DHEA-EA.Docosahexaenoyl ethanolamide

An omega-3 cousin of anandamide, this N-acylethanolamide stands out for a target outside the classic cannabinoid system: the adhesion receptor GPR110 (ADGRF1), identified in 2016 as the receptor for docosahexaenoyl ethanolamide. Its activation engages a Gαs pathway, raises cAMP and recruits PKA, a mechanism to which the neuritogenesis, synaptogenesis and dampening of NF-κB nuclear translocation described in cells and in mice are attributed (Lee 2016; Park 2019). Cannabinoid activity exists but stays secondary: the affinity is 633 nM at CB1 on mouse brain membranes and 3843 nM at human CB2, far from the nanomolar potencies recorded at GPR110, and several effects attributed to the molecule persist when CB1 and CB2 are blocked (Brown 2010). Work in mice nevertheless shows a raised seizure threshold suppressed by a CB1 antagonist, confirming a genuine though minor cannabinoid contribution (Ghanbari 2021). Inactivation runs through FAAH and through COX-2 and lipoxygenase oxygenations producing metabolites that are themselves active on macrophages (Yang 2011; de Bus 2019). Human data are lacking: no administration study, no clinical trial, the molecule being documented in humans only by its endogenous presence, notably in breast milk (Smith 2018). No therapeutic benefit is established.

Source

An endogenous mammalian molecule, humans included: it has been detected in human breast milk (Smith 2018). It does not exist in cannabis and derives from no phytocannabinoid: it comes from docosahexaenoic acid (DHA), a dietary omega-3 fatty acid supplied mainly by oily fish and marine oils. In rats, dietary fat intake changes tissue N-acylethanolamine levels, a fish-oil-enriched diet sparing precisely docosahexaenoyl ethanolamide and EPEA from the liver decrease seen for the others (Artmann 2008). Not to be confused with hormonal DHEA, dehydroepiandrosterone, an adrenal steroid that shares with it neither structure, nor formation pathway, nor pharmacology: only the acronym is close.

Formation through the classic N-acylethanolamide pathway: a DHA residue carried by a phospholipid is transferred onto phosphatidylethanolamine by an N-acyltransferase, which produces N-docosahexaenoyl-phosphatidylethanolamine, a precursor subsequently hydrolysed by NAPE-phospholipase D to release the ethanolamide. Alternative pathways independent of NAPE-PLD have been described for this family of lipids. The availability of dietary DHA directly governs the quantities formed in tissues.

European Union

No international classification: the molecule appears neither in the United Nations conventions of 1961 and 1971, nor in the lists of the EUDA, formerly the EMCDDA, devoted to new psychoactive substances. It circulates in the European Union as a laboratory reagent and as an analytical standard. Any marketing intended for human beings would remain subject, depending on the claim made, to the novel foods regulation or to medicinal product regulation.

France

An endogenous substance, produced naturally by the human organism from a dietary fatty acid. It is named in no French decree classifying narcotics or psychotropics, nor is it caught by the generic clause of the decree of 22 February 1990, annex III, which covers the tetrahydrocannabinols, their esters, ethers, salts and the salts of those derivatives: this compound is neither a tetrahydrocannabinol nor a tetrahydrocannabinol derivative. Its status is therefore that of an unscheduled molecule, neither by name nor by clause. Placing it on the market as a food ingredient or as a supplement would, on the other hand, fall under the European novel foods regulation and the corresponding national assessment, a framework in which no specific authorisation is known.

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. 1Bisogno T. et al., Biosynthesis and inactivation of N-arachidonoylethanolamine (anandamide) and N-docosahexaenoylethanolamine in bovine retina, Arch Biochem Biophys 1999 (new tab)PMID 10577359
2. 2Kim H.-Y., Spector A.A., Xiong Z.-M., A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development, Prostaglandins Other Lipid Mediat 2011 (new tab)PMID 21810478
3. 3Lee J.W. et al., Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function, Nat Commun 2016 (new tab)PMID 27759003
4. 4Park T. et al., GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine, J Neuroinflammation 2019 (new tab)PMID 31730008
5. 5Brown 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
6. 6Ghanbari M.-M., Gharibi Loron A., Sayyah M., The omega-3 endocannabinoid docosahexaenoyl ethanolamide reduces seizure susceptibility in mice by activating cannabinoid type 1 receptors, Brain Res Bull 2021 (new tab)PMID 33581310
7. 7Yang R. et al., Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals, J Biol Chem 2011 (new tab)PMID 21757729
8. 8de Bus I. et al., The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation, Prostaglandins Other Lipid Mediat 2019 (new tab)PMID 31260750
9. 9Smith S. et al., N-docosahexaenoylethanolamine detected in human breast milk, Prostaglandins Leukot Essent Fatty Acids 2018 (new tab)PMID 30293591
10. 10Artmann 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
11. 11PubChem CID 5283451, Synaptamide (identifiers, formula, InChIKey) (new tab)

SMILES

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

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