CBD and the Endocannabinoid System (ECS)

“How a single molecule [CBD] can show such a wide range of therapeutic potential with a favorable safety profile is a mystery that is far from being solved.”¹

These words are from a recent scientific journal article, and they convey well why, these days, CBD is being touted as a cure-all for everything from anxiety to cancer. It’s not just consumers that are excited about CBD – many doctors and scientists around the world are also giving praise, although others show a range of skepticism ranging from healthy to hostile. How can it be that one molecule can supposedly help with so many aspects of human health? Does the hype live up to the promise? The answer to that question is both compelling and complex. Read on: this is the CBD story, from an evidence-based perspective.

What is CBD? 

CBD, or cannabidiol, is one of two major cannabinoids found in cannabis. Specifically, CBD is a “phytocannabinoid,” meaning it is derived from plants, in contrast to endogenous cannabinoids, which are made in the body. Both phyto- and endogenous cannabinoids share similar molecular targets in the body, although our understanding of this complexity is far from complete. The other major cannabinoid is THC, or Δ9-tetrahydrocannabinol. Cannabis sativa L that contains more than 0.3% THC is often referred to as cannabis, while cannabis sativa L that contains less than 0.3% THC is referred to as hemp. In an odd technical peculiarity, in the US, only CBD from hemp is currently legal. 

CBD is often referred to as being “non-psychoactive,” because unlike THC, it does not cause the user to feel “high.” But as we will see, CBD does act on the brain, affecting things like anxiety and sleep. In this way, CBD is psychoactive, although not in the usual mood altering way. CBD also has effects on many other organs and systems in the body, as described later.

CBD was discovered in 1940 and its molecular structure was characterized in 1963. The cannabis plant does not actually make CBD; rather, it manufactures CBGA (cannabigerolic acid), the “parent” cannabinoid, which is converted to CBDA (cannabidiolic acid) in the live cannabis plant. CBDA then converts to CBD following exposure to heat, light, time and oxidants. It is usually stated that CBD is the dominant cannabinoid in hemp, but in fact, in the live plant the dominant cannabinoid is CBDA. With aging, exposure, harvest, and drying, CBDA virtually disappears through conversion to CBD. In harvested hemp plants, CBD is by far the most dominant cannabinoid².

Following the 2018 Farm Bill, production of hemp as an agricultural commodity was legalized and CBD was removed from the DEA list of controlled substances. The FDA also approved the prescription drug Epidiolex in 2018, which consists of highly concentrated CBD oil, to treat two rare forms of childhood epilepsy. Epidiolex was later further approved to treat of seizures in tuberous sclerosis, a rare genetic disease. Although CBD products are now legal in most US states, there are no production, labeling, or testing standards³. This makes it very important for health care professionals and consumers to be informed about what CBD is, how it works in the body and may benefit health, how to choose products, and how to use it safely.

CBD and the Endocannabinoid System 

The endocannabinoid system (ECS) is known as the “Ur-regulator“ or “master modulator” in the body⁴. This designation is especially interesting considering ECS was not discovered until the 1990’s. Most health care providers don’t know much about the ECS, and it is not commonly included in undergraduate or professional training curriculums. This is unfortunate, as the ECS plays a critical role in health and disease. 

The ECS is very complex and we have only scratched the surface in our understanding of how it works. However, we do know that CBD interacts with the ECS. CBD acts to affect levels of endogenous cannabinoids; that is, cannabinoids that are made in the body. Endogenous cannabinoids include anandamide (AEA) and 2-arachidonylglycerol (2-AG), which are involved in the main ECS functions: “eat, sleep, relax, protect, and forget”⁵. 

CBD has been associated with increases in AEA in three ways. First, CBD binds to the fatty acid binding proteins that carry AEA to its degrading enzyme fatty acid amide hydrolase (FAAH), which indirectly blocks AEA breakdown and raises levels⁶. Second, CBD may stimulate AEA production through effects on its synthesizing enzyme NAPE-PLD⁷. And third, CBD may slow down the breakdown of AEA by interacting with its degrading enzyme, fatty acid amide hydrolase (FAAH)^8,9, although it should be noted that there is some question as to how much this occurs in humans¹⁰. In this way, AEA has more time to act on CB1 and CB2 receptors, which are its primary targets.  In addition to effects on AEA, CBD may raise the levels of 2-AG by reducing the activity of lipoxygenase enzymes that are a minor source of 2-AG breakdown¹¹. 

CBD also affects how CB1 and CB2 cannabinoid receptor function, although CBD itself has a low affinity for these receptors. Instead, CBD acts as a “negative allosteric modulator” at CB1¹². This means that it binds to a secondary site to decrease binding at the main site. Since THC is a CB1 receptor agonist, taking CBD at the same time can dampen its effects. At the CB2 receptor, CBD is a partial agonist¹³. This means that it can bind to the CB2 receptor, but when it does it has only a moderate effect, in contrast to a full agonist which would have a maximal effect. The main molecules that bind to CB1 and CB2 are AEA and 2-AG, respectively¹⁴. This means that CBD acts differently than the endogenous cannabinoids, but as we just saw, CBD also has other effects than may increase concentrations of both AEA and 2-AG. 

Clearly, the story is getting complicated.

Endocannabinoid System Dysfunction

There are some very good reasons for suspecting that taking CBD to modulate the ECS may benefit health. In 2004, Dr. Ethan Russo hypothesized that several chronic diseases were due reduced functioning of the ECS. Specifically, he proposed that migraine, fibromyalgia, and irritable bowel syndrome might be due to a “clinical endocannabinoid deficiency (CECD)”, since they shared common clinical, biochemical, and pathophysiological patterns that suggested an underlying “deficiency” in the ECS¹⁵. In a 2016 follow up article, Russo presented an analysis of research published over the subsequent decade that validated the CECD hypothesis and extended the list of conditions to include neonatal failure to thrive, cystic fibrosis, causalgia,brachial plexopathy, phantom limb pain, infantile colic, glaucoma, dysmenorrhea, hyperemesis gravidarum, repetitive miscarriages, post-traumatic stress disorder (PTSD), and bipolar disease¹⁶. 

Foundational to CECD is the concept of “endocannabinoid tone”, which is a reflection of the levels of AEA and 2-AG, their production and metabolism, and the density of cannabinoid receptors¹⁶. The relationship between endocannabinoid tone and pathology is becoming increasingly well established, with a recent article describing 30 diseases in which levels of 2-AG or AEA are altered. In these diseases, the ECS is said to be upregulated to protect the organism, although the authors note that there are some diseases in which upregulation of the ECS is harmful, rather than protective¹⁷. Phytocannabinoids like CBD might enhance or promote this type of protective ECS upregulation. 

How can the endocannabinoid system become dysfunctional? One of the major culprits is stress, which affects more than 75% of US adults¹⁸. With chronic stress, repeated activation of the hypothalamic pituitary axis (HPA) results in insufficient levels of endogenous cannabinoids and decreases the activation of cannabinoid receptors. This has been described as a “hypocannabinoid” state¹⁹. 

In addition to chronic stress, poor dietary choices also downregulate the ECS. Sugary, high fat foods seem to be especially problematic²⁰. In contrast, dietary patterns like the Mediterranean Diet that include lots of vegetables, fish, and healthy fats such as omega-3’s, have been shown to positively influence ECS tone²¹.  

As is becoming increasingly evident, alterations in the ECS system may result from many common lifestyle factors. Through effects on the ECS, such as raising endogenous cannabinoid levels, CBD could help restore homeostasis to otherwise imbalanced systems. Although this has not yet been explored in clinical research, CBD might work best when combined with other ECS modifiers, such as regular aerobic exercise and a healthy diet.

This blog is the first in a three-part series on CBD. In The CBD Story – Part 2, we will explore the effects of CBD in the body, and the role of CBD in several clinical conditions.

Dr. Genevieve Newton, DC, PhD  has spent the past 19 years as a researcher and educator in the field of nutritional sciences. A series of personal health crises led her to discover the benefits of cannabinoids, and she soon found herself engrossed in studying the endocannabinoid system and therapeutic applications of cannabis/cannabinoids in mental health, pain, sleep, and neurological disorders. She has recently taken a position as the Scientific Director at Fringe, a new medical CBD and education company.

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