There’s some debate about who truly discovered the first cannabinoid compound. An article in Cannabis Digest claims that experiments with THC were being done in the United States as early as World War II, and that an American organic chemist named Roger Adams was in fact the first person to discover THC back in the 1940s, along with CBD and other cannabinoids. But it is more widely accepted that Raphael Mechoulam, whom one might call the patriarch of cannabinoid science, is the man responsible for first discovering cannabinoids and, more important, how they work in the body. His initial pioneering innovations around CBD and THC paved the way for the discovery of the endocannabinoid system (ECS), and arguably the movement toward researching and understanding cannabis and cannabinoid compounds as medicine.

An overview of the ECS and its story:
According to many sources, when Raphael Mechoulam was a professor of medicinal chemistry at Hebrew University in Jerusalem during the 1960s, he discovered the first cannabinoids. It’s said that he actually discovered CBD first, in 1963, and THC in 1964, and that he was the first scientist to synthesize THC in a lab setting. For years, the scientific exploration of cannabis moved slowly, but in the late 1980s, new research led Mechoulam to discover a compound within the mammalian body that chemically looked a lot like the cannabinoids he’d discovered nearly thirty years before. Mechoulam was able to identify anandamide—a naturally occurring neurotransmitter—so named after the Sanskrit “ananda,” meaning “bless” or “delight.” Anandamide, chemically known as N-arachidonoylethanolamine (or AEA), is an endogenous cannabinoid compound (meaning it’s a cannabinoid made in the body). Its discovery is what ultimately led to the revelation of the ECS, which was discovered by Dr. Lisa Matsuda and colleagues at the National Institute of Mental Health in 1990.

Although a relatively new discovery, the ECS, it turns out, is incredibly important in the healthy functioning of a wide variety of systems and organs throughout the body. Your ECS can be seen as a kind of homeostatic regulator for many vital functions, influencing sleep, mood, appetite, hormonal response, pain response, immune system response, and more. As our internal and external environments affect our baseline state of balance, the ECS is there to correct things when they swing one way or the other.

All vertebrate species have an ECS, which is made up of millions of cannabinoid receptor sites. There are two primary types of ECS receptor sites: CB1, which are concentrated primarily in the brain and central nervous system (CNS), and CB2, which are concentrated more in the peripheral nervous system (PNS) and throughout the immune system. These receptors facilitate communication along our neural pathways to trigger homeostatic activities and appropriate hormone responses. The ECS is also dependent on two primary endocannabinoids: anandamide (AEA), mentioned above, and 2-arachidonoylglyceride (2-AG). Broadly put, these chemical compounds interact with the CB1 and CB2 receptors to inhibit or induce different homeostatic effects. We’ll get to more specifics in a minute, but it’s worth noting that CBD is similar in chemical structure to these compounds. It’s also interesting to note that these naturally occurring endocannabinoids are found in human breast milk, with 2-AG present in higher concentration than AEA.

Since its discovery, the ECS has been shown to be involved in a growing number of physiological functions. Researchers continue to find that by modifying the ECS, it’s possible to manage a number of diseases and pathological conditions, including multiple sclerosis, cancer, stroke, obesity, metabolic syndrome, anxiety disorders, neuropathic pain, Huntington’s disease, Parkinson’s disease, cardiovascular issues, movement disorders, glaucoma, epilepsy/seizure disorders, arthritis, and more.

What’s a cannabinoid?
Cannabinoids are fat-soluble 21-carbon molecules (meaning they have 21 carbon atoms in their makeup) that are essentially neuromodulators. By interacting with the ECS receptors, these compounds alter the release of neurotransmitters in the body. Much of the current information out there oversimplifies how this works by saying that cannabinoids and the CB1 and CB2 receptors work in a “lock-and-key” fashion, and that cannabinoid compounds “bind” to these ECS receptors. This isn’t always the case, but for now, suffice it to say that cannabinoids serve to block or stimulate the ECS receptors, triggering changes across a variety of physiological functions.

In addition to the endocannabinoids described above, there are many phytocannabinoids (cannabinoids found in plants), the most famous of which is delta-9-tetrahydrocannabinol (THC), commonly associated with the high you get from smoking marijuana. CBD is the second most well-known cannabinoid, and is increasingly being studied and praised for the beneficial effects it has for a variety of ECS-linked ailments while remaining noneuphoric. There are many other phytocannabinoids, their subtle structural differences allowing them to interact with the ECS in different ways, but the current research is most focused on THC and CBD. Phytocannabinoids occur in plant species other than cannabis, too, most notably the Echinacea species. Anandamide has also been shown to be present in black truffles.

There now exist synthetic cannabinoids that have been created in labs, primarily so that scientists can study the way that different chemical structures influence how they interact with the body. There are a few new/experimental cannabinoid-based pharmaceutical medications such as Sativex, Marinol, Cesamet (nabilone), and Rimonabant (which was approved in 2006 in Europe as a treatment for obesity, but withdrawn in 2008 due to major psychiatric side effects).

ECS receptors (CB1 and CB2):
The two major cannabinoid receptors are attached to the membranes of the cells in organs and tissues that make up the ECS. They are part of a large family of what are known as G-protein-coupled receptors (GPCRs) that detect compounds outside of the cells and use the information they take in to “couple” with stimulatory or inhibitory intracellular G-proteins. This interaction in turn modulates neurohormonal signals and ultimately creates cellular responses. GPCRs are implicated in many diseases, and are the target of many modern pharmaceutical drugs.

CB1 receptors occur primarily in the brain, and tend to be most concentrated in its subcortical structures, including the cerebellum, basal ganglia, and hippocampus. CB1 receptors are found throughout the CNS as well, and also in the liver, gut, uterus, prostate, adrenals, and cardiovascular system. CB2 receptors tend to be more localized to PNS and immune system cells. Very broadly speaking, one might say that CB1 receptors are implicated in more behavioral, psychological, and metabolic systems, while CB2s are focused on more when it comes to inflammation, autoimmune problems, and pain.

It’s important to understand that different cannabinoids interact with the CB1 and CB2 receptors in different ways. For example, THC binds with both CB1 and CB2 receptors, as do both endocannabinoids—anandamide and 2-AG. But CBD, on the other hand, does not bind directly to cannabinoid receptors. It actually works more by competing with the body’s own endocannabinoids, and thereby changing their levels within the body. For example, the endocannabinoid anandamide is normally broken down by fatty acid amide hydrolase (FAAH) as part of its natural life cycle. But CBD likes to attach to this fatty acid binding protein (or FABP), thereby reducing its ability to break down anandamide. This results in a higher level of anandamide in the ECS, which is beneficial for many reasons. For more specifics on CBD and how it works with the ECS, see How CBD Works.

Maintaining the ECS:
Given that the ECS is vital to the regulation of a range of physiological functions, and that cannabinoids are fat-soluble, “lipophilic” compounds, it should stand to reason that the health of the ECS and adequate cannabinoid levels are to some degree influenced by diet and nutrition.

Recent studies have shown that ECS function and endocannabinoid levels tend to decline when there is a lack of omega-3 fatty acids in the diet. Omega-3s are the “good fats” you so often hear about in the world of diet and nutrition, the ones that help to lower triglycerides and bad cholesterol and contribute to the health of joints, skin, vision, the heart, and brain. They are even said to boost fertility. There are three main types of omega-3s: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA). EPA and DHA are found mainly in cold-water fish and shellfish. ALA is found more in plant sources like walnuts and flaxseed. Omega-3s are one of two major classes of polyunsaturated fatty acids (PUFAs) along with omega-6s. PUFAs are distinguished from other fatty-acid categories (saturated, monounsaturated) by slight differences in their chemical structure.

Omega-3s are now said to be the precursors to the body’s natural endocannabinoid synthesis—in other words, the body needs these nutrients to make endocannabinoids. Some research suggests that an omega-3-deficient diet can both destabilize behavior and deform or “break” CB1 receptors in brain cells. A study published in Nutritional Neuroscience in July 2017 states:

“Western diet as well as restriction of micronutrients and fatty acids, such as DHA, could be related to altered production of pro-inflammatory mediators (e.g. eicosanoids) and ECs, contributing to the progression of cardiovascular diseases, diabetes, obesity, depression or impairing conditions, such as Alzheimer’ s disease. Here we review how diets based in PUFAs might be linked to ECS and to the maintenance of central and peripheral metabolism, brain plasticity, memory and learning, blood flow, and genesis of neural cells.”

Omega-3s help to repair and grow CB1 receptors—the ECS cannot work properly if they are starved of these PUFAs. Ideally, whether or not you incorporate phytocannabinoids in your diet, you should be taking in adequate omega-3s to make sure that your ECS works efficiently.

Among the many studied benefits of omega-3s are:

  • Increased lubrication of joints to ease wear and tear, reduce pain and inflammation
  • Anti-aging effects on the skin, helping to influence response to UV rays, keeping skin more hydrated, combating inflammation, reducing wrinkles
  • Protection of the eyes—eye health is closely connected to liver health, because the liver helps to metabolize the fat-soluble nutrients that maintain the ocular membranes
  • Maintaining heart health by lowering triglycerides, stabilizing heartbeat, making platelets less “sticky,” and even helping to lower blood pressure
  • Clearing “bad” LDL cholesterol while boosting “good” HDL and helping keep arteries clear
  • Aiding in the activity of neurotransmitters involved in mood/depression
  • Improving fertility by helping sperm motility in men and aiding in overall fertility health in women
  • Helping pregnancy—omega-3s have a direct effect on fetal brain development, making them crucial for expectant mothers

Some of these benefits are still being researched and understood, but the thing to note here is how closely omega-3s and the ECS are related—without omega-3s, your ECS suffers, leading to imbalances across all the physiological systems it influences. In truth, in an optimally functioning body, a diet rich in omega-3s and other essential nutrients should be sufficient to maintain and nurture the ECS; the body wasn’t necessarily designed to require an outside source of cannabinoids. But the modern-day diet and schedule are often far less than optimal for many people. Other factors affect whether or not the body can meet its endocannabinoid demands, too. Acute or chronic stressors, systemic compromises due to genetics or digestive issues, physical and even emotional traumas, environmental pollution, and buildup of toxins can all put pressure on the body’s endocannabinoid needs. At the root of many common health conditions are hormone imbalances—think of diabetes and how it requires insulin supplementation. If the body’s homeostasis is in flux and it is unable to produce sufficient endocannabinoids, the cannabis family of plants can be a natural next line of defense in mitigating ECS-related problems. For a bit more on this subject, check out our piece on Clinical Endocannabinoid Deficiency.

So why don’t more people know about the ECS?
The current scientific wisdom has estimated the ECS to be over 600 million years old. If this is the case, how is it not more widely known and understood? If the ECS is so crucial to physiological homeostasis and implicated in so many diseases, why don’t we read about it in our biology textbooks?

Unfortunately, the obscurity of the ECS is tied to the simple fact that its discovery was an extension of the study of cannabis and its active cannabinoid compounds. When cannabis was ruled a Schedule 1 controlled substance, these compounds were technically declared to have no medical use. This classification both hindered further study and the dissemination of information (and this still holds true even today), at least in the United States.

Greg Gerdeman, Assistant Professor of Biology at Eckerd College in Florida, is quoted as saying: “The thing is that the Schedule 1 status is so extreme that it creates all of these barriers to research. The DEA has stonewalled researchers to be able to look at herbal cannabis and study its outcomes. For this reason, just the whole intensity of the scheduling has made it difficult to make progress.”

In 2013, Dr. David B. Allen commissioned a survey that revealed that only 13% of U.S. medical schools included the ECS in their curriculum in any way. Evaluating these findings, he declared that “research and education of medical students involving the ECS is being intentionally restricted by politics.” This stands in sharp contrast to other countries such as Spain, where the ECS is taught in many if not all medical schools.

Times are changing, though, and one might say that the discovery of the ECS is one factor that is helping to pave the way for reformed cannabis laws in the United States. Gerdeman says: “Discovering the ECS is liberating cannabis from the Schedule 1 paradigm where it hasn’t really ever belonged. And naturally it feeds into the narrative that cannabis in some shape or form could be beneficial to so many different people.”

In summary:
There is still much to be learned about the intricacies of the ECS and how it works, even though it’s now established that this vital system has been a part of us, and all vertebrate creatures, for millions of years. ECS and cannabinoid science have been crippled by the stigma associated with marijuana and by outdated legislation, but we have still managed to uncover some of its inner workings. When you examine the way that phytocannabinoids like CBD have positive effects on a range of health issues, it’s difficult not to have an “aha” moment as you come to understand the ECS and how it works across various systems in the body. We predict that over the next few years, as legislation changes and studies advance, you’re going to hear more and more about the ECS as our understanding of this amazing regulatory network widens. We look forward to sharing new findings and information with our readers as it emerges.




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