Understanding The Endocannabinoid System

Bridging the gap between the mind and body
Your body is the ultimate machine. When it is well-oiled and maintained, it functions at optimum performance. But just like a machine, neglect, damage, or natural aging can result in malfunctioning parts and deteriorating systems. In order to operate effectively, your body requires homeostasis, or a stable internal environment. Approximately 30 years ago, scientists discovered the endocannabinoid system, a system that all vertebrates share which connects brain activity with physical health and disease. It functions to help the body return to a state of balance and homeostasis. Researchers are still learning more about how it works to regulate cellular function within our bodies, but their findings so far offer great promise for advancement in treating a variety of illnesses and disorders.

What is The Endocannabinoid System?

The endocannabinoid system (ECS) is a cell-signaling system, made up of a network of three key components: receptors, endogenous cannabinoids, also referred to as “endocannabinoids,” and enzymes designed to break down these endocannabinoids when they have performed their duty. Endocannabinoids are a finite resource and deficiency results in a lack of regulation and balance provided by the endocannabinoid system. In addition to following a healthy diet and participating in stress-relieving activities such as yoga, meditation, and acupuncture, phytocannabinoids can also stimulate the cannabinoid receptors.

Phytocannabinoids (phyto = plant in Greek) are cannabinoids found in plants which mimic or counteract the effects of some endogenous cannabinoids. THC and CBD are the most prevalent (and most researched) phytocannabinoids found in cannabis.

What do endogenous cannabinoids do?

Endogenous cannabinoids are small molecules that are found naturally in our bodies, identified as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These compounds activate CB1 and CB2 receptors, found on the surface of the cells, to signal the endocannabinoid system to take action. Endocannabinoids can bind to and communicate with either cannabinoid receptor, but most commonly, AEA binds with CB1 and 2-AG binds with CB2. (Scientists have found more cannabinoid receptors in the body, but these two have been most extensively studied, so far.)

Endocannabinoids are made from fat-like molecules with cell membranes and are created on demand to be used exactly when they are needed. Once the endocannabinoids carry out their function, they are broken down by two main enzymes: Fatty Acid Hydrolase (FAAH), which specifically breaks down AEA, and Monoacylglycerol Acid Lipase (MAGL), which breaks down 2-AG.

How does the endocannabinoid system maintain balance within the body?

The endocannabinoid system plays a major role in maintaining homeostasis in brain cell firing and the inflammatory response of the immune system and is only engaged when it is needed. This system is responsible for the regulation of various physiological and pathophysiological processes, including neurotransmission, mood, appetite, nerve function, addiction, inflammation, metabolism and reproduction. Let’s look a little closer at how exactly researchers believe the ECS works to achieve homeostasis.

Brain Cell Firing:
Highly specialized brain cells, also known as “neurons,” are connected to each other by synapses, or communication sites where neurotransmitters are released. Neurons only receive a specific message if they have a receptor that fits the neurotransmitter, much like a socket fits a plug. All neurons contain multiple receptors and can respond to some neurotransmitters but not others. Neurons that release chemical neurotransmitters are considered “presynaptic,” while neurons that have the receptors for neurotransmitters are known as “postsynaptic.” If the presynaptic neurons are overactive and sending too many signals, the neurons receiving the message will make endocannabinoids which specifically connect to the overactive neuron and send them backwards across the synapse, in a process known as “retrograde signaling” to bind to the “loud” neuron’s CB1 receptors and calm the chemical messages coming from the brain cell.

By doing this, postsynaptic target cells can actually influence their own incoming synaptic signals. CB1 receptors have been densely located in major brain regions which mediate a wide variety of behavioral functions, such as homeostatic processes (such as temperature control, pH balance, water and electrolyte balance, blood pressure, and respiration), learning and memory, emotional reactions, sensory and motor response, and decision making. Neurotransmitters (such as serotonin or dopamine) are produced naturally, but other chemical messengers produced outside the body (such as the phytocannabinoids THC or CBD) bind to neuron receptors as well. When these phytocannabinoids are ingested, they travel through the bloodstream to the brain where they interact with specific receptors on neurons to influence brain activity.

Inflammation:
Inflammation’s purpose is to remove pathogens (aka germs) and damaged tissue. The inflamed area allows the immune cells to move into the area to do their job and fight the intruding infection. Too strong of an immune response can cause chronic inflammation or auto-immunity, where the inflammation lasts too long or is directed at healthy cells. The endocannabinoid system suppresses or limits immune system response to inflammatory signals in order to regulate and allow the immune system to function as it was intended.

What do phytocannabinoids do?

THC, the psychoactive phytocannabinoid found in cannabis plants, also binds to both CB1 and CB2 receptors. THC binds to CB1 receptors in a way similar to anandamide, but instead of exactly replicating anandamide’s function, THC results in the “high,” for which marijuana plants are known. The enzymes that work within the cannabinoid system don’t break down THC like endogenous cannabinoids, which results in more potent and longer lasting effects.

CBD is another phytocannabinoid found in the cannabis plant that affects the endocannabinoid system. Unlike THC, it doesn’t bind directly to CB1 and CB2 receptors, but it interacts with numerous receptor types and can affect overall levels of endocannabinoids in the brain. Scientists have a couple theories on how CBD interacts with the endocannabinoid system. One theory is that CBD interacts with the enzyme FAAH to prevent anandamide from breaking down in order to increase CB1 stimulation.

While CBD doesn’t bind directly to CB1 receptors, studies have shown that CBD can get in the way of THC, affecting its ability to bind directly to the receptor and cushioning the impact of the compound, muting more negative effects, such as anxiety and paranoia. Outside of the endocannabinoid system, CBD interacts with the same neuron receptors that many drugs interact with, such as opioid receptors for pain regulation and dopamine receptors which regulate behavior and cognition.

Animal studies demonstrate that CBD directly activates multiple serotonin receptors in the brain as well, which regulate mood, social behavior, appetite, digestion, sleep, memory, and sexual desire and function. CBD also modulates Glutamate, the most abundant excitatory neurotransmitter in the vertebrate nervous system, which, when overstimulated, can result in anxiety and other psychological disorders. Or, it’s possible that CBD may just bind to a cannabinoid receptor that hasn’t yet been discovered.

A delicate balance

Studies relating to Clinical Endocannabinoid Deficiency (CECD), a genetic disorder resulting in a variation in the genes encoding CB1 receptors and other endocannabinoid system components, are still in development. It’s believed that this can affect their phytocannabinoid sensitivity and cause disorders related to the endocannabinoid system, such as Migraine, Fibromyalgia, Autism-spectrum disorders and IBS. But, activating the endocannabinoid system isn’t a cure-all. It’s a complicated and powerful feedback system controlling many physiological and emotional components of our bodies.

Ongoing research aims to make sense of neural processing involving the endocannabinoid system in normal brains to determine how to combat its dysfunction. However, since the endocannabinoid system affects so many different and dissimilar functions in the body, it makes it difficult to target the endocannabinoid system for specific therapeutic purposes. Over-inhibiting the enzymes which break down endocannabinoids can prove problematic as well. anandamide activates CB1 receptors, but it also stimulates TRPVI receptors, non-cannabinoid receptors that have been found to play a role in inflammation and anxiety.

Additionally, globally elevating 2-AG by decreasing MAGL response can overload the endocannabinoid system resulting in a protective shutdown or down regulation of many CB1 receptors in the brain. The most consistent results so far have shown that peripheral pain signals can be lowered by raising anandamide and 2-AG levels just near the site of origin of the pain. This may explain why many users prefer topical CBD use for pain relief.

One example of a problematic endocannabinoid system response was a study at the pharmaceutical company Sanofi-Aventis, which spanned thousands of clinical trials over many years and achieved brilliant success in a controlled environment. The study targeted the body’s feeding control center located in the hypothalamus region of the brain. This region has a high concentration of CB1 receptors, which, when stimulated with THC, is responsible for the “munchies.” This receptor also controls the normal desire to eat. In theory, preventing the activation of this receptor should suppress the urge to eat. CB1 receptors are also found outside the brain, where they regulate the energy metabolism in the liver and fat tissue. In animal studies, blocking CB1 resulted in less body weight, even when the same amount of food was consumed. In the Sanofi-Aventis study, researchers administered “Rimonabant,” a CB1 antagonist, to obese individuals. Users lost weight and girth across the board, and only about 10% of users reported negative effects such as depression, anxiety, and nausea.

However, the trials excluded people susceptible to psychiatric illness, so when used by obese people outside the trials, these negative effects were reported at a much higher frequency and intensity, since many people who suffer from obesity also deal with psychiatric disorders such as depression. When suppressed, CB1 successfully reduces appetite, but also may create a deficit in endocannabinoids which regulate mood for those affected by mental illness.

However, when CB1 receptors are activated, they can help restore homeostasis within mental function by helping the brain “cope” and leave behind traumatic life experiences. One example of CB1 receptor function can be observed in fear conditioning tests. These tests commonly investigate the development of anxiety by pairing a subtle tone with a light shock. Over time, the tone repeatedly precedes and accompanies a shock, which conditions the animal to recognize the tone as a bad omen and respond with fear, even without the shock. CB1 receptors allow the healthy animal to cope and cease responding to a tone when there’s no longer a shock. However, genetically engineered mice without CB1 receptors quickly respond with fear and cannot forget or cope when the shock is no longer present. In theory, stimulation of the CB1 receptors may play a major role in treating PTSD and anxiety disorders.

In Summary:

Homeostasis is key to allow the body to operate at peak mental and physical health. A crucial component in monitoring and regulating homeostasis within the body is the endocannabinoid system. This system, comprised of endogenous cannabinoids, receptors, and enzymes, can also be affected by phytocannabinoids which directly and indirectly interact with cannabinoid receptors to stimulate or inhibit their response. THC is widely recognized for its interaction with CB1 and CB2 receptors, but CBD’s interaction with the endocannabinoid system is a little more complex.

More research is needed to explain precisely how endocannabinoids and phytocannabinoids interact within the body’s endocannabinoid system and with each other to excite or inhibit neurotransmitter response. As we learn more about how exactly the endocannabinoid system works, it may be possible to provide more targeted balance for systems relating to neurotransmission, mood, appetite, addiction, and inflammation–and more!

Other sources:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997295/
https://www.healthline.com/health/endocannabinoid-system#deficiency
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576607/
https://www.medicalnewstoday.com/articles/232248
https://www.leafly.com/news/science-tech/what-is-the-endocannabinoid-system
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241751