What is the Endocannabinoid System?

The endocannabinoid system (ECS) is a biological system with ancient beginnings whose elements work throughout the body and brain to balance health and disease. Everything and everyone on Earth that has a backbone — vertebrates, in other words — has an ECS. And what the ECS has to do with cannabis is this: It’s the only reason cannabis works in the body and brain. But that’s not all it does, by far.

The ECS has three elements — enzymes, endocannabinoids and receptors, all made in the body.

Cannabinoids are some of the chemical constituents of cannabis — researchers have found 120 of them so far in the cannabis plant. They are also called plant cannabinoids, or phytocannabinoids. Among them are delta-9 tetrahydrocannabinol, or THC, the main psychoactive element in cannabis, and cannabidiol, or CBD, the main non-psychoactive element in the plant.

Another kind of cannabinoid, very much older than the ones in cannabis, the body makes on its own. This is called an endogenous cannabinoid, or endocannabinoid. There are two main endocannabinoids, and for now we’ll just call them anandamide and 2-AG.

Together, these endocannabinoids are one of three main elements of the endocannabinoid system. The other two are cannabinoid receptors (two main receptors, CB1 and CB2) and enzymes (four main enzymes).

In more detail, the receptors are a network of proteins that are embedded in cell surfaces, called membranes, throughout the brain and body. Receptors are where the endogenous cannabinoids do their work in the body. Anandamide and 2-AG bind to these receptors and in doing so they pass along information that helps the body and brain coordinate their many biological functions.

The third element of the ECS, the enzymes, synthesize anandamide and 2-AG when they’re needed from elements already in the cell, and they break down the endocannabinoids after anandamide and 2-AG have had their effects. We’ll examine the endocannabinoid system in more detail in HOW CANNABIS WORKS (to balance health & disease) after it’s completed.

Dr. Maurice Elphick. Photo by Dr. David Hone.

But here’s the thing. The enzymes, at least a primordial version of them, first appeared in the earliest forms of life on Earth. That’s 1 billion or 2 billion years ago, maybe longer.

“Way, way back,” Dr. Maurice Elphick said in a recent interview, “long before anything that we would describe as a cannabinoid receptor existed on Earth.” Elphick is a biologist in the School of Biological and Chemical Sciences at Queen Mary University of London, and an expert on the evolution of the ECS.

Time, you know, passed.

Then, sometime after about 600 million years ago, all vertebrates, and even a couple of animals without backbones, arose on Earth with all you need for a complete endocannabinoid system: four main enzymes, two main endocannabinoids (anandamide and 2-AG) and two main receptors (CB1 and CB2). This was way before cannabis even existed, so cannabis isn’t the reason that the ECS evolved.

Cannabis Rising

Flowering plants arose beginning at least 100 million years ago, and cannabis itself arose no earlier than 34 million years ago. Then about 5,000 years ago, cannabis showed up in the Chinese pharmacopeia as a treatment for a bunch of illnesses, and it spread around the world from there.

Cannabis receptors CB1 and CB2.

Lots more time passed, and scientists didn’t figure out that THC was the active (psychoactive) constituent of cannabis until 1964. The CB1 receptor was discovered around 1990 and CB2 in 1993. In 1992 the first endocannabinoid, anandamide, was discovered and in 1995 they found the second one, 2-AG. And the four main enzymes were discovered in 1993, 2002, 2003 and 2004.

Even with all the essential elements identified, it took several years before the big picture started taking shape. Eventually the researchers learned how the system works:

All over the body and brain are cannabinoid receptors. CB1 and CB2 are pretty much everywhere, but there are more CB1 receptors in the brain and more CB2 receptors in the immune system and around the body. Now, the endocannabinoids — anandamide and AG-2 — are made inside cells in the body and brain work by binding to those receptors.

The body itself makes the endocannabinoids using two of the enzymes, and after the endocannabinoids have had their effects at the receptors, uses two more enzymes to break them down. And anandamide and 2-AG  are called signaling molecules because they carry their messages (signals) by binding to receptors.

Going Backward is Good

The standard procedure for other cells and receptors and signaling molecules in the body and brain is this: signaling molecules go from a presynaptic cell, across the gap between cells called the synapse, to the postsynaptic cell where they bind to a receptor to deliver their message. Everything travels in one direction. Presynaptic, synapse, postsynaptic. Easy.

Presumed mechanism of endocannabinoid-mediated retrograde signaling in the nervous system. From Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches: The American Academy of Pain Medicine, Textbook on Patient Management (pp.181-197), Jan. 2013, by Russo and Hohmann.

But pretty soon researchers began to understand that the endocannabinoid system didn‘t work that way. It went backwards.

It turned out that anandamide and 2-AG were created in the POSTsynaptic cell, then traveled backward across the synapse to bind to receptors on the PREsynaptic cell and deliver their message. This is called retrograde signaling. But why? What was the message?

Basically, it was ‘calm down.’

According to neuroscientist and endocannabinoid researcher Dr. Gregory Gerdeman, the easiest way to explain this in terms of controlling seizures and neurotoxicity, which is one of the things the ECS does in the brain, “is that the transmitter glutamate — which is sort of a primary ‘on’ switch, an excitatory transmitter in the brain — is also toxic when there’s too much of it. And one of the primary roles of this endocannabinoid retrograde mechanism may be the context in which it evolved in the first place, in that when a cell receives a very strong onslaught of excitation, [the ECS] acts as a simple negative feedback.”

Dr. Gregory Gerdeman. Courtesy photo.

The cell is driven so strongly, he said during a recent interview, “that it releases endocannabinoids, which hit the presynaptic terminal’s receptors and turn down, or inhibit, the release of glutamate. … Too much excitation, turn it down. That is precisely what goes on with epilepsy, with seizure activity in the brain. And we now understand the endocannabinoids to be a sort of primary on-demand defense against excitotoxicity in the brain.”

Protecting the Brain

Gerdeman added, “These endocannabinoids are part of our brain’s mechanism of resilience in response to trauma and electrical activity gone crazy. [The brain is] an electrical organ of unimaginable complexity, in our case, and it can get turned up too high and cause damage.”

The endocannabinoid system “evolved to turn that system down, scale it down, to protect it,” he said. “And I’m rather convinced that the evolutionary emergence of the endocannabinoid system in this way was a necessary prerequisite for the evolution of the complex brains of vertebrates.”

Dr. Ethan Russo. Photo by Cheryl Pellerin.

And the ECS isn’t just protective of the brain.

Neurologist and cannabinoid researcher Dr. Ethan Russo, in a 2015 white paper about the endocannabinoid system, says the ECS “is an essential regulatory mechanism in the body’s biochemistry and physiology, the basic machinery of everyday life.”