Palmitoylethanolamide (PEA) is an endogenous endocannabinoid receptor agonist and naturally occurring fatty acid amide in the N-acylethanolamines family. As an autocoid local injury antagonist amide, it plays a role in lipid metabolism, nociceptor inhibition, and downregulation of inflammation. These actions have led to researchers looking into its potential for supporting a normal pain response.

Studies have found that PEA downmodulates mast cells and associated proinflammatory modulators by modulating the immune system and inflammatory response. It also inhibits glial cells. PEA stimulates the endocannabinoid system (ECS), which is involved in pain and other disorders. PEA works directly or indirectly by activating key ECS receptors including proliferator-activated receptor alpha, cannabinoid receptor type 1 and 2, transient receptor potential cation channel subfamily V member 1/vanilloid receptor 1 (TRPV1), and the orphan G-coupled protein receptor 55. By enhancing the levels of two endocannabinoid agonists (N-arachidonoylethanolamine and 2-arachidonoylglycerol), it supports the activation of CB2, CB1, and TRPV1 to create an entourage effect that stimulates endogenous endocannabinoid activity.

Clinical studies have found that these actions may support chronic pain in a variety of conditions. In one study, supplementing with 600 mg PEA twice daily either alone or as an adjunct therapy for 3 weeks and then downgrading to once daily for 4 additional weeks led to a significant decrease in the mean score pain of all patients in the study. This was independent of the pathological condition associated with chronic pain.

Two meta-analyses also support the potential for PEA to contribute to a significant reduction in pain. The findings showed that PEA treatment led to a fivefold more rapid reduction of pain intensity over time compared to the control group. The PEA-treated group also experienced a reduction in the pain scale of 1.04 points every 2 weeks (with a 35% variability) compared to 0.20 points (1% variability) in the control group. PEA treatment for 60 days also led to a pain score ≤3 in 81% of the patients compared to 40.9% in the control. The researchers also confirmed the safety of PEA, including that it does not interfere with poly-drug therapies.As these clinical studies and more demonstrate, the properties of PEA, particularly its actions on the ECS, show potential for supporting a variety of chronic pain conditions alone or as an adjunct therapy. PEA can be found in food sources such as peanuts, soybeans, eggs, milk, tomatoes, and black-eyed peas. Some people may find it beneficial to supplement with higher levels to promote a natural pain response.* 

By Kendra Whitmire, MS, CNS