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The Endocannabinoid System: A Medical Introduction

Have you ever wondered why we react the way we do to marijuana? The answer lies in one of the systems our body uses to regulate itself, the endocannabinoid system.

Overview of the Endocannabinoid System

The endocannabinoid system (ECS), named after the Cannabis sativa plant, is an internal communication system that regulates many processes in humans and other vertebrates1. Some of the activities guided by the ECS include: nerve and brain development, pain perception, stress and emotional responses, immune function, appetite, metabolism, digestion, reproduction, bone development, the sleep-wake cycle, and cardiovascular function2 3.

It is through this system that synthetic and herbal cannabinoids can do their work. Understanding how the ECS works is crucial for determining how to make the best use of the medicinal and wellness effects of cannabis.

Components of the Endocannabinoid System

The ECS is comprised of three main components:

1. Cannabinoid receptors: structures on the surface of cells that react to the presence of cannabinoids by increasing or decreasing a bodily process, such as stimulating or suppressing appetite

2. Endocannabinoids: naturally occurring molecules that bind to the receptors and influence bodily processes

3. Enzymes: molecules that break down endocannabinoids after they are used and stop the process they have stimulated 

We know the ECS encompasses many molecules, but few of them have been studied in detail. Our knowledge of the ECS family, however, continues to expand as research into this area progresses.

Cannabinoid Receptors

There are two endocannabinoid receptors, called CB1, and CB2.

The first endocannabinoid receptor, CB1, was discovered while trying to determine why delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, affects our bodies4.

Based on where CB1 receptors are present in the body, it's thought they are involved in the control of fear and anxiety, the feeding response and digestion, and more5. CB1 receptors are abundant in the brain6, with a small amount also present in the spinal cord and nervous tissue associated with pain perception7. They are also present in low levels in the lungs, vascular tissue, digestive tissue, reproductive tissue, and in immune cells8 9 10 11 12 13 14.

The second major cannabinoid receptor identified was CB2. These are predominantly located in the spleen and cells connected to the immune system15, and to a lesser extent in the brain, liver, and nerve cells 16 17. CB2 is thought to help regulate immune responses and inflammatory reactions, among other things18.

Endocannabinoids

Identifying CB1 and CB2 has helped researchers understand the molecules that naturally bind to them—the endocannabinoids. There are five known endocannabinoids produced by the body, among which anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most well-known and studied.

AEA, named from the Sanskrit word Ananda (meaning "bliss") primarily binds to CB1 in the brain, while 2-AG binds to both CB1 and CB219. AEA and 2-AG can also bind to non-endocannabinoid receptors, which suggests these compounds have a variety of functions throughout the body.

Overall Mechanism of Action of the ECS

The overall action of the ECS is pro-homeostatic, meaning it helps to maintain a stable environment within our bodies. In situations where homeostasis is destabilized, the ECS is turned on to re-establish "balance."

To do this, endocannabinoids are made “on-demand” in response to destabilizing stimuli.

In neural cells, AEA and 2-AG are released and bind to CB1 receptors, which can either inhibit or stimulate a neural response, depending on what type of neural cell CB1 is present on. In immune cells, activation of CB2 modulates the immune and inflammatory responses20.

Once homeostasis is re-established, endocannabinoid activity is rapidly turned off by the reuptake of AEA or 2-AG into the cell where they are broken down by enzymes.

In many chronic disorders and diseases,  endocannabinoid levels are often altered, and the activity of endocannabinoid receptors modified. Our body then struggles to restore homeostasis. For example, a dysfunctional ECS has been implicated in depression, autism, schizophrenia, addiction, stress and anxiety 21 22, and in diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and multiple sclerosis (MS)23.

The ECS and Medical Cannabis Use

Knowing that synthetic and plant-derived cannabinoids(also known as phytocannabinoids) can mimic our body's naturally occurring compounds allows us to investigate how cannabis will affect a variety of conditions and symptoms.

The main phytocannabinoid present in cannabis, THC, can activate both CB1 and CB2 receptors. Researchers believe that CB1 receptors in the brain are responsible for THC's intoxicating effects24.

In clinical studies, there is substantial evidence showing that synthetic THC therapies, dronabinol and nabilone, are highly effective for treating chemotherapy-induced nausea and vomiting25.

Another abundant phytocannabinoid, cannabidiol (CBD), is a non-intoxicating component of cannabis. It does not bind well to CB1 and CB2, and its primary mechanism of action in the body is not well understood. Some evidence suggests that CBD slows the breakdown of AEA26 27 and can stop THC and 2-AG from activating CB1 receptors28.

 

Learn More: A Medical Introduction to CBD

 

Not all diseases and symptoms treatable by cannabis have been studied equally. A limited number of studies have indicated that CBD can be used to treat sleep disturbances, anxiety, and symptoms of epilepsy29. There has been a lot more research on the use of THC/CBD combinations to treat specific conditions. For example, studies using Sativex, an oral spray which contains both THC and CBD in an approximately 1:1 ratio, have shown strong evidence that this formulation can treat chronic pain and MS symptoms 30 31.

In addition to THC and CBD, cannabis contains over 100 other cannabinoids. Other molecules, known as terpenes, can also activate CB1 and CB2, as well as other non-cannabinoid receptors throughout the body 32 33.

This added level of complexity makes it challenging to determine how to use medical cannabis to treat diseases and other conditions.

Summary

The ECS is a crucial communication system within the body that helps keep the body in balance.

Dysfunction of the ECS has been implicated in many diseases and conditions. The ability of synthetic and plant-derived cannabinoids to mimic the body's natural endocannabinoids has opened the door for using medical cannabis as a potential treatment.

While substantial clinical evidence exists for the use of medical cannabis to treat some conditions, more high-quality clinical research studies are needed so we can zero in on the best ways to use these body-mimicking compounds.

 

References 

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