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How CBD Can Improve Immune System Function and Efficiency: An Overview

CBD, or cannabidiol, is a cannabinoid compound produced by varieties of C. Sativa L along with over 100 other phytocannabinoids. THC is the most well-known component of cannabis plants thanks to its psychotropic effects, but CBD has gained much notoriety over the past quarter century for its therapeutic effects, which lack psychotropic activity.1 Research on phytocannabinoids and the cannabis species has spurred congruent research into the mammalian endocannabinoid system (ECS), which mediates (most of) the effects of cannabis-derived products.

Specifically, the endocannabinoid system (ECS) is integral to the way that our immune system regulates itself and maintains a healthy balance of self-defense without causing self-harm. The immune system exists to sense any damage or threat and to respond to it in a way that removes the threat and repairs the damage. However, sometimes the immune response is disproportionate to the degree of damage. This results in an immune attack on healthy tissue, a condition known as autoimmunity. Autoimmunity is the harmful component of numerous common conditions, from arthritis to Crohn’s disease to Alzheimer’s.

While autoimmunity produces the symptoms of many common conditions, the exact cause of the autoimmune reaction is often not clear. However, the overwhelming majority of common autoimmune conditions coincide with abnormal activity within the endocannabinoid system, which regulates the immune system. CBD and phytocannabinoids in general are reputed by the medical research community to possess extensive immunoregulatory properties. Furthermore, the majority of the effects of CBD on the immune system only modulate abnormal or pathological activity, with a negligible effect on typical immune system activity.

This overview discusses the various ways that CBD can improve immune system function and efficiency: ways in which it can shore up the healthy immune system and possibly prevent autoimmune reactions from happening in the first place.

First, let’s get some context.

How does the immune system work?

Many pathological (disease-related) conditions of the immune system are a result of dysregulation of how our immune system should respond to a given stimulus. In people who are allergic to cats or peanuts, certain molecules unique to cat dander and peanut oil set off the biological equivalent of a fire alarm inside the body. This is an example of an immune system response which is disproportionate to the danger posed by the threat to which it is responding: peanuts won’t kill you, but if you have a peanut allergy, then your immune system might kill you while “protecting” you from peanuts.

So what causes the immune system to act in a way that threatens the life of the organism which it exists to protect? The answer isn’t as simple as it may seem. The immune system is a complicated, well-oiled machine, with countless hormones and compounds called cytokines that it uses to mediate its activities. They are intricately balanced thanks to a few robust regulators including the endocannabinoid system. The machine that is the immune system has thousands of moving parts, and if any single one fails, it can disrupt the entire system.

There are three basic steps to our immune system’s functionality.

First, the immune system senses the presence of injury (damage) or a threat (infection).

Immune cells (macrophages, endothelial cells, dendritic cells, etc.) located in our blood stream and comprising all of our mucous membranes react to chemical tags unique to bacteria and viruses. They also respond to distress signals released by injured endogenous cells (cells belonging to your body).

The threshold amount of a threat or injury required to stimulate the immune system has a very specific range in which it must remain: if the threshold drops too low then the immune system will react to a stimulus that isn’t really dangerous; too high a threshold will cause the immune system to ignore threats that may actually be harmful to the organism. This is known as sensitivity, and both hyper- (too much) and hypo- (too little) sensitivity result in negative consequences.

Second, the immune cells that sensed the threat or damage tell the rest of the immune system how to respond.

Depending on their sensitivity, immune system cells called helper cells produce compounds known as cytokines: these include interleukins (IL), interferons (IFN), tumor-necrosis factors (TNF), and several other classes of chemical signals that all either increase or decrease the overall activity of the immune system. If the wrong combination of cytokines is produced by an immune cell (based on “wrong” sensitivity to the initial stimulus), then an abnormal immune response will occur.

This is the case in many autoimmune conditions, but again, exactly why the wrong combination of cytokines is produced remains a mystery. As with sensitivity, issues involving cytokine signalling are just as detrimental to immune function.

Third, effector cells act on the response of the helper cells, carrying out an immune reaction.

In this step, the immune system actually carries out processes either to heal damaged tissue or to kill pathogens and endogenous cells that are past repair.

…Back to sensitivity; if effector cells are too responsive or not responsive enough to the signalling from helper cells, then an immune reaction will occur that is detrimental to the health of the organism as well.

How does CBD improve immune system sensitivity and signalling?

While CB2 cannabinoid receptors are vital to the normal function of immune cells, many of the therapeutic effects of CBD on immune system function are mediated by separate mechanisms than the classical cannabinoid receptors. In fact, much of the therapeutic effect of cannabidiol is due to CBD’s rare ability to alter which genes get expressed by cells.3 In the immune system, this affects both sensitivity and signalling. CBD limits the combinations of genes that get expressed, which limits the combinations of cytokines that cells are able to produce (proinflammatory vs. anti-inflammatory) and also the combination that they are able to respond to (the cytokines for which they have receptors).

CBD increases the expression of immunosuppressant genes

Every cell in our body contains a full copy of our all of our genes. Each of our genes (humans have about 20,000) codes for a specific protein. The whole point of DNA – its only function – is to create the thousands of different proteins that our cells need to operate. Proteins are massive functional molecules that serve some technical purpose for the function of our cells.

Proteins in muscle cells physically change their shape to contract the muscle fiber. Proteins in the retina react differently to the different wavelengths of light, allowing us to see. Proteins, quite literally, do it all. Seriously. Every single activity inside every single one of your cells depends on a protein. All “chemical signalling” involves some molecule that was created by an enzyme protein, interacting with a receptor protein. Usually, the only non-protein piece of the puzzle is the actual signalling molecule itself.

All cellular functions depend on proteins, and each kind of cell is different because of the specific proteins that it expresses: of course, each cell doesn’t need to express all of the genes in the human genome (remember every cell contains all of the genes). A protein is “expressed” when the specific gene that codes for that protein is activated by the cell to then produce that protein.

In the immune system, there are hundreds of genes that code for cytokines, and for the signals that determine whether immune stem cells differentiate into repair cells (ambulances) or killer cells (tanks): these signals are called transcription factors because they “factor into” which genes get transcribed, or activated.

Transcription factors are also proteins themselves, that need to be produced by their own genes. If the immune system has to choose between building tanks or ambulances, then transcription factors are the executive officers that decide which machines (cells) to produce more of. If the transcription factors build more tanks than ambulances, then the destruction caused by the immune system will outweigh any repairs it can make. This is one of the common characteristics of immune system disorders: too many killer cells are created and not enough repair cells to clean up the damage.

CBD activates a receptor known as PPARγ (PPAR gamma). When activated by certain transcription factors, PPAR receptors modulate the expression of genes in their cell. PPARγ (PPAR gamma) receptors increase the expression of genes that code for immunosuppressant proteins, proteins that will build ambulances, not tanks. Essentially, by activating PPARγ receptors, CBD goes straight to the executive board of the immune system and tells it to produce machinery that will help to repair the body and prevent damage rather than machinery that causes unnecessary damage.2, 3

In essence, CBD activates a PPAR receptor on immune cells that causes the immune system to become less active and to produce more machinery associated with repair and prevention than with inflammation and destruction.4

CBD decreases the production of proinflammatory genes and reactive oxygen species (ROS)

When the immune system has decided that it needs tanks to destroy a pathogenic enemy, the killer cells that it creates flood the infected area in the form of inflammation. These cells exert their damage by releasing reactive compounds containing oxygen (reactive oxygen species), which act in the same way that Oxyclean or bleach acts on a stain: by breaking down any molecules they come into contact with.

Most stains in clothing are a product of food, which means they almost certainly came from a once-living thing. The large molecules produced by all living things are sensitive to oxygen-containing compounds. Just like Oxyclean degrades the biological molecules making up a stain, ROS released by killer cells degrade the cell membrane and DNA of cells they come into contact with.

People from all corners of the nutrition and health industries emphasize the importance of antioxidants in your diet, but why are antioxidants necessary and why do so many bloggers talk about them? Antioxidants are compounds like vitamin E and CBD which attract ROS before important cell components get damaged. Antioxidants are like little filters that constantly remove dangerous ROS as they float around the cell. The balance of natural antioxidants produced by the immune system’s repair cells and of ROS produced by its killer cells is completely relevant to whether or not it works properly.

CBD increases the amount of natural antioxidants that our bodies produce. This is at least partially a result of its ability to alter the genes that get expressed by immune cells, however CBD itself has antioxidant properties at least as potent as vitamin E. This has lead some to propose that CBD itself takes some of the antioxidant load off of the body’s own antioxidant ability, leaving higher levels circulating in the blood.5

Another proposed mechanism for CBD’s overall effect on the immune system has to do with a different aspect of its activation of PPARγ receptors. PPAR, a class of receptors, controls which genes get expressed in a given cell. In immune cells, PPARγ happens to increase expression of genes that are mainly immunosuppressive. Its activation has the secondary effect of decreasing the expression of other PPARs that increase the expression of proinflammatory genes. CBD increases the good and decreases the bad.6

References:

  1. Martin-Santos R, Crippa JA, Batalla A, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18:4966–4979
  2. Libro R, Scionti D, Diomede F, et al. Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Frontiers in Physiology. 2016;7:559. doi:10.3389/fphys.2016.00559.
  3.  Hegde VL, Singh UP, Nagarkatti PS, Nagarkatti M. Critical role of mast cells and peroxisome proliferator-activated receptor gamma (PPARγ) in the induction of myeloid-derived suppressor cells by marijuana cannabidiol in vivo. Journal of immunology (Baltimore, Md : 1950). 2015;194(11):5211-5222. doi:10.4049/jimmunol.1401844.
  4.  Kozela E, Juknat A, Gao F, Kaushansky N, Coppola G, Vogel Z. Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells. Journal of Neuroinflammation. 2016;13:136. doi:10.1186/s12974-016-0603-x.
  5. De Filippis D, Esposito G, Cirillo C, et al. Cannabidiol Reduces Intestinal Inflammation through the Control of Neuroimmune Axis. Gaetani S, ed. PLoS ONE. 2011;6(12):e28159. doi:10.1371/journal.pone.0028159.
  6. Liu D, Hu C, Huang C, Wey S, Jan T. Cannabidiol attenuates delayed-type hypersensitivity reactions via suppressing T-cell and macrophage reactivity. Acta Pharmacologica Sinica. 2010;31(12):1611-1617. doi:10.1038/aps.2010.155.

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