Endocannabinoid System 101: A Beginner's Guide

In a previous article, we discussed the promises of cannabidiol (CBD) and its proliferation as a holistic health remedy for seemingly infinite ailments. But we didn’t get a chance to dive into the vaunted endocannabinoid system (ECS) in that article, and it seems prudent to address some of the concepts tied to the ECS. 

Since we are a brand built upon evidence-based formulas, we are naturally skeptical of “breakthrough” ingredients that claim to be a panacea or marketed like they will help you pack on ten pounds of solid muscle in two weeks.

However, if you look at the claims behind medical marijuana and the therapeutic benefits of Cannabis products, there is ample evidence to support them. But we still have a long way to go before we can translate those theories into praxis, and this is ostensibly due to the elusive nature of the endocannabinoid system. 

There’s quite a bit we still don’t know about the ECS or how it works to heal the body and treat disease. It’s similar to the gut microbiome in that regard; we know it’s integral to our wellness and longevity, but pinpointing the underlying mechanisms is tricky.

As scientists search for clues about the mysterious endocannabinoid system, we gain more insight into how cannabis products work on a molecular level. This article will get you up to speed on what we know (so far).

What Is the Endocannabinoid System?

The endocannabinoid system (ECS), short for endogenous cannabinoid system, is appropriately named after the Cannabis plant genus that ultimately led to its discovery. The endocannabinoid system is arguably the most vital physiological system for the foundation and maintenance of life as we know it [1].

The substances that interact with the endocannabinoid system are known as cannabinoids and come in two varieties: endocannabinoids and phytocannabinoids. Cannabidiol (CBD) is a heavily researched and promising phytocannabinoid derived from Cannabis species. Tetrahydrocannabinol (THC) is another one of the myriad phytocannabinoids known to exist in Cannabis. 

Your body naturally produces cannabinoids, which are endocannabinoids (short for endogenous cannabinoids). The two most prominent endocannabinoids are 2-arachidonoylglycerol (2-AG) and anandamide. These endocannabinoids are created on-demand from arachidonic acid derivatives in cell membranes, producing a localized effect before being broken down via enzymes like fatty acid amide hydrolase (FAAH) [2].

What Does the Endocannabinoid System Do?

What makes the endocannabinoid system integral to human health is that it intersects with many other bodily systems. Endocannabinoid receptors are present in vital organs, glands, connective tissue, and even immune cells [3]. Within each part of the body, the endocannabinoid system works to accomplish one specific goal: homeostasis.

If you recall from biology class, homeostasis is how your body maintains fixed internal conditions when faced with external changes. The simplest example of this is your body sweating when it’s hot outside. The human body naturally stays around 98 degrees Fahrenheit internally; sweating is a "cooling" mechanism that dissipates heat to maintain that temperature. 

The endocannabinoid system is suggested to promote homeostasis at every level of life, from the subcellular level to the organismal level (and likely even at the community level by influencing our relationship with the external environment) [4]. 

Here's one example: When you experience an injury, like an ankle sprain, endocannabinoids work to reduce the secretion of chemical activators from tissue surrounding your ankle, thereby stabilizing your neurons and inhibiting excessive action potential firing. In turn, the associated pain is reduced.

Those endocannabinoids also coordinate with proximal immune cells to block the release of inflammatory signaling molecules. That’s three distinct mechanisms of action across three distinct types of cells for one purpose: attenuate your pain and alleviate the structural damage induced by the ankle sprain.  

Key takeaway: The ECS, with its intricate actions throughout the central nervous system, immune system, and virtually every organ, is the veritable interface between mind and body. 

What Are Cannabinoid Receptors?

A receptor is a proteinaceous molecule that binds a specific molecule or set of molecules. It might help to think of receptors as being like receivers of signals (e.g. cannabinoids like anandamide and 2-AG). When a molecule binds to a receptor, it may activate it, inhibit it, or prevent it from binding to other molecules.

As such, receptors are crucial for relaying chemical messages from signaling molecules on the outside of cells into the interior space of cells (i.e. the cytosol). Typically, receptors are found on membranes of cells and cellular organelles, but they may also reside in the cytosol of cells or be translocated to the cell membrane as part of various biological stimuli.

Receptors of the Endocannabinoid System

In the context of the endocannabinoid system, there are cannabinoid receptors that bind endocannabinoid molecules like 2-AG as well as phytocannabinoids (the cannabinoids found in plants such as Cannabis). When these molecules bind to cannabinoid receptors, cellular pathways are activated to produce a physiological effect, like pain relief (analgesia).

Researchers have characterized two distinct cannabinoid receptors that modulate the endocannabinoid system: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) [5]. The CB1 receptor type is primarily found throughout the central nervous system, organs, gonads, and connective tissue; CB2 receptors are located throughout the immune system and associated components.

However, many body tissues have both types of cannabinoid receptors, each with its own unique actions. Scientists postulate that humans have a third cannabinoid receptor, but it remains unidentified [6].

It’s important to note that the feelings of euphoria (“high”) you may experience after ingesting THC arise through activation of CB1 receptors. CBD doesn't appear to elicit the same psychoactive effects as THC since it has a much lower affinity for CB1 receptors than it does for CB2 receptors [7].

What Are the Evidence-Based Benefits of Cannabinoids?

At the time of this writing (August 2021), a search on PubMed for scientific journal articles containing the word "cannabinoid" that have been published in the past two decades produces over 24,000 results. That means over the last 20 years, an average of three or more scientific papers relating to cannabinoids have been published every single day! Seems pretty crazy, right? 

Considering all the different health conditions that cannabinoids are suggested to treat, it’s really not that crazy; researching medical cannabis intensively is prudent if we want to adopt it as a more mainstream form of treatment for disease and prophylactic purposes. 

Yet, the skepticism among the general population and politicians remains a barrier when it comes to the widespread use of cannabis-related products, especially recreational marijuana. Regardless of political or personal beliefs on marijuana and cannabis-related products, clinical and preclinical research (both cell culture and animal studies) has demonstrated unequivocal health benefits from ingesting THC, CBD, and other phytocannabinoids, including [8]:

• Reducing inflammation
• Protecting brain function and the nervous system
• Preventing seizures
• Fighting pain (analgesic properties)
• Controlling anxiety and stress
• Enhancing learning and memory

And these are just the benefits of phytocannabinoids that we are aware of!

Endocannabinoid Deficiency

The endocannabinoid system is an appealing therapeutic target in the treatment of many health conditions. Intuitively, when the body lacks endocannabinoids, deficiency becomes an issue [9]. Supplementing with arachidonic acid and other fatty acid precursors may help the body produce more endocannabinoids, but research on this topic is still evolving [10].

However, modest doses of CBD and other phytocannabinoids stimulate the body to produce additional endocannabinoids and synthesize more cannabinoid receptors [11]. Hence, cannabis-related products are one way to combat endocannabinoid deficiency.

But don't expect a miracle overnight if you're using CBD oil or recreational marijuana for a chronic health condition. It takes time to heal the body, so consistency is key.

The Connection between the ECS, Cannabis, and Your Well-being

From the time of your conception to nursing and maturation, to fighting off pathogens and healing wounds, the endocannabinoid system helps you adapt and survive in the fast-paced and ever-changing world we live in.

The scientific and clinical research behind cannabis and the endocannabinoid system continues to grow, and one thing remains patently clear: a properly functioning ECS is the basis of good health and longevity. Sure enough, endocannabinoid deficiency has the opposite effect.

Having this rudimentary understanding of the ECS and how cannabinoids interact with it is only scratching the surface of the convoluted physiological underpinnings that govern the benefits of cannabinoids in humans. Rest assured, research in the coming years will help illuminate just how important anandamide, 2-AG, CBD, THC, and other cannabinoids are for our well-being.