The Endocannabinoid System Explained

6 min read

The human body is comprised of a variety of systems, many of which we know fairly well.

For instance, if asked, most people could explain that the digestive system is responsible for helping our bodies turn food into energy, and the respiratory system takes oxygen to our cells while simultaneously removing carbon dioxide.

However, another system that we’re just now learning exists and is, therefore, not as well understood is the endocannabinoid system.

If you break down the word endocannabinoid, endo means within[1] and cannabinoid is defined as “any of various naturally-occurring, biologically active, chemical constituents (such as cannabidiol or cannabinol) of hemp or cannabis including some (such as THC that possess psychoactive properties.”[2]

Thus, the endocannabinoid system—which is sometimes referred to as the endogenous cannabinoid system—refers to how the human body utilizes cannabinoids that are both found naturally in the body and those ingested when using cannabis-containing substances.

Though cannabis has been used to bolster immune systems for thousands of years, it hasn’t been well-studied in laboratory settings until recently, which is why this entire bodily system has gone undetected until recently.

In fact, it wasn’t until 1988 that we began to gain some insight that our body is naturally wired to use these chemical compounds called cannabinoids, as this was the year that Allyn Howlett and William Devane first identified cannabinoid receptors in the brains of rats.[3]

Since that time, we have learned even more about the endocannabinoid system and the benefits it provides, such as the important role it plays in helping the human body effectively utilize cannabinoids to provide a higher level of health and wellness.

This positive health effect is caused by the endocannabinoids’ interactions with the nervous system—both the central nervous system (brain and spinal cord) and peripheral nervous system (the nerves)—ultimately improving immune function.

Various pieces of research have confirmed that the endocannabinoid system’s physiological activities—which includes those related to the central nervous system, peripheral nervous system, and peripheral organs—play a number of crucial roles in providing better mental and physical health.[4]

For instance, by helping to create a stronger immune system, endocannabinoids can aid in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. They can also help provide relief for movement disorders like Parkinson’s disease (where it impacts the basal ganglia circuits[5]) and Huntington’s disease, as well as positively impacting mental health issues related to anxiety or mood disorders.

It is also theorized that clinical endocannabinoid deficiency can potentially lead to more issues with treatment-resistant conditions such as migraine headaches, fibromyalgia, and irritable bowel syndrome.[6] Under this clinical endocannabinoid deficiency theory, cannabis is suggested as a remedy to help block the pain and muscle spasms characteristic of these types of conditions.

To understand exactly how the endocannabinoid system helps improve health and wellness requires having a better understanding of its two main parts: endocannabinoids and cannabinoid receptors.


Research published in the journal Cerebrum explains that endocannabinoids are neurotransmitters that act as “a bridge between body and mind” because they tell the brain what actions it needs to take within the body to create a therapeutic health effect.[7]

Sometimes these neurotransmitters are made by the body itself. Other times they are introduced in the body via cannabis-containing substances, the latter of which contains cannabinoids.

In addition to impacting health, research has also found that endocannabinoids can potentially impact how much we eat. For instance, according to an article published in Frontiers in Psychology, they can affect our appetite.[8] The way they do this is by binding to cannabinoid receptors located in the brain, where they become participants in macronutrient metabolism involving the gastrointestinal system, liver, and muscles.

To explain further, endocannabinoids are biosynthesized from two different polyunsaturated fatty acids. From there, they are converted to endogenous ligands that either stimulate our desire to eat or changes the endocannabinoid system to lower food intake.

One of the most well-known cannabinoids is cannabidiol, or CBD. CBD is found in the resinous flower of the cannabis plant and has been deemed a safe, non-addictive substance that provides benefits to individuals who struggle with many different conditions.[9]

Among them are metabolic syndrome (which includes diabetes and obesity), neuropsychiatric illnesses such as autism and attention-deficit hyperactivity disorder, conditions involving the gastrointestinal tract (Crohn’s and colitis), cardiovascular dysfunctions, skin diseases, and more.

CBD is different than delta-9-tetrahydrocannabinol, commonly known as THC, in that it doesn’t create the high effect commonly attributed to this second cannabis compound. This is because CBD interacts with cannabinoid receptors differently than THC.


Cannabinoid receptors are the binding sites responsible for translating the messages received from endocannabinoids so the human body creates the appropriate response. Essentially, they are tasked with decoding endocannabinoid signaling in a way the body can understand.

Research has discovered that there are two types of cannabinoid receptors in the central nervous system. [10],[11] The first type is cannabinoid receptor 1, or CB1 for short.

CB1 receptors are made up of 472 amino acids and can be found within the brain and skeletal muscles. CB1 receptors are also located in the liver and pancreas, where they impact metabolism.

The second type of cannabinoid receptor is referred to as cannabinoid receptor 2, or CB2. In humans, CB2 receptors are comprised of 360 amino acids and, sequentially, are only 44 percent similar to CB1 receptors. That said, like their CB1 counterparts, CB2 receptors can also be found in the brain, in the lower level specifically. They’re also in the spleen.

Research published in Current Medicinal Chemistry shares that CB1 receptors are G-protein receptors that can influence memory and learning.[12] These G-protein receptors, such as GPR55, also play a role in addiction disorders, motor dysfunction, and mental health disorders such as depression, anxiety disorders, bipolar disorder, and schizophrenia.

The way the endocannabinoid system works is that the endocannabinoids regulate synaptic function within the brain, thereby activating the corresponding cannabinoid receptors.[13]

This regulation of synaptic function occurs through endocannabinoid signaling that moves backward across the synapse, which is why it is called retrograde signaling.

Put simply, endocannabinoids regulate functions and behaviors in the nervous system via suppressed neurotransmitter release. However, some endocannabinoids also appear to be non-retrograde and work by engaging different receptors, creating a postsynaptic neuron response.

Other factors can impact the endocannabinoid signaling pathways as well. For instance, monoacylglycerol lipase links the pathways, sometimes even offering a protective effect against liver injury.[14]

Additionally, the body’s response to endocannabinoids can be changed based on whether endocannabinoid metabolism or transport antagonists and inhibitors are present. For instance, one study reports that two of the main cannabinoid-bonding molecules—2-arachidonoylglycerol (2-AG) and anandamide (AEA)—sometimes lose their effectiveness when broken down with enzymes.[15]

The National Institute of Health explains that 2-AG binds to both CB1 and CB2 receptors and is a fatty acid derivative that is targeted by Delta-9-tetrahydrocannabinol, the active principle in cannabis sativa plants. Research in this area further indicates that 2-AG and other plant cannabinoids target other receptors as well.[16]

Depending on the levels of cannabinoids in the 2-AG and AEA, these two molecules can potentially have a positive impact on pain.[17] Additionally, AEA is similar to 2-AG in that it also participates in the receptor expression process, effectively mimicking the psychoactive properties of cannabis-based drugs.[18]

However, some enzymes inhibit these molecules from acting as they normally would. One such enzyme that is capable of breaking down endocannabinoids like 2-AG is fatty acid amide hydrolase, or FAAH. In fact, research has found that inactivating FAAH can create positive responses within the body, some of which are anti-inflammatory and analgesic in nature.[19]

In some cases, AEA and 2-AG production is also reduced by displacing arachidonic acid from cell membranes.[20] This is because arachidonic acid is a derivative of these two substances.

While all of this new research is promising, that the endocannabinoid system can help fight against illness and disease, not all cannabinoids come with such positive side effects.

For example, the National Institute on Drug Abuse (NIDA) shares that synthetic cannabinoids such as K2, Spice, Black Mamba, and Kush are psychoactive substances that have no medicinal value and, instead, are used to create the same types of effects as those achieved by using various illegal drugs.[21]

The NIDA further states that, though synthetic cannabinoids like these bind to the same cannabinoid receptors as delta-9-tetrahydrocannabinol, some studies have found that they bind more strongly, making them “unpredictable and dangerous” to use.

Different batches can also have different impacts, sometimes causing physical responses such as rapid heart rate, vomiting, and violent or suicidal behaviors and thoughts. They can have psychotic effects as well, some of which include feeling confused, excessively anxious, paranoid, and experiencing hallucinations.

Thus, when it comes to cannabinoids, natural is a safer choice.


[1] “Endo-.”

[2] “Cannabinoid.” Merriam-Webster.

[3] Granowicz, J. “A History of Endocannabinoids and Cannabis.” UTT BioPharma.

[4] Pacher, P, et al. “The Endocannabinoid System as an Emerging Target of Pharmacotherapy.” Pharmacological Reviews. Feb 2013. Doi: 10.1124/pr.58.3.2.

[5] Benarroch, E. “Endocannabinoids in basal ganglia circuits: Implications for Parkinson Disease.” Neurology. Jul 2007;69(3):306-9. Doi: 10.1212/01.wnl.0000267407.79757.75.

[6] Smith, S. & Wagner, M. “Clinical Endocannabinoid Deficiency (CECD) Revisited: Can This Concept Explain the Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and Other Treatment-Resistant Conditions?” Neuro Endocrinology Letters. 2014;35(3):198-201.

[7] Alger, B. “Getting High on the Endocannabinoid System.” Cerebrum. Nov-Dec 2013.

[8] Watkins, B. & Kim, J. “The Endocannabinoid System: Directing Eating Behavior and Macronutrient Metabolism.” Frontiers in Psychology. 2014;5:1506. Doi: 10.3389/fpsyg.2014.01506.

[9] “What is CBD?” Project CBD.

[10] Zou, S. & Kumar, U. “Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.” International Journal of Molecular Sciences. Mar 2018. Doi: 10.3390/ijms19030833.

[11] Pertwee, RG. “Pharmacology of Cannabinoid CB1 and CB2 Receptors.” Pharmacology & Therapeutics. 1997;74(2):129-80.

[12] Howlett, A et al. “CB1 Cannabinoid Receptors and Their Associated Proteins.” Current Medicinal Chemistry. Sep 2011;17(14):1382-1393.

[13] Castillo, P. et al. “Endocannabinoid signaling and synaptic function.” Neuron. Oct 2013. Doi: 10.1016/j.neuron.2012.09.020.

[14] Cao, Z et al. “Monoacylglycerol Lipase Controls Endocannabinoid and Eicosanoid Signaling and Hepatic Injury in Mice.” Gastroenterology. Apr 2013;144(4):808-817.e15. Doi: 10.1053/j.gastro.2012.12.028.

[15] Goparaju, SK et al. “Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand.” FEBS Letters. Jan 1998; 422(1):69-73.

[16] Di Marzo, V & Piscitelli, F. “The Endocannabinoid System and Its Modulation by Phtocannabinoids.” Neurotherapeutics. Oct 2015; 12(4):692-698. Doi: 10.1007/s13311-015-0374-6.

[17] Guindon, J & Hohmann, A. “The Endocannabinoid System and Pain.” CNS & Neurological Disorders-Drug Targets. Dec 2009;8(6):403-421.

[18] “Anandamide.” ScienceDirect.

[19] Ahn, K et al. Fatty Acid Amide Hydrolase as a Potential Therapeutic Target for the Treatment of Pain and CNS Disorders.” Expert Opinion on Drug Discovery. Jul 2009; 4(7):763-784. Doi: 10.1517/17460440903018857.

[20] Naughton, S et al. “Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism.” International Journal of Endocrinology. Volume 2013. Doi: 10.1155/2013/361895.

[21] “What are Synthetic Cannabinoids?” National Institute on Drug Abuse. Feb 2018.