The Endocannabinoid System

What is the endocannabinoid system? It’s only been a few decades since we uncovered this unique and critical physiological system in the body, though it’s been with humans (and all other vertebrates) for millions of years. Unbeknownst to us, it’s been busy playing a pivotal role in our health.

When it was first discovered around 1990, the endocannabinoid system (ECS) was recognized for its role in modulating the psychoactive effects of cannabis but beyond that, the function of the system remained mysterious. What else within the body, scientists wondered, could this new system possibly have been intended for?

Thirty years later, the endocannabinoid system (ECS), named for the plant that helped in its discovery, has been described by researchers as “one of the most important physiologic systems involved in establishing and maintaining human health.”

The ECS seems to be primarily concerned with homeostasis or keeping the body at just the right physical conditions to keep it running optimally. There are many regulatory systems in the body, from the pH of your blood to body temperature and more, and the ECS may mediate most of them. That means tweaking the system could hold therapeutic potential for a number of conditions.

So far, the ECS has been connected with a wide range of disorders, from “mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few.”

Research on the ECS may even be expanding the limits of what we consider biology. “The endocannabinoids are literally a bridge between body and mind,” says the author of this paper. “By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.”

So, what do we know so far about the endocannabinoid system and its impact on human health? Fair warning: there is molecular biology ahead, but all efforts were made to keep it interesting.

How the endocannabinoid system was discovered

Cannabis has been enjoyed by humankind for millennia, with evidence of its use dating back to at least 2,500 years ago.

When scientists finally characterized THC in 1964, they couldn’t understand quite what they had found. Δ-9-tetrahydrocannabinol, the compound within cannabis to produce the characteristic high, turned out to be a lipid (a fat-soluble molecule).

This was very puzzling given that, at the time, all known neurotransmitters or otherwise neuroactive compounds were water-soluble. Researchers failed to comprehend how this fatty, water-repelling molecule was capable of interacting significantly with anything in the aqueous environs of the brain, let alone produce such a striking psychoactive effect. It was a bit as if they had discovered new and strange-looking keys, but ones that fit no known locks.

Finally, in the early 90s, they found the “locks” they were looking for in the form of two new types of cellular receptors, named cannabinoid receptor type 1 and 2 (CB1 and CB2, or CBRs, collectively), both of which interacted with THC as well as other cannabinoids— defined as the biologically-active compounds found within the cannabis plant.

While discovering these receptors finally helped explain how THC actually worked to get you high, it led to bigger questions. Beyond cannabis, what were these cannabinoid receptors ostensibly for? As the author of this paper puts it, “they did not evolve to react with rarely ingested, plant-derived chemicals.”

For one thing, both CBRs have been found all over the body, on many different types of cells. In fact, CB1 has been found throughout the central nervous system and turns out to be the most abundant receptor in the mammalian brain. CB2 is found mostly on cells within the immune system, such as T-cells, but also on peripheral nerves, where it’s thought to mediate pain signals, among other things.

It wasn’t long after this that the first endogenous cannabinoids–the ones made within the body–were discovered, adding the final piece to the decades-long puzzle. These compounds were the biologically intended binding partners of the previously discovered receptors, and together with the helpful enzymes that synthesize and break down other components, the Endocannabinoid System was defined.

In the last few decades, research has focused on further understanding of the ECS and how it works. Although research is still preliminary, the glimpse so far looks promising.

How the endocannabinoid systems works

To better understand the function of the ECS, let’s take a mini molecular biology lesson.

Your body is, of course, made up of lots of different cells of lots of different types (brain cells, skin cells, etc.). All cells have receptors on their surface—my favorite analogy for receptors is a port on a device or outlet on the wall.

When you plug a cord into a port, activity happens—electricity starts flowing to the device, for example. A cell receptor is very similar: when a ligand binds to it, it “activates” the receptor, and activity happens; but this time, it’s cellular activity.

Just as different ports or outlets have different functions, so do different receptors. Each type generally performs a particular function. And, like ports, you can’t plug in just any old cord—the only cord that will charge your phone is the one with the correctly shaped plug. Likewise, cell receptors don’t activate when any old ligand passes by—receptors require very specific ligands to bind to them if they’re going to activate. They have to “fit” just right.

We can take this analogy one step further; in biology, while some ligands will activate receptors, some will bind to, but intentionally do not activate the receptor. In the port analogy, this would be just like plugging up all of your spare outlets with outlet covers, like the kind parents use to prevent toddlers from electrocuting themselves with forks. The end result is exactly the same in the cell: so blocked, the outlet isn’t usable.

THC and CBD, the two most well-known cannabinoid examples, are good examples of this distinction. THC binds to CB1 and activates it, starting a cascade of cellular activity that culminates in the psychoactive effect. CBD, on the other hand, binds to the CB2 receptor but keeps it off–since activity from the CB2 receptor leads to a pain signal, CBD can therefore block pain by preventing the activation.

The ECS has a unique mechanism of action. Typically in brain cells or neurons, messages are passed from one neuron to the next in a bucket brigade-type fashion. Neurotransmitters (chemical messengers) are released from one cell (called the presynaptic neuron), where they cross a gulf between cells called the synapse and are received by receptors on the next neuron (called the postsynaptic neuron).

But in the ECS, the chemical messengers (cannabinoids, in this case) travel backward across the synapse, from post- to pre-synaptic neuron. This feature of the ECS essentially allows the receiving (postsynaptic) neuron to modulate its own incoming signals.

The neuron is, essentially, screening its calls.

In this manner, the ECS has the role of an air traffic controller, managing communication between neurons for a number of different systems, from neural pathways that affect your mood via serotonin or dopamine, to fight or flight reactions via cortisol.

While we’ve been able to study the effects of cannabis on various aspects of human health for a while now, the discovery of the ECS means it’s not all about cannabis–there are lots of ways to tweak the system.

Each part of the ECS–the cannabinoid receptors, the cannabinoids, and their associated enzymes–is a potential target.

Sometimes it’s about finding the right ligand/cannabinoid that results in the kind of activity you’re looking for, whether that’s by manipulating levels of endogenous cannabinoids or their enzymes or adding exogenous or synthetic cannabinoids. Other times, it’s about controlling the balance of receptors, which can be up- or down-regulated as needed. Lastly, one can harness the ECS by altering the behavior of the enzymes responsible for making and breaking down the constituents.

Actual cannabis is just one source of cannabinoids being studied; research also includes synthetic cannabinoids, man-made analogs to THC and other natural cannabinoids, as well as looking into the mechanisms of our own endogenous cannabinoids.

Where endocannabinoid system research is headed

Many areas of research into the ECS involve trying to get around the psychoactive effects, which are not universally welcomed. The fact that CB1 receptors are found primarily within the brain presents an opportunity to hack the system. Once anything makes it into your bloodstream, it has access to just about anything in the body, with the exception of the brain.

The brain is a gated community, and anything that wants in must pass through the blood-brain barrier, a selective bouncer that only lets certain things in. THC, for example, passes right on through. A slightly different molecule, however, might be similar enough to bind to CBRs throughout the body while being denied access to the brain, mitigating possible psychoactive effects.

Other research is looking at the effects of stimulating versus blocking CBRs. On one hand, many conditions, including anxiety, seizures, etc., are calmed by activation of CBRs. However, as most who have partaken can attest, the munchies are a very real side effect. There is considerable research being done looking at the blocking of CBRs to treat obesity.

The entourage effect

Some of the research being done on the ECS uses purified versions of THC and/or CBD, in which the compound of interest is isolated from all other compounds found in the cannabis plant. This is a natural thing for scientists to do in order to reduce confounding variables and test the effects of each molecule alone.

However, many have suggested that cannabis exhibits an “entourage effect,” the name given to the synergistic interactions observed between various cannabinoids when used together, as is typically the case if one is simply smoking actual cannabis flower versus a chemical isolate. It’s possible that studies using the whole cannabis plant may see quite different outcomes from those using isolated cannabinoids.

How you take cannabinoids matters

The route of administration (ROA) of cannabis, or how it enters the body, makes a big difference in terms of the effects. That’s because the bioavailability, or the percentage of the compound that makes it to the bloodstream, varies depending on the ROA.

Inhalation

There’s a pretty good reason why smoking (and now vaping) cannabis has been the preferred method of consumption for thousands of years: it works well and it works fast. At about 30% bioavailability, it’s one of the most potent ways to consume. When you inhale cannabis, cannabinoids quickly reach the bloodstream via the lungs and pretty much head straight for the brain, where the effects are felt within minutes.

Oral

In the beginning, there was the pot brownie. Today, there are thousands of edible cannabis products from gourmet culinary oils to fruity beverages. However, eating your cannabis provides a very different experience from smoking or vaping. For one thing, before cannabis can reach the bloodstream after being eaten, it must pass through the liver, where it undergoes first-pass metabolism. In an attempt to do its duty, the liver breaks down many of the cannabinoids present, which gives oral cannabis a bioavailability of anywhere from 4-20%.

Buccal/sublingual/mucosal

Another increasingly common ROA for cannabis products is the sublingual route, utilized by cannabis oils and tinctures. These products are intended to be held in the mouth without being swallowed so the product can absorb through the lining of the mouth. This ROA avoids first-pass metabolism and bioavailability rivals if not trumps that of inhalation.

Topical

Not to be confused with transdermal, topical products are local, not systemic–they don’t reach the bloodstream, so they only affect the area applied. This can be great for pain relief or skin conditions, and it avoids any potential unwanted psychoactive effects. Although the bioavailability is smaller, it’s often worth the mitigation of unwanted side effects.

The bottom line

The Endocannabinoid System plays a major role in our overall health, and opportunities for therapeutic potential seem to be almost endless. With any system that affects so many areas of the body, we see both the power to heal and the tendency for unwanted side effects. But research on the ECS is in its infancy, and hope is on the horizon–for those who suffer from so many various conditions, research into the ECS may help pave the way toward a happier, healthier life.

 

References

cannabinoid. (n.d.). The Merriam-Webster.Com Dictionary. https://www.merriam-webster.com/dictionary/cannabinoid

Chiarlone, A., Bellocchio, L., Blazquez, C., Resel, E., Soria-Gomez, E., Cannich, A., Ferrero, J. J., Sagredo, O., Benito, C., Romero, J., Sanchez-Prieto, J., Lutz, B., Fernandez-Ruiz, J., Galve-Roperh, I., & Guzman, M. (2014). A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proceedings of the National Academy of Sciences, 111(22), 8257–8262. https://doi.org/10.1073/pnas.1400988111

De Petrocellis, L., Melck, D., Palmisano, A., Bisogno, T., Laezza, C., Bifulco, M., & Di Marzo, V. (1998). The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proceedings of the National Academy of Sciences, 95(14), 8375–8380. https://doi.org/10.1073/pnas.95.14.8375

Gaoni, Y., & Mechoulam, R. (1964). Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society, 86(8), 1646–1647. https://doi.org/10.1021/ja01062a046

Getting High on the Endocannabinoid System. (n.d.). PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997295/

Ren, M. (2019, June 1). The origins of cannabis smoking: Chemical residue evidence from the first millennium BCE in the Pamirs. Science Advances. https://advances.sciencemag.org/content/5/6/eaaw1391

Rossi, F., Punzo, F., Umano, G., Argenziano, M., & Miraglia Del Giudice, E. (2018). Role of Cannabinoids in Obesity. International Journal of Molecular Sciences, 19(9), 2690. https://doi.org/10.3390/ijms19092690

Routes of administration and cannabis products with therapeutic. (n.d.). Fundacion Canna. https://www.fundacion-canna.es/en/routes-administration-and-cannabis-products-therapeutic-purposes

The Science Behind the Entourage Effect. (n.d.). Cannabis Tech. https://www.cannabistech.com/articles/what-is-the-entourage-effect-in-cannabis/

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