Suspected endocannabinoid. Does not bind classical cannabinoid receptors (CB1/2) but targets additional cannabinoid receptors PPARα, GPR119 and GPR55.

Chemical Name: 
IUPHAR entry: 
Wikipedia entry: 
Synthetic Pathways: 

NAT: N-acyltransferase (Ca2+-dependent)

Produces NAPE from phospholipids.

iNAT: N-acyltransferase (Ca2+-independent)

Produces NAPE from phospholipids. Low abundant in brain.

NAPE-PLD: N-acyl-phosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D

Produces PEA from NAPE

Lyso-PLD: lyso-phospholipase D

GDE1: glycerophosphodiester phosphodiesterase 1

PTPN22: protein tyrosine phosphatase, non-receptor type 22  


Degradation Pathways: 

FAAH-1: fatty acid amide hydrolase-1

FAAH-2: fatty acid amide hydrolase-2

NAAA: N-acylethanolamine-hydrolyzing acid amidase  

Literature Discussion: 


Amyloid beta plaques, a hallmark of Alzheimer’s, induce neuroinflammation and astrogliosis. Endogenous PEA levels rise with astrogliosis. PEA, in turn, blocks pro-inflammatory cytokines through PPARα (Scuderi et al., 2011). This suggests that the PEA-PPARα interaction functions to curtail neuroinflammation and inhibit the progression of Alzheimer’s.

Alzheimer’s patients have higher serum levels of 2AG and PEA. In these patients, 2AG is positively correlated with cognitive performance suggesting therapeutic potential. PEA was inversely correlated with cognitive performance, underlining the differential characteristics of cannabinoids (Altamura et al., 2015).


Hippocampal Anandamide, OEA and PEA were increased after social exposure (Kerr et al., 2013) once more stipulating the involvement of the endocannabinoid system in autism.


Another rat study found that endocannabinoid PEA and CB1 were upregulated, PPARα was downregulated and CB2 was unchanged upon induction of Cystitis (Pessina et al., 2014). PEA attenuated pain and bladder voiding. This effect was blocked by CB1 and PPARα antagonists. Several studies found that CB2 was upregulated with Cystitis (Merriam et al., 2008; Tambaro et al., 2014) and that activation of CB2 with Anandamide or PEA attenuated pain and inflammation (Jaggar et al., 1998; Wang et al., 2013, 2014).


In an experimental mouse model of Eczema endocannabinoids AEA and PEA were increased and TRPV1 and PPARα were upregulated (Petrosino et al., 2010). PEA enhances AEA activity at CB1CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1CB2 or PPARα-dependent way.

Functional Gastro-Intestinal Disorders

In patients with diarrhea-type IBS higher levels of 2AG and lower levels of OEA and PEA were found. In contrast, patients with constipation-type IBS had higher levels of OEA and lower levels of FAAH. Also, PEA levels were inversely correlated with abdominal pain suggesting substantial involvement of the endocannabinoid system in the pathophysiology of IBS (Fichna et al., 2013).

Hypoxic-ischemic encephalopathy

cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013).

multiple sclerosis

In a mouse study, plant cannabinoid CBD and endocannabinoid PEA each individually reduced inflammation and neuronal demyelination (Rahimi et al., 2015).


In patients with Chronic Widespread pain, the endocannabinoid PEA was found to provide homeostatic pain control through the PPARα receptor (Ghafouri et al., 2013).


Similarly, systemic application of OEA, and to a lesser extent PEA, was found to inhibit pro-inflammatory cytokines and thus to protect against neurodegeneration (Sayd et al., 2014).


Altamura, C., Ventriglia, M., Martini, M.G., Montesano, D., Errante, Y., Piscitelli, F., Scrascia, F., Quattrocchi, C., Palazzo, P., Seccia, S., et al. (2015). Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer’s Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline. J. Alzheimers Dis. JAD.

England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358

Fezza, F., Bari, M., Florio, R., Talamonti, E., Feole, M., & Maccarrone, M. (2014). endocannabinoids, related compounds and their metabolic routes. Molecules (Basel, Switzerland), 19(11), 17078-17106.

Fichna, J., Wood, J.T., Papanastasiou, M., Vadivel, S.K., Oprocha, P., Sałaga, M., Sobczak, M., Mokrowiecka, A., Cygankiewicz, A.I., Zakrzewski, P.K., et al. (2013). endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study. PloS One 8, e85073.

Ghafouri, N., Ghafouri, B., Larsson, B., Stensson, N., Fowler, C.J., and Gerdle, B. (2013). Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity. pain 154, 1649–1658.

Jaggar, S.I., Hasnie, F.S., Sellaturay, S., and Rice, A.S. (1998). The anti-hyperalgesic actions of the cannabinoid Anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory painpain 76, 189–199.

Kerr, D.M., Downey, L., Conboy, M., Finn, D.P., and Roche, M. (2013). Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav. Brain Res. 249, 124–132.

Lara-Celador, I., Goñi-de-Cerio, F., Alvarez, A., and Hilario, E. (2013). Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury. Neural Regen. Res. 8, 731–744

Merriam, F.V., Wang, Z., Guerios, S.D., and Bjorling, D.E. (2008). cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats. Neurosci. Lett. 445, 130–134.

Pessina, F., Capasso, R., Borrelli, F., Aveta, T., Buono, L., Valacchi, G., Fiorenzani, P., Di Marzo, V., Orlando, P., and Izzo, A.A. (2014). Protective Effect of Palmitoylethanolamide in a Rat Model of Cystitis. J. Urol.

Petrosino, S., Cristino, L., Karsak, M., Gaffal, E., Ueda, N., Tüting, T., Bisogno, T., De Filippis, D., D’Amico, A., Saturnino, C., et al. (2010). Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy 65, 698–711.

Rahimi, A., Faizi, M., Talebi, F., Noorbakhsh, F., and Naderi, N. (2015). Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL/6 mice. Neuroscience.

Sayd, A., Antón, M., Alén, F., Caso, J.R., Pavón, J., Leza, J.C., Rodríguez de Fonseca, F., García-Bueno, B., and Orio, L. (2014). Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP 18.

Scuderi, C., Esposito, G., Blasio, A., Valenza, M., Arietti, P., Steardo, L., Carnuccio, R., De Filippis, D., Petrosino, S., Iuvone, T., et al. (2011). Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide. J. Cell. Mol. Med. 15, 2664–2674.

Tambaro, S., Casu, M.A., Mastinu, A., and Lazzari, P. (2014). Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial Cystitis. Eur. J. Pharmacol. 729, 67–74.

Wang, Z.-Y., Wang, P., and Bjorling, D.E. (2013). Activation of cannabinoid receptor 2 inhibits experimental Cystitis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R846–R853.

Wang, Z.-Y., Wang, P., and Bjorling, D.E. (2014). Treatment with a cannabinoid receptor 2 agonist decreases severity of established Cystitis. J. Urol. 191, 1153–1158.

Clinical Trials: 


Several clinical trials have tested the therapeutic potential of cannabinoids after stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after stroke (England et al., 2015). Specifically activating CB1 and/or CB2 receptors had the strongest protective effect but other receptors such as 5-TH1a and PPARα are also likely to be involved.


England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.