Palmitoylethanolamide (PEA) is a naturally occurring compound gaining scientific attention for its potential health benefits. This fatty acid amide is found within the body and in certain foods, playing a role in cellular balance and various physiological processes.
What is Palmitoylethanolamide
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, naturally produced within the body. It is present in trace amounts across all mammalian tissues, including the central nervous system, where it is synthesized in response to injury or inflammation as a protective mechanism. PEA is also found in foods like egg yolks, soybeans, alfalfa, and peanuts. First identified in the 1950s for its anti-inflammatory properties, PEA has since been classified as an endocannabinoid-like compound. This reflects its structural and functional similarities to the body’s own endocannabinoids and highlights its involvement in regulating numerous bodily functions.
How Palmitoylethanolamide Interacts with the Body
Palmitoylethanolamide exerts its effects through several molecular pathways, primarily involving the endocannabinoid system. While PEA does not directly bind to classical cannabinoid receptors (CB1 and CB2) with high affinity, it indirectly modulates their activity [2, 3, 5, Browse 2]. This occurs by inhibiting the enzyme fatty acid amide hydrolase (FAAH), which breaks down anandamide (AEA), an endogenous cannabinoid [2, Browse 2]. By slowing AEA degradation, PEA increases AEA levels, enhancing AEA’s effects on CB1 and CB2 receptors in what is known as the “entourage effect” [2, 5, Browse 2].
PEA also directly activates peroxisome proliferator-activated receptor alpha (PPAR-α), a nuclear receptor [2, 3, 4, 5, Browse 1, Browse 2]. Activation of PPAR-α regulates gene networks involved in controlling pain and inflammation, contributing to PEA’s anti-inflammatory and neuroprotective properties [2, 3, 4, Browse 1, Browse 2]. This direct interaction also modulates immune cell activity, such as mast cells, which are involved in inflammatory processes [2, 4, Browse 2].
PEA interacts with other targets, including the G protein-coupled receptor 55 (GPR55) and the transient receptor potential vanilloid receptor 1 (TRPV1) [3, 4, 5, Browse 1, Browse 2]. Its actions on TRPV1 channels contribute to its pain-relieving effects through desensitization [Browse 1].
Research on Palmitoylethanolamide and Anxiety
Scientific investigations have explored PEA’s potential to alleviate anxiety symptoms, with promising results in both animal models and human trials. Studies indicate that PEA may reduce anxiety-like behaviors by influencing various neurological and physiological pathways. For instance, in obese mice, PEA treatment improved anxiety-like behavior and reduced systemic inflammation [Browse 2]. This was associated with increased dopamine turnover and gamma-aminobutyric acid (GABA) levels in the amygdala, a brain region involved in emotional processing, alongside reduced pro-inflammatory mediators [Browse 2].
PEA may also counteract overactivation of the hypothalamic-pituitary-adrenal (HPA) axis, a system involved in the body’s stress response [Browse 2]. In mouse models of chronic restraint stress, PEA demonstrated antagonistic effects on anxiety and depression-like behaviors, possibly by regulating HPA axis function and increasing serotonin (5-HT) levels in the hippocampus [Browse 4]. These findings point to PEA’s potential to modulate neurochemical imbalances often associated with anxiety.
Clinical findings also support PEA’s anxiolytic potential. A double-blind, randomized, placebo-controlled study involving osteoarthritis patients noted that PEA supplementation reduced stress and anxiety, in addition to improving knee pain [Browse 1]. In a trial for major depressive disorder with anxious distress, PEA as an adjunctive therapy with citalopram resulted in greater improvement in depressive symptoms [Browse 1, Browse 3]. These findings suggest PEA’s broader role in mood regulation and stress resilience.
Using Palmitoylethanolamide Safely
Typical dosages of PEA in studies range from 300 mg to 1,200 mg per day, often divided into multiple doses [1, Browse 1, Browse 2, Browse 4]. Some research explores higher doses, up to 1.8 grams or 2.4 grams per day, particularly for certain conditions [3, Browse 5]. PEA supplements are available in various forms, including powders and capsules, with micronized and ultra-micronized formulations often used to improve absorption and bioavailability [3, 5, Browse 2].
PEA is generally well-tolerated, with a low incidence of side effects [2, 3, Browse 1, Browse 2, Browse 3, Browse 4]. Reported mild side effects include gastrointestinal discomfort, headache, dizziness, nausea, and occasional fatigue or drowsiness [1, 3, Browse 1, Browse 2, Browse 3].
While limited reports exist on specific drug interactions, caution is advised when combining PEA with medications affecting the endocannabinoid or immune systems, such as anti-inflammatory drugs [1, Browse 1, Browse 3]. Always consult a healthcare professional before starting any new supplement, especially if you have existing health conditions or are taking other medications [1, Browse 1, Browse 3].
Insufficient evidence exists regarding PEA’s safety during pregnancy or breastfeeding, so it is generally recommended to avoid its use unless directed by a doctor [1, Browse 2, Browse 3]. While short-term use (up to approximately three months) appears safe, the effects of longer-term use are less extensively documented, though no serious concerns have been consistently reported [Browse 2, Browse 3, Browse 4].