history of the endocannabinoid system

History of the Endocannabinoid System

Along with other cannabinoids (cannabis plant compounds), CBD has become increasingly popular over the last several years for the treatment of an array of health conditions from stress and sleep issues to aches and pains. But why are cannabinoids so effective and how can they treat so many different issues? It’s all because they interact with the endocannabinoid system (ECS) — the largest regulatory system in the body.

It’s hard to believe that with the vital role the ECS plays in our health that this system was only discovered just a little over three decades ago. But while the history of the endocannabinoid system is a short one, it’s filled with fascinating discoveries that have revolutionized our understanding of the human body and its interaction with cannabinoids. Keep reading for a brief overview of some of the most important milestones.

But first: What is the endocannabinoid system?

Before we dive into the history, what exactly is the ECS? Essentially, the endocannabinoid system is a regulatory system that helps maintain physical and emotional homeostasis (balance) within the body. It’s composed of cellular receptors and signaling chemicals that interact with each other to produce an array of responses. Here’s a breakdown of its main components:

  • ECS receptors are present nearly everywhere in the human body and are heavily concentrated within the central nervous system, reproductive system, and gut. Like vigilant cellular gatekeepers, they carefully monitor and regulate the flow of signals throughout the body's endocannabinoid system.
  • The signaling chemicals endocannabinoids (cannabinoids created within the body) and metabolic enzymes act as chemical choreographers, so to speak, orchestrating the intricate dance of biochemical reactions within the cell.

When Was the Endocannabinoid System Discovered?

In 1963, Israeli scientists Raphael Mechoulam and Yechiel Gaoni successfully identified and isolated tetrahydrocannabinol (THC), and later cannabidiol (CBD), in the cannabis sativa plant. This led Mechoulan and his team to the discovery of the endocannabinoid system in 1988 over twenty years later, which opened the doors to a host of other discoveries spanning three decades (and counting).1 2

Notable Events in the History of the ECS

While the endocannabinoid system has been around for over 600 million years, we’ve only been aware of it for the last 35 years. Since 1988, there have been several milestones in ECS research, and further discoveries continue to be made.3 Some notable events include: 

The First ECS Receptor - CB1 (1988)

In 1988 — the same year that Mechoulan and his team made their discovery of the ECS — scientists at the St. Louis University Medical School established that there were receptor sites within a rat’s brain that were activated by THC. This cannabinoid receptor was named “CB1” and was later found to exist abundantly within the brains of all mammals, including humans.

The First Endocannabinoid - the "Bliss" Molecule (1992)

Just a few years later, Raphael Mechoulam, along with William Devane and Lumir Hanus, made another pivotal discovery — they identified the first endocannabinoid in 1992. The trio of researchers dubbed this compound, “anandamide,” a Sanskrit word meaning bliss

Anandamide interacts with CB1 to regulate our appetite, pain sensitivity, and even our mood. Our cells will actually create this endocannabinoid during stressful situations to help us stay calm and maintain — well, bliss.

The Second ECS Receptor — CB2 (1993) 

The second ECS receptor, CB2, was identified in 1992. It was found to be present in the peripheral nervous system, immune cells, metabolic tissue, and in many internal organs. The discovery of CB2 got scientists thinking about cannabinoid therapy and how it might help with inflammation and autoimmune disorders, among other things.

The ECS Enzymes (1997)

Nearly a decade after the discovery of CB1, scientists managed to clone two of the metabolic enzymes present within the ECS. These enzymes create endocannabinoids as needed and then break them down once they’ve served their function, acting as a sort of check and balance within the ECS. As mentioned above, certain enzymes interact with specific cannabinoids and endocannabinoids. 

The “Entourage Effect” (1998)

1998 marked the year of a particularly influential discovery that has had a profound impact on the cannabis community (and on our team at Cornbread Hemp) — S. Ben-Shabat and colleagues first used the term “entourage effect” in a paper published in the European Journal of Pharmacology to describe a notable phenomenon: a cannabinoid taken in conjunction with other cannabinoid compounds produces greater effects than one taken on its own

This explains why experts recommend a full spectrum CBD supplement — which contains all of the cannabinoids found in cannabis as well as other compounds like terpenes and flavonoids (aroma- and color-producing compounds) — instead of a CBD isolate (which only contains CBD in its isolated form).

ECS Deficiency (2004) 

Neurologist and cannabinoid scientist Dr. Ethan Russo coined the term "clinical endocannabinoid deficiency." In his 2004 study, he speculated that reduced endocannabinoid function contributes to various disorders. In the medical community, the concept of ECS deficiency is a controversial subject and continues to be hotly debated.4

CB1 Receptors and Mitochondria (2012)

Mitochondria are the energy-producing structures found in nearly every cell in the human body. They convert nutrients into fuel, making it possible for the cells to perform their proper functions. As we age, mitochondria become less efficient and produce harmful free radicals (unstable and reactive molecules). 

In 2012, French scientists discovered the presence of CB1 receptors on mitochondrial membranes. This important discovery illuminated the endocannabinoid system’s potential role in regulating mitochondrial activity.

ECS Research Today

As we’ve only been aware of the endocannabinoid system for the last three decades, there’s still a lot to learn. Scientists and researchers are currently exploring ways to modulate the ECS through the use of cannabinoids for improved health and function.

“There’s been an abundance of excellent research on the ECS and cannabis coming out of Israel for decades,” says Mandy Bliss, MSN, APRN, FNP-BC, PMHNP-BC, who sits on the Cornbread Hemp Medical Advisory Board. “The most recent studies being conducted in the U.S. are not only validating this existing body of evidence but opening the door for further discoveries and applications.”

Some current ECS research includes:

Therapeutic Applications

Research continues on the therapeutic potential of modulating the endocannabinoid system (through the use of cannabinoids and other compounds) to treat a variety of ailments and diseases. According to their paper, “Modulating endocannabinoid system in human health and disease—successes and failures,” researchers Pál Pacher and George Kunos suggest that “modulating ECS activity may have therapeutic potential.”5

    ECS Malfunction and Mental Health

    Research studies carried out in humans have consistently shown that the endocannabinoid system plays a crucial role in emotional balance and cognitive function. 6

    Endocannabinoids and Exercise

    Another study found a correlation between exercise and increased levels of endocannabinoids in the body. It was observed that “runner’s high” (a euphoric state attributed to exercise) may have more to do with the bliss molecule (anandamide) than with endorphins.7

    The Importance of Full Spectrum in Regulating Your ECS

    From isolating the endocannabinoid system and its component parts to discovering the myriad benefits possible through cannabinoid supplementation, there’s no doubt we’ve made great strides in the short 30 years since the ECS was discovered. Today, full spectrum CBD supplements are reported by consumers to successfully reduce stress, improve sleep, and manage aches and pains, among other benefits. 

    At Cornbread Hemp, we understand the importance of cannabinoid quality when it comes to promoting optimal ECS function. This is why we offer the highest-quality CBD products, made from the flower only, containing the full spectrum of cannabis compounds including 2 mg of THC, and USDA-certified organic through every step of the process. Shop our CBD collection now.


    About the Author
    Jim Higdon

    A native of Lebanon, Kentucky. He holds degrees from Centre College, Brown University, and Columbia University’s Graduate School of Journalism. Jim published Cornbread Mafia in 2012, Full author bio here.


    1) Pertwee R. G. (2006). Cannabinoid pharmacology: the first 66 years. British journal of pharmacology, 147 Suppl 1(Suppl 1), S163–S171. https://doi.org/10.1038/sj.bjp.0706406 

    2) Springer Publishing Company. (n.d.). Chapter 3. In Medical Cannabis Handbook. Springer Publishing Company. Retrieved from https://connect.springerpub.com/content/book/978-0-8261-3573-5/chapter/ch03 

    3) Lee, M. A. (2020, July 1). Endocannabinoid Research Timeline. Project CBD. Retrieved from https://projectcbd.org/science/endocannabinoid-research-timeline/  

    4) Russo E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?. Neuro endocrinology letters, 25(1-2), 31–39. https://pubmed.ncbi.nlm.nih.gov/15159679/ 

    5) Pacher, P., & Kunos, G. (2013). Modulating the endocannabinoid system in human health and disease--successes and failures. The FEBS journal, 280(9), 1918–1943. https://doi.org/10.1111/febs.12260 

    8) Ibarra-Lecue, I., Pilar-Cuéllar, F., Muguruza, C., Florensa-Zanuy, E., Díaz, Á., Urigüen, L., Castro, E., Pazos, A., & Callado, L. F. (2018). The endocannabinoid system in mental disorders: Evidence from human brain studies. Biochemical pharmacology, 157, 97–107. https://doi.org/10.1016/j.bcp.2018.07.009 

    9) Marusak, H. A. (2022, January 3). The runner's high may result from molecules called cannabinoids, the body's own version of THC and CBD. Wayne State University. https://today.wayne.edu/news/2022/01/03/the-runners-high-may-result-from-molecules-called-cannabinoids-the-bodys-own-version-of-thc-and-cbd-46709