The Endocannabinoid System Revisited: A Deep Dive into Its Lesser Discussed Impacts on Your Body

Last reviewed by Daniel Gana, MSc, Dr. Abraham Benavides, MD, and Brent Ristow PhD, JD 1/28/2025

The endocannabinoid system (ECS) is a fascinating and complex regulatory network that plays a vital role in maintaining balance within the body. While many people associate it solely with hemp and cannabinoids, there’s much more to this system than meets the eye. This article will explore some of the unique features of the ECS which have been neglected for so long. 

Fact 1: There Are More Than Two Endocannabinoids

It is common to say that there are two endocannabinoids, however, this statement is not entirely true as these are just the core endocannabinoids. So far, scientists have discovered more than 10 endocannabinoids and endocannabinoids-like compounds. These are all lipid-based molecules that interact with the cannabinoid receptors in some way, and they include:
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1. 1. Anandamide (AEA): Anandamide (AEA), the first-discovered endocannabinoid, plays a key role in mood, memory, and pain regulation. It is a partial agonist at both CB1 and CB2 receptors, with a higher affinity for CB1 receptors. AEA is best known for causing the “runner’s high” and stress-induced pain relief after prolonged exercise.
   2. 2-arachidonoylglycerol (2-AG): 2-arachidonoylglycerol (2-AG) is a major endocannabinoid, acting as a full agonist for CB1 and CB2 receptors. It plays crucial roles in immune response, stress-induced pain modulation, and neuroprotection with functional recovery.
   3. Pentadecanoylcarnitine (PDC): PDC was identified in 2022 as a full agonist of CB1 and CB2 receptors. Additionally, it exhibits agonist activity at 5-HT1A and HT1B receptors, and antagonist activity at histamine H1 and H2 receptors. It is directly involved in regulating inflammation, pain, mood, sleep, and stress, promoting physical and mental health. 
   4. Docosahexaenoyl ethanolamide (DHA-EA or synaptamide): is an endocannabinoid-like derivative of docosahexaenoic acid (DHA) produced in the brain. It binds weakly to CB receptors and stimulates neurite growth, synaptogenesis, and glutamatergic synaptic activity in developing hippocampal neurons. It also possesses some anti-inflammatory properties. 
   5. Docosahexaenoyl-glycerol (2-DHG or DHG): 2-DHG is an omega-3-based endocannabinoid that shares structural similarities with 2-AG. It demonstrates weak agonist activity at CB1 receptors. Interestingly, a diet high in omega-3 and low in omega-6 has been shown to significantly increase 2-DHG levels, while 2-AG levels decrease. Additionally, the levels of DHG rise in human milk as it matures. Notably, an increase in 2-DHG is correlated with a decrease in pain.
   6. Eicosapentaenoyl ethanolamide (EPEA): EPEA comes from eicosapentaenoic acid (EPA). It activates CB1 and CB2 receptors in vitro with significant potency. The agonist activity is stronger for CB1 receptors. However, its potency as a CB1 or CB2 receptor agonist is lower compared to other endocannabinoids. Researchers also believe EPEA might produce similar anticancer effects as anandamide by activating cannabinoid receptors in these cells.
   7. Docosahexaenoyl ethanolamide (DHEA): DHEA is an endocannabinoid that also activates CB1 and CB2 receptors with significant potency. Acting as a receptor agonist, DHEA produces anticancer effects by stimulating these receptors in cancer cells. Its concentration-dependent activity highlights its therapeutic potential in targeting synergistic cannabinoid pathways for medical applications, including cancer treatment.
   8. Eicosapentanoylglycerol (EPG): EPG is an endocannabinoid derived from omega-3 polyunsaturated fatty acids (PUFAs). EPG is structurally similar to 2-AG, and shows promising therapeutic potential. They are CB1 agonists and increase cAMP levels via CB1 receptors. They exhibit anti-inflammatory effects by reducing pro-inflammatory markers like NF-κB and COX-2. Its levels rise in human milk during lactation, suggesting biological significance. Additionally, it is shown to decrease cell growth in human colorectal carcinoma cells, inducing apoptosis in a dose-dependent manner.
   9. Palmitoylethanolamide (PEA): PEA is an endocannabinoid-like lipid mediator known for its anti-inflammatory, analgesic, antimicrobial, immunomodulatory, and neuroprotective properties. Found throughout the body, including the brain, PEA indirectly activates CB1 and CB2 receptors by inhibiting the degradation of anandamide, contributing to the ‘entourage effect.’ It acts through several targets, including CB1 and CB2 receptors, TRPV1 ion channels, PPAR-α, and GRR55, all key in controlling intestinal inflammation.
   10. Oleoylethanolamide (OEA): OEA is an endocannabinoid that plays a crucial role in regulating food intake. Its levels increase with feeding and decrease during food restriction. OEA interacts with peroxisome proliferator-activated receptor-α (PPAR-α) to mediate anti-inflammatory processes. Synthesized in the gastrointestinal tract, OEA is involved in several homeostatic functions, including immune response, stimulation of lipolysis, and fatty acid oxidation. 

Fact 2: The ECS Isn’t Activated Solely by Hemp Compounds

A common misconception is that the ECS relies exclusively on cannabinoids like THC or CBD, for activation. However, the ECS can also interact with non-cannabinoid molecules like dietary fats, terpenes like beta-caryophyllene, and flavonoids like quercetin. The ECS also responds to lifestyle factors like exercise, meditation, and sleep, which increase levels of endocannabinoids, promoting homeostasis.

Endocannabinoid Receptors in Unique Places

Endocannabinoid receptors are found throughout the body within every other organ system, especially on cell surfaces, where they play a key role in modulating their activity. The location of these CB receptors dictates the instructions they provide to cells and influences their actions. 

Here are some unique places where CB receptors are located and how they function.
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• Gastrointestinal system: CB1 receptors in the gastrointestinal system play key roles in relaxing the lower esophageal sphincter, inhibiting gastric acid secretion, and regulating intestinal motility and fluid secretion. 
• Human malignant glioma cells: CB1 receptors are functional in U87MG human malignant glioma cells, where cannabinoids suppress PGN-induced NF-κB activation and cell growth. This effect occurs in a CB1-dependent manner.
• Human colon: CB1 and CB2 receptors are expressed on plasma cells in the lamina propria, while CB2 is found on macrophages. CB2 immunoreactivity is also observed in the epithelium of colonic tissue in inflammatory bowel disease. Cannabinoids promote epithelial wound closure, either alone or with lysophosphatidic acid, via a CB1-lysophosphatidic acid 1 receptor complex.
• Human vascular endothelial cells: CB1 receptors are reported to modulate nitric oxide production and calcium transient in vascular endothelial cells.   
• Murine embryonic stem cells: CB1 and CB2 receptors play a crucial role in regulating the survival and differentiation of murine embryonic stem cells.
• Alveolar type II cells in the lung: CB1 receptors are found on alveolar type II cells, where they regulate surfactant production, influencing lung function and respiratory health by helping maintain alveolar stability and reducing inflammation.
• Mitochondria of striated muscles: CB1 receptors are localized in striated muscle mitochondria and play a role in regulating mitochondrial respiration and energy production. Therefore, mtCB1 receptors may help regulate oxidative activity within the mitochondria, influencing cellular energy production and metabolic processes.
• Human anterior eye and retina: Cannabinoid receptors are found in various parts of the front of the eye and retina at the back of the eye, explaining the different effects of cannabinoid use on eye function. First, receptors in the ciliary pigment epithelium suggest cannabinoids could affect fluid production in the eye. Second, receptors in the trabecular meshwork and Schlemm’s canal indicate that cannabinoids might influence the drainage of eye fluid. Lastly, receptors in the ciliary muscle suggest how cannabinoids may affect the flow of fluid through other pathways in the eye.
• Human endocrine pancreas: CB1 receptors are found mainly in glucagon-secreting alpha cells and less in insulin-secreting beta cells, while CB2 receptors are present in somatostatin-secreting delta cells. In vitro studies show that CB1 activation boosts insulin and glucagon secretion, while CB2 activation reduces insulin secretion, confirming the functional roles of these receptors.
• Human sperm cell: Functional CB2 receptors are present in human spermatozoa and that their activation modulates sperm cell motility.
• Human placenta: Cannabinoid receptors are found in the human placenta and in BeWo cells, where they help regulate the activity of the serotonin transporter, a protein involved in controlling serotonin levels.
• Sickle cell anemia: In sickle cell anemia, cannabinoid receptors help reduce pain by preventing mast cell activation and neurogenic inflammation. This is done through both CB1 and CB2 receptors, which work together to lower inflammation and provide relief in sickle cell mice.

Conclusion

The endocannabinoid system is deeply embedded in the fabric of our existence, guiding us from conception to every moment of our daily lives. It plays a pivotal role in maintaining balance, ensuring that every cell functions in harmony with nature’s design. 

Active-Spectrum™ products take a unique approach in activating the ECS. Unlike traditional methods, they harness a range of natural compounds that engage the ECS receptors in several ways, enhancing its ability to restore balance and support overall well-being. By working with the ECS at a deeper level, Active-Spectrum™ products offer a more holistic and effective way to support your body’s natural processes.

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