What Functional Nutritionists Need to Know About the Endocannabinoid System

March 15th, 2022

Most of us are probably familiar with the major body systems. Of course, as functional nutritionists, we’re trained to zero in on the digestive system, but there’s another key body system to consider: the endocannabinoid system (ECS).

The ECS interacts with the other body systems to. And you may not realize it, but nutrition has a significant influence on its operation.

In this article, we’ll discuss what the ECS is and how dysfunction in this system is connected to a variety of disease states. We’ll also break down how nutrition impacts the ECS, as well as practical ways to support healthy ECS function.

What is the Endocannabinoid System?

While it can be somewhat difficult to define, the ECS is a complex signaling system within the body that works to restore and maintain homeostasis. This system was first described more than 30 years ago and has since been the topic of intense research and debate (1).

The ECS is comprised of cannabinoid receptors, endocannabinoids (eCBs), and degrading enzymes. Among its functions include the regulation of (1):

  • Inflammation
  • Pain
  • Appetite
  • Immunity
  • Cancer
  • Fertility
  • Mood
  • Memory
  • Sleep

What Are Cannabinoid Receptors?

The cannabinoid receptors are G-protein-coupled receptors that are located throughout the body. Cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are the most well-studied, but a cannabinoid receptor 3 (CB3) has also been proposed related to the ability of some cannabinoids and non-cannabinoid ligands to bind to the G protein-coupled 55 receptor (1).

CB1 receptors are largely found in the central nervous system (CNS) and CB2 receptors are mainly in the periphery and on immune cells. However, CB1 receptors have also been found outside the CNS and CB2 receptors have been found in the brain (1).

What Are Endocannabinoids?

Endocannabinoids (eCBs) are fatty-acid-derived signaling molecules created on demand by the body to act on and interact with cannabinoid receptors to regulate homeostasis.

The most well-studied eCBs are anandamide-N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), which are derived from dietary omega-6 fatty acids. But more recently, eCBs created from omega-3 fatty acids have been discovered, namely docosahexaenoyl ethanolamide (DHA-EA or synaptamide), docosahexanoyl-glycerol (DHG), eicosapentaenoyl ethanolamide (EPA-EA), and eicosapentanoylglycerol (EPG)(2).

Each eCB has a different physiological action based on its source.

How Does the Endocannabinoid System Restore Homeostasis? 

The ECS is not yet fully understood, but when it detects an alteration in your internal balance, a negative feedback loop is initiated whereby eCBs are immediately synthesized from their lipid precursors and are released to target the cannabinoid receptors, which directly control the signals from eCBs to restore homeostasis. Once balance has been reestablished, eCBs are quickly degraded (3).

In the case of inflammation, for example, eCBs interact with CB2 receptors to upregulate CB2-mediated intracellular signaling and peroxisome proliferator-activated receptors (PPARs), which decrease proinflammatory mediators limiting the inflammatory response (4).

The Omega-6 to Omega-3 Fatty Acid Ratio and Clinical Endocannabinoid Deficiency

To create eCBs, the body must first have an adequate supply of the omega-6 fatty acid (arachidonic acid) and the omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid).  Of course, the standard American diet is abundant in omega-6, but often lacking in omega-3 with an average ratio of 15:1 (5,6). A detailed dietary recall is a good way to estimate an individual’s omega-6 to omega-3 fatty acid ratio, but red blood cell fatty acid testing is also an option. A lower omega-6 to omega-3 ratio is associated with improved health outcomes. For example, a ratio of 4:1 has been associated with a 70 percent decrease in total mortality from cardiovascular disease, a ratio of 2.5:1 has reduced cancer cell proliferation in those with colorectal cancer, and a ratio of 2-3:1 has curbed inflammation in those with rheumatoid arthritis (5).

An excessive ratio of omega-6 to omega-3, on the other hand, is thought to be a contributing factor to the prolonged inflammation seen in a myriad of chronic diseases such as obesity and metabolic dysfunction, cardiovascular disease, cancer, chronic pain, and autoimmune and neurodegenerative diseases (3).

The imbalanced omega-6 to omega-3 fatty acid ratio may also underlie clinical endocannabinoid deficiency syndrome (CECD) (7).  The theory of CECD has been proposed as one causative factor in treatment-resistant conditions such as migraines, fibromyalgia, and irritable bowel syndrome (7).

While research has not yet fully elucidated this theory, some supportive evidence exists:

  • People with migraines have lower cerebrospinal fluid levels of the endocannabinoid AEA (7).
  • Post-traumatic stress disorder (PTSD) patients have dysfunctional endocannabinoid signaling based on advanced imaging studies (8).
  • Patients with treatment-resistant conditions who are treated with cannabidiol (CBD, a phytocannabinoid) experience symptom improvement (7).

Optimizing ECS Function

ECS dysfunction has been observed in a variety of chronic disease states and improving its function may lead to improvements in health and quality of life (9). ECS tone can be impacted by a number of lifestyle factors, so improving ECS function can usually be accomplished by making healthy changes in those same areas (10).


The Mediterranean diet, which is rich in fish, olive oil, fruits, vegetables, whole grains, nuts, and legumes has been found to improve plasma concentrations of eCBs (11.  In addition to this anti-inflammatory eating style, it’s important to focus on:

  • Optimizing the omega-6 to omega-3 fatty acid ratio, which is one of the most effective ways to modulate eCB tissue levels (11). Focus on limiting processed foods and inflammatory oils and increasing intake of fatty fish, chia seeds, and walnuts.
  • Consuming adequate prebiotics and fiber to maintain gut microbiome balance, since an altered gut microbiome has been shown to alter ECS function (10).
  • Increasing consumption of fruits and vegetables with flavonoids, such as kaempferol which is found in arugula and blackberries and may increase AEA levels and improve ECS tone (10).
  • Consuming a variety of spices such as rosemary, black pepper, and cloves which contain beta-caryophyllene, a dietary cannabinoid and CB2 receptor agonist (10), (11).


We’ve probably all heard of the “runner’s high,” which is now known to be related to the release of endorphins and eCBs and their interactions with opioid and cannabinoid receptors (11). Altered levels of AEA have been found in sedentary patients when compared to those who are active and moderate-intensity aerobic activities like jogging, hiking, and biking have been show to increase eCB concentrations (10).

Stress Management

The acute stress response is an important physiological mechanism to restore homeostasis and the ECS is an important regulator of this response. Chronic stress not only alters the levels of eCBs, but also results in the downregulation and loss of CB1 receptors, which is associated with anxiety, the decreased ability to feel pleasure, and psychiatric illness. In animal studies though, treatments to strengthen the ECS prevent many of these symptoms (12).

Incorporating a daily stress management technique such as meditation has been shown to modulate both eCB and brain-derived neurotrophic factor (BDNF) levels (11). In one study, participants who completed a 4-day yoga and meditation program experienced increased levels of AEA, 2-AG, and BDNF after meditation (11).


Phytocannabinoids are compounds contained in the Cannabis sativa plant (as well as other plant species such as Echinacea purpurea) that interact with cannabinoid receptors to support health. There have been over 120 different phytocannabinoids identified in C. sativa, the two most well-known being Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (10), (13).

Research is confirming what has been observed for centuries about the beneficial physical and psychological effects of these compounds. Let’s take a look at a few examples:

  • CBD increases AEA levels thus activating CB1 receptors to decrease anxiety, depression, and psychosis (10).
  • CBD and THC have been successfully used as adjunctive treatments for brain tumors, Parkinson’s and Alzheimer’s diseases, multiple sclerosis, pain, and seizure disorders (14).
  • Echinacea provides an anti-anxiety effect by interaction with CB2 receptors and indirectly by AEA reuptake inhibition (10).
  • Beta-caryophyllene, a terpene and the first identified dietary phytocannabinoid, acts as a CB2 receptor agonist to reduce chronic inflammation (15).

The Bottom Line

A properly functioning ECS seems to be important for overall health and quality of life. Functional nutritionists can support healthy ECS function in their patients by focusing on maintaining an optimal omega-6 to omega-3 fatty acid and prescribing a personalized anti-inflammatory diet that includes adequate prebiotics, fiber, and spices.  Additional lifestyle measures, including the use of phytocannabinoids, can also be very effective.

To learn more about the exciting field of functional nutrition, join us for Track 1 where we discuss the foundations.

by Kellie Blake, RDN, LD, IFNCP


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