One thing that has always impressed and fascinated me about the way our body works is how simultaneously complex and simple the design is. When a mechanism works, it’s repeated over and over again throughout our body – sounds obvious, right? There’s no reason to “reinvent the wheel”; it’s a waste of resources. Our body gets that. Then how do our heart, brains, lungs, intestines, skin, and immune cells all use the same mechanism but perform vastly different functions in our body? Context is everything.
Take buttons on a keyboard, for example. Each one uses the same basic concept and materials, but the act of using each one produces a very different result. If you use the same movement, speed, and pressure to activate the “a” key as you do the “s” key, even though they are located right next to each other, you get two different results – one “a” and one “s.” The results of a simple button press on a keyboard is dependent upon the surrounding context. How the “a” button is connected downstream, whether or not the “A” key pressed along with another key, even when the “a” is pressed in relation to other keys being pressed can change the outcome. Which can make a large difference (which cAn mske s lrage difference), especially in places like your body where one small little change can mean the difference between proper function and dysfunction, between health and disease, or even between life and death.
This is where we meet our endocannabinoid system. This system is made up of endogenously produced cannabinoids (endocannabinoids), the receptors that bind and react to them (cannabinoid receptors), and the enzymes that assist with the creation as well as the breakdown of endocannabinoids. Two endocannabinoid molecules have been characterized, anandamide and 2-arachidonoyl-glycerol (2-AG), and while there is some evidence that there may be other endocannabinoid molecules, more research is needed to understand the function of those molecules. There are multiple enzymes that play a role in the synthesis or the breakdown of endocannabinoid molecules that can vary slightly from system to system. There are two widely studied cannabinoid receptors (CBRs), CB1R and CB2R, each of which has a different expression pattern throughout the body.
Endocannabinoid molecules are produced, with the assistance of enzymes, by certain cell types and released into the extracellular space. It is here that they interact with cannabinoid receptors on the surface of other cells, and this changes the activity going on within those cells. Enzymes not only exist to aid in synthesis of endocannabinoids within cells, they also exist to degrade them once they’ve had enough time to interact with CBRs; the amount of time that endocannabinoids are floating around in the extracellular space can have a strong influence on not only the cells expressing CBRs but also the way the ECS regulates itself.
Some combination of this cast of characters is present throughout every system in our body – the cardiovascular system, the immune system, the nervous system, the digestive system, etc. – but has different outcomes depending upon the context of the system in which they are being expressed. Overall, the endocannabinoid system (ECS) acts to help maintain homeostasis, which is a state of equilibrium or balance. The activity of the ECS in each system of our body helps to restore balance to a system after a triggering event tips the scales in one direction. While “triggering event” sounds negative, it doesn’t necessarily have to be a major threat to our wellbeing. This type of imbalance can be part of the transition between states such as hunger and satiation that happens on a regular basis. Researchers have shown that fasting increases levels of endocannabinoids in the small intestine of rats, and that shortly after eating endocannabinoid levels return to baseline. If the rats were fed anandamide, it increased their feeding behavior, but if the rats were fed a CB1R antagonist (a drug that blocks endocannabinoids from activating CB1Rs), they decreased their feeding behavior. This indicates that the ECS is a key part of the cycle we go through multiple times a day of maintaining stability of food intake and energy balance.
The endocannabinoid system also likely participates in restoring balance after negative “triggering events,” as well. For example, the ECS may participate in the body’s attempt to reduce inflammation. Researchers investigating the role of the ECS in rheumatoid arthritis (an inflammatory disease affecting joints) have observed that both anandamide and 2-AG can be detected in the fluid between arthritic joints, but they didn’t observe endocannabinoids in healthy joints. This suggests that the ECS may increase in tone in inflammatory states in an attempt to decrease pain and inflammation. Consistent with this idea, researchers observed when they administered a drug that binds to the CB2R it decreased pain responses.
The ECS is a set of tools that our bodies use over and over throughout our body, but depending upon the context surrounding the elements of the ECS the outcome can be dramatically different. Each system of the body serves a different purpose, and uses the ECS in a way that contributes to inner workings of that specific system. This design has implications for how we respond to exogenous compounds (compounds from outside our body), as well, which we can explore in future articles.
Biol Psychiatry. 2016 Apr 1;79(7):516-25. An Introduction to the Endogenous Cannabinoid System. Lu HC1, Mackie K2.
Cannabis Cannabinoid Res. 2016; 1(1): 67–77. Endocannabinoids in the Gut. Nicholas V. DiPatrizio.
Am J Physiol Regul Integr Comp Physiol. 2015 Oct 15;309(8):R805-13. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways. DiPatrizio NV, Igarashi M, Narayanaswami V, Murray C, Gancayco J, Russell A, Jung KM, Piomelli D.
Eur J Rheumatol. 2017 Sep; 4(3): 210–218. The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease. Nicola Barrie and Nicholas Manolios.