The Endocannabinoid System

Understanding how cannabis works within the human body.

Excerpted from Weed: A Connoisseur’s Guide to Cannabis

Since it is a relatively recent scientific discovery, many traditional medical professionals are still unaware of the endocannabinoid system (ECS) and its crucial role in establishing balance within our bodies. Present in all humans as well as animals, plants, and fungi (essentially anything that has a cellular structure with an envelope-enclosed nucleus), the endocannabinoid system is a full-body signaling network that includes receptor sites CB1 and CB2, configured to respond to cannabinoids. These receptors are in the brain, organs, connective tissues, bones, glands, and immune cells and the ultimate goal of their activation is so the body can achieve homeostasis—that is, maintain stability—to prevent disease. A properly balanced endocannabinoid system is incredibly vital to our health; its balance affects inflammation, pain, appetite and mood. In fact, fully understanding the endocannabinoid system could unlock the therapeutic potential to treat almost all diseases. Cannabinoids are present at our earliest stages of development: they play a part in fertility and are in breast milk, and they continue to take part in many essential roles of survival (regulating stress, anxiety and appetite and preserving neurons to slow the progression of disease) throughout the course of life. By communicating and coordinating between different cell types, the ECS regulates our physiology and moods.

“How well we can apply our understanding of the ECS will have a great impact on medicine and our health, as we continue to navigate an ever increasingly chaotic and stressful world,” says Jahan Marcu, editor and chief of The American Journal of Endocannabinoid Medicine. “Since the dawn of time, the ECS has helped humans adapt and overcome seemingly insurmountable odds, and the hope of the modern, scientific understanding of the ECS continues to sharpen our ability to adapt to stress while preserving our health. The more we understand the ECS, the more we increase our chances of flourishing and surviving.”

Cannabinoids function like neurotransmitters, they are involved in sending chemical messages between nerve cells, or neurons, throughout the brain, nervous and immune systems. Interacting with the body’s internal receptors are two types of cannabinoids: endocannabinoids, those produced internally, and phytocannabinoids, those found in the cannabis plant. Scientists also create synthetic cannabinoids in lab settings. 

History of Cannabinoid Science

While cannabis has been an aid to humanity since ancient times, the first insight into its chemical properties came in the 1930s, with the identification and isolation of cannabinol (CBN). Another cannabinoid, cannabidiol (CBD) was discovered and isolated in the 1940s and scientists edged closer to isolating the most well-known cannabinoid, tetrahydrocannabinol (THC). Enter Raphael Mechoulam, the father of cannabis research. In 1963 Mechoulam, a biochemist in Israel, discovered more about the structure of CBD. By 1964, he and his colleagues made a breakthrough by isolating and discovering the rock star of all cannabinoids, THC.

By the 1980s, a detailed picture of the pharmacology of plant cannabinoids was emerging, but exactly how they worked to produce their effects was still unknown. Scientists assumed the chemical properties of cannabis must be working with a receptor within our bodies, but it wasn’t until the late 1980s and early 1990s that they were able to uncover this receptor, CB1, followed by another, CB2. CB1 receptors are primarily found in brain and spinal cord nerve cells, while CB2 receptors are mainly in immune tissues. The discovery of the CB1 receptor, which interacts with THC’s psychoactive properties, was a significant breakthrough for cannabinoid science. 

“The cloning of the cannabinoid receptor was crucial,” cannabis author Martin Lee writes in an article for the medical marijuana-focused publication O’Shaughnessy’s. “It opened the door for scientists to sculpt molecules that ‘fit’ these receptors like keys in a slot. Some keys —’agonists’— turned the receptor on, others —’antagonists’— turned it off.”

“By tracing the metabolic pathways of THC, scientists stumbled upon a unique and hitherto unknown molecular signaling system that is involved in regulating a broad range of biological functions,” Lee explains.  

The endocannabinoid system (ECS) is an internal signaling system present in every animal except insects and has a long evolutionary history, which helps explain its importance. In 1992, Mechoulam joined colleagues in making another surprising finding, a cannabinoid generated within the human body, an endocannabinoid. Named anandamide after the Sanskrit word ananda, meaning “bliss,” this discovery was a revelation. It showed that internally-generated cannabinoids worked within a full-body system and helped uncover how cannabinoids from plants can also tap into these networks.

“I understand that there are more than a hundred plant cannabinoids,” Mechoulam tells me. “There are also a huge number of anandamide-like endogenous [internal] cannabinoids in the animal body.”

The Bliss Molecule

Anandamide was an amazing breakthrough because it shows how our bodies regulate our ECS internally: Whether or not we are also supplementing it with cannabis, the ECS plays an active role in our health. When anandamide interacts with the cannabinoid receptors within our body, it creates a sensation of bliss. The body produces anandamide when we exercise and it’s responsible for the “runner’s high” that’s both exhilarating and euphoric. The euphoria associated with exercise shows that our endocannabinoid system interacts with the elements in the cannabis plant, but can also be boosted by other activities and plants. Exercise and massage and eating leafy greens loaded with caryophyllene and foods high in omega-3s also activate the ECS. After the discovery of anandamide, 2-arachidonoylglycerol (2-AG), a second endogenous cannabinoid, was uncovered. The full functioning of 2-AG is still unknown, but it plays a part in regulating the circulatory system. 

The Entourage Effect

The entourage effect is the idea that cannabinoids and terpenes work best in synergy with each other. This widely recognized theory suggests that the properties present in cannabis work together to create effects and explain why cannabinoids in isolation, such as Marinol, a synthetic form of THC, don’t work as well as medications that incorporate other chemical elements of the plant.

Turning this theory into a marketing tactic, many cannabis oils and tinctures advertise “full-spectrum” extract offerings, meaning that the product includes a range of cannabinoids and terpenes. The idea is that these products maintain the full profile of the plant and are therefore more beneficial.

Creating New Cannabinoids

Within the cannabis plant, cannabinoids concentrate in the resinous, tiny microscopic mushroom-looking heads (trichomes) found on the flowers and leaves. In 2019, researchers at UC Berkeley announced they had successfully produced cannabinoids on yeast, eliminating the need to work with the plant altogether. By engineering the yeast to transform fatty acids into cannabinoids, researchers said that they could create new types that did not previously exist. The idea behind creating cannabinoids through the fermentation process centered around enabling manufacturers to produce cannabinoids more cheaply, efficiently and reliably than plant-based cultivation.

Clinical Cannabinoid Deficiency

The concept of a critical cannabinoid deficiency was introduced in the early 2000s and hypothesizes that a lack of cannabinoids is the trigger for conditions like migraines, irritable bowel syndrome, fibromyalgia and clinical depression. These common conditions lack objective signs and often overlap. The idea behind clinical cannabinoid deficiency suggests that the body is not producing enough cannabinoids to keep systems in their natural balance, and therefore cannabinoids should be supplemented to maintain homeostasis.


The discovery of the endocannabinoid system was a total game-changer and spurred the creation of organizations devoted to spreading the word about the nascent field of endocannabinology. An activist group called the Alliance for Cannabis Therapeutics (founded in 1981) was already studying the medicinal effects of cannabis; a new organization called Patients out of Time evolved from that group and started holding regular conferences in 1995. Alongside that organization was another more exclusive group made up of the world’s most well-respected cannabinoid researchers, the International Cannabinoid Research Society. Incorporated in 1992, it is a consortium of about 650 botanists and scientists who study the ECS. The group’s mission is to promote the exchange of scientific research surrounding cannabinoids and serve as a source of information regarding the chemistry, pharmacology, and therapeutic uses of cannabis. The organization hosts annual symposiums at locations worldwide and releases an official journal that publishes a broad range of human and animal studies.

Medical professionals are also coming around to cannabis therapeutics. A small group of dedicated nurses founded the American Cannabis Nursing Association (ACNA) in 2006 to represent the emerging field of endocannabinoid therapeutics to professional nurses, thus providing them with the tools to understand and advocate for patient needs when it comes to the proper functioning of the ECS. Nurses trained by the ACNA learn about things such as appropriate dosing and cannabinoid interaction with other drugs.

Courtesy of The Quarto Group
  1. “Manipulation of the endocannabinoid system will save more lives than the invention of sterile technique.”
    Think about that…

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