PEA: The Multiple Target Molecule Palmitoylethanolamide (PEA): The Multiple Target Molecule KEY PLAYER IN THE ENDOCANNABINOID SYSTEM By Dr. Traj Nibber, Founder and CEO of Advanced Orthomolecular Research BACKGROUND: THE ENDOCANNABINOID SYSTEM The body has multiple systems that help regulate and referred to as the Endocannabinoidome. maintain normal housekeeping – nervous, circulatory, In common parlance, however, it is still referred immune, endocrine and gastrointestinal systems, to to as the Endocannabinoid System, hence the name a few. These systems not only modulate different title of this White Paper. tissues and organs to function properly, but also facilitate communications both within the system and INTRODUCTION: PALMITOYLETHANOLAMIDE (PEA) with other systems. Palmitoylethanolamide (PEA) is an 18-carbon long- As recent as the 1990s, another system was identified chain fatty acid that is typically found in eggs, milk, and termed the Endocannabinoid System. It also cheese, meats and peanuts, and is especially abundant helps with communication, and it prepares the body in soy lecithin (Appendix 1). against attack by a variety of harmful insults: stress, carcinogens, pain, inflammation, infections, UV PEA is an intriguing health molecule that has been damage, etc. Initially the definition was confined to studied for over eighty years. What makes it unique what were referred to as the endocannabinoids (ECs), is being a natural molecule made by the body that being two molecules – arachidonoylethanolamide whenever the demand arises; for example, during or anandamide (AEA) and 2-arachidonoylgycerol stress (psychological and physical), infections (viral (2-AG) – produced by the body which act on the and bacterial [e.g., colds and flu]), various forms of two cannabinoid receptors (CB1 and CB2) located inflammation, trauma, allergies, pain, cardiac disease, throughout the body (mainly the central nervous kidney disease and obesity. It is responsible for system and immune system, respectively). The maintaining overall cellular health or homeostasis. enzymes that help in the synthesis and breakdown of ECs were included as part of the system. In the body, PEA is synthesized from the phospholipids which make up all membranes. Since all cells are Further research has since identified more players made up of membranes, it is no wonder PEA is found thought to have critical roles in this system, including everywhere in the body and is available to all cells additional enzymes, other receptors (including efficiently and quickly. PEA is significant not only as a some “orphan” receptors), as well as other molecules cellular messenger, relaying information to and fro in that the body produces including fatty acids the body, but also in acting as a quick fix or solution to palmitoylethanolamide (PEA), oleolylethanolamide cellular needs. In short, PEA is a go-to-molecule which (OEA), stearolyethanolamide (SEA), linoylethanolamide maintains optimal cellular health throughout the body. (LEA) etc. As a result, the definition of this vital system has been expanded within the scientific Synthesis of PEA takes place by the enzyme community to be more encompassing, and now is N-acylated phosphatidylethanolamine–phospholipase AOR Canada AOR US 3900 - 12 Street NE 30 Industrial West Calgary, AB Canada T2E 8H9 Clifton, NJ 07012 1-800-387-0177 | aor.ca 1-866-215-0450 | aorhealth.com PEA: The Multiple Target Molecule D (NAPE-PLD). Once PEA has performed its function, researcher Rita Levi-Montalcini and her work in the it is rapidly broken down by two enzymes, fatty acid early 1990s. Italian scientists remain world leaders in amide hydrolase (FAAH) and N-acylethanolamine acid the field of PEA research. amide hydrolase (NAAA) (Fig. 1). PEA has actions both in the central nervous system and the peripheral nervous system. However, PEA does not have a direct effect on CB1 or CB2 receptors, which differentiates it from the action of specific phytocannabinoids derived from marijuana or hemp (e.g., cannabidiol [CBD] or tetrahydrocannabinol [THC]). Instead, PEA works through a number of different mechanisms (Fig. 2). • Direct action by down-regulating the mast cells. Mast cells are present throughout the body and play a key role in immunity, inflammation, allergies and neural health. PEA has been shown to either prevent their recruitment to the site of damage and/or inhibit their degranulation or release of histamine and other key inflammatory mediators in many pathological conditions. Researchers have shown that when treated with PEA, mast cells switch from an “active” stage to a “resting” phenotype, meaning they become Figure 1. Diagrammatic representation of the synthesis dormant. This suggests PEA could be a powerful and breakdown of PEA. molecule for immune health, inflammation, pain, (Source: Skaper et al., 2018, p. 15) neuro-protection and especially allergies. • Direct action on orphan receptors like GPCR55 and GPR119 that produce results similar to the ORIGIN classical activation of the CB1 and CB2 receptors by phytocannabinoids like THC and CBD. Alvin F. Coburn first studied PEA while researching the effects of egg yolk in preventing the recurrence • Direct action on the perioxisome proliferator of rheumatic fever in poor children living in New York activated receptor alpha and delta and gamma in 1939. He found that the phospholipid fraction in (PPAR-alpha, delta and gamma). PPARs are egg yolk could effectively prevent streptococcal transcription factors in the nucleus that can switch infection. Additional follow-up studies in New York as on and off genes that control pain and inflammation. well as Chicago confirmed the effectiveness of the PPARs also have other functions in obesity and phospholipid fraction during outbreaks of infection. glucose metabolism. Later, soy phospholipids were found to be a more plentiful and cheaper source, and it was confirmed • Indirect action on other receptors like transient that PEA was indeed the active fraction. Since then, receptor potential vanilloid-type 1 (TRPV1, also PEA has been extensively studied in numerous health known as capsaicin receptor), which opens or closes conditions (Appendix 2). ion channels allowing a flow of sodium, magnesium and potassium ions into cells and is associated with MECHANISM OF ACTION transferring pain signals. • Direct action by inhibiting enzymes such as fatty It is important to know how a drug works, especially acid amide hydrolase (FAAH) and monoacylglycerol at the molecular level. Knowing a drug’s “mechanism (MAGL) that degrade the naturally produced of action” allows researchers to develop optimal endocannabinoids (ECs) AEA and 2-AG respectively, formulations, dose and delivery systems to be tested thus allowing for prolonged therapeutic action of in clinical trials. It took almost fifty years after PEA’s these ECs on CB2 receptors. initial discovery before its mechanism of action was finally worked out. The credit for this goes to Italian AOR Canada AOR US 3900 - 12 Street NE 30 Industrial West Calgary, AB Canada T2E 8H9 Clifton, NJ 07012 1-800-387-0177 | aor.ca 1-866-215-0450 | aorhealth.com PEA: The Multiple Target Molecule FIGURE 2. DIAGRAMMATIC REPRESENTATION OF MECHANISMS OF ACTION OF PEA. A shows synthesis and breakdown. B depicts a direct effect of PEA on PPAR-alpha and GPR55 receptors. C depicts a direct effect of PEA by inhibiting FAAH enzyme, thereby elevating AEA and 2-AG levels which activate CB2 and TRPV1 receptors. D depicts an indirect effect on TRPV1 by having a direct effect on AEA and 2AG. E shows a direct effect of PEA on PPAR-alpha. (Source: Petrosino & Di Marzo, 2017, p. 1351) UNIQUE EFFECTS OF PEA Cannabinomimetic effects A remarkable feature of PEA is that its chemical structure is very similar to the ECs (both AEA and Entourage Effect 2-AG), even more so than the phytocannabinoids The entourage effect is an indirect mechanism of (derived from various sources, chiefly hemp and action whereby the biological effects of ECs and marijuana) (Fig. 3). In fact, the structural similarities phytocannabinoids are enhanced by related naturally allow PEA to produce effects similar to the produced molecules like PEA, which do not produce ECs as well as enhancing the effects of those effects by themselves. The enhanced effect exogenous phytocannabinoids. may occur either by preventing the breakdown of ECs or phytocannabinoids through inhibiting the enzymes that degrade them, or by increasing the receptor PEA Formulation and Bioavailability binding affinity of ECs or phytocannabinoids. PEA PEA is a lipid molecule so it has poor solubility, has been shown to display the entourage effect in absorption and overall bioavailability. In order to different health conditions. An elegant demonstration overcome these hurdles, novel delivery systems are of this occurred in hypertensive rats, where it was required, including nano-emulsions, liposomes, solid observed that blood pressure was reduced with the lipid particles and other nano-delivery systems (Conte addition of PEA to otherwise ineffective doses of AEA et al., 2017). Alternatively, bioavailability may also be (Garcia et al., 2009). improved through by-passing the first-pass effect of the liver, so that absorption occurs via the lymphatic system as opposed to the circulatory system (Zgair et al., 2017). AOR Canada AOR US 3900 - 12 Street NE 30 Industrial West Calgary, AB Canada T2E 8H9 Clifton, NJ 07012 1-800-387-0177 | aor.ca 1-866-215-0450 | aorhealth.com PEA: The Multiple Target Molecule FIGURE 3. CHEMICAL STRUCTURES OF PEA, ENDOCANNABINOIDS AND PHYTOCANNABINOIDS. (Source: Tsuboi et al., 2018, p. 2) CLINICAL APPLICATIONS (Ghaufori et al., 2013). This deficiency theory is not unlike the hypothesis of Ethan Russo, a long time As stated previously, PEA is the body’s go-to- researcher of cannabinoids, who first proposed in molecule and is made on demand when required under 2004 that a deficiency in the ECs may exist and be disease conditions. Due to its ubiquitous nature the causative factor in many pathological conditions and presence in all cells, PEA has wide-ranging (Russo, 2004). Several studies have shown that when therapeutic applications.