Due to the popularity of cannabidiol (CBD), hemp oil, and other cannabis-based supplements and natural medicines, the endocannabinoid system is getting more attention than ever before. But hemp is far from the only nutrient that supports the receptors and natural cannabinoids produced by the body. And the endocannabinoid system and its close relatives are a much bigger family than we may have realized.

Docosahexaenoic acid (DHA) is the major omega-3 fatty acid in the brain, and it is considered a key nutrient for cognitive health. But one of the reasons why DHA is so important seems to center around one of its metabolites called N-Docosahexaenoylethanolamine, or more simply, “synaptamide.”

Synaptamide, as its name suggests, is involved with creating new neurons and moderates potentially damaging inflammation in the brain. The receptor for synaptamide—and just for synaptamide—is expressed especially during neural development. That makes this endocannabinoid-like factor critically important for mothers and their children. And, since the levels of synaptamide depend on a robust source of DHA, getting a strong supplemental source is important, too. One of the best ways of ensuring optimal levels of DHA is to supplement with a form that is bound to phospholipids rather than triglycerides —the phospholipids are simply more reliable carriers of the omega-3 fatty acid, and they provide their own health-promoting abilities as well.

Abstract:
Kim HY, Spector AA. N-Docosahexaenoylethanolamine: A neurotrophic and neuroprotective metabolite of docosahexaenoic acid. Mol Aspects Med. 2018 Mar 20. pii: S0098-2997(18)30024-4.

N-Docosahexaenoylethanolamine (synaptamide) is an endocannabinoid-like metabolite endogenously synthesized from docosahexaenoic acid (DHA, 22:6n-3), the major omega-3 polyunsaturated fatty acid present in the brain. Although its biosynthetic mechanism has yet to be established, there is a closely linked relationship between the levels of synaptamide and its precursor DHA in the brain. Synaptamide at nanomolar concentrations promotes neurogenesis, neurite outgrowth and synaptogenesis in developing neurons. Synaptamide also attenuates the lipopolysaccharide-induced neuroinflammatory response and reduce the deleterious effects of ethanol on neurogenic differentiation of neural stem cells (NSCs). These actions are mediated by a specific target receptor of synaptamide GPR110 (ADGRF1), a G-protein coupled receptor that is highly expressed in NSCs and the brain during development. Synaptamide binding to GPR110 induces cAMP production and phosphorylation of protein kinase A (PKA) and the cAMP response element binding protein (CREB). This signaling pathway leads to the expression of neurogenic and synaptogenic genes and suppresses the expression of proinflammatory genes. The GPR110-dependent cellular effects of synaptamide are recapitulated in animal models, suggesting that synaptamide-derived mechanisms may have translational implications. The synaptamide bioactivity transmitted by newly deorphanized GPR110 provides a novel target for neurodevelopmental and neuroprotective control as well as new insight into mechanisms for DHA’s beneficial effects on the central nervous system.