For decades, we have known about the health benefits of omega-3 fatty acids (FAs), the widespread deficiency of these fats in the Western diet, and crucial roles they play in modulating inflammatory pathways. The force with which research targeted the health benefits of omega-3 FAs has, fortunately, given way to the mass recognition of the need for supplementation (usually in the form of fish oil) in almost all individuals, alongside a high-quality multivitamin. In fact, even the most uninformed layperson has probably heard some accolades about fish oils at this point.

More recently, research has been focusing on a relatively close acquaintance of omega-3 FAs – cannabinoids – and finding that they also play vital roles in modulating inflammation throughout the body. At first, these compounds were studied individually to ascertain their actions and health implications; however, newer research is discovering close interplay between the activities of omega-3 FAs and cannabinoids.

Omega-3FAs (particularly DHA and EPA) are simply the precursors to a large repertoire of bioactive lipid mediators; however, the metabolic pathways of these compounds overlap with the endocannabinoid system in the body. One of the pathways that convert omega-3 FAs into bioactive lipid metabolites includes the conversion of DHA and EPA into docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) through the N-acyl ethanolamine synthesis pathway, which is similar to the process used to convert arachidonic acid (AA) into anandamide (AEA). All three metabolites – DHEA, EPEA, and AEA – activate endocannabinoid receptors, CB1 and CB2. Generally, the body produces two primary endogenous cannabinoids – anandamide (AEA) and 2-arachidonoylglycerol (2-AG) – from the fatty acid, arachidonic acid.

Not only are omega-3 FAs and endocannabinoids connected through metabolic pathways; their individual biological activities also overlap so as to enhance the clinical outcome. For example, the brain is highly enriched with EPA and DHA, which have been shown to be beneficial in promoting learning and memory, decreasing neuroinflammatory processes, and enhancing synaptic plasticity and neurogenesis. Similarly, the brain also contains rich sources of arachidonic acid, the precursor to the endocannabinoids, 2-AG and AEA. These endocannabinoids are important for promoting neuroprotection and pro-neurogenic processes, such as attenuating chronic neuroinflammation, regulating pro-inflammatory cytokine release, and enhancing synaptic plasticity and adult neurogenesis.  Therefore, both omega-3 FAs and endocannabinoids can function to enhance neurocognitive health and function.

Neuroinflammation is one area in which both omega-3 FAs and cannabinoids play important roles. The endocannabinoid system is upregulated during neuroinflammation, as evidenced by an increased expression of CB receptors on microglia in brain tissue from patients with Alzheimer’s disease, multiple sclerosis and amyotrophic lateral sclerosis. Heightened endocannabinoid receptor expression on astrocytes, specifically, is helpful in mitigating the release of cytokines during neuroinflammation. Astrocytes help regulate FA metabolism and endocannabinoid signaling and promote endocannabinoid crosstalk with other lipid mediators which modulate endocannabinoid activity and neuroinflammation.

Both omega-3 FAs and endocannabinoids help regulate synaptic plasticity and, therefore, help improve learning and memory. A plethora of research has already shown DHA and EPA to be useful in cognitive function, but modulation of the endocannabinoid system may be a part of this outcome. When rats were given DHA and the spatial memory analyzed, it was found that spatial memory improved with DHA supplementation, but had dose-dependent effects. The effects corresponded to dose-dependent upregulation of the CB1 receptors in cultured hippocampal neurons. The endocannabinoid system has been shown to modulate aspects of synaptic plasticity, but studies have suggested that these effects are dependent on omega-3 FAs since a deficiency resulted in decreased synaptic activity.

DHA, EPA, and AEA have been shown to increase neurogenesis in various animal models. Both DHA and EPA increase the production of endocannabinoid 2-AG, and EPA utilizes the endocannabinoid signaling pathways (and CB1/2 receptors) to increase cell proliferation.

The interactive roles of omega-3FAs and cannabinoids in various metabolic pathways, but especially in modulating inflammation, are complex. Research has just barely begun to scratch the surface of this network of compounds; however, there is little doubt that they closely interact to help regulate inflammation. Since inflammation is a foundational element in most chronic health conditions, the dual power of both omega-3 FAs and cannabinoids seems to offer another tool for optimizing health beyond the ability of each individual compound.