The Very Basics: Cellular communication, of the non-mobile device kind

Before we get into what the endocannabinoid system actually is, I first want to review a few basics of cell signalling.

In general, the function of a cell can be changed by receiving a message. The message can be sent by itself, or from another cell (nearby or not). This message is typically in the form of chemicals (like administered drugs, or stuff your body produces on its own), electricity (think neurons), or even mechanical stimuli. This message will be received by something called a receptor, and will cause some type of response in that cell. There are lots of different types of receptors, and where and when they exist can vary by cell type and other cellular activity.

The location of the receptors and the specificity of that message to that receptor will greatly impact the function of the message. Think of this a bit like a lock and key. If you want to keep your house safe, you’ll want to lock it with a key that only you (or people you’ve given a copy to) can use. If your lock can be opened by everyone’s different keys, that might not be a super effective way of keeping your valuables in and unwanted house guests out. But, on the other hand, a key that might open both your front and back doors could be useful in some circumstances.

The Endocannabinoid System 101

Let’s start with a few easy definitions:

Cannabinoid = either cannabis-derived compounds or things that act like them (note: there isn’t a consensus on this definition, yet)

= either cannabis-derived compounds or things that act like them (note: there isn’t a consensus on this definition, yet) Endocannabinoid = endogenous cannabinoids (the cannabinoids that your body makes naturally)

= endogenous cannabinoids (the cannabinoids that your body makes naturally) The endocannabinoid system = includes endocannabinoids, the enzymes that help make them and break them down, and the receptors that (endo)cannabinoids bind to.

Note: Given the root “cannabinoid” you might be persuaded to think that this system relies on the presence of cannabis. It does not. In fact, the reason why it was named this way is because cannabis and its effects were described first, then the receptors were found later (this is similar to opium and the opiate receptors, and nicotine and the nicotinic receptors). The endocannabinoid system is present without you ever being exposed to cannabis, or any extrinsic cannabis-related compounds. Your body, on its own, will produce substances which act on and change these systems in some way, whether short-term or long lasting.

There are two main endocannabinoids which we’ve discovered so far, anandamide (AEA) and 2-arachidonylglycerol (2-AG). Both of these compounds were only discovered within the last two decades (1992 and 1995). Endocannabinoids can be produced in a couple of different ways (some we know more about than others), but in general, we know a couple important points about their production: they seem to be made on-demand (your body doesn’t store them for later), and made locally (eg, they’re not shipped out through the blood, or sent to nearby organs). Endocannabinoids are also broken down very quickly to a variety of different products. In fact, AEA is quite unstable, which makes it quite difficult to study. Many of these breakdown products are also active and produce a variety of responses on their own. For example, both 2-AG and AEA can break down to arachidonic acid, which can then be further broken down to a variety of different substances called prostaglandins, some of which can be anti-inflammatory.

Endocannabinoids and other cannabinoids can make changes to cellular function by binding to several types of receptors, including cannabinoid receptors (like cannabinoid receptor 1, or CB1, and CB2), certain G protein-coupled receptors (like GPR55 and GPR119), as well as some typically sensory-type receptors (like TRPV1). The response caused by binding to the receptors will depend on the area in the body (receptors exist in specific places, and only on certain types of cells), and also on what else is going on in that cellular environment at that time. There’s a lot of moving parts to the endocannabinoid system (like other systems), and it can get very complicated.

The More We Know, the More We Grow

There are a couple of issues which make studying the endocannabinoid system very difficult. As I mentioned earlier, endocannabinoids don’t stick around long, or go very far, so it makes them very very difficult to measure in a person. One can’t, for example, take a blood test and measure your endocannabinoid levels and get an accurate reflection of what might be happening in the brain. Endocannabinoid levels have to be measured by taking a fresh tissue sample, and prepared for later analysis immediately. Even still, there have been lots of issues getting consistent readings which has led to variable findings.

Further, if endocannabinoids were keys, they’d open a heck of a lot of locks (many of which we’re still discovering). When compounds have a lot of different actions, they can give off a lot of mixed signals (literally), and it becomes really difficult to tease out and understand exactly what is going on. In order to get a good grasp on this extremely complex system, we need really good tools. It’s best to have compounds which are really selective for one receptor (the one key, one lock scenario), and is why a lot of researchers use synthetic chemicals (made by researchers in laboratories, like WIN and CP).

As time goes on, we’re learning more about a lot of our tools, and building new ones. In some instances we’re finding out that some of our tools weren’t as good as we thought they were (for example, binding to more than one receptor when we thought they were selective for only one). This has caused some controversy about interpreting certain previous results (eg, whether or not CB2 is actually expressed in the eye), but overall, has led to refinement and further understanding.

Getting a good grasp on all the pieces will let us put the puzzle together, and let us understand how the endocannabinoid system works as a unit. Then, we can learn how to balance manipulation of parts of the endocannabinoid system while minimizing unwanted effects, and ultimately hopefully lead to the development or new (or old) therapeutics.

In summary: