Food and Behaviour Research

Donate Log In

Alcohol: What Women Need to Know - BOOK HERE

Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair

Dyall SC (2017) Lipids 52(11) 885-900. doi: 10.1007/s11745-017-4292-8. Epub 2017 Sep 5. 

Web URL: Read this and related abstracts on PubMed here. Free full text of this article is available online


The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis.

ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. 

Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids.

Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules.

This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.


This review provides a summary of the interactions between key long-chain polyunsaturated fatty acids (derived from diet) and the 'endocannabinoid' system, with particular reference to brain development and function, and protection from brain disorders.

Both the long-chain omega-3 fatty acids found in fish and seafood (EPA and DHA) and the long-chain omega-6 found in meat, eggs and dairy products (arachidonic acid - AA, or ARA) are substrates or 'raw materials' for the production of 'endogenous' cannabinoids - i.e. ones that are made within the body and brain.

Modern, western-type diets are relatively deficient in omega-3, while providing an excess of omega-6 fats. This serious imbalance would be expected to have effects on the balance of endocannabinoids, which like omega-3 and omega-6, also affect numerous aspects of brain development and function. Research has already shown that this imbalance in early life can permanently abolish normal endocannabinoid signalling and raise the risks for anxiety, depression and other mental health conditions. See:

This excellent new review explains the basic relationships between omega-3, omega-6 and key endocannabinoids - highlighting the complexities of their interplay.  It explains how the balance between these substances can affect the development of new brain cells (neurogenesis), the making of new connections between brain and nerve cells (synaptogenesis - the basis of all learning and memory) and the protection of brain cells from damage, with particular reference to their roles in promoting or controlling inflammation.