Dive into the endocannabinoid System (ECS), a regulatory system within all of us that is crucial for maintaining homeostasis. Homeostasis is all about keeping balance and stability in a system, to be able to run smoothly. Homeostasis is maintained between all the systems in our body by complex signal regulation. The ECS is the largest regulatory system in our bodies, and regulation impacts sleep, immune response, mood, inflammation, temperature, metabolism, memory, appetite, and digestion, among others. These functions all contribute to homeostasis, stability of the internal environment. This system is critical in restoring the body when it is out of balance, including when sick, injured or under high stress. The body must have a way to communicate with every system to get the body stable again. The ECS takes charge to re-establish harmony within the body.

You can imagine this system as a complicated music mixer. It contains many sliders that can increase or decrease regulation to a specific function. For example, one slider can regulate internal temperature, increasing or decreasing to stay at a stable level. The ECS is the master control that tells the body what needs to be changed to achieve internal stability.

The endocannabinoid system has been conserved throughout evolution due to its important role in homeostasis. It is present in most animals, ranging from mammals, birds, and fish to worms, reptiles, and amphibians. The fact that it has been conserved throughout evolution in most animals shows it was beneficial to have a system regulating internal activity.

Parts of the Endocannabinoid System

What are the components of the ECS?

The ECS consists of three main parts:

Endocannabinoids
Endocannabinoids are the signaling molecules of the system. They signal the body if activity needs to be turned up or down.
Receptors
The receptors are located throughout the body and receive the chemical signal (endocannabinoids).
Enzymes
Enzymes are proteins that speed up chemical reactions, they are needed to degrade the endocannabinoids into its components to be reused again later.

Endocannabinoids

Endocannabinoids are made on demand and used quickly. They influence the release of neurotransmitters, regulating how fast they fire. They are produced as needed after stimulation and stay in a localized region. They are special signaling molecules because they travel in two directions. The bidirectional signaling is important in regulating negative feedback loops. This is called retrograde signaling when the signal travels backwards across the synapse. This is how the brain protects itself from overstimulation or inflammation.

The two main endocannabinoids are anandamide and 2-AG. Anandamide is more active during development and 2-AG is more active in adults. In development, anandamide acts mainly as a growth factor, but in adults it regulates stress response. Anandamide can flood the brain causing a euphoric feeling during exercise, this is known as a “runners high”. 2-AG on the other hand, acts primarily as a neuromodulator, influencing the activity of neurons. These endocannabinoids are crucial for maintaining homeostasis throughout the body.

Receptors

The endocannabinoid system is loaded with receptors throughout the body. The two types of cannabinoid receptors are CB1R and CB2R.

CB1R is expressed in the:

• Central Nervous System (brain, spinal cord)
• Heart
• Liver
• GI Tract
• Blood vessels
• Fat

CB2R is expressed in the:

• Peripheral nervous system
• Immune system

Although it is not located throughout the entire brain, the CB1R is the most abundant receptor in the brain.

Enzymes

Deactivating enzymes of the endocannabinoid system are important in breaking down and recycling endocannabinoids. This recycling process ensures there is no buildup of endocannabinoids in the system. Fatty acid amide hydrolase (FAAH) breaks down anandamide, and monoacylglycerol acid lipase (MAGL) breaks down 2-AG. Once broken down, the components can be recycled for future use.

Cannabis and The Endocannabinoid System

How did cannabis help lead the path to discover the ECS?

Cannabis opened the window to discovering the main regulation system of our bodies. Δ-9-tetrahydrocannabinol (THC) was first discovered and isolated in 1964, before anything was known about the endocannabinoid system. The CB1 receptor was not discovered until 1988, but this opened the floodgates of questioning: Why would our body have so many receptors for a plant metabolite? In 1992, anandamide was identified. They discovered that anandamide binds to the CB1R, finally finding a ligand that binds to the receptor discovered back in 1988. Structurally, anandamide and THC look different, but they behave similarly when binding to the CB1R. It wasn’t until 1993 that the CB2 receptor was identified. Scientists discovered that THC could bind to the CB1R and the CB2R, but anandamide had low binding affinity to the CB2R so there must be another endocannabinoid. Fast forward to 1995 and 2-AG was identified in gut tissue of a dog. When studied, scientists found that 2-AG was more prevalent and potent than anandamide.

How does cannabis interact with the ECS?

Now knowing how many bodily functions the endocannabinoid system regulates, it makes sense that cannabis has a wide range of effects on the body. THC binds to both CB1 and CB2 receptors creating a psychoactive effect. The effects are seen throughout the body because receptors are found throughout the body. Unlike endocannabinoids that are active in a localized region, THC floods the entire system. CBD does not bind the same way as THC, it has a weak binding affinity to the CB1 and CB2 receptors. CBD influences other parts of the system, modifying the activity of enzymes and receptors. CBD has no psychoactive properties but has been shown to counter the psychoactive effects of THC. The same enzymes that degrade endocannabinoids degrade phytocannabinoids, but they are not as efficient, resulting in a longer high time.

The Bottom Line

Although we already know of the endocannabinoid systems’ importance, it isn’t taught in grade school, universities, or most medical schools. It is an entire system in everyone’s body that regulates other systems to maintain homeostasis. More research should be put towards understanding the ECS and what disorders can occur if imbalanced.