EPEA.Eicosapentaenoyl ethanolamide

EPEA is the omega-3 congener of anandamide: the same ethanolamide head, but an eicosapentaenoyl chain with five double bonds derived from EPA. Its pharmacology was established on membranes and cell lines: a partial agonist at CB1 and CB2, with an affinity clearly below that of anandamide and a partial maximal effect in G-protein coupling assays, CB1 being measured on mouse brain membranes and CB2 on the human receptor expressed in CHO cells (Brown 2010). The considerable gap between the Ki values measured with and without a hydrolase inhibitor, 55 nM against 2000 nM at CB1, indicates that the molecule is hydrolysed very fast by FAAH, which limits its duration of action and complicates the interpretation of binding assays. It also activates the TRPA1 channel, with no significant effect at TRPV1 (Abate 2025). The antiproliferative effects reported in prostate cancer cell lines occur at concentrations that do not match its activity at CB1 or CB2, which points to mechanisms independent of the cannabinoid receptors, involving in particular the epoxides formed by cytochromes P450 (McDougle 2017). No clinical trial has evaluated EPEA: human data are lacking, and nothing in the literature allows any therapeutic benefit to be attributed to it.

Source

An endogenous molecule, absent from cannabis. EPEA is produced by animal tissues from eicosapentaenoic acid (EPA, 20:5 n-3), an omega-3 fatty acid supplied by oily fish and marine oils. Its tissue concentrations follow dietary intake: in rodents, a fish-oil-enriched diet increases EPEA in plasma, ileum and adipose tissue, and spares it from the hepatic fall observed for most other N-acylethanolamines. It has been measured in the brain, the liver and the small intestine, as well as in cultured adipocytes.

EPEA follows the N-acylphosphatidylethanolamine pathway, the same one as anandamide. An N-acyltransferase transfers an eicosapentaenoyl residue from a membrane phospholipid onto the amine function of a phosphatidylethanolamine, which forms a NAPE; a specific phospholipase D (NAPE-PLD), or alternative pathways passing through lyso intermediates, then releases the ethanolamide. The quantity produced depends directly on the proportion of EPA esterified in the membrane phospholipids, hence on the diet, which makes EPEA a mediator whose level is driven by substrate rather than by dedicated enzymatic regulation.

European Union

No listing under the international conventions of 1961 and 1971, no evaluation by the WHO Expert Committee on Drug Dependence, no notification to the European Union's early warning system managed by the EUDA (formerly the EMCDDA). Member States treat EPEA as an endogenous lipid metabolite and not as a controlled substance. Commercial use outside research would fall under the Union's food or cosmetic frameworks, not under narcotics law.

France

EPEA is an endogenous lipid, produced by the body from dietary omega-3 fatty acids. It is named in no French decree scheduling narcotic drugs or psychotropic substances. Nor is it caught by the generic clause of annex III of the decree of 22 February 1990, which covers tetrahydrocannabinols, their esters, their ethers, their salts and the salts of the aforementioned derivatives: EPEA is neither a tetrahydrocannabinol nor a derivative of that kind, it is the amide of a fatty acid. It is therefore unscheduled, and its natural presence in tissues as in EPA-rich foods carries no regulatory consequence. Placing on the market a product containing isolated EPEA would fall under food law or cosmetics law depending on the use claimed, and not under narcotics regulation.

Sources: EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA. Our method.

Family

Endocannabinoid or related mediator › Endocannabinoidome

Verification

Every fact on this entry was checked against its primary sources on 20 October 2026.

Wikipedia (English)

No dedicated article.

1. 1Brown I. et al., Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in prostate cancer cell lines, Carcinogenesis 2010 (new tab)PMID 20660502
2. 2Artmann A. et al., Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine, Biochim Biophys Acta 2008 (new tab)PMID 18316044
3. 3Sheskin T., Hanus L., Slager J., Vogel Z., Mechoulam R., Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor, J Med Chem 1997 (new tab)PMID 9057852
4. 4Abate A. et al., Polyunsaturated fatty acids and their endocannabinoid-related metabolites activity at human TRPV1 and TRPA1 ion channels expressed in HEK-293 cells, PeerJ 2025 (new tab)PMID 40151457
5. 5McDougle D.R. et al., Anti-inflammatory ω-3 endocannabinoid epoxides, PNAS 2017 (CYP450 pathway, EEQ-EA, 17,18-EEQ-EA) (new tab)PMID 28687674
6. 6PubChem CID 5283450, N-eicosapentaenoylethanolamine (formula and identifiers) (new tab)

SMILES

CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCO

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