The Endocannabinoid System for Dummies

Most people understand the role of the lungs and stomach in the human body. The lungs and respiratory system exchange oxygen and carbon dioxide, sustaining the vital process of breathing. The stomach and the rest of the digestive system efficiently convert food into energy. Another equally crucial but less well-known system is the endocannabinoid system or ECS. 

Whether you use cannabis or not, the endocannabinoid system constantly creates cannabinoids (endocannabinoids). Endocannabinoids are natural cannabinoids produced and processed by receptors in our body. The receptors are the same routes used and activated when cannabis cannabinoids, like THC or CBD, are introduced to the body.

Cannabis appears to be the only plant that stimulates the endocannabinoid receptors in the body. 

You probably didn’t learn about the endocannabinoid system in high school biology. Although it is essential to the human body (and other mammals and invertebrates), scientists didn’t know it existed until recently. 

While the medicinal use of cannabis goes back thousands of years and was a common remedy, precisely how it worked remained a mystery.

The discovery of the endocannabinoid system began in the 1960s with a significant breakthrough by Raphael Mechoulam and Yechiel Gaoni. They identified delta-9-tetrahydrocannabinol, or THC, a compound in cannabis that is responsible for the intoxicating high. The team went on to isolate many cannabinoids, but how they interacted with the body remained unknown. 

In 1988, William Devane and Allyn Howlett discovered the CB1 receptor in the brains of rats and humans. They found this receptor translates the cannabinoids into messengers or neurotransmitters. A few years later, the same team identified another neurotransmitter, anandamide. They named anandamide in reference to the Sanskrit word ānanda, which means bliss, happiness, or pleasure.

From this beginning, the endocannabinoid system emerged as a widespread brain signaling system that plays a role in thought, emotion, and regulation of body and mind.¹ 

What is the Endocannabinoid System?

The endocannabinoid system (ECS) is a network of messengers and receptors throughout the body. These messengers and receptors send signals to control and regulate almost every bodily function.

The ECS keeps multiple systems in homeostasis or balance with each other. From brain function to sleep cycles, mood, and thought, the ECS releases endocannabinoids, or signaling messengers, to transmit instructions to cells.  

The endocannabinoid system takes form in utero and aids in growing the central nervous system. It plays a role in how the brain develops, how cells communicate and adapt, and how the brain responds to internal and external stressors or injuries. The ECS multitasks to support multiple signaling pathways, ensure the brain functions smoothly, and adapts to changes and challenges.

The ECS is composed of endocannabinoids, receptors, and enzymes. It exists and is active in the body, regardless of whether cannabis is used or not.

The Body's Endocannabinoids

Endocannabinoids are natural molecules produced within the body, similar to cannabinoids or phytocannabinoids from the cannabis plant. They are essentially signaling lipids that activate cannabinoid receptors and multiple bodily functions.

The primary endocannabinoids are 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoyl ethanolamine, AEA). These interact with the cannabinoid receptors CB1 and CB2 but also engage with other receptors, like N-arachidonoyl dopamine.² 

2-AG and anandamide keep body system processes running smoothly. The body naturally produces them as needed, and the level of production varies.

Endocannabinoid Receptors

The endocannabinoid system has two primary receptors. CB1 receptors are mainly located in the brain and central nervous system and influence mood, memory, and pain sensation. CB2 receptors in the peripheral nervous system manage immune responses and inflammation.

CB1 receptors are most abundant in the brain and dial up or down the activity of neurotransmitters. CB1 and CB2 receptors are present in the skin, influencing processes like skin barrier development and inflammation.³ CB2 receptors are commonly found in immune cells and can modulate the immune response. In peripheral organs, CB2 receptors help nerve cells monitor and control responses. 

Additionally, the influence of the endocannabinoid system goes beyond CB1 and CB2 receptors. 

Endocannabinoids can activate receptors known as PPARs (peroxisome proliferator-activated receptors). This interaction can be direct or indirect and is essential in processes such as protecting nerve cells (neuroprotection), reducing inflammation (anti-inflammation), and relieving pain (analgesic action).

Anandamide activates specific TRP channels, particularly TRPV1, under particular conditions. This activation can lead to various responses, depending on the situation and the type of cell involved. Anandamide also activates two kinds of PPARs, alpha, and gamma, which can impact gene expression in cells.⁴

While CB1 and CB2 receptors are the primary mediators of endocannabinoid effects, these compounds also interact with TRP channels and PPARs, contributing to a wide range of biological functions and processes in the body.^3,4

For instance, the activation of CB1 receptors by these endocannabinoids mediates natural rewards, like social interactions, food enjoyment, and the effects of certain drugs.⁵

What is the Role of the Endocannabinoid System in the Body?

Overall, the endocannabinoid system's role is to maintain homeostasis and keep the body’s internal environment stable and optimized, no matter what affects the body externally.

The ECS impacts the nervous system in multiple ways. The nervous system runs through the entire body, from the brain and spinal cord's central nervous system to the peripheral nervous system that covers the rest of the body. The endocannabinoid system monitors and moderates the neural activity and function through this network. All cognitive functions and controls begin here, from memory to motor control.² 

The skin is the body’s largest organ and the first line of defense against external changes that affect overall wellness. CB1 and CB2 receptors are present in outer layers, nerve fibers, the dermis layer, pigment cells, sweat glands, and hair follicles.³ The ECS monitors and manages pain, body temperature, and skin barrier protection for the immune system. 

Activated CB1 receptors mediate responses, from natural pleasures like enjoying good food or sex to discomfort such as nausea or pain.⁵ 

Endocannabinoids connect with other receptors, too. TRP (transient receptor potential) channels maintain the skin’s protective barrier and stimulate skin cell growth. PPARs (peroxisome proliferator-activated receptors) protect nerves against inflammation and pain.⁴ 

Neurotransmitters, such as dopamine acetylcholine, glutamate, opiate peptides, and GABA, influence pleasure response, mood, and behaviors.⁵ 

Researchers have also identified a mutation in some people that alters the CB1 receptor, leading to nicotine, alcohol, or other substance abuse disorders.⁵ This discovery opens the field to using the ECS to treat mood and anxiety issues.

Ongoing studies look to harness the endocannabinoid receptors, the endogenous cannabinoids, and the plant-based cannabinoids of cannabis to discover beneficial ways to treat many conditions and diseases. 

What are Cannabinoid Receptors?

In humans, CB1 receptors form on the instruction of the CBR1 gene and CB2 on the instruction of the CBR2 gene. CB1 has 472 amino acids, and CB2 has 360 amino acids. Each receptor's specific number of amino acids indicates its size and structure.

Variations in this genetic encoding forming the CB1 and CB2 receptors may show potential for cannabis dependence.⁶ 

The CB1 and CB2 receptors respond to cannabinoids, both those found in cannabis and those naturally produced in the body. Both are G protein-coupled receptors (GPCRs), which respond to chemical signals outside the cell and trigger responses inside the cell. 

CB1 receptors are abundant in the brain, spinal cord, and organs, including the liver, fat tissue, and skin. They modulate memory, attention, appetite, pain, mood, and sleep and maintain a stable blood-brain barrier.

CB1 receptors can also pair with other types of GPCRs, like dopamine, hypocretin, and opioid receptors, to regulate reward-seeking stimuli.

CB2 receptors are found in the immune system’s microglia cells, supporting anti-inflammatory defenses.² 

How Do Cannabinoids Interact With CB1 and CB2 Receptors?

THC (tetrahydrocannabinol) binds to CB1 and CB2 receptors. THC triggers these receptors but less effectively than more potent agonists like anandamide.

THC’s impact on CB1 receptors is responsible for the intoxicating effects of cannabis, such as euphoria and altered sensory perception. THC also interacts with CB2 receptors in the immune system, potentially affecting inflammation and pain.

CBD (cannabidiol) has a lower affinity for CB1. It doesn’t activate these receptors like THC does. 

CBD modulates endocannabinoid signaling indirectly, possibly by inhibiting the breakdown of endocannabinoids or binding to other receptor types, like serotonin 5-HT1A and TRPV-1 (transient receptor potential vanilloid 1) receptors.⁷ 

CBD regulates fear and chronic stress by blocking CB2 receptors (CB2R) to slow the breakdown of anandamide. 

CBD limits inflammation response by binding with different receptors. It binds to the adenosine A2A receptor, inhibiting adenosine uptake to limit inflammation. 

CBD works with the PPAR-y receptor to reduce brain inflammation caused by beta-amyloid (Aꞵ), which is related to Alzheimer’s disease. Through the same receptor, CBD also promotes the creation of new neurons in the brain.  

By lowering GPR55 receptor activity, CBD controls inflammation by reducing the release of certain pro-inflammatory substances (like IL-12 and TNF-α). By blocking the GPR55 receptor, CBD offers pain relief for neuropathic pain and reduces inflammation in diseases such as inflammatory bowel disease.⁵

Understanding endocannabinoids and the importance of cannabinoid receptors, including CB1 and CB2, helps researchers develop new treatments based on their therapeutic properties.

Why Do We Have Cannabinoid Receptors?

Scientists believe cannabinoid receptors, especially CB1, existed in mammals for 400 million years. Since there are significant differences in the genetic makeup of CB1 and CB2 receptors, gene duplication of CB2 allows the endocannabinoid system to carry out new functions. 

From rudimentary functions of brain plasticity and development, the need for survival likely linked behavioral activity with food availability. Food deprivation and reduction increased the production of two endocannabinoids, anandamide and 2-AG. 

Goldfish show a decrease in movement when given a CB1 receptor agonist, so it’s likely that simple vertebrates developed an endocannabinoid response.⁸

Modern fetal brains form cannabinoid receptors by week 14 of gestation. The roles of the adult brain, like memory, learning, and motor function, are established during fetal development. By week 20, brain regions are rapidly developing and functionally active.²

Plant cannabinoids, like THC and CBD, act on the ECS, but are there other plant cannabinoids that mimic the effects of cannabis?

Cannabimimetic ligands are compounds that mimic the effects of cannabinoids. They can act as activators or blockers of cannabinoid receptors or inhibit enzymes of the ECS.

A plant cannabinoid called amofrutin, found in everlasting flowers, is used to destroy parasitic worms but can also cause nausea, diarrhea, vomiting, and respiratory tract infections. 

Other, more pleasant, cannabimimetic ligands include terpenes and phenols derived from cannabis or other non-cannabinoid plants. 

The β-caryophyllene and α-caryophyllene terpenes bind to CB2, but not CB1. They offer a range of potentially beneficial effects, including acting as natural repellents, fighting against microbes, cancer cells, and fungi, enhancing neurotransmitter levels, protecting cells from oxidative damage, and reducing inflammation.⁹ 

Both occur in cannabis, but also in many other plants, including black pepper, cinnamon, lemon balm, clove, oregano, and hops.¹⁰  

Intense physical activity also generates endocannabinoids. A “runner’s high” is triggered by endocannabinoid release and is believed to reduce anxiety, alleviate pain, and induce relaxation and euphoria. Exercise equivalent to 70-80% of the age-adjusted maximum heart rate will increase AEA levels. This is a great way to increase the production of our body’s natural anandamide (AEA).¹¹

What Are Endocannabinoids (and Why Do We Have Them)?

Endocannabinoids are signaling lipids that interact with the body’s cannabinoid receptors to complete essential roles in physiological processes. 

Naturally occurring endocannabinoids 2-AG (2-arachidonoyl glycerol) and anandamide (N-arachidonoyl ethanolamine, AEA) are part of a broader group of other signaling lipids that also engage cannabinoid receptors. They act on many cannabinoid receptors, including the CB1 and CB2 GPCRs (G protein-coupled receptors).

Lipids produce endocannabinoids on demand, activating when body stimuli signal enzymes to release them. The activity ends with hydrolysis or breaking down, 2-AG by enzymes monoacylglycerol lipase (MAGL) or ABDH6, AEA by fatty acid amide hydrolase (FAAH). Or, endocannabinoid function can change to form different biological signals.² 

AEA partially activates the CB1 receptor in the nervous system but is almost inactive at the CB2 receptor. Beyond its role in the endocannabinoid system, AEA also activates the TRPV1 receptor, regulating pain and neuron communication.  

2-AG fully activates both CB1 and CB2 receptors and binds to the receptor to regulate nerve cells in memory and learning and response to stress and pain.  

Endocannabinoids communicate between synapses and regulate appetite, inflammation, stress, and pain perceptions.⁶

When you see delicious food, anandamide revs up. CB1 receptor activation by AEA tells the body to consume more food and store energy. Fortunately, the hypothalamus sends out a hormone, leptin, to regulate your appetite.¹²

Elevated 2-AG levels occur during systemic inflammation. Conditions like cirrhosis, hepatitis C infection, congestive heart failure, atherosclerosis, and even sunburn can increase 2-AG levels. 

Stress can also affect both 2-AG and AEA levels. AEA is more affected by stress.  Lowered levels of both endocannabinoids occur with depression, although the duration of the depression and the gender of the patient can alter the concentration levels. 

Endocannabinoids may lower pain levels but, in specific pathways, increase the perception of discomfort. COX-2 enzyme converts 2-AG to arachidonic acid, increasing pain. If AEA activates TRPV1 channels, it heightens the pain. Endocannabinoids can heighten or lessen pain response depending on the mechanism of action.¹²  

The endocannabinoids produced within the body (AEA and 2-AG), as well as plant cannabinoids (THC and CBD from cannabis), can produce varied effects due to differences in interactions, binding of the receptor, and response strength. 

How Do Various Drugs Affect the ECS?

Drugs interact with the endocannabinoid system in different ways. Here’s a roundup of the effects of various drugs and medications.

THC 

The CB1 receptor controls the enjoyment of natural rewards like social interaction, sexual intercourse, and delicious food. THC acts on this receptor and generally produces positive effects on mental health over a short duration.  

CBD

Many endocannabinoid receptors interact with CBD. Serotonin 5-HT1A, TRPV-1, and, to a lesser extent, CB1 activation mediates stress, anxiety, fear, and compulsive behaviors. Positive effects on cardiovascular health occur as PPAR-y receptors inhibited by CBD decrease blood pressure, atherosclerosis, and beta-amyloid inflammation while increasing available nitric oxide. CB1 may also benefit metabolic health by glycemic control and maintaining lipid and glucose levels for Type 2 diabetes. Protective benefits for skin health come from CB1 activation. Other endocannabinoids produce strong anti-inflammatory and immune-suppressive properties through CB1 and CB2 receptors.⁵ 

Minor Cannabinoids (e.g., CBDA, CBDV, THCV, CBN, CBC, CBG)

Minor cannabinoids offer diverse profiles and therapeutic benefits. Some exhibit activity at CB1 and CB2 receptors. With the exception of THCV, none of the minor cannabinoids have shown intoxicating effects.  

• CBN (cannabinol) weakly binds with CB1 and CB2 receptors compared to THC. It has potential pain-killing and anti-inflammatory properties. 
• THCV (Tetrahydrocannabivarin) binds to both CB1 and CB2 receptors. It occurs in small amounts in cannabis flowers. The claimed pharmacological effects, such as appetite suppression, are not confirmed. It acts as both an antagonist and inverse agonist at the receptors.
• CBG (cannabigerol) offers anti-inflammatory effects, possibly from binding to the CB2 receptor, TRP channels, PPAR-y, and other channels. It displays weak partial agonist properties as it binds to CB1 and CB2 receptors but only produces a partial response. 
• CBC (cannabichromene) may be beneficial in cancer treatment. It increases blood levels of AEA, inhibits breast cancer cell growth, and induces death of colon cancer cells. It also blocks pain by stimulating adenosine A1 receptors, CB1 receptors, and TRPA1 channels. 
• CBDV (cannabidivarin) is similar to CBD in its anti-epileptic properties. It has a low binding affinity for CB1 and CB2 receptors. 
• CBDA (cannabidiolic acid) and CBGA (cannabigerolic acid) may aid binding properties when combined with the minor cannabinoid THCA. Both have a low affinity for CB1 and CB2 receptors. 
• THCA (tetrahydrocannabinolic acid) binds effectively with PPARy receptors when combined with CBDA and CBGA. It has roughly a 60- and 125- lower affinity for the CB1 and CB2 receptors than Δ9-THC.¹³ 

Prescription Cannabinoids

• Dronabinol (Marinol) and Nabilone (Cesamet) act like THC but are synthetic. They are approved to treat nausea and vomiting in cancer patients.  
• Sativex® (nabiximols) contains whole plant CBD and Δ9-THC. In a mouse study of induced Parkinson’s Disease, it increased anandamide binding to CB1 and TRPV1 receptors. Sativex decreased gene code CNR2 in peripheral blood mononuclear cells (PBMCs) immune cells. CBD and Δ9-THC together provided a 200-fold increase in low-dose effectiveness without side effects. Sativex lessens neuropathic pain and improves the quality of life in several diseases, including cancer, multiple sclerosis, and rheumatoid arthritis.¹⁴

Delta-8 and Other Delta Cannabinoids

Little research exists on the effect of delta-8 cannabinoids on the endocannabinoid system. They likely interact similarly to delta-9 THC, but at a lower or higher potency (delta-8, delta-10, or 11). The lower potency of Δ8-THC in the body compared to Δ9-THC is due to the lower binding affinity for the CB1 receptors.¹⁵

Lab-Made Cannabinoids

Synthetic cannabinoids on the illicit market, such as spice or K2, have an inconsistent pharmacological profile. They have much higher binding affinity to CB1 and CB2 compared to THC. They also bind to other receptors. Due to the high potential for liver, kidney, heart damage, and psychosis, these products are not for medical use.¹⁶ 

LSD

Whether psychedelics affect the endocannabinoid system remains unknown. In the hippocampus, several receptor mediators reduced levels of anandamide following repeated LSD treatment.¹⁷

Ayahuasca

Ayahuasca produces a strong influence on the peripheral endocannabinoid system. After ayahuasca intake, anandamide increased in plasma, while 2-AG decreased.¹⁸ Ayahuasca and other psychedelic drug studies are beginning to be examined in therapeutic use in psychiatry and medicine.

References

1. Crocq MA. History of cannabis and the endocannabinoid system. Cannabinoids. 2020;22(3):223-228. doi:https://doi.org/10.31887/dcns.2020.22.3/mcrocq ↩︎
2. Lu HC, Mackie K. Review of the Endocannabinoid System. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2020;6(6). doi:https://doi.org/10.1016/j.bpsc.2020.07.016 ↩︎
3. Filipiuc S-I, Neagu A-N, Uritu CM, Tamba B-I, Filipiuc L-E, Tudorancea IM, Boca AN, Hâncu MF, Porumb V, Bild W. The Skin and Natural Cannabinoids–Topical and Transdermal Applications. Pharmaceuticals. 2023; 16(7):1049. https://doi.org/10.3390/ph16071049 ↩︎
4. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry. 2016;79(7):516-525. doi:https://doi.org/10.1016/j.biopsych.2015.07.028 ↩︎
5. Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. International Journal of Molecular Sciences. 2021;22(17):9472. doi:https://doi.org/10.3390/ijms22179472 ↩︎
6. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International Journal of Molecular Sciences. 2018;19(3):833. doi:https://doi.org/10.3390/ijms19030833 ↩︎
7. Martin-Santos R, Crippa JA, Batalla A, et al. Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers. Current Pharmaceutical Design. 2012;18(32):4966-4979. https://www.eurekaselect.com/article/45750 ↩︎
8. Elphick MR. The evolution and comparative neurobiology of endocannabinoid signaling. Philosophical Transactions of the Royal Society B: Biological Sciences. 2012;367(1607):3201-3215. doi:https://doi.org/10.1098/rstb.2011.0394 ↩︎
9. Cavalli J, Dutra RC. A closer look at cannabimimetic terpenes, polyphenols, and flavonoids: a promising road forward. Neural Regen Res. 2021;16(7):1433-1435. doi:10.4103/1673-5374.301011 ↩︎
10. Aly E, Khajah MA, Masocha W. β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain. Molecules. 2019;25(1):106. doi:https://doi.org/10.3390/molecules25010106 ↩︎
11. Matei D, Trofin D, Iordan DA, et al. The Endocannabinoid System and Physical Exercise. Int J Mol Sci. 2023;24(3):1989. Published 2023 Jan 19. doi:10.3390/ijms24031989 ↩︎
12. Hillard CJ. Circulating Endocannabinoids: From Whence Do They Come and Where are They Going? Neuropsychopharmacology. 2017;43(1):155-172. doi:https://doi.org/10.1038/npp.2017.130 ↩︎
13. Walsh KB, McKinney AE, Holmes AE. Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses. Frontiers in Pharmacology. 2021;12. doi:https://doi.org/10.3389/fphar.2021.777804 ↩︎
14. Mlost J, Bryk M, Starowicz K. Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action. International Journal of Molecular Sciences. 2020;21(22):8870. doi:https://doi.org/10.3390/ijms21228870 ↩︎
15. Tagen M, Klumpers LE. Review of delta‐8‐tetrahydrocannabinol (Δ ⁸ ‐THC): Comparative pharmacology with Δ ⁹ ‐THC. British Journal of Pharmacology. 2022;179(15). doi:https://doi.org/10.1111/bph.15865 ↩︎
16. Alzu’bi A, Almahasneh F, Ramada Khasawneh, Ejlal Abu-El-Rub, Worood Bani Baker, Al-Zoubi RM. The synthetic cannabinoids menace: a review of health risks and toxicity. European Journal of Medical Research. 2024;29(1). doi:https://doi.org/10.1186/s40001-023-01443-6 ↩︎
17. Inserra A, Giorgini G, Lacroix S, et al. Effects of repeated lysergic acid diethylamide (LSD) on the mouse brain endocannabinoidome and gut microbiome. British Journal of Pharmacology. 2022;180(6):721-739. doi:https://doi.org/10.1111/bph.15977 ↩︎
18. Madrid-Gambin F, Álex Gómez-Gómez, Arnau Busquets-García, et al. Metabolomics and integrated network analysis reveal roles of endocannabinoids and large neutral amino acid balance in the ayahuasca experience. Biomedicine & Pharmacotherapy. 2022;149. doi:https://doi.org/10.1016/j.biopha.2022.112845 ↩︎

The information in this article and any included images or charts are for educational purposes only. This information is neither a substitute for, nor does it replace, professional legal advice or medical advice, diagnosis, or treatment. If you have any concerns or questions about laws, regulations, or your health, you should always consult with an attorney, physician or other licensed professional.