How the Endocannabinoid System Works and Where PEA Fits In.

Perhaps the most important body system you never learned about in school, the endocannabinoid system (ECS) is a relatively new discovery. First characterized by the discovery of an endocannabinoid receptor in 1988, scientific understanding of the ECS and how it works grows every year. In short, the ECS plays a central role in helping the body and mind stay in balance, a process known as homeostasis.

What Is the ECS?

The ECS is a communication network that creates a bridge between the body and the mind, helping the body adapt to everyday physical and environmental demands. The goal of the ECS is to maintain balance, or homeostasis, in the face of stress. Many of the body’s most important functions are regulated by the ECS, including:

• Sleep

• Pain Control

• Temperature Regulation

• Emotional Processing

• Learning And Memory

• Appetite

• Immune And Inflammatory Responses

Rather than controlling these functions directly, the ECS helps coordinate how they respond to internal and external stressors.

Three Components of the ECS

In order to better understand how the ECS communicates, it’s helpful to identify and define the three core components - receptors, endocannabinoids, and enzymes. Receptors are sites on cells that receive and respond to signals, endocannabinoids are chemical messengers, and enzymes are responsible for both creating and breaking down chemical messengers. Let’s take a deeper look at each component, starting with receptors.

Like many body systems, communication within the ECS happens along a series of receptors, and the ECS has the largest receptor network in the body. Cellular receptors are specialized proteins found on the cell surface, inside the cell membrane, or in intracellular compartments, such as mitochondria, where chemical signals (usually hormones or neurotransmitters) dock and stimulate some type of response or action. You can think of this process like putting a key in a lock and then turning it, which results in being able to open the door and interact with whatever is on the other side. 

The two most abundant ECS receptors are called cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). In the brain, CB1 receptors are found in large quantities in the cortex, hippocampus, basal ganglia, and cerebellum. Outside of the brain, CB1 receptors are also found on immune, liver, pancreas, small intestine, spleen, cardiovascular, skeletal muscle, reproductive, and fat cells.^1,2

CB1 receptors modulate - increase or decrease based on need -  neurotransmitter release. This impacts communication between neurons in the brain and affects learning, memory, pain perception, motor control, appetite, sleep cycles, and mood regulation.^1,2

CB2 receptors are abundant in immune and spleen cells and can be found in the same organ systems as CB1, plus skin and bone. Like CB1, CB2 receptors are also found in the brain, but to a lesser extent. Interestingly, CB2 receptors actively interact with and modulate CB1 activity. In fact, CB1 and CB2 receptors can physically bind together to work in pairs.^1,2

Along with receptors, the second component of the ECS, endocannabinoids, are needed for the ECS to function properly. While endocannabinoids may not be a term you are familiar with, you might be making the connection between “cannabinoids” and “cannabis” while reading this. THC was the first cannabinoid that was discovered, but it’s important to note that the body makes its own cannabinoids, which is why they are called endocannabinoids. Some of the most well-known and well-studied endocannabinoids are Anandamide, 2-arachidonoyl glycerol (2-AG), N-arachidonoyldopamine (NADA), and the endocannabinoid-like palmitylethanolamide (PEA).

While the body produces its own endocannabinoids, there are also external compounds - exogenous cannabinoids - that can interact with the ECS. The exogenous cannabinoids include phytocannabinoids (plant-based compounds) and synthetic cannabinoids (lab-created compounds). Of the phytocannabinoids that have currently been identified, most do come from the Cannabis sativa plant, including CBN, CBD, and THC. In fact, there are more than 100 phytocannabinoids that come from the cannabis plant alone.^{3, 4} 

Along with phytocannabinoids, plants also produce molecules that can interact with cannabinoid receptors even though they may not have the characteristic cannabinoid backbone found in the cannabis-derived phytocannabinoids. You might be familiar with some of these, such as curcumin (from turmeric) and EGCG (from green tea), among others.⁵

The third component of the ECS is the enzymes, which are responsible for both stimulating production of endocannabinoids and breaking down excess endocannabinoids, depending on what is needed at the time. The enzyme component is especially important with the ECS because endocannabinoids are produced on demand, unlike other neurotransmitters which are stored in intracellular compartments. 

Why the ECS Matters for Everyday Balance

Think of the ECS like a traffic control system. When all of the traffic lights are timed well, traffic moves smoothly and stays in balance. When a series of traffic lights gets out of sync or cars refuse to zipper merge in heavy traffic, slow or even stopped traffic can occur. The ECS regulates other neurotransmitters and body systems in a similar way. It controls both levels and activity of neurotransmitters based on signals the body and brain are sending to ECS receptors. The goal of the ECS is to always keep the body in balance, maintaining internal stability (homeostasis).

ECS activity occurs across a spectrum - up or down-regulated as needed - rather than all or nothing, like an on/off switch. This balance of the system is sometimes called ECS tone - or how well the different ECS components are working together at any given time. An ECS with healthy tone is resilient in the face of stressors. When the ECS tone is imbalanced, the body becomes less resilient and may have a harder time adapting to physical or environmental stressors.

Introducing PEA: A Naturally Occurring ECS-Related Compound

PEA is a fatty acid-based molecule that is in the same chemical family as endocannabinoids (like Anandamide) and is naturally produced by the body. However, PEA is often called an endocannabinoid-like signaling molecule because, unlike Anandamide, it doesn’t directly interact with CB1 or CB2 receptors. 

In the 1950s, long before its discovery as part of the endocannabinoid system, PEA was isolated from foods and identified as an inflammation balancing molecule.⁶ There are many food sources of PEA, with some of the highest amounts found in soy, coffee beans, peanuts, wheat, barley, walnuts, and others. PEA is also currently available in dietary supplements. 

How PEA Interacts with the Endocannabinoid System

The body naturally produces endocannabinoid-like PEA in response to pain, inflammation, and stress. It has been studied for decades for its role in cellular signaling and immune communication. When the body experiences a stressful stimulus - such as injury, inflammation, or pain - immune cells in the area produce PEA to act like a “brake” on the body’s natural inflammatory response at the site of the stimulus.⁷ 

The process of stimulus → PEA production → ECS activation is one way in which the body maintains homeostasis. PEA directly activates receptors associated with the ECS and has an indirect effect on CB1 and CB2 receptors. It can then influence activation or inhibition of cellular activity via its indirect CB1 and CB2 action, thus helping the body maintain balance during physiological challenges.⁶ In this way, PEA works alongside the ECS, influencing signaling and communication dynamics. 

In addition, research has shown the PEA response is particularly strong within the spinal cord and areas of the brain related to pain sensing (nociception).⁷ In this elegant system (the ECS), PEA can be produced exactly where and when it is needed, allowing it to act locally to help restore balance.

This balancing action is important because if the natural inflammatory process goes unchecked, it could lead to worsening of an injury or potentially longer healing times. In addition, pain pathways could become “wind-up” or “stuck-on” leading to overly sensitive pain receptors.

Furthermore, PEA may influence how long certain endocannabinoids remain active in the body. Sometimes described as an “entourage-like” effect, in vitro studies have shown the potential for PEA to both increase and decrease anandamide levels, an endocannabinoid with direct modulating effects on CB1 and CB2 receptors. 

Via the ECS, PEA helps the body balance inflammation and regulate pain signals. It also helps protect nerve cells and modulates immune-system responses. PEA is an important endocannabinoid-like compound produced by the body to support immune function, brain health, joint health, sleep, and recovery.⁸ 

Important Aspects of PEA Supplementation

Interest in dietary supplementation containing PEA as a strategy to support overall health* has grown significantly in recent years. And while PEA is found in a variety of food sources - and can be produced through fermentation - bioavailability of PEA sources can vary. Bioavailability describes how well a substance is absorbed and made available for use by the body. In dietary supplements, better bioavailability can be achieved through specific formulations or combinations of nutrients. For example, chelated minerals - a mineral attached to an organic acid, such as magnesium glycinate or zinc picolinate - are more bioavailable than elemental forms.

PEA is one such ingredient that is not well-absorbed and utilized on its own. PEA does not dissolve well in water or other solvents. In this case, newer technologies create nutrient forms with improved absorption and bioavailability. Phytosome technology combines a fat-soluble ingredient (sunflower lecithin, a natural source of phosphatidylcholine) with an active ingredient (PEA) to create a complex that is better absorbed than the active ingredient alone. In a pre-published clinical trial, PEA phytosome had up to six times better bioabsorption compared to normal PEA - which means more efficient absorption and consistent availability in the body.

Conclusion

The ECS is a foundational communication network that helps the body maintain balance in response to everyday physical and environmental demands. Rather than acting as an on-off switch, the ECS continuously adjusts to support coordination across multiple systems in the body. Both internally and externally created cannabinoids can play a role in ECS function. PEA is a naturally occurring compound that plays a meaningful role within this system. By interacting with ECS-related pathways and supporting signaling processes, PEA represents a natural support to engage with the body’s own balance mechanisms.*

References

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