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Cannabinoids and Inflammation

Many health problems prevalent in western cultures stem from inflammation. From arthritis to psoriasis, inflammation is a key influencer in the progression of many chronic diseases, and much has been made lately of cannabinoids and their anti-inflammatory potential. These phytocannabinoids and endocannabinoids now have a wealth of scientific evidence demonstrating their therapeutic value and in this article I shall summarise some of the anti-inflammatory research to date:


Pytocannabinoids


Cannabichromene (CBC):


Cannabichromene has had its anti-inflammatory properties studied since at least 1980 when it was discovered that CBC was as effective as phenylbutazone (a non-steroidal anti-inflammatory drug commonly used on animals) at equivalent doses in rats, yet CBC is less toxic and so could be given in larger doses to achieve better therapeutic effects 1.

CBC seems to exert some of its anti-inflammatory properties without utilising the two Cannabinoid Receptors present in the human body (CB1 & CB2). This was determined by administering a cannabinoid receptor antagonist to rats that negated them from being used. CBC still produced pharmacological effects despite the receptor antagonist. There was also shown to be an additive relationship between the anti-inflammatory effects of CBC and tetrahydrocannabinol (THC), whereby administration of both cannabinoids increased their anti-inflammatory ability better than when administered alone 2.

Cannabichromene is also thought to be a direct CB2 receptor activator, binding almost twice as well as THC, but CBC seems to be a fairly inert CB1 agonist 3. Due to CB2 receptors being expressed mainly in immunological cells this is another route of CBC’s anti-inflammatory activity as immune cells are key mediators of inflammation.

Many people sometimes focus too heavily on the cannabinoid receptors, but cannabinoid receptor-independent pathways are also an important area of study. CBC can interact with transient receptor potential (TRP) ion channels which have been shown to inhibit the inactivation of endocannabinoids like 2-AG and Anandamide, increasing the concentration of these endocannabinoids in the body 4. Aspects like this, that are sometimes overlooked, can play an important part in the ‘Entourage Effect’. Cannabis products seem to be effective anti-inflammatory agents due to the variety of different mechanisms through which they act simultaneously.


Cannabidiol (CBD):


Cannabidiol, alongside THC, is one of the cannabinoids that are now widely known across the globe for its therapeutic potential with a global projected market worth of $23.6 billion by 2025 5. It is used to help treat or alleviate a huge variety of diseases and ailments, some of which is strongly backed by scientific research and some of which is mainly anecdotal, but its use is justified. CBD has scientific research showcasing its ability to help with anxiety and depression, easing aches and pains, helping with sleep and some neurological problems 6.

Part of CBD’s anti-inflammatory ability comes from its antioxidant properties. This receptor-independent pathway prevents the formation of superoxide radicals, inflammatory molecules, in rat paw inflammation tests 7.

With regards to the endocannabinoid system, CBD binds to both cannabinoid receptors in the human body, albeit weakly, so it also contributes to reducing inflammation via CB receptor-dependent mechanisms. It has shown potential through its interaction with the CB2 receptor whose activation leads to a decrease of reactive oxygen species and Tumour Necrosis Factor-alpha (TNF-a) both of which contribute to inflammation 8.

CBD also reduces inflammation via TRP receptors, particularly vanilloid receptors (TRPV) where it has influence due to the increase in Anandamide (AEA) that CBD promotes 9.


Cannabigerol (CBG):


CBG is also an antioxidant, presenting similar properties to CBD, and while it is known to be anti-inflammatory it could do with more study to further explore its potential. There are already studies that have shown CBG has potential in helping with gut issues such as Inflammatory Bowel Disease (IBD) 10 and shows promise at reducing neuroinflammation 11. Some of the mechanisms through which CBG reduces these two types of inflammation focus on the reduction in the expression of pro-inflammatory cytokines (a class of signalling proteins secreted by certain immune cells), such as TNF-a, interleukin-1b (IL-1b) and interferon-y (IFN-y) which all promote inflammation. It’s also been shown that CBG, when administered alongside CBD, has great potential as a combination therapy that delivers strong anti-inflammatory and antioxidant properties 12.


Delta-9-Tetrahydrocannabinol (THC):


THC is the most widely known cannabinoid of Cannabis sativa. It is the psychotropic cannabinoid responsible for the global recreational use of cannabis and has a bad reputation among some people for its association with criminality. Aside from the psychoactive properties it possesses, THC actually has a wide range of therapeutic uses including being a useful compound against inflammation.

THC binds very well to the CB1 receptors that are expressed in our central nervous system, but also binds to the CB2 receptors expressed in immune tissue. It is believed that the CB receptor-dependent anti-inflammatory mechanism of THC occurs through its interaction with CB2 receptors 13 where it suppresses the release of pro-inflammatory cytokines decreases the expression of other inflammatory markers.

Another mechanism of action for THC’s anti-inflammatory properties is Its ability to induce apoptosis (programmed cell death) in immune cells 14. This may sound like a detrimental quality, as immune cells are vital for the body’s defences, but immune cells are actually involved heavily in inflammation arising within the body. THC has been shown to work on reducing chronic inflammation by impacting the immune cells that promote the inflammation. It Is important to note though that cannabinoids do also protect other cells in the central nervous system from apoptosis – they do not cause all of your cells to commit cell suicide 15.

It is also interesting to note that a study from 1998 showed THC actually promoted inflammation in some cell types at some concentrations 16.


Endocannabinoids


2-arachidonoyglycerol (2-AG):

2-AG is an endocannabinoid that is the primary endogenous ligand (a substance that binds to a receptor or enzyme) for the CB2 receptor as well as being able to activate the CB1 receptor. Due to its strong binding affinity to CB2 receptors 2-AG has a role in the process of inflammation and it has been shown that introducing more 2-AG in mice reduced the levels of pro-inflammatory cytokines and also reduced the proliferation of the immune cells creating the inflammatory cytokines 17. Research has shown that 2-AG (and Anandamide) not only influences inflammation via CB receptor interactions, but also through its metabolites which create a complex web of interactions and by products that can work together to reduce inflammation 18 (Fig 1).



Anandamide (AEA):

Anandamide is another endocannabinoid and a key component of the endocannabinoid system. It influences inflammation by activating both CB1 and CB2 receptors whereby it reduces inflammatory cytokines like TNF-a and Interleukins 19. However, anandamide is thought to be physiologically less important than 2-AG which interacts more in inflammatory diseases 20.


Cannabinoids, whether endo- or phyto-, appear to be a very strong potential therapy for inflammatory diseases in the future. More research is needed to understand the mechanisms of action in greater detail, as well as understanding the effects of cannabinoid metabolites and their influences and mechanisms. With promising research in treating inflammatory diseases ranging from the brain to the gut, their potential truly needs to be explored further to benefit potentially hundreds of millions of people.


Written by Joseph Wardle, MSc, BSc.

References:

1: https://doi.org/10.1016/0024-3205(80)90631-1

2: 10.1016/j.drugalcdep.2010.05.019

3: https://www.analyticalcannabis.com/articles/cbc-the-therapeutics-effects-of-this-major-but-poorly-understood-cannabinoid-311238

4: 10.3389/fnmol.2018.00487

5: https://www.grandviewresearch.com/industry-analysis/cannabidiol-cbd-market#:~:text=The%20global%20cannabidiol%20market%20is,share%20of%2061.4%25%20in%202019.

6: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569602/

7: 10.1016/j.ejphar.2006.11.006

8: 10.1093/cvr/cvp240

9: 10.1111/j.1476-5381.2010.01166.x

10: 10.1016/j.bcp.2013.01.017

11: 10.3390/ijms19071992

12: 10.3390/medicina55110747

13: https://doi.org/10.1155/2015/362126

14: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

15: 10.1002/jnr.10165

16: 10.1016/s0162-3109(98)00041-1

17: 10.1002/eji.201546181

18: https://doi.org/10.1189/jlb.3RU0115-021R

19: 10.1159/000339113

20: https://doi.org/10.1186/s41232-018-0086-5

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