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How Does The Endocannabinoid System Work?

Updated: Jan 26, 2023

The Endocannabinoid System is thought to be 600-million years old and one of the most evolutionarily preserved biological systems known. It is present in every animal species except for insects and evolved as a stress and harm regulation network that functions to restore homeostasis following cellular stressors. The evolutionary goal being to keep the body in healthy cellular range. Too much or too little activity, tone, or receptor activity in the endocannabinoid system has the potential to cause disease. The ECS is made up of a series of cannabinoid receptors throughout the central nervous and immune system, lipid signaling molecules (endocannabinoids), and the enzymes that build and break down these signaling molecules. The ECS is so prevalent in fact that in the brain alone, each of our 86 billion neurons host many cannabinoid receptors. Cannabinoids are fatty acid amide molecules that attach to CB1 and CB2 receptors working to thermostatically alter a function within a local cellular internal body environment. Unlike hormones cannabinoids are not released in large enough quantities to travel systemically in the body. The two most prevalent endocannabinoids in the body Anandamide and 2-AG are synthesized by several different routes and released from postsynaptic neurons to travel retrograde (backwards) to pre-synaptic neurons. These cannabinoids are produced in extremely small amounts and exist only for a brief period of time, seconds to several minutes. In this way the post synaptic neuron can regulate its own signaling. ECS tone is therefore determined by plasticity and functionality of the system, its ability adapt, and regulate a healthy body.

The Endocannabinoid system interacts closely with both the Central Nervous System and the Immune System. The Hypothalamic-Pituitary Adrenal Axis is located in the CNS and plays a parallel role to the ECS in maintaining bodily homeostasis.. The Hypothalamus is the highest regulatory center for the autonomic nervous system and endocrine function. The Autonomic Nervous System regulates involuntary physiologic processes such including heart rate, blood pressure, respiration and digestion. Endocrine Function uses hormones to control and coordinate your body's metabolism, energy level, reproduction, growth and development, and response to injury, stress, and mood. In the instance of ingesting THC it is very apparent the effects that cannabinoids can have on the nervous system.

The ECS is in many ways is an extension of the eicosanoid system which regulates inflammation, function in reproduction, gastric secretion, and regulation of blood pressure. In fact many cannabinoids are broken down into arachidonic acid or other fatty acids that may later be used to create prostaglandins or Leukotrienes within the eicosanoid system. Endocannabinoids are similar to serotonin in function as they both function in immune response as well as in neurotransmission.

Endocannabinoids are the signaling molecules of the endocannabinoid system. They are fatty acid neurotransmitters that protect the body systems by coordinating and tuning intracellular biochemical across all physiological systems in the body. The synthesis, enzyme function, receptor expression, and degradation of cannabinoids all may play roles in altering pathological conditions. The two most well studied endocannabinoids Anandamide and 2-Arachidonoylhlycerol (2-AG) were identified as recently as 1992, and 1995 respectively. These fatty acid amides bind orthosterically (directly) to Cannabinoid receptors. While these two are the most studied there are many other endocannabinoid – like mediators that have not been classified yet.

Anandamide (AEA) is a high affinity, partial agonist of both CB1 and CB2 receptors. This means that AEA binds to a lot of receptors but cannot fully activate the potential of that receptor. After which, AEA is degraded by enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine (NAAA) among others. Inhibiting the breakdown of Anandamide is being studied as a possible avenue for treating a wide variety of disorders.

2-Arachidonoylhlycerol (2-AG) is very similar to AEA in chemical structure but has a moderate affinity for CB1 and CB2 receptors and a full agonist. 2-Ag is broken down by different enzymes, namely diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL). 2-Ag is the most abundant endocannabinoid in the central nervous system (CNS) and plays a major role in CNS development and synaptic plasticity. It is this process which allows the brain to change the strength of connection between neurons too evolve learning memory.

Some consideration must be given as well to other molecules that interact allosterically (indirectly) with cannabinoid receptors as part of the ECS. For example endogenous Palmitoylethanolamide (PEA). Phytocannabinoids N-alkylamides from Echinacea, and CBD from hemp both bind to TRPV1 receptors and effect endocannabinoid receptors activity allosterically. In this way multiple interactions within the body can result in an entourage effect. Recent investigation into the endocannabinoid system continues to broaden our knowledge of the complex interactions within.

Endocannabinoid Receptors have two major classifications CB1 and CB2. CB1 receptors have their highest concentration in the central nervous system while CB2 are more prevalent in the immune system. In retrospect it may have been more appropriate to name these receptors after their endogenous counterparts as phytocannabinoids in general have a lower affinity for CB1 and CBD2 receptors compared to that of our bodies own natural endocannabinoids.

CB1 receptors are widely distributed throughout the Central Nervous System but can also be found in immune system, liver, muscle, reproductive tissue, kidneys and lungs. CB1 are absent from cardiac and respiratory centers of the brainstem explaining why cannabis does not effect respiration or heartbeat. CB1 receptors are most closely associated with CNS development, synaptic plasticity, and response to endogenous and environmental stimuli. The majority of CB1 receptors are located on axion terminals and pre axion segments where normal neurotransmitter release occurs.

CB2 receptors are much less prevalent in the CNS compared to CB1 and are primarily found on Microglia and macrophage cells which function as the immune cells of the CNS. In a healthy brain, Microglia are highly dynamic, moving constantly to actively survey the brain for infection and inflammation. Outside the Central Nervous System, CB2 receptors are mainly found on white blood cells and play an important role in cytokine release. Cytokines are small proteins that control the growth and activity of other immune system cells and blood cells. Macrophages play a similar role in the immune response of blood cells by enveloping and killing microorganisms, cancer cells, and dead cells. Selective Cb2 receptor agonists have become increasingly popular subjects of research for their potential anti-inflammatory and anti-cancer effects.

Anti microbial actions of cannabinoids are due to the CB2 receptor's role in the immune response. When an infection enters the body, helper T cells immediately react by producing a storm of cytokine substances and pro-inflammatory macrophages that kick the immune system into high gear. Inflammation is the immediate result. In response to inflammation 2-AG and Anandamide are released and bind to CB2 receptors on Macrophages Type M1 and helper T cells and mesenchymal stromal cells. This signal limits the release of pro-inflammatory cytokines and shifts the macrophage phenotype towards the anti-inflammatory M2 Type enhancing the immune-modulating properties of mesenchymal stromal cells. This response mediates the inflammatory state as needed and keeps homeostasis. It is important to note that compounds interacting with inflammatory processes could either compromise or improve the body's response during infection as some infections benefit from body inflammation and others are inhibited by it.

Clinical Endocannabinoid Deficiency is a substantiated theory by Dr. Ethan Russo attempting to explain the underlying commonality between treatment resistant syndromes, chief among them migraine, fibromyalgia, and irritable bowl syndrome. The common symptoms of these conditions suggest that a clinical endocannabinoid deficiency might characterize their origin. In many of these conditions whether present from birth or acquired, endocannabinoid tone is significantly deficient. Furthermore many of the common symptoms of these conditions are known to me mediated by the endocannabinoid system. Recent studies have shown elevated levels of anandamide in cerebral fluid during migraines and advanced imaging studies have revealed ECS hyperfunction in posttraumatic stress disorder. Further studies have produced evidence for decreased pain, improved sleep, among other benefits as a result of lifestyle approaches affecting the endocannabinoid system.

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