Palmitoyl ethanolamide (PEA) is an endogenous fatty N-acyl ethanolamine and a derivative of the endocannabinoid arachidonoyl ethanolamide (AEA).^1,2 It selectively activates peroxisome proliferator-activated receptor α (PPARα; EC50 = 3.1 µM) over PPARβ/δ and PPARγ in HeLa cells expressing the human receptors.³ PEA binds to RBL-2H3 basophil membranes (IC50 = 1 nM), which endogenously express cannabinoid 2 (CB2), but not CB1, receptors, and inhibits antigen-induced serotonin release from RBL-2H3 cells (EC50 = 0.27 µM).² It prevents decreases in paw withdrawal latency in a radiant heat hypersensitivity test, an effect that can be reversed by the CB1 receptor antagonist SR141716 (rimonabant), PPARγ antagonist GW 9662 , and transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine , in a mouse model of neuropathic pain induced by chronic constriction injury of the sciatic nerve.⁴ PEA (10 mg/kg) decreases carrageenan-induced paw edema in wild-type, but not Ppara-/-, mice.³ It inhibits tonic convulsions induced by pentylenetetrazole (PTZ) in rats when administered at a dose of 40 mg/kg.⁵ Formulations containing palmitoyl ethanolamide have been used as dietary supplements.