Endocannabinoid System

Jul 1, 2021 | Immuno Boosters

The endocannabinoid system[1] (ECS system) is present in the human body, which you may know if you have read previous articles on our blog. It may sound quite daunting hearing that phrase thrown in when all you wanted to know about is CBD, but the endocannabinoid system is vital to understand if you’re going to gain more knowledge of how CBD interacts with the body. In this article, we will discuss the role of the endocannabinoid system, the different parts of the system, the function of the system, and how CBD affects it.

What is the Endocannabinoid System, and What is its Role?

The endocannabinoid system[2] (short for endogenous cannabinoid system) is a biological system in our bodies that helps with endocannabinoid regulation for many of our bodily functions. The system achieves a state of stability in the body (homeostasis) by acting like a messaging system using a network of endocannabinoids (receptor signaling molecules) produced in our bodies. These molecules happen to be a lot like the plant cannabinoids in cannabis.

Suppose the homeostasis in the body is disturbed. In that case, it can lead to impairment in our bodies, such as acute and chronic headaches or more severe conditions. These conditions include people with neurological disorders like Alzheimer’s disease[3], cancer, Parkinson disease (including levodopainduced dyskinesia[4]), amyotrophic lateral sclerosis, and Huntington disease. There is also arthritis, strokes, epilepsy, obesity, tourettes syndrome, and glaucoma that could occur. Therefore, if people have an endocannabinoid deficiency, the body’s ability to maintain homeostasis can cause these health problems. It could explain why some people develop fibromyalgia, migraines, irritable bowel syndrome, and neurodegenerative diseases. Therefore, the endocannabinoid system is one of the most important physiological systems in maintaining our health with a lot of therapeutic potential.

Although the endocannabinoid system is still a part of many clinical studies, it has been discovered that the system could help regulate cognitive and physiological processes, particularly when it comes to the reproductive system and helping with pre and postnatal development, pregnancy, and fertility. They also help significantly with the immune system, memory, pain sensations, appetite, mood, and, of course, mediating the pharmacological effects of cannabis.

More About the Endocannabinoids in the Endocannabinoid System

The endocannabinoid levels in our endogenous cannabinoid system are endogenous lipid-based retrograde neurotransmitters. These endocannabinoids are called anandamide and 2-arachidonoylglycerol (2-AG). They work to regulate the levels of receptors and ligands[5] travelling our vertebrate central nervous system and peripheral nervous system.



Endocannabinoid anandamide (also known as N-arachidonoylethanolamine) is synthesised from N-arachidonoyl phosphatidylethanolamine and is a fatty acid neurotransmitter. Anandamide levels in the body were the first endocannabinoids discovered. It comes from the non-oxidative metabolism of arachidonic acid (an omega-6 fatty acid). Another interesting fact about the role of cannabinoid anandamide is that the name comes from a Sanskrit word meaning joy, bliss, and delight due to its helpful pain-relieving properties.


Like anandamide, 2-Arachidonoylglycerol is an endocannabinoid and is also formed from omega-6 fatty acid amide hydrolase and arachidonic acid, and glycerol. There are high levels of it in the central nervous system.

A Brief History of Linking the Cannabis Plant to the Endocannabinoid System

Dr. Raphael Mechoulam, a scientist and researcher of cannabis, first identified tetrahydrocannabinol in 1964 and, later on, successfully isolated cannabidiol. He associated these with neuroprotectant and antioxidant properties, which were eventually named phytocannabinoids (due to them naturally occurring in plants). He also thought they connected to the immune response and receptor activity. The discovery of these plant cannabinoids was the perfect stepping stone to discovering the endocannabinoid system. Notable clinical studies continuing his research are by Vincenzo Di Marzo and ‪Luciano De Petrocellis‬.

The Difference Between the Molecules in the Endocannabinoid System and the Cannabis Sativa L. Plant

Because of biosynthesis[6], the endocannabinoid system is in the plant kingdom as well as us humans. The endocannabinoid system works by molecular phylogenetic distribution[7] using biosynthetic plasticity. Biosynthesis is a process where compounds are converted into more complex products in living organisms, both humans and plants among other things. Neuroplasticity is the neural networks in the brain that have the ability to change by reorganising and growing.

The Cannabis Sativa L. plant[8] has compounds called cannabinoids. The most well-known cannabinoids are phytocannabinoid tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is the psychoactive compound in cannabis (which is what makes you high![9]), whereas, CBD is not psychoactive and it has recently shown the ability to block the effects of THC in the nervous system. However, there are at least 113 other cannabinoids in the cannabis plant, which exhibiting various effects, but they are all found in trace amounts.

The Primary Cannabinoid Receptors in the Endocannabinoid System

There are two types of cannabinoid receptors[10] in the body that we know of, however, there are studies being conducted saying there could be a third one. The two G protein-coupled receptors of cannabinoids and endocannabinoids are called CB1 and CB2.

CB1 receptors[11] are usually found in the brain and central nervous system. They have also been found in the reproductive system of both males and females as well as the cerebellum. They are in charge of mediating the psychoactive effects of cannabinoids. On the other hand, CB2 receptors are found throughout the immune system and they are responsible for many immune-related functions such as anti-inflammatory activities.

How Does CBD and THC Affect the Endocannabinoid System?

CBD doesn’t typically cause any negative effects and that’s why there are many studies taking place to get it legalised due to it helping with a number of conditions. Even with these studies, experts still aren’t 100% sure of how CBD interacts with the endocannabinoid system, but they know that it isn’t capable of binding our CB1 or CB2 receptors and that is why cannabidiol cannot make you high like THC. It is thought to prevent the endocannabinoids from breaking down in the body, so they have more effect.

On the other hand, THC can get you high and that is because they do bind our receptors, like anandamide and 2-arachidonoylglycerol (the endocannabinoids that we naturally produce) which can have different effects on the body and mind. Tetrahydrocannabinol may help reduce pain and relax you, but it can also increase the appetite and cause paranoia and anxiety.

Potential Functions of the Endocannabinoid System

Let’s get into the nitty gritty parts of how our endocannabinoid system functions and how it helps our body. This will also explain why CBD could help enhance these functions due to it helping prevent the breakdown of anandamide and 2-arachidonoylglycerol, causing them to have a longer lasting effect on our body.


The Endocannabinoid System: Sleep

It has been found that when increased endocannabinoid signalling occurs, it promotes sleep because it is interacting with the central nervous system. In a study[12] on rats, anandamide decreased their wakefulness and encouraged the rats to fall into a strong REM sleep[13] because of increased amounts of adenosine in the basal forebrain. So, this is the reason why taking CBD has helpful effects on sleep for people.

The Endocannabinoid System: Exercise

Like mentioned before, anandamide is an endogenous cannabinoid neurotransmitter which binds to cannabinoid receptors. The endocannabinoid system helps regulate the voluntary exercise response[14] in both humans and animals, mainly because it contributes to the exercise-induced euphoria (this is what people often refer to as the runner’s high[15]). It was found that endocannabinoid levels like anandamide rise when people exercise, making them happier.

The Endocannabinoid System: Temperature Regulation

Temperature regulation (or thermoregulation) has been linked to anandamide[16] and N-arachidonoyl dopamine. Strangely, the active component of chili peppers, exogenous ligand capsaicin, is structurally similar to endocannabinoids and they are one of the temperature-sensing TRPV1 channels (official name is transient receptor potential cation channel subfamily V member 1, a big mouthful!). With both anandamide and N-arachidonoyl dopamine being active in these channels shows how the endocannabinoid system is partially responsible for our temperature regulation.

The Endocannabinoid System: Memory

The endocannabinoids have effects on the brain network in control of learning and memory. A study[17] on mice showed that CBD resulted in the stimulation of neural growth in the hippocampus, helping the endocannabinoid system improve declarative and spatial memories in the limbic system.

The Endocannabinoid System: Anxiety and Social Behaviour

The endocannabinoid system helps regulate anxiety-dependent behaviour[18], according to some studies. It showed that glutamatergic cannabinoid receptors in the system are in charge of balancing our aggression and excessive excitability (which can trigger anxiety).

The Endocannabinoid System: Depression

Like previously mentioned, endocannabinoids influence the synaptic plasticity[19], so it is thought to help reign in the potential of long-term depression (not to be mixed up with psychological depression, just neuronal firing). The different parts of the brain that the endocannabinoid system interacts with are the hippocampus, the nucleus accumbens, the brain stem, the cerebellum, the amygdala, the cerebral cortex, the ventral tegmental area, and the superior colliculus. Also, endocannabinoids have been suggested to aid in the balance of synaptic depression. The brain can limit the amount of endocannabinoids needed in order to balance the neuronal excitability.

The Endocannabinoid System Regulating Stress


The endocannabinoid system has also been found to play a part in the balancing of hypothalamic-pituitary-adrenal axis, which basically means it helps restrain the body’s exposure to repeatable stress[20]. Anandamide was found along the axis and 2-AG was found in the amygdala. This means the anandamide helps release corticosterone, which regulates stress responses, and 2-arachidonoylglycerol prevents the body from excreting too much glucocorticoids. This shows that anandamide and 2-AG both help regulate the HPA axis when responding to stress.

Metabolism and Energy

The endocannabinoid system has been found to control some metabolic processes[21] such as the transportation of nutrients and the storage of energy. It acts on tissues in the body like the skeletal muscles, the gastrointestinal tract, the endocrine pancreas, hepatocytes, and adipocytes. This is why the endocannabinoid system can cause conditions such as obesity, atherosclerosis and diabetes if it isn’t working correctly.


You may have heard of cannabis giving people the munchies and there is evidence of the endocannabinoid system enacting food-seeking behaviour in many studies. The CB1 receptors in the system found in the hypothalamic nuclei directly increase our appetite because the endocannabinoids are directly linked to regulating hunger[22] and the amount of leptin (a type of hormone) in the blood. Without leptin, in a study[23] with mice, it caused them to become obese and have levels of hypothalamic endocannabinoids as a coping mechanism for the body to compensate. A related study[24] also found the consumption of cannabis enhanced dopamine release increasing the pleasure value of food, especially things including sugar because endocannabinoids affect our taste perception of particularly sweet things.

Immune System

Like previously mentioned, the immune system[25] is also affected by the endocannabinoid system because it activates the GTPases (a group of hydrolase enzymes which bind to the nucleotide guanosine triphosphate). This occurs in bone marrow cells, macrophages, and neutrophils.

Autonomic Nervous System

Before getting into how the autonomic nervous system connects to the endocannabinoid system, what is it? The autonomic nervous system is a division of the peripheral nervous system. It regulated some bodily functions such as pupillary response, respiratory rate, urination, heart rate, sexual arousal, and digestion. It also happens to be the main system controlling our fight-or-flight response.

Researchers investigated the role of cannabinoids in the autonomic nervous system[26] because of the peripheral expression of the cannabinoid receptors in the body. It was found that the endocannabinoids help regulate the noradrenaline release from sympathetic nervous system nerves, helping control all of the body functions named above.

Female Reproduction

It has been found that anandamide is secreted in the uterus when women are pregnant, allowing the developing embryo to express cannabinoid receptors early on in development. This is important because it regulates embryonic implantation and uterine receptivity. These studies[27] have suggested that the use of CBD could fertility levels for women not producing enough anandamide[28], and the same goes for women producing too much as well.

Sense of Pain connected to the Endocannabinoid System

Sense of Pain

Our sense of pain (or lack of) is called analgesia. Cannabinoids suppress our noxious-stimulus-evoked responses at the spinal cord in the neurons in the dorsal horn. The most researched endocannabinoid associated with pain is called palmitoylethanolamide (a fatty acid related to anandamide) and it was found to be effective and safe[29] for its analgesic actions in response to different pain indications.

N-arachidonoyl-phentolamine through metabolism regulation in the endocannabinoid system has also been discovered to be a mechanism for analgesia by acetaminophen[30] (or paracetamol). This is also why endocannabinoids are used in some placebo-induced analgesia responses.

The Endocannabinoid System and Your Overall Health

Perhaps this article hurt your head a little after reading all the long medical terms, it was certainly not easy to research! However, by breaking all of this down, perhaps you can now see what an important impact the endocannabinoid system has on our body and overall health. This also suggests why having CBD as a part of your daily habits, whether taken as supplements, added into food, or used topically, can be beneficial for you. We have plenty of products to purchase if you want to try CBD. We hope you enjoyed reading and learning about the endocannabinoid system.


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