Like the conductor of an orchestra, your endocannabinoid system directs when you get hungry or sleepy; how you remember tasks and process trauma; how severely you react to mental and physical stress and a host of other functions. The endocannabinoid system (ECS) is the part of your central nervous system that tempers seemingly all other aspects. The ECS helps you maintain balance and homeostasis on physiological, cognitive and emotional levels.

The CB2 and CB1 receptors are shown here with their 3-dimensional structures mapped. Down the center are the formulas for different agonists. The YinYang infographic shows how CB1 and CB2 modulate one another and how those respective activation levels relate to disease (in theory). Courtesy of the journal Cell.
The CB2 and CB1 receptors are shown here with their 3-dimensional structures mapped. Down the center are the formulas for different agonists. The YinYang infographic shows how CB1 and CB2 modulate one another and how those respective activation levels relate to disease (in theory). Courtesy of the journal Cell.

Marijuana contains the phytocannabinoids (plant-based cannabinoids) Delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as less potent cannabinoids, terpenes and other compounds. Consuming cannabis, its distillates or synthetic copies of its cannabinoid molecules is the best way to hack your endocannabinoid system. Cannabis-based treatments for anxiety, post-traumatic stress disorder, chronic neuropathic pain, nausea, anorexia, insomnia, irritable bowel disease, arthritis and more have all shown promise in preliminary research.

Unfortunately, because of draconian drug laws in the U.S. and Europe throughout most of the 20th century, cannabis medicine is in its infancy. Still, the field is opening up in the wake of the state-by-state pot legalization wave. In 2018, for instance, the U.S. Food and Drug Administration approved Epidiolex, the first CBD-based prescription drug to treat childhood seizures.

What is the anatomy and physiology of the endocannabinoid system?

The endocannabinoid system is a complex of microscopic molecular machinery anchored by nerve cells. Two types of cannabinoid receptors (CB1 and CB2) sit on the cell membranes of billions of different nerve cells throughout your brain, gut and, to a lesser degree, nerves throughout your body. CB2 receptors are denser in the nerves of your limbs as opposed to the nerves in your brain-gut axis for reasons discussed later.

The stars of endocannabinoid research, though, are the neurotransmitter molecules AEA (anandamide) and 2-AG (2-arachidonoylglycerol). These two chemicals (“ligands” to the CB1 and CB2 receptors) have molecular shapes that fit just right with the CB1 and CB2. When they stick in there, they act as keys in locks, kicking off a cascade of physiological functions.

phytocannabinoids fit into the keys of the CB1 and CB2 receptors

Anandamide was discovered first, and that’s one of the reasons it’s the most studied. Subsequently, it’s become clear that AEA is actually several times less abundant than 2-AG, which appears to be the more important neurotransmitter in the endocannabinoid system. 

When a ligand fully couples with a receptor and activates it to full potential, that ligand is called a “full agonist.” If a ligand only partially activates a receptor, that ligand is called a “partial agonist.” Anandamide is a partial agonist ligand of CB1 and CB2, but 2-AG is a full agonist ligand of CB1 and CB2. 

It seems 2-AG activates a bunch of other different receptors in different signaling systems to varying degrees. For instance, 2-AG is where the endocannabinoid system dovetails with the nerve receptors that sense pain caused by burning and, in part, governs inflammation from allergens, among other general functions. 

These receptors are called TRPV1 receptors, and their general function makes them numerous and dense in the peripheral nervous system. Part of the therapeutic benefit of cannabis may be in the way phytocannabinoids mimic 2-AG in interacting with the TRPV1 receptors.

Retrograde Signalling in the ECS

The endocannabinoid system runs backwards.

In general, nerve cells are set up end-to-end, axon — the cell’s back door — to dendrite, the front door of the next cell. In the typical flow of a nerve impulse, a stimulus — a pinprick, let’s say — sends an electric signal through the cells of the nerve.

The electric charge caused by the pinprick travels along the first cell to its axon (back end). From the axon, the cell fires a bunch of little neurotransmitter molecules to the dendrite (front end) of the next cell.

This happens millions and millions of times in a fraction of a second to let your brain know you just poked your finger on a pin, then again from your brain back to your finger to make your hand jerk away from the pain.

But the endocannabinoids shoot from the front door (dendrite) to the back porch (axon) of the previous cell. At the most basic level, the endocannabinoids tell the cell behind the impulse to calm down and get back into resting position, primed for the next impulse. 

Peripheral components of the ECS

The endocannabinoid system’s receptors and ligands don’t function on their own. Like an orchestra needs Teamsters and instrument techs to haul the equipment and tune the strings, endocannabinoids need help with transport to the receptors at the right time and in the right place.

The endocannabinoid system relies on a bunch of support molecules to handle cannabinoid synthesis and metabolism, draw cannabinoids into or push them out of cells, and ferry them around the nervous system.

FAAH and MAGL

This alphabet soup of a section title refers to two enzymes stored in little sacks (vesicles) inside nerve cells that act as the chop shops for AEA and 2-AG. FAAH is an enzyme that couples with anandamide and breaks it into its component parts, the most important of which is arachidonic acid.

MAGL does the same for 2-AG; this endocannabinoid is also based on arachidonic acid.

Fatty Acid Binding Proteins (FAPBs) and the concentration gradient

Though the science is far from settled, researchers theorize that cells control the amount of 2-AG and AEA inside them through a concentration gradient. Because endocannabinoids (and phytocannabinoids, for that matter) are fat-soluble, they can pass in and out of the cholesterol which forms the cell membrane.

Be sure to read our full article on endocannabinoid transport.

Unlike water-soluble neurotransmitters that may need special proteins to shepherd them in and out of the cell, endocannabinoid levels inside the cell are controlled through diffusion. MAGL and FAAH break down the 2-AG and AEA, respectively, meaning there are fewer endocannabinoid molecules inside the cell than out. Because of the laws of fluid mechanics, the endocannabinoids in solution outside the cell rush to equal out the concentrations inside the cell.

endocannabinoids can FAPBs can be transported using a concentration gradient

Once the endocannabinoids couple with the receptors and perform their function, however, fatty acid binding proteins inside the cell carry the cannabinoid molecules to the cell’s enzyme-containing vesicles for destruction.

The Genetic Basis of the Endocannabinoid System

Like every other part of your body, the endocannabinoid system blueprints exist as specific genes in your DNA. The core endocannabinoid system genes are CNR1, CNR2, DAGLA, MGLL and FAAH. FADS2 also has a hand in creating the endocannabinoid system, as do multiple other genes that code for different chemical precursors to all the endocannabinoid system components. 

Genetics play a crucial role in the endocannabinoid system

Genes have a bunch of different nomenclature systems — cataloging human chromosomes is a big task, given humans have about 25,000 genes. The most popular one and the one we’re using is the system in which the genes are named more or less after the proteins they code. 

(This can be confusing too, however, as there isn’t a worldwide standard for naming proteins either).

CNR1 and CNR2 direct the body to build the cannabinoid receptors CB1 and CB2, respectively. MGLL and FAAH make the two enzymes that break down 2-AG and anandamide respectively. DAGLA codes for components necessary to build the endocannabinoids, as does FADS2, which makes a general fatty acid used in a ton of different vital compounds in the body — including the production of arachidonic acid, the basis of both endocannabinoids.

Genetics of the endocannabinoid system are important because mutations and aberrations in these genes have implications for neuroses and psychoses, predisposition to drug and alcohol addiction, increased pain sensitivity and a host of other issues. 

Learning through a service like StrainGenie how your own endocannabinoid genes are expressed is important if you’re seeking therapeutic cannabis; ideally, all medicine in the future will be so personalized.

For more information, read our full article on the genetics of the endocannabinoid system 

The Endocannabinoid System and Homeostasis

The above explanation is theoretical in many aspects and still controversial in others (especially inter- and intra-cellular cannabinoid transport), but it gives a general idea of current thinking about ECS function in the body. At its most basic level, the nature of this system is to maintain balance in function, or homeostasis. 

This is the reason for the near panacea potential of cannabis; it hacks the system responsible for keeping all your other systems in check and running smoothly. It’s also the reason why alterations within the endocannabinoid system can cause things to go terribly awry, like in the case of cannabis-induced psychosis.

endocannabinoid system helps homeostasis -- reaching balancing like a yin yan

To illustrate, let’s continue the symphony conductor metaphor. In an orchestra, if one of your flute players just can’t nail a passage in the music, you can either retrain the flutist over time to learn the music better, you can order that particular flutist to remain silent during the difficult passage and lean on the other flutists to make up the sound. Or, and here’s where the endocannabinoid system comes in, the conductor can direct the faulty flutist by signaling important timing points, and help the flutist out by directing the other sections to play louder to mask the errors in playing.

Similarly, if you get your nerves fried from an emergency surgery after a car wreck, you can take opioids for the immediate pain. Those flood your system with feel-good chemicals that blot out the pain. Or you can take a non-steroidal antiinflammatory drug (NSAID) like ibuprophen, which reduces inflammation and therefore may reduce pain, or you can take acetaminophen which actually makes you less sensitive to pain.

All those approaches are great for the immediate pain of a laceration, surgical incision or shattered bone, but they are less effective for chronic nerve pain. Worse, they’re rife with side effects like liver damage and crippling addiction.

Using cannabis medicine to treat chronic nerve pain, however, hacks your secondary response to the nerve pain. The pain itself may not go away, but the cannabinoids can calm all the stress hormones and inflammatory signallers that come with your body’s response to pain. 

Cannabis for chronic pain is still in the development phases; pharma researchers are still figuring out dosage and delivery issues. Some tested formulations have so far failed to perform better than placebo in clinical trials, but the therapeutic potential is so strong, researchers rushed right back to the drawing board.

Pain, of course, is only one potential condition that may respond to cannabis treatment. Cannabis for PTSD, insomnia and digestive disorders may be more promising research avenues. As researchers hash our more and more of the basic functioning of the endocannabinoid system, the possibilities for new treatments will only expand.