To give you an idea of how important cannabis research has been for the entire medical sector, we’re going to share a little story. It starts in a laboratory with some scientists researching cannabis plants between the 60s and 90s. They played with cannabis flowers and laboratory equipment, and they made the most important medical discovery of the 21st century: they found the human endocannabinoid system.

Yes, that’s correct. The entire system of cannabinoid receptors and endogenous cannabinoids that we now know as the endocannabinoid system was discovered in the process of cannabis research.

Why is this so important?

Aside from the fact that the endocannabinoid system is essentially the mediator between cannabis and humans, it’s also a regulator of multiple physiological processes. The endocannabinoid system is how the human body achieves homeostasis in its many activities. The endocannabinoid system governs things such as sleep, appetite, learning, and mood. And it has secondary roles to play in virtually every other system including the digestive system, the endocrine system, and the nervous system.

You could argue that the endocannabinoid system is equal in importance and size to the central nervous system. This is arguably why so many different people, with so many different medical complaints, get some kind of benefit from cannabis. There are some researchers that even suggest that at the root of many treatment-resistant conditions is a clinical endocannabinoid deficiency.

The endocannabinoid system is probably the most fascinating aspect of the human body. It acts somewhat “in the background”, does not contain an “organ” the way the respiratory system does, for example, and it governs some of the most basic aspects of our everyday lives. 

Knowing more about the endocannabinoid system doesn’t just give you the scoop on your very own body, but it also helps you to understand how cannabis moves through the body and how it can be used medically. In this article, we’re talking biology — of the best kind. Let’s follow the journey of cannabis through the endocannabinoid system and the human body.

What is the endocannabinoid system?

The endocannabinoid system is, at its basis, a chemical signaling system in the human body. Signals are sent and received by endogenous cannabinoids (cannabinoids produced by the human body) and cannabinoid receptors. There’s no specific “location” for the endocannabinoid system — receptors are dotted all around the body and brain.

Here are three important facts about the endocannabinoid system:

The role of the endocannabinoid system: homeostasis

Balance rocks against th background of crashing waves.

Before we get into some of the mechanisms of the endocannabinoid system, it’s important to recognise its primary role. Homeostasis is one of the most fundamental concepts of biology, and you could argue that the endocannabinoid system is what introduces this concept to the human body.

Homeostasis is essentially the regulation and maintenance of a biological process within a narrow range. This isn’t an uncommon practise for the human body. Your blood has to maintain a very specific acidity (pH), and if it doesn’t remain homeostatic in that sense, you get sick. The same is true of blood sugar, the amount of water retained in the body, body temperature etc. Homeostasis is maintenance of that healthy ebb and flow of states.

The endocannabinoid system is a molecular system for achieving homeostasis. The most prime example is how the endocannabinoid system checks and balances the nervous system. You have neurons firing all the time — they deliver thoughts, pain sensations, hunger sensations, the need to sleep, etc. But those neurons necessarily must stop firing at some point, otherwise problems ensue. For example, if you kept feeling hungry after eating, there would be a problem. The endocannabinoid system acts somewhat like the “off switch” of the central nervous system. Here we have one example of homeostasis.

As you’re going to discover, the concept of homeostasis is incredibly important. When there is too much or too little activity in a certain organ or system, disease is the outcome. As the patriarch of homeostasis in the body, the endocannabinoid system is an increasingly important target for the treatment of so many conditions.

Key parts of the endocannabinoid system

Now, to understand the mechanisms of the endocannabinoid system, we have to look at what it’s made up of.

There are three main components: 

  • Cannabinoid receptors: proteins that live on cells all around the body.
  • Endocannabinoids: short for “endogenous cannabinoids”, produced from inside your very own body. They activate cannabinoid receptors.
  • Metabolic enzymes: the chemicals that break down endocannabinoids after they’re used.

Let’s check out these primary aspects of the endocannabinoid system in a bit more detail.

Cannabinoid receptors

Receptors are funky shaped proteins that sit on cell surfaces. They’re constantly receiving information from both inside and outside cells, then using that information to generate cellular responses. You could say that they’re like a bridge between two worlds.

Receptors possess the quality of specificity. Their shapes are unbelievably specific, meaning only a handful of molecules typically fit on a receptor’s surface. Needless to say, cannabinoids happen to fit almost perfectly on cannabinoid receptors, which is why cannabis generates the response that it does.

There are multiple cannabinoid receptors, but the two that were first to be discovered were CB1 and CB2. They are also the most well-researched, which means we know a lot about them. Let’s check them out.

The CB1 receptor

The CB1 receptor’s primary location is in the brain or central nervous system. It is the cannabinoid receptor thought to be at the crux of the THC experience — when THC contacts the CB1 receptor, a psychedelic high happens.

The most pertinent mechanism of the CB1 receptor, as we discussed earlier, is the inhibition of neurotransmitter release. The CB1 receptor’s presynaptic localization is perfect for inhibiting electrical impulses across the synapse. When it’s activated, it does just that, and acts as an “off switch” to the central nervous system.

The cascade of events that happens after that off switch (or the cascade of events that doesn’t happen) varies, depending on the receptor’s location and the molecule that activated or deactivated it. The receptor’s response is heavily dependent on what activates it. As we’ll see when we talk about different endocannabinoids, the same receptor can generate multiple different responses, depending on what initiates that response.

The CB2 receptor

The CB2 receptor is less expressed in the central nervous system, and more prevalent in the immune system and other places around the body. It is the most common target receptor for endocannabinoid-mediated inflammatory processes.

However, think of the CB2 receptor as much like the CB1. It generally generates responses from an inhibition of an activity rather than the excitation of an activity. It’s why we think of cannabis as having anti-inflammatory effects: when the CB2 receptor is activated, it can dampen immune responses, and therefore reduce inflammation.

Endogenous cannabinoids; i.e., endocannabinoids

The next most important part of the endocannabinoid system puzzle is endogenous cannabinoids. These are chemicals produced from within your very own body that are essentially cannabinoids. Yes — your body produced chemicals from the very same class and category that cannabis does. 

Endocannabinoids are different to neurotransmitters

Sometimes, the words “endocannabinoid” and “neurotransmitters” are thrown around interchangeably. This is inherently wrong for a couple of reasons. Endocannabinoids are different to neurotransmitters in the direction that they travel.

For example, the typical series of events in the central nervous system goes like this:

Presynaptic excitation → electrical impulse through the synapse → the postsynaptic neuron fires. It’s a very forward bearing motion.

Endocannabinoids, on the other hand, are not stored in neurons. They are generated on demand in the postsynaptic neuron and they travel backwards to the presynaptic neuron. So you could say that the typical series of events in the endocannabinoid system goes like this:

Generation of endocannabinoid in the postsynaptic neuron → transmission of the endocannabinoid through the synapse → the presynaptic neuron stops firing. 

It’s backwards. It stops the generation of nervous impulses. This is essentially what constitutes an endocannabinoid. If it is a neurotransmitter, it follows the first series of events. If it is an endocannabinoid, it travels in reverse.

Depending on endogenous cannabinoid itself, it takes part in different activities and responses. It may agonize (create a response) or antagonize (dampen a response) a CB receptor. That’s to say, when an endogenous cannabinoid fits into a cannabinoid receptor, it can heighten that receptor’s activity or it can dampen it. All in the name of homeostasis.

Let’s check out the most common ones.

Anandamide a.k.a. The Bliss Molecule

An old woman smiles while holding petaled flowers.

Anandamide was the first endogenous cannabinoid to be discovered. Researchers, after studying the cannabinoid receptor, realised that there must be an endogenous compound that activates this receptor. That research lead to the discovery of anandamide (this discovery was also what completed the concept of an existing endocannabinoid system). It is derived from the Sanskrit word ananda, meaning bliss.

It’s otherwise known as “the bliss molecule”, because of the many ways it is thought to act on mood. In fact, Raphael Mechoulam said that it was the molecule of forgetfulness. In order to be happy, a person had to forget many things, and anandamide was the molecule that assisted the process.

Anandamide is thought to play a role in pain, mood, learning, appetite, addiction, reward, inflammation, and pre and postnatal development. It very closely resembles THC in its chemical structure, and it’s why it’s referred to as the body’s own “bliss molecule”.

2-ArachidonoylGlycerol, a.k.a. 2-AG

2-ArachidonoylGlycerol, otherwise known as 2-AG, was the second endocannabinoid to be discovered. Scientists have only known about 2-AG since 1992, so there’s a lot we still don’t know about this endogenous cannabinoid and how it works in the body. 

Though we don’t know an awful lot about 2-AG, research is mounting, and it’s quickly becoming a target for many therapeutics. It has a role to play in the circulatory system (and therefore, in cardiovascular health), as well as in seizure suppression. It also joins anandamide in affecting learning, memory, pain perception, and anxiety. 

Finally, 2-AG has actually been found in breast milk. Israeli scientists hypothesize that 2-AG in breast milk is what stimulates the continual suckling response from the infant. The more the infant sucks, the greater the amount of 2-AG produced, and therefore more breast milk is produced. When the infant stops suckling, breast milk production ceases.

Metabolic enzymes of the endocannabinoid system

Metabolic enzymes of the endocannabinoid system are what help to break down, degrade, and recycle endogenous cannabinoids. The two primary metabolic enzymes of the endocannabinoid system are:

  • FAAH (fatty acid amide hydrolase)
  • MAGL (monoacylglycerol lipase)

FAAH is responsible for the breakdown of anandamide, while MAGL is responsible for the breakdown of 2-AG.

You might think that these actions are extraneous to the importance of the endocannabinoid system. But they’re not. Even these metabolic enzymes can be targets for therapeutic actions. Here’s one example.

CBD, a cannabinoid found in cannabis, is often celebrated for its anti-anxiety properties. But CBD doesn’t have a great affinity for CB receptors, so how does it achieve anxiolytic effects? Well, CBD has a special ability to inhibit the production of FAAH. As we just mentioned, FAAH breaks down anandamide. Inhibition of FAAH means greater serum levels of anandamide (it’s not broken down so readily), therefore encouraging good feelings and moods. So actually, CBD generates an anti-anxiety response by acting on the endocannabinoid system’s metabolic enzymes.

The endocannabinoid system in action 

A close up of a dandelion conceptualising systems.

Now, you have a pretty solid understanding of the basic mechanisms of the endocannabinoid system. Let’s check out what all of that looks like in action.

Endocannabinoid regulation of inflammation

The inflammatory process is an essential function of human health, as it helps to kill pathogens and repair damaged tissues. However, the immune system is the most likely of all systems to get “out of hand” and continue producing inflammatory responses even after recovery. It can also happen that inflammatory responses are not localized to the site of injury, but affect other tissues, too. 

The CB2 receptor is a protective faculty of the immune system, as it inhibits the release of pro-inflammatory cytokines. In the inflammatory response, immune cells will typically release toxic chemicals to kill the pathogen, and then try to consume and dispose of pathogenic material. However, at a certain threshold, the CB2 receptor is triggered, inhibiting further inflammatory responses.

This is a simplified example, but a perfect one to demonstrate the endocannabinoid system’s regulation of inflammation.

Cannabinoid receptor expression in anxiety 

We don’t fully understand how endogenous cannabinoids and cannabinoid receptors affect the development of anxiety symptoms. But a lot of research has demonstrated that there is actually a role.

For example, in one study, researchers genetically deleted the 2-AG endocannabinoid and its metabolic enzyme, MAGL. This lead to increased anxiety-like brain behaviour

In another study, researchers investigated CB1-knockout mice. This is a murine subject without CB1 receptors. Researchers also observed anxiety-like brain behaviour in mice without CB1 receptor expression. 

There are multiple studies that identify the connection between endogenous cannabinoids, cannabinoid receptors, and the anxiety response. It seems that when researchers remove a cannabinoid receptor, a metabolic enzyme, or the biological production of an endogenous cannabinoid, there is some disruption in the subject’s ability to regulate anxiety. 

Phytocannabinoids and the endocannabinoid system

A close up of a premature cannabis flower

Phytocannabinoids are the kind that we find in plants such as cannabis. The reason the effect of phytocannabinoids is so profound in the human body is because of the very fact that we possess an endocannabinoid system. Without an endocannabinoid system, THC and CBD might have absolutely no effects at all.

When we ingest phytocannabinoids, there is typically a direct or indirect effect on the endocannabinoid system. For example, THC is a full agonist at the CB1 receptor. The activation of this receptor by THC generates the “stoned” effect, increased appetite, plus a myriad of other therapeutic responses. CBD, on the other hand, has no real affinity for CB receptors. It acts in more peripheral ways, such its behaviour on the FAAH enzyme, as we discussed earlier.

Sometimes, phytocannabinoids also affect other receptors in different parts of the body. This can also lead to a response by the endocannabinoid system. This is another example of indirect effects from phytocannabinoids. It also shows that cannabinoids don’t just affect the endocannabinoid system, but other systems in the body too.

The introduction of a phytocannabinoid into the picture we have of the endocannabinoid system makes things necessarily more complex. You could say this is why we’re still unpacking the rest of the iceberg of cannabis and its phytocannabinoids.

Finding balance and tying it all together

The body is constantly in a state of change — in fact, it must be in order to exist. If your body didn’t respond to the change incurred by eating or having sex or drinking water, for example, it would mean that your body isn’t working properly. It has to be “in tune” and responsive to what’s stimulating it.

The endocannabinoid system is what helps all of the systems of the body maintain balance between each other. When the immune system is working hard but potentially damaging tissues, the endocannabinoid system can dampen it. When the central nervous system is firing strongly, but has been doing so for too long, the endocannabinoid system comes along to quiet it down.

So you could say that the endocannabinoid system is, very much like the nervous system, a method of communication between different systems of the body. It is how the immune system knows that it’s damaging tissues in other parts of the body. It’s how the central nervous system knows that it’s firing neurons too quickly, at the expense of its host!

The concept of balance or homeostasis doesn’t necessarily mean “a constant state of affairs”. It is a balanced, constant state of change, but within a narrow range. Without the endocannabinoid system, there are many functions of the body that would not be able to perform within that narrow range. That narrow range is like the Goldilocks zone, and the endocannabinoid system is how we get there. 

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