Now Reading
The Endocannabinoid System- All You Need to Know

The Endocannabinoid System- All You Need to Know


Humans are always very thirsty for knowledge and desirous to finding out new things. They have been trying to know about the systems of the human body from ancient times. But it was only around 30 years ago that they knew about the endocannabinoid system. So there is a lack of sufficient studies on this system.

For the illegality of tetrahydrocannabinol (THC) from marijuana, we are not getting sufficient studies. So many things are yet to know about the endocannabinoid system and the numerous health benefits and functions of CBD.

Nevertheless, this article explains everything about the endocannabinoid system you need to know before diving into the topic. It is an endocannabinoid system 101, explaining the endocannabinoid system, structure, and functions, the interactions of the endocannabinoid system and CBD, the endocannabinoid system and THC, endocannabinoid deficiency.

What Is The Endocannabinoid System?

The endocannabinoid system (ECS) is a neuromodulatory biological system comprising endocannabinoids and enzymes. They are responsible for the synthesis and degradation of endocannabinoids. This system delivers vital services in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults.

The word ‘endocannabinoid’ first came to light in the mid-1990s after finding out membrane receptors for the psychoactive rule in cannabis, delta9-tetrahydrocannabinol, and their endogenous bonding. It now indicates a whole gesturing system composed of cannabinoid receptors, endogenous bonding, and enzymes for binding biosynthesis and inertia. This system seems to have links to an ever-increasing number of pathological conditions.

The endocannabinoids- also called endogenous lipid-based retrograde neurotransmitters- act by making them bind with cannabinoid receptors (CBRs) and cannabinoid receptor proteins. These are revealed via the vertebrate central nervous system (adding with the brain) and peripheral nervous system. The endocannabinoid system may be related to controlling different physiological and cognitive processes.

The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, first cloned in 1990, and CB2 cannabinoid receptors- first cloned in 1993. The peroxisome proliferator-activated receptors (PPAR’s) and transient receptor potential (TRP) channels are also used by some cannabinoids. Some researchers hypothesize that there might have a third (CB3R), undiscovered one, as well.

CB1 receptors are prevailing in the brain and nervous system and also in peripheral organs and tissues. These receptors are the prime molecular concentration of the endogenous partial agonist, anandamide, also known as N-arachidonoyl ethanolamine (AEA), and exogenous THC, which is the most known active constituent of cannabis.

THC, the extrinsic cannabinoids, produce their biological effects along with their interactions with the cannabinoid receptors. Cannabidiol (CBD) is a phytocannabinoid engaging in action as a relatively weak antagonist at both CBRs and a more powerful agonist at TRPV1 and antagonist at TRPM8.

How Does It Work?

The EC system acts as a unique communication system between the brain and body, affecting many essential functions- how a person feels, moves, and reacts. It was named after the marijuana plant- Cannabis sativa and its operative ingredient delta-9-tetrahydrocannabinol (THC).

The body delivers some different natural chemicals to keep up interactions within the EC system. These chemicals are called cannabinoids. Like THC, these cannabinoids interact with receptors to regulate those essential body functions.

The brain cells- neurons are found to maintain communications among themselves and the rest of the body by sending chemical “messages.” These messages help coordinate and control everything we feel, think, and do.

The chemicals- neurotransmitters are derived from a presynaptic cell, the neuron in general. They travel across the synapse, a small gap, and then attach to the specific receptors on a nearby postsynaptic cell- neuron, which inspires the receiving neuron into action by triggering a set of events to let the message pass along.

But the EC system builds communication with its messages in a different way. It works “backward.” When the postsynaptic neuron is activated, the chemical messengers of the EC system- cannabinoids- are made “on-demand” from lipid precursors, the fat cells, which are already present in the neuron. Then getting released from that cell, they start traveling back to the presynaptic neuron. There they get attached to the cannabinoid receptors.

By working on presynaptic cells, cannabinoids can realize and manage what happens next after these cells are activated. The cannabinoids work like a “dimmer switch” for presynaptic neurons by limiting the number of neurotransmitters. That work affects the way messages get sent, received, and processed by the cell.

Endocannabinoid System Structure and Function

The endocannabinoid system is existing almost everywhere in the human body functions maintaining the homeostasis of the body. Fundamentally, homeostasis is the effort of your body to keep everything on the right track. It struggles hard to keep your internal environment stable and optimal no matter what’s going on in the environment around you. A negative feedback loop working by activating a postsynaptic neuron synthesizing and releasing the endocannabinoids targeting various cannabinoid (CB) receptors helps to gain it. At least two types of cannabinoid receptors are available in cannabinoids such as:

  • CB1- CB1 receptors are concentrated in the spinal cord’s central nervous system- brain and nerves. Still, they are found in the enteric nervous system, intestinal mucosa, adipose tissue, bone, skin, eye, liver, skeletal muscle, cardiovascular system, and reproductive system.
  • CB2- CB2 receptors are concentrated on immune cells in the peripheral nervous system- nerves in your extremities, the digestive system, and specialized cells in the immune system and the gastrointestinal tract.


The cannabinoid receptor agonists. The left one is a structure of four arachidonic acid derivatives identified as endogenous ligands for both the cannabinoid CB1 and CB2 receptors. The right one is the structure of delta 9-tetrahydrocannabinol (THC), the principal cannabinoid receptor agonist present in Cannabis compositions, and that of the aminoalkylindole WIN-55,2122. This synthetic cannabinoid receptor agonist is active at CB1 and CB2 receptors.

CB1 receptors are a significant part of the most common G-protein-coupled receptors in the central nervous system, allowing the endocannabinoids to influence the incoming signals. This function is regarded as an “override” signal, which differs from most other cells. CB1Rs preferentially reside on presynaptic neurons across diverse regions adding with the neocortex, striatum, and hippocampus.

The neuron is “overriding” the other cells because those cells have signal modifiers, which can perform anything from amplifying to diverging signals. A fracture in the toe, for example, would result in cell death. Then the resulting lymphatic response would increase blood flow and the migration of white blood cells to the surrounding areas. Then recognizing the excess lymphatic signals, the ECS would decide that the increase of inflammation is no longer needed. As a result, the CB receptors in the surrounding immune cells and tissues will start to bind with cannabinoids and slowly reduce the inflammatory responses.

The exact process occurs with pain signals in the brain. The binding and stimulating of CB1 receptors will force out the gamma-aminobutyric acid (GABA) neurotransmitters and will reduce pain signals throughout the brain thereby.

CB1 receptors are found basically within brain cells, including the hippocampus, amygdala, and hypothalamus but not limited, and are not so densely expressed as in the CNS, PNS, and the immune system. On the contrary, the CB2 receptors are found chiefly in the CNS, PNS, immune system, and within white blood cells.

Since the past decade, the main focus is on CB1 receptors for their physiological functions, including the psychoactive effect of delta9-tetrahydrocannabinol (THC). It is a phytocannabinoid in cannabis.

The ECS comprises of three key components:

  • Endocannabinoids: The two main identified endocannabinoids are:
  • Anandamide (AEA)
  • 2-Arachidonoylglycerol (2-AG)
  • Endocannabinoid Receptors: These are proteins embedded on the cell membrane to bind to the endocannabinoids and to react later. They do so by initiating neural activity in the nervous system and around your body.
  • Enzymes: These are to help break down endocannabinoids and cannabinoids in the nerve cells. The two principal enzymes are found in the endocannabinoid system, which are:
  • Fatty acid amide hydrolase (FAAH) to break down AEA
  • Monoacylglycerol lipase (MAGL), which breaks down 2-AG

The cannabinoid receptors ( CB1R, CB2R), the endogenous ligands for binding to the cannabinoid receptors- anandamide and 2-arachidonoylglycerol (2-AG), and enzymes for their biosynthesis and degradation- fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the constitutive elements of the ECS.

Through these receptors, the ECS can help regulate many essential functions, including:

  • Appetite
  • Pain-sensation
  • Digestion
  • Immune function
  • Stress response
  • Inflammation, including neuroinflammation
  • Mood
  • Sleep
  • Reproduction
  • Motor control
  • Temperature regulation
  • Drug addiction
  • Pleasure/Reward
  • Fertility
  • Pregnancy
  • Pre-and postnatal development
  • the various acts of the immune system
  • Memory
  • In mediating the pharmacological effects of cannabis

The ECS also plays a vital role in various aspects of neural functions and the normal functioning of the body’s systems which are-

  • Central nervous system
  • Cardiovascular system
  • Gastrointestinal system
  • Reproductive system
  • Skeletal system
  • Immune system
  • Metabolic processes
  • The control of movement and motor coordination
  • Learning and memorizing
  • Emotion and motivation
  • Addictive-like behavior and pain modulation

The widespread distribution permits them to guide a host of functions. Endocannabinoids themselves function as neuromodulators released by postsynaptic neurons and make bonds to the presynaptic CB1Rs to control the reveal of neurotransmitters, which include gamma-aminobutyric acid (GABA), glutamate, and dopamine (DA). During the specific CB1R functions depending on the cell population and areas they reside in, their role in retrograde signaling allows them to control signaling activity through cognitive, emotive, and sensory functions, lending therapeutic capacity.endocannabidiol system

How Does CBD Interact with ECS?

Cannabinoids make interactions with the naturally existing endogenous endocannabinoids in the body. The effective functioning of the ECS can be achieved from their unique way of interaction through receptors and enzymes.

Cannabidiol (CBD) is a phytocannabinoid found in cannabis plants that have recently appeared as a promising treatment for many conditions. CBD is a non-rewarding cannabinoid, which works on several receptor systems like the opioid, serotonergic, and cannabinoid systems.

CBD is one of the main cannabinoids existing in cannabis, which doesn’t have the psychoactive effects to make you feel high, and it doesn’t cause any adverse or harmful effects in general. The experts aren’t entirely sure about the ways how CBD interacts with the ECS. But they know the difference between CBD and THC and how they interact with the body’s endocannabinoid system.

  • THC binds with the receptors and mimics the actions of the ECS, producing psychoactive effects.
  • On the contrary, CBD does not bind with the receptors of the ECS. Instead, it permits the ECS access to its endocannabinoids and allows the ECS to complete its functions effectively.

In the cannabinoid system, CBD is a non-contesting antagonist of CB1R with a low affinity for CB1Rs’ leading ligand site, instead of acting through harmful allosteric modulation.

Many of the experts believe that CBD prevents endocannabinoids from being broken down. Others believe that CBD binds to an unknown receptor that is not discovered yet.

Although the details of how it works are still unclear or under debate, research says that CBD can help soothe pain, nausea, and other symptoms related to many different conditions.

How Does THC Interact with ECS?

Tetrahydrocannabinol (THC), which has the psychoactive effects of getting you high, is another famous cannabinoid found in cannabis. After entering into your body, THC interacts with your ECS by binding to receptors, right like endocannabinoids. It’s powerful because of its capacity for binding to both CB1 and CB2 receptors. It has a range of effects on your body and mind together. For example, THC can help you to alleviate pain and stimulate your appetite. But it can also cause paranoia and anxiety in some cases.

The interactions between THC and the endocannabinoids with CB1 receptors are pretty complex. This interaction has been observed and found out in several systems. THC and anandamide got in other systems, work just like an efficacious CB1 receptor agonist.

The acute responses to cannabis involve both agonism and antagonism of CB1 receptor signaling. It is observed that very high doses of the CB1 receptor antagonist, rimonabant, gently attenuate the properties of “high,” with the condition of suppressing essentially the tachycardia that is persuaded by cannabis.

The low efficacy of THC may result in milder acute effects in people when it binds with the infrequent receptor occupancy likely acquired in casual cannabis use.

Generally, the use of highly potent and efficacious cannabinoid receptors agonists found prevailing in synthetic marijuana composition shows a greater incidence of unfavorable psychiatric effects, which can be attributed to their higher congenital efficacy.

The interactions of THC, CB1, and endocannabinoids are complex. Experts are now trying to find out alternate ways to produce synthetic THC cannabinoids that interact with the ECS only in beneficial ways.

What about Endocannabinoid Deficiency?

Some experts believe in a theory of clinical endocannabinoid deficiency (CED). According to that theory, low endocannabinoid levels in your body or ECS dysfunction can help develop certain conditions such as migraine, fibromyalgia, and irritable bowel syndrome.

Similarly, deficiencies in the neurotransmitter can bring about other illnesses- like serotonin deficiency in depression. In another way, the theory discloses that the cause of these syndromes is inadequate endocannabinoids functioning in the ECS.

From the paper: “If endocannabinoid functions were decreased, it follows that a lowered pain threshold would be operative, along with derangements of digestion, mood, and sleep among the almost universal physiological systems subserved by the endocannabinoid system (ECS).”

The CED theory also claims that such deficiencies could happen due to genetic reasons or the result of a disease or injury.

The endocannabinoid system is explained thoroughly. But yet the functions of the endocannabinoid system are not clearly understood. Those conditions don’t have a clear underlying cause. They’re also often found as resistant to treatment and sometimes occur alongside each other. Some studies claim that endocannabinoid deficiency and disturbed homeostasis may be the cause for those specific conditions.

Research is going on the roles the endocannabinoids play and their potential therapeutic uses too.

Wrap Up

The ECS plays a significant role in keeping your internal processes well active and balanced. The ECS also has a crucial role in some apoptotic diseases, mitochondrial function, and brain function. But there’s still a lot of things we have to know. A better understanding of the experts about the ECS will eventually open the door to treating several conditions of the human body.

Scroll To Top
Skip to content