The Endocannabinoid System, Cannabinoids, and Brain Health

The hemp-derived CBD market is expected to be a $1.3 billion industry in the U.S. by 2022 (1). Is society ready for this? One issue to overcome is the fundamental misunderstanding of the body's own endocannabinoid system (ECS), and how non-psychoactive, non-euphoric cannabinoids can actually complement the ECS’ productivity. The cannabinoids in the hemp plant are associated with a long list of health benefits (2); however, consumers have historically made the mistake of confusing non-psychoactive CBD products with the euphoria associated with THC found in marijuana. Cannabinoids in the hemp plant are not addictive, habit-forming or psychoactive (3). 

The Endocannabinoid System 

Cannabinoids from the hemp plant interact with the body’s endocannabinoid system, which is an innate signaling system that performs different tasks in each part of the body. The goal of the ECS is always the same: maintain bodily homeostasis despite fluctuations in the external environment (4). Since the discovery of the ECS in the late 1980’s, research has shown it integral to normal physiology, including brain health, and it has been implicated in the pathology of neurodegenerative diseases and a number of neurological and neuropsychiatric conditions (4, 7, 10, 12, 13). This opens new perspectives on hemp’s involvement in brain function.

The ECS consists of the cannabinoid receptors CB1 and CB2, endogenous cannabinoids (endocannabinoids) produced by the body, and the enzymes that synthesize and degrade the endocannabinoids.

Two Endocannabinoid Molecules: Anandamide and 2-AG

The two major endocannabinoid molecules, anandamide (AEA) and 2-arichidonylglycerol (2-AG), activate the cannabinoid receptors that sit on the surface of cells throughout the body. Unlike classical neurotransmitters and neuropeptides, endocannabinoids are produced “on demand,” meaning they get made and used exactly when and where they’re needed rather than pre-made and saved for later use (4).  

Anandamide is a lipophilic compound whose name originates from the Sanskrit word ananda, which translates to “bliss” or “joy,” an indication of its ability to support emotional balance. AEA can bind to both CB1 and CB2 receptors but has a much greater affinity for CB1 receptors, which are abundant in the brain. Anandamide production is triggered by elevated intracellular Ca2+ concentration, indicating that AEA is produced during moments of intense exercise. AEA crosses the blood-brain barrier and binds to cannabinoid receptors in the brain, yielding the infamous “runner’s high” felt during and post-workout (4). The main enzyme responsible for degradation of AEA is FAAH (Fatty Acid Amide Hydrolase). Drugs targeting the FAAH enzyme have been extensively studied for the treatment of endocannabinoid-related disorders, such an anxiety, depression, inflammation and neuropathic pain (5).

CB1 Receptors and The Brain

CB1 receptors are the most abundant receptors in the brain, especially the hippocampus and cerebellum (6, 7), but also found in the olfactory bulbs, prefrontal cortex (mood), basal ganglia (motor), amygdala (emotions) and the brainstem (information transfer) (6, 8). CB1 receptors are located on distinct types of axon terminals throughout the brain, including GABAergic and glutamatergic synapses, and cannabinoids can effectively modulate neurotransmission at inhibitory (GABA) and excitatory (glutamate) synapses (6, 9). In general, endocannabinoids serve as mediators in neuronal communication, which differs from synaptic and nonsynaptic transmission in its range and function (6).

CB2 Receptors and The Brain

The CB2 receptors are most abundant peripherally in the circulating immune cells, the spleen, microglia in the CNS, and on macrophage-derived cells including osteocytes, osteoclasts, and hepatic Kupffer cells (10). However, more than 70% of the total cell population in the brain are immune cells and represent the first line of defense against inflammation and other insult, which means they have CB2 receptors associated with them (10, 11). Following situations of acute inflammation or injury, CB2 expression is highly inducible on immune cells in the CNS and activating the CB2 receptor may be part of the active process of limiting or downregulating the acute inflammatory process (10). As a result, CB2 receptors are shown to have potential as a therapeutic target in diseases, such as neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease, where activation of the microglia and neuroinflammation are present (10, 12).

It's very easy to throw the ECS out of balance. Stress levels, diet and exercise all influence the body’s ECS, and a modern lifestyle may be taking its toll on this natural system. Since homeostasis is always the ECS’s goal, legalization of hemp in many states has made it possible for people to more easily achieve that balanced state. There are over 100 different plant cannabinoids, and each one has a slightly different interaction with the CB1 and CB2 receptors throughout the body. A growing number of people are using cannabinoids (ie: CBD) as one way to support mental and emotional brain-related conditions (4, 7, 10, 12, 13).

Tips For Choosing a CBD Product

The number of CBD product available for purchase on the market seems to increase daily. At this point, it's like the wild-wild-West as far as quality, testing, regulations and standards, making it very confusing for consumers. It's important to educate the marketplace on the priorities to consider when purchasing or manufacturing a CBD product. Here are five things to consider when purchasing, manufacturing and marketing a CBD product.

1. Understand the difference between Broad-Spectrum vs. Full-Spectrum vs. CBD Isolate. Many experts believe in the “entourage effect,” which suggests all the plant compounds work together to offer the greatest natural benefits compared to taking isolated CBD alone. This is what you get with a full-spectrum product, which contains

2. 3rd party testing is a must, and it’s even better if the company is transparent enough to show the results. The product should be tested for heavy metals, microbial contaminants (ie: mold, bacteria), and the exact quantities of CBD and all cannabidiol derivatives. The product should ensure purity and potency.

3. Organic is a must because hemp is a known bio-accumulator, meaning it draws toxins from the soil (ie: heavy metals, glyphosate). For this reason, it’s crucial to know the type of soil the hemp is grown in because conventionally grown hemp is potentially exposed to petroleum-based chemical fertilizers, pesticides, or insecticides. Healthy hemp starts with healthy soil.

4. Know where the hemp is sourced. Knowing its sourced in the United States isn’t enough. Learn as much as you can about the farm location, how the soil is maintained, and how the plants are cared for. 

5. Verify how the CBD is extracted. CO2 extraction is standard practice because it’s safe and delivers a pure product. Unsafe extractions use high heat or toxic solvents like butane and hexane, which can leave harmful residue behind in the final product.

Supplementing the body’s own supply of cannabinoids with hemp-based compounds supports the ECS’s desire to maintain homeostasis and more specifically supports brain health. The ECS’s exact role within the brain is complex and future research will hopefully shed light on its involvement in normal brain operations, disease mechanisms that are poorly understood, and brain diseases characterized by cognitive impairment and neurological defects (13).


Kelly Harrington is the Registered Dietitian Nutritionist (RDN) for Healthy Goods, and has a Master’s degree in Human Nutrition. She is a holistically-minded RDN with over 20 years of experience in a variety of nutrition fields. She follows an intuitive eating and functional nutrition approach for addressing individual health and nutrition needs. In addition to her professional life as a RDN, Kelly loves spending time with her husband and two sons and enjoys the outdoors, traveling, cooking healthy meals for her family and friends and is an enthusiastic yogi.


1. New Frontier Data Hemp Business Journal. Dec 16, 2018. 

2. Kogan NM and Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci. 2007 Dec; 9(4): 413-430.

3. World Health Organization. Cannabidiol (CBD) Critical Review Report. Geneva, 4-7 June 2018.

4. De Laurentiis A, Araujo HA, Rettori V. Role of the endocannabinoid system in the neuroendocrine responses to inflammation. Curr Pharm Des. 2014;20(29):4697-4706.

5. Ahn K et al. Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin Drug Discov. 2009 Jul; 4(7): 763-784.

6. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003 Jul; 83(3):1017-66.

7. Hampson, R. E. & Deadwyler, S. A. Cannabinoids, hippocampal function and memory. Life Sci 65, 715–723 (1999).

8. Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005; (168):299-325.

9. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, et al. 2002. Classification of cannabinoid receptors. Pharmacol. Rev. 54:161-202.

10. Bihua B et al. An overview of the cannabinoid type 2 (CB2) receptor system and its therapeutic potential. Curr Opin Anaesthesiol. 2018 Aug; 31(4):407–414.

11. Romero-Sandoval EA, Horvath RJ, Deleo JA. Neuroimmune interactions and pain: Focus on glial-modulating targets. Curr Opin Investig Drugs. 2008;9:726.

12. Onaivi ES et al. 2008b. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

13. Basavarajappa BS et al. Endocannabinoid system in neurodegenerative disorders. J Neurochem. 2017 Sep; 142(5):624-648. 

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