Endocannabinoid system review: a)cannabinoid receptors CB1, CB2; b) endocannabinoids and c) enzymes
Endocannabinoid functions- summary
Endocannabinoid system research (including endocannabinoid system deficiency)- in the next article (Part 2)
ECS in the brain
ECS in inflammation and the immune system
ECS in the gut
ECS in heart diseases, diabetes, obesity and more
ECS in the skin
The reason why medical marijuana has so many effects on humans is very simple: we have a built-in system called the endocannabinoid system (ECS) that the plant cannabinoids can interact with.
However, there is more about ECS you should know. This system can be modulated without using marijuana, as the body is making its own chemicals (called endocannabinoids). In addition, other herbs, supplements, and therapies can effectively modulate ECS, too.
Abbreviations:
ECS= endocannabinoid system. Also known as the endogenous cannabinoid system. ECS includes:
CB1 and CB2= cannabinoid receptors
AEA and 2-AG= endocannabinoids (act as neurotransmitters)
FAAH and MAGL= metabolic enzymes that break down AEA and 2-AG
Is the ECS important to your health? What is the role of the endocannabinoid system?
The reason why you didn’t hear much about ECS is because it was discovered only a few decades ago, in the 1990s. However, ECS is one of the most important physiologic systems of the body, being essential to maintaining human health. Researchers are currently looking into a number of therapies targeting the ECS to various conditions.
Endocannabinoids and their receptors are found throughout the body (including the brain, major organs, and immune cells). ECS is critical to human survival because it regulates homeostasis. Homeostasis keeps the body in “balance”. ECS modulates pain, inflammation, appetite, mood, sensation, stress response, eye ocular pressure and much more. ECS connects the nervous system with the immune system, hormones, the mind with the body.
Like any other system, ECS can also become deficient or dysfunctional, and impairments along ECS had been linked with a number of diseases.
ECS has 3 components:
Receptors (Cannabinoid receptors), which are found on the surface of cells. The key receptors are. CB1 and CB2.
Endocannabinoids (ECBs). These are small molecules that activate cannabinoid receptors. The main ECBs are AEA and 2-AG.
Enzymes (metabolic enzymes) that break down endocannabinoids after they are used. The key enzymes are: FAAH (for AEA) and MAGL (for 2-AG)
Cannabinoid receptors
The most researched cannabinoid receptors are CB1 and CB2. CB1 is abundant in the brain (particularly high levels in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem) and in the peripheral neurons. The CB1-THC interaction creates that feeling of “getting high”.
CB2 receptors are more abundant outside of the nervous system, found predominantly in lymphatic organs and digestive tract (where most of the body’s immune system is located): spleen, tonsils and thymus and other tissues of the immune system. I wrote about the lymphatic system here and the glymphatic system here.
However, both CB1 and CB2 receptors can be found throughout the body ie. CB1 is found in reproductive organs, digestive and urinary tracts, white blood cells, spleen, and eye. In the central nervous system, CB2 receptors are also found mainly in some brain cells (ie microglia) and their expression is associated with inflammation [1] also in the brain areas associated with emesis (vomiting) [2].
Endocannabinoids: AEA and 2-AG. What is the function of endocannabinoids?
Endocannabinoids (ECBs) are THC- like molecules that produced naturally in the body. Just like THC, they bind to and activating the cannabinoid receptors. You can also think about cannabinoids like dopamine, serotonin or GABA, as they act like these neurotransmitters.
The two main endocannabinoids are anandamide (AEA) and 2-AG. These are created and used on demand, rather than being stored and utilized later.
Phytocannabinoids or plant cannabinoids (ie THC) are the cannabinoids found in medical marijuana.
Synthetic cannabinoids (ie found in prescription meds like Marinol) also fit the receptor sites but don’t work as efficiently as the natural ones (and have significant side effects as well)
Metabolic Enzymes: FAAH and MAGL
Endocannabinoids (ECBs) are created and used as needed. Once this job is done, the metabolic enzymes will break them down, to prevent being used for too long. There are 2 key metabolic enzymes: FAAH breaks down AEA and MAGL breaks down 2-AG. This system is somehow different from other signal molecules in the body (ie hormones which can be stored for later use). Technical: eCBs synthesis is typically triggered via increased intracellular Ca2+ at postsynaptic sites in response to sustained synaptic activity; are rapidly deactivated by FAAH and MAGL. AEA and 2-AG are dominant and orthosteric and they are agonists for CB1 and CB2 but bind CB1 with higher affinity. Allosteric eCBs (ie pregnenolone, lipoxin A4) can modulate CB1 signaling as well [3].
2. Endocannabinoid system- functions
CB1 (key roles): modulate pain, anxiety, energy metabolism, and the conversion of carbs into fatty acids (lipogenesis)
CB2 (key roles): modulate the immune system (immunosuppression) and decrease free radicals (oxidative stress). Some immune cells have more CB2 than others (B lymphocytes> natural killer cells >macrophages, ≥monocytes ≥ neutrophils>T-cells) [4].
Besides CB1 and CB2, some endocannabinoids activate other receptors in the body, including the transient receptor potential (TRP) and peroxisome proliferator-activated receptors (PPARs).
ECS helps maintain the body’s homeostasis in two major ways: by influencing the nervous system (the connections/firing of brain cells), and the immune system (modulation of the inflammatory response). ECS has many other functions. Here is a short endocannabinoid system review, more details in the next article.
ECS in the brain: ECS regulates mood, pain, perception, learning, and memory. Offers neuroprotection and reduces inflammation. It is involved in neuroplasticity, as it stimulates the formation of new neurons and new synapses. When working optimally, ECS promotes healthy emotions (anti-stress, anti-anxiety and anti-depression effects).
ECS and inflammation/immune/lymphatic system. ECS works by suppressing or limiting the inflammatory response, and strengthen the connection immune system-nervous system and gut (see below). Although ECS is helpful during a normal inflammatory response (ie an infection of injury), it is even more helpful in cases of autoimmunity, cancer and generally speaking low grade, chronic inflammation which is an underlying issue for virtually any disease.
ECS in the gut. ECS particularly AEA plays a critical role in maintaining immunological health in the gut. ECS is a key player in the enteric nervous system, the “second brain” we have in the gut. Controls gut peristalsis, acid secretion, food intake. ECS interacts with gut microbiome and controls intestinal permeability. ECS is involved in other digestive/brain functions related to nausea, vomiting, pain.
ECS in diabetes, obesity, heart diseases (metabolic syndrome). Although ECS is generally thought to promote increased food intake (and therefore obesity), be aware that this happens only when the food is abundant (typical in Western word). Otherwise, ECS adjusts behavior and metabolism to food availability, thus being beneficial when food is limited/unpredictable. Healthy ECS helps maintain heart function, while increased ECS tone is linked with atherosclerosis and coronary heart diseases, while CB2s show protective effects. ECS is also heavily involved in fat metabolism, as well as sugar and protein metabolism.
ECS and skin: ECS maintain skin homeostasis in a few different ways: controls the proper and well-balanced growth, multiplication and survival of the skin cells. It also plays a role in the immune function (skin contains immune cells) and fat metabolism (actually skin contains 50% of body fat).
