How The Endocannabinoid System Works

Isn’t modern climate control great? No need to carefully-feed a wood burner and constantly regulate vents. No harsh drafts; no billowing smoke. Set a desired level, once. Too hot inside? No need to tell the structure; it’s already kicking on the A/C. Too cold? Time to fire up the furnace. In this magnificent thermostat/furnace/freon/duct-filled world, we don’t need to consciously read air temps and fan boiler flames to keep our building climates balanced. Rather, we go about our lives while the automated components regulate this function for us.

With these systems in place, we’ve been able to lead more productive and fulfilling lives at 72 degrees – freed up largely from brittle hands, freezing fluids, choking heat, and other elemental dangers. We as people owe a lot of our modern advancement to the simple ubiquity of climate control technology.

Our bodies have a function similar to this too. We call it the endocannabinoid system.

What is the Endocannabinoid system (ECS)?

Just as humans have spent recent decades automating our own buildings to maintain comfortable and productive indoor states – millions of years of evolution have worked on the biological structures of our ancestors and our animal cousins alike to produce a system of sub-conscious mechanisms our bodies use to maintain homeostasis – a balanced state where our tissues and enzymes can optimally function.

We call this balance-seeking symphony of receptors and enzymes the body’s endocannabinoid system (ECS).

Considering our HVAC analogy above and that the endocannabinoid system resides in all warm-blooded mammals [2], we should note it has been observed in multitudes of cold-blooded creatures too [2]. Beyond its parallels with our climate control systems – regulating body temperatures [4] is not the ECS’s only function:

It also helps regulate appetite, sleep patterns, pain, and immuno-responses in every known classification of animal EXCEPT the Phyla Protozoa (single-celled creatures) and Class Insecta (bugs) [2].

The Endocannabinoid System in other species.

These functions were summed up famously and elegantly by research professor Vincenzio Di Marzo in 1998:

“relax, eat, sleep, forget and protect.”
Dr. Vincenzio Di Marzo, 1998 [5]

Your body’s ECS doesn’t stop here either. The endocannabinoid system has involvement in everything from the feeling of itch, to digestion, to reproduction, pleasure, and pain sensitivity. [1]

Another way to think of the endocannabinoid system is like a smart home’s core AI, programmed to maintain stable and optimal indoor temperature, humidity, light, and ambient noise conditions against a changing, sometimes turbulent, outdoors:

Our endocannabinoid system is constantly reacting to changes in our physical environments, signaling other systems to regulate our body back toward its most stable and optimal state.

What is the Endocannabinoid System (ECS) made up of?

There are three major components that make up our body’s endocannabinoid system: [2]

Endogenous Ligands
G-Protein Coupled Receptors (GPCRs) or Membrane Receptors
Degradation Enzymes

It may be easy to remember the three in shorthand as simply ligands, receptors, and enzymes.

Endogenous Ligands

Ligands are loose molecules that irreversibly bind to receiving proteins, or the body’s receptors.

In the “lock & key” visual often used to explain the endocannabinoid system, ligands represent the key that unlocks the receptor. Arguably, a more apt explanation than “unlocks” is that the ligand “locks in” to release a given receptor’s function. This “lock in” mechanism makes more sense to this author and may to you the reader as well after we describe the ECS’ third major component.

Phytocannabinoids like THC and CBD, as well as some terpenes like linalool and caryophyllene act as ligands in this ensemble, mimicking the effects of our body’s most studied endogenous cannabinoids: anandamide and 2-arachidonoyl glycerol (2-AG).

Anandamide

With proper chemical name arachidonoyl ethanolamide (AEA), anandamide was given its common name in 1992 after being discovered as a key endogenous ligand in our body’s ECS. [2]

It’s name comes from the word “Ananda” which in Sanskrit means “bliss”. [5] As one of the two most-prominent endocannabinoids, it is produced on-demand and binds strongly with CB1 receptors in the brain and nervous system [1], in a way similar to the supplemented phytocannabinoid THC.

2-Arachidonoyl Glycerol (2-AG)

First discovered in 1994, the endogenous cannabinoid 2-AG is involved with down-modulating pain during periods of bodily stress. It can stimulate both the body’s CB1 and CB2 receptors, but acts as a full agonist to the CB2, meaning it will trigger the receptor’s maximal response. In simplest terms, CB2 receptors are more heavily-associated with the body, while CB1s are more associated with the mind.

While 2-AG levels spike with acute stresses, higher levels have also been measured (despite lower anandamide levels) during long periods of chronic stress too.

G-Protein Coupled Receptors (GPCRs) or Membrane Receptors

Receptors, just as the name sounds, receive chemical signals from ligands (like THC or anandamide) throughout the system to either inhibit or promote certain neurotransmitter activity for signaling pain, hunger, sleepiness, and more.

The most well-known receptors in the endocannabinoid system are the CB1 and CB2 receptors, but there are numerous others that either aide CB1 and CB2 function, or provide their own effects.

CB1 Receptors

CB1 receptors are present largely throughout the brain and peripheral nervous system, closely associated with feelings of happiness, relaxation or sensory-related pain.

THC binds directly with CB1 receptors, while CBD doesn’t bind to them the same way, but acts as an “allosteric modulator”, affecting the shape of the CB1 to acutely diminish THC’s affect.

CB2 Receptors

CB2 receptors can be found in the central nervous system, closer-related to the body’s involuntary functions, chronic stress response, and immunity.

THC also binds to CB2 receptors in the body to effectively reduce pains and stress, but beyond some calm or relief, the ‘high’ affect cannabis users feel is courtesy of THC’s interaction with the CB1.

Other Cannabinoid Receptors

Beyond the two primary endocannabinoid receptors that bind with anandamide, 2-AG, and popular cannabinoids like THC, there are numerous others that help regulate body function too.

Among the most well-known of these ‘second-tier’ ECS receptors are the TRPV1, GPR55, and PPARS receptors.

The first of these, TRPV1 is a mainstay for any who like spicy food. Sometimes called the “capsaicin receptor”, it produces the feeling of searing heat in response to certain stimuli and is heavily involved in temperature regulation and pain signaling. [1]

Two others, GPR55 and PPARS work with CBD in distinct ways. CBD is known to block GPR55’s signaling, while promoting the functions of PPARS. Modulating both may have positive effects on numerous conditions including inflammation, bone health, cancers, diabetes, neuropathic pain. [1]

Degradation Enzymes

In physical terms, it’s useful to think of ligands or cannabinoids within the endocannabinoid system as disposable but constantly-replenishing biological signal keys. This is where degradation enzymes come in.

Stepping back to our ~~“lock & key”~~ “locked in” idea of received ligands, they act much like a zip tie or safety cuff, where once that ligand is notched in, it’s fully-committed and must be destroyed or “degraded” by enzymes for its effect to be turned ‘off’. This is the function of your ECS’ degradation enzymes – to dissolve, i.e. “turn off” and recycle old endogenous ligands.

When the locked in ligand is sufficiently degraded, its coupled receptor goes back to its neutral state and becomes ready, once again, to receive another signal.

These enzymes exist as various fatty acids like hydrolase (FAAH) which primarily degrades active anandamide, and monoacyl-glycerol lipase (MAGL), which is the primary degradation agent for 2-AG.

While it’d be easy to assume this all happens after and outside of ligands’ effects on their receptors, this degradation process takes some time and is a key factor in regulating anandamide and 2-AG levels. It’s also been shown that CBD can inhibit FAAH’s breakdown of anandamide, prolonging and boosting the effectiveness of anandamide’s positive effects, while still modulating acute effects of THC. [2]

When and How did we discover the Endocannabinoid System (ECS)?

The endocannabinoid system’s discovery is a tale of multiple parts:

After Irish Physician William O’Shaughnessy was credited with bringing cannabis to the west in 1830, it quickly became prevalent in many classical remedies and home concoctions. Scientists began their attempts to isolate the active chemicals in cannabis in the late 1800s, but it wasn’t until the 1960’s that the first real breakthrough happened: [6]

Rapheal Mechoulam and Yechiel Gaoni mapped cannabinol (CBD) in 1963, and in 1964 they finally identified and mapped the delta-9 tetrahydrocannabinol (THC) molecule. Cannabinol has the name it does because it was originally thought to be the primary cannabinoid in cannabis. [4] By the next year, 1965, the team had successfully synthesized both compounds.

A decade later, in 1973, scientists discovered opiate receptors. Prior to this, the idea of a “cannabis receptor” had never been seriously considered. With the discovery, other investigations into cannabis’ effects ensued.

In the 1980’s significant progress was finally made in Allyn Howlett’s lab at St. Louis University. By 1988, new radiolabeling technology and a synthetic cannabinoid allowed Howlett’s team to observe areas of high binding-affinity for cannabinoids – the first active observation of cannabinoid receptors.

In 1990, CB1 receptors were successfully identified and then cloned in rats by the U.S. National Institute of Health, and in humans by a team in Brussels. By 1993, CB2 had been identified and successfully cloned at Sean Munro’s lab in Cambridge. [6]

Discoveries of the primary endogenous cannabinoids anandamide and 2-AG happened around these discoveries, in 1992 and 1995 respectively.

By the end of the 1990’s we had a strong understanding of the endocannabinoid system’s primary components and function, but new findings continue to trickle in. In 2022, many threads still remain for researchers to follow. As mainstream acceptance increases, our ability to follow these threads does as well.