The Human Endocannabinoid System
The human body has many different signaling systems controlling many different physiological functions.
People may be familiar with blood pressure medications like Prinivil, which is an angiotensin converting enzyme inhibitor, targeting the Renin-Aldosterone-Angiotensin System (RAAS). This system, and many others have critical regulatory functions that can be leveraged for better health.
What does this have to do with the endocannabinoid system? Therapeutic benefits from plants, such as the hemp plant, or from pharmaceutical synthesis all work by modifying physiological systems to improve health and outcomes.
What do the endocannabinoid systems work in the human body?
- The endocannabinoid system (ECS) helps regulate a vast array of physiological functions
- The ECS can get off balance during times of stress, and cannabinoids may help bring it back to homeostasis
- Almost all cell types in the body are plugged into the endocannabinoid system, making the cannabinoid receptors a naturally occurring target for medical use.
- Defining what the endocannabinoid system is
- A healthy endocannabinoid system
- What are endocannabinoids
- What are the cannabinoid receptors
- Physiological roles of the endogenous cannabinoid system
Defining what the endocannabinoid system is
A biological system in the body involves many cellular processes, and the endocannabinoid system (ECS) revolves around the creation, actions, and degradations of the endocannabinoid compounds. Breaking down the endocannabinoid system, we can broadly look at the 3 main parts:
- The endocannabinoids: the body produces two main endocannabinoids, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide). These are regulated by enzymatic pathways that produce 2-AG and anandamide, and those that degrade them.
- The cellular targets: these are typically cannabinoid receptors located on the cell surface that the endocannabinoids bind and activate. The activation of these targets elicit a response by the cell, which is how the endocannabinoid system regulates its associated physiological properties.
- Physiological outcomes: these are the outcomes that you see, such as mood, inflammation, blood pressure etc., which is the sum of the endocannabinoid system actions along with other systems that are at play in your body. These physiological responses will also effect cellular production of endocannabinoids 2-AG and anandimide, creating positive and negative feedback loops within the endocannabinoid system.
The interplay between these three different components determines how well the system is functioning, and when a single process goes awry it can throw everything else into disarray.
A healthy endocannabinoid system
Like any system with different parts, a healthy, working process requires balance between all the different components. In a healthy human, when all the physiological functions are working normal, the endocannabinoid system is in balance between itself and the rest of the body. This is referred to as homeostasis.
Often when things get out of balance, lack of sleep, too much sugar, chronic pain or chronic stress, functions in our body become abnormal, and this includes the endocannabinoid system. We lose our homeostasis and problems arise.
Getting our endocannabinoid system back to homeostasis helps us heal and brings balance to our body.
Many people have turned to hemp oil and cannabis sativa for help with their endocannabinoid system. It is often the case that people find great benefit by targeting their cannabinoid receptors using hemp derived cannabinoid oils, such as CBDA (cannabidiolic acid) or CBD (cannabidiol).
What is it about the endocannabinoid system (ECS) that seems to go awry, and why do cannabinoids provide relief so often?
Below we outline some of the critical components of the endocannabinoid system, its endocannabinoid receptors, and endocannabinoids themselves.
What are the endocannabinoids?
The endocannabinoid system signals between cells using the endocannabinoids 2-AG and anandimide. The cells regulate endocannabinoid signaling in many ways, one of them is through controlling the production and degradation of 2-AG and anandimide.
Production of endocannabinoids
The production of 2-AG and anandimide stem from different precursor lipids, and are the basis for the endogenous cannabinoid system. The initiating signal for production can vary, but is often started by the activation of G protein coupled receptors which stimulate relevant lipid cleaving from the cell membrane.
- The majority of anandimide is produced from N-arachidonoyl phosphatidyl ethanol (NAPE) by the NAPE-PLD (phospholipase D) enzyme. However, it can also be made from glycero-phospho (GP)-N-arachidonoyl phosphatidyl ethanol with the Glycerophosphodiester Phosphodiesterase 1 enzyme.
- 2-AG synthesis is primarily derived from the ubiquitous membrane lipid PIP2 (phosphatidyl inositol bis-phosphate), which is converted to diacylglycerol via PLC-beta (phospholipase C-beta). Diaglycerol lipase then converts diglycerol to 2-AG completing the endocannabinoid synthesis.
Degradation of endocannabinoids
Removal of endogenous cannabinoids are critical for proper endocannabinoid system regulation, and is also a more complex process with multiple potential pathways than the synthesis of the endocannabinoids.
- 2-Ag can be metabolized into basic phospholipid constituents, or into other bioactive lipid molecules depending on the metabolizing enzymatic pathways that are upregulated in that specific cell. 1) Monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), serine hydrolase α-β-hydrolase domain 6 (ABHD6), and serine hydrolase α-β-hydrolase domain (ABHD12) all hydrolyse 2-AG into AA (arachidonic acid) and glycerol.
- A very interesting finding is that COX-2 (cyclooxygense 2) can convert 2-AG into PGE2 (prostaglandin E2), a potent lipid that leads to enhanced inflammatory and neuropathic pain in multiple neuronal injury models. Recently, it was reported that CBDA decreased COX-2 activity and expression, which is novel since COX-2 is not an endocannabinoid receptor.
- Anandimide degradation is closely related to 2-AG as well since both FAAH (the primary metabolizing enzyme) and COX-2 can degrade this endocannabinoid. This brings an interesting point since blocking one enzyme, like FAAH, may raise the levels of the endocannabinoid, but could also shunt its metabolism to a secondary enzyme like COX-2, thus inducing pro-inflammatory production of prostaglandins.
Where are endocannabinoids produced?
The endocannabinoid system is vast, and while normally associated with the central nervous system, it is found in almost all cells of the body. If we look at cells that are known to produce endogenous cannabinoids, we find:
- Fat cells
- Brain cells, such as neurons and glial cells
- Immune system cells all posses the ability to produce endocannabinoids
- Cardiovascular cells, such as endothelial and smooth muscle cells
While a short list, its important to remember that the endocannabinoid system is involved in many physiological functions throughout the body.
What are the cannabinoid receptors?
Endogenous and exogenous cannabinoids can only exert an effect if they are sensed by the cell. Cells can only pick up the signaling by cannabinoids if they have cannabinoid receptors. This cannabinoid receptor system is responsible for taking the cannabinoid and endocannabinoid signaling and translating it into a cellular response.
While there are two primary cannabinoid receptors (CB1 and CB2), multiple other receptors have also been identified that are regulated by cannabinoids or endocannabinoids.
An important note here – just because a cannabinoid or endocannabinoid regulates a receptor, does not mean it activates it.
CB1 receptors are well known for their localization in the central nervous system, and as a primary target for psychoactive component of the cannabis plant, delta 9 THC. The CB1 receptor is a G protein inhibitory membrane protein, and inhibits adenylyl cyclase.
CB2 receptors are found throughout the body, and are well recognized for their effects on the immune system. Both CBD (cannabidiol) and CBDA (cannabidiolic acid) are known to regulate the CB2 receptors, which may explain some of their effects on the immune system and anti inflammatory properties.
TRPV1 (transient receptor potential of vanilloid type-1)
This receptor was discovered after CB1 and CB2, and was found that anandimide activates TRPV1, but the receptor is resistant to 2-AG binding. TRPV1 is commonly found in neurons at presynaptic cleft, but is also in the peripheral nervous system. The actions of TRPV1 is often associated with pain propagation, and is a target for many cannabinoids.
5HT1A serotonin receptor
Cannabinoids interact with 5HT1A, a prominent serotonin receptor located in the central and peripheral nervous system. A common target for the SSRI (selective serotonin reuptake inhibitor) class of depression drugs, and is thought to be partly responsible for some of the mood effects by full spectrum CBD oil.
Where are cannabinoid receptors located?
In short, everywhere.
A complete list would be extensive, especially since other receptors besides just CB1 and CB2 receptors are associated with the endocannabinoid system.
Physiological roles of the endocannabinoid system
The endocannabinoid system plays important roles throughout, as the body produces endocannabinoids as chemical messengers and deploys a vast array of endocannabinoid receptors in most organs.
The literature on all the physiological associations is beyond the scope of this article, but we will highlight some of the larger motifs below:
Inflammatory and neuropathic pain along with chronic pain are commonly associated with the endocannabinoid system. Partly due to the ubiquitous presence of cannabinoid receptors in human brain, and the production of endocannabinoids during pain signaling.
Many mental disorders, such as schizophrenia and depression have been associated with abnormal changes in the endocannabinoid system. Multiple studies have connected changes in different neurotransmitter release and cannabinoid receptors in post mortem tissue analysis as well as animal models.
Metabolism and metabolic disorders
Metabolic disorders have found a potential niche within the cannabis community, as the endocannabinoid system is partly responsible for regulating key metabolic enzymes, like PPAR-gamma. New drug discovery for the potential therapeutic benefits of cannabinoids are have garnered new research, and could help supplement the obesity fight.
Cardiovascular tone, or blood pressure, is partly regulated by endocannabinoid signaling, and is these signaling processes are known to go awry during cardiovascular pathology. Researchers are looking towards targets in the endocannabinoid system that are integral to cardiovascular health as a means for new drug discovery today.
Cannabinoid receptors in the intestinal epithelial are know to play important roles in secretion, GI propulsion and inflammation. This makes the endocannabinoid system a prime target for inflammatory diseases like IBS and others in the gastrointestinal tract.
Inflammation is a critical system your body produces when under attack by a foreign organism, or during acute injuries. However, in modern society, most of the inflammation is damaging because it is uncontrolled and brought on by poor diet, sedentary life style, and exposure to novel chemicals. The endocannabinoid system is found to regulate many of the inflammatory processes through its cannabinoid receptors on immune system cells.
The vast array of physiological functions that use the endocannabinoid system highlights how critical a healthy homeostasis is. We believe the clinical implications are barely being realized, and the improvement in the legal status of hemp in 2018 has been a boon to everyone.
Cannabis sativa research has been an ongoing field of study, but the rise in hemp popularity is helping drive research into the medicinal properties of cannabinoids and bringing light to their therapeutic benefits.