For thousands of years, people worldwide have used cannabis for its numerous therapeutic and relaxing effects on our bodies. However, only in the last century have we begun to truly understand how this versatile plant triggers these reactions.
The discovery of the endocannabinoid system in the 20th century led to increased research, not only into cannabis and its primary compounds—the cannabinoids—but also into a range of compounds produced within the body itself. This research has led to several important findings on the role of the endocannabinoid system and its implications for the development of new medical therapies.

The Role of the Endocannabinoid System in the Body

The endocannabinoid system (ECS) was first identified following the discovery of two receptors in the body, now known as Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). Today, the ECS, which includes these two receptors, is involved in a wide range of vital cognitive and physiological functions in the human body.

The Basics of the Endocannabinoid System

What is the Endocannabinoid System?

The endocannabinoid system consists of three main components: receptors (CB1 and CB2), enzymes, and neurotransmitters that interact with these receptors. These neurotransmitters are naturally produced in our bodies and have a similar chemical structure to cannabinoids produced by the cannabis plant—thus the name endocannabinoids.
Studies have shown that interactions between CB1 and CB2 receptors and endocannabinoids—as well as with cannabinoids from the cannabis plant (phytocannabinoids)—can trigger various responses affecting mood, temperature regulation, pain signaling, fertility, and more.

Understanding Cannabinoid Receptors

The endocannabinoid system is distributed throughout the body, with CB1 and CB2 receptors found in the immune system, central nervous system, and virtually every organ. The existence of specific cannabinoid receptors in the bodies of humans and animals was debated for decades. However, in the mid-1980s, researchers at Saint Louis University claimed they had made key discoveries providing conclusive evidence of such receptors.
This was confirmed in 1990 with the cloning of the rat CB1 receptor by Gérard and colleagues in Brussels and in 1993 with the cloning of CB2 in Sean Munro’s lab in Cambridge. Since their discovery, we have learned much about these receptors and their role in a range of bodily functions. Among the most important findings is that CB1 receptors inhibit the release of neurotransmitters (endocannabinoids) in the body, while CB2 receptors likely modulate the release of cytokines and the migration of immune cells.

Neurotransmitters and the Endocannabinoid System

Since the discovery of cannabinoid receptors, a number of endogenous cannabinoids have also been identified, many of which can directly stimulate these receptors. Additionally, it was found that phytocannabinoids, such as THC and CBD, interact with these receptors and may trigger various processes.
The development of synthetic cannabinoids has also been an important area of cannabis research in recent decades. These lab-created compounds have a similar chemical structure to endocannabinoids, allowing them to interact with cannabinoid receptors in our bodies.

Endocannabinoids: The Body’s Natural Cannabinoids

The neurotransmitters that naturally stimulate CB1 and CB2 receptors in the human body are called endogenous cannabinoids—or endocannabinoids. The first endocannabinoid discovered was anandamide, named after the Sanskrit word ananda, meaning “bliss.”
Anandamide (AEA) was discovered in 1992 and classified as a cannabinoid receptor agonist, but researchers soon realized it was not the only endocannabinoid. They quickly identified that mammalian tissue contains a range of other fatty acid derivatives that act like endocannabinoids, with 2-arachidonoylglycerol (2-AG) being the most studied. Evidence suggests these endocannabinoids are synthesized as needed, rather than stored—likely due to cannabinoid receptor stimulation.

How Does Your Endocannabinoid System Work?

Now that we know the key components of the endocannabinoid system, let’s examine how they work together. As mentioned, cannabinoid receptors (CB1 and CB2) are found throughout the body, including on the surface of immune cells and neurons. CB1 receptors, in fact, are more numerous than many other receptor types in the brain, essentially acting as modulators that regulate the levels and activity of numerous other neurotransmitters—including, but not limited to, endocannabinoids.
Endocannabinoids produced by our bodies to stimulate CB1 and CB2 receptors are now considered crucial in regulating a variety of functions. These compounds bind to cannabinoid receptors at specific sites.

Functions and Regulation of the Endocannabinoid System

CB1 receptors are found primarily throughout the central nervous system. They have been shown to regulate neurotransmission and other important physiological processes, including pain, inflammation, memory, and feeding behavior. This receptor can be activated by a variety of endogenous, synthetic, and plant-based compounds, including endocannabinoids and THC.
In contrast, CB2 receptors are primarily located in the immune system, highlighting the potential immunomodulatory role of the endocannabinoid system. Various in vitro and animal studies have shown that the CB2 receptor modulates immune cell functions in models of inflammatory diseases. Therapeutic approaches that modulate CB2 signaling could thus offer promising treatment options for inflammatory diseases like rheumatoid arthritis and inflammatory bowel disease.

Regulating ECS Activity

Evidence suggests that cannabinoid exposure is not the only factor that can regulate ECS activity. For example, exercise has significant health benefits, including the activation of endocannabinoids. Studies show that our bodies release endocannabinoids in response to high-intensity activities like running. This increase in endocannabinoids reportedly has a temporary analgesic effect after exercise, often known as a “runner’s high.”
Other factors shown to regulate ECS activity include stress and even eating behavior.

Significance and Implications for Research

The discovery of the endocannabinoid system has accelerated research into the therapeutic and medical potential of phytocannabinoids such as CBD and THC. In recent decades, medical cannabis research has surged after a long period of stagnation during the prohibition era in the 20th century.
Much of this research is driven by the need for alternative, effective therapies for various diseases, including chronic pain, epilepsy, and cancer. Current treatments for these and other conditions are often of limited efficacy and carry significant risks of unwanted side effects (e.g., opioids for chronic pain). Further research into the potential role of endocannabinoids in these conditions is therefore an important area for developing new treatments.

Medical Cannabis and the Endocannabinoid System

Medical cannabis is a widely recognized term for medical products derived from the Cannabis Sativa plant, including cannabinoid extracts and whole-flower products. Cannabis has been used medicinally for thousands of years to treat a variety of illnesses. However, only since the discovery of the endocannabinoid system have we begun to understand the mechanisms of medical cannabis—though much remains to be learned.
Current evidence, however, suggests that medical cannabis may be beneficial in treating various illnesses. In recent years, an increasing number of countries and jurisdictions have legalized medical cannabis, allowing its use to treat a range of conditions such as chronic pain, multiple sclerosis, epilepsy, and anxiety.

Benefits of Medical Cannabis for Various Conditions

Chronic pain is the most commonly cited reason for medical cannabis use worldwide. Data from clinical practice show that patients with chronic pain conditions often consider medical cannabis to be a useful therapy for pain and the comorbid symptoms of their condition, including anxiety and depression, as well as improving their quality of life. However, high-quality clinical evidence in this area is still limited.
In recent years, medical cannabis has also increasingly been considered a potential therapy for treatment-resistant epilepsy. Several studies have demonstrated the anticonvulsant potential of medical cannabis, particularly the non-toxic cannabinoid CBD. Medical cannabis (most commonly the CBD-based drug Epidyolex) is now approved in several countries for the treatment of various forms of epilepsy.
There is also growing evidence that cannabis and its derivatives may be useful in treating other conditions. Encouraged by these studies, more consumers are turning to over-the-counter CBD products for the treatment of complaints such as anxiety, stress, sleep problems, and general wellness; however, there is a notable lack of evidence for the efficacy of non-medical CBD products in these areas.

Endocannabinoid Deficiency: Signs to Watch For

Given the perceived importance of the endocannabinoid system and the resulting roles of endocannabinoids like anandamide and 2-AG, many have theorized that a deficiency of these compounds could significantly affect overall health. Although this theory was previously unsubstantiated, a 2016 study found that reduced endocannabinoid concentrations and ECS dysfunction were observed in several conditions, including migraine and post-traumatic stress disorder.
While more research is needed to fully understand this phenomenon, some signs that may indicate endocannabinoid deficiency include a lower pain threshold as well as changes in mood and sleep.

Conclusion

There is no doubt that the endocannabinoid system plays a critical role in our overall health and well-being. This receptor system is responsible for a wide range of essential processes and functions, making it a primary target in the development of future medical therapies and treatments.