sela G. Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies. Oncologist. 2019 Jan 22. pii: theoncologist.2018-0383. doi: 10.1634/theoncologist.2018-0383.