Too much of a good thing can be a bad thing…
Originally published in May 2019 issue of Natural Practitioner Magazine as a Special Report
The Endocannabinoid System and the known effects of LCPUFAs Omega-3 and Omega-6
While both Omega-3 and Omega-6 fatty acids are considered essential to human health and we must obtain them from our diets, we hear so often how the North American population is plagued by inflammation and how our overconsumption of Omega-6 fatty acids is contributing to this. At least, those of us practicing Integrative Medicine and Nutrition hear about it frequently. The rest of the continent seems to be oblivious as they continue to consume copious amounts of industrial-solvent-refined oils from soy, corn, canola, cottonseed, peanuts, sunflower, safflower, and various forms of margarine and shortening. While these are full of Omega-6 Polyunsaturated Fats, that may not be their worst offense. Soy, Corn, Canola, and Cottonseed will almost always be from genetically modified crops. Thus they will contain Bt Toxin and also residues of glyphosate from being doused in roundup which the plant itself has been modified to tolerate. Additionally they may contain solvent residues from the methods used to extract oils from plants that are not inherently very oily, and lack nutrient balance and antioxidants due to the same extraction methods. Nut and seed oils are also high in Omega-6 fatty acids, but are typically pressed and maintain other valuable nutrients. However, in my practice I tend to caution people not to use any more nuts and seeds than they would be willing to crack open themselves with rudimentary tools. We also find Omega-6 fatty acids in the animal products we eat, due to the plant foods they consume as they grow to maturity. Now, what is wrong with consuming Omega-6 fats from a whole foods, solvent-free, GMO-free diet? Nothing. So long as the ratio of Omega-6:Omega-3 remains within a reasonable range such that our immune and inflammatory systems can remain in balance. We are only just beginning to discover how much of a role the Endocannabinoid System plays in this and how our diet can turn “good” endocannabinoids “bad”.
Arachidonic Acid (ARA), Eicosapentaenoic Acid (EPA), and Docosahexaenoic Acid (DHA) are the fatty acid precursors to a host of bioactive molecules, including the endocannabinoids. (Lipids) Simply put, ARA converts to Anandamide and 2-AG, while EPA and DHA convert to competitive endocannabinoids like DHEA and 2-DHG, all of which are active all over the body.(1) While 50% of the brain is a blend of 120 different fats, it is highly enriched with ARA and DHA, and DHA is the most abundant. In the liver EPA is converted to DHA, and the brain has been analyzed to contain about 3.5mL of DHA at any given time. (GOED and Richard Bazinet, PhD) Enriching the diet with DHA and EPA has been shown to positively benefit learning, memory, neuro-inflammatory processes, neurogenesis, and synaptic plasticity. We also know that the Endocannabinoid System (ECS) plays a critical role in neuro-inflammation, neurogenesis, and synaptic plasticity—thus we can easily draw the conclusion that there are overlapping neuroprotective effects from ingestion of appropriate PUFAS and the proper ratios.(3)
Our ECS spans our entire body, but the locations of different receptors can vary. The ECS includes the cannabinoid receptors, their endogenous ligands called endocannabinoids, and the enzymes to synthesize and degrade these ligands.(3) CB1 receptors are mainly located in the Brain and CNS, as well as the peripheral nervous system. CB2 receptors are mostly located in the immune system at many sites throughout the body and in the brain. ECS imbalances can include anxiety, depression, inflammation, and neuropathic pain. Peripheral receptors are abundant in adipose tissue, the immune system, musculoskeletal tissue, the gonads, and the cardiovascular system.(1) We start to see the connection here as we consider the kinds of health concerns, discomforts, and disorders for which our clients and patients have sought phytocannabinoid products. We should also now begin to see the connections between a Standard American Diet of processed foods and an imbalanced ECS, as it relates to health issues in the various systems just covered. What exactly is the role of the Omega-6 to Omega-3 ratio in our intake of dietary fats? It becomes ever more intriguing as we circle around and see the connections.
The two most abundant and well-understood endocannabinoids are Arachidonoyl Ethanolamine and 2-Arachidonoylglycerol, otherwise known as “Anandamide” or AEA and 2-AG. Much has been made about how AEA got the name “Anandamide” as it is nicknamed the “Bliss Molecule”. Certainly, when the ECS is balanced and the dietary intake of PUFAs is balanced, AEA production and binding to the CB receptors for which these endocannabinoids have great affinity can produce a bliss-like effect that gives us an overall sense of well-being. Many of us have probably asked, “Gee, where can I get more of that?” as it would seem that more bliss would be better, no? Well, the complicated part of this story is that AEA and 2-AG are produced from the infamous Arachidonic Acid (ARA) and, after being rapidly degraded by FAAH or LOX and COX enzymes, return to ARA, as well as ethanolamines or glycerol, respectively. Thus, the more AEA and 2-AG we make, the higher residual pool of ARA we create. Residual ARA goes on to become inflammatory initiators via COX and LOX and Cytochrome P450 pathways. Well, dang! Guess where ARA comes from? It comes from dietary LNA, Linolenic Acid, found in Omega-6 fats specifically. Guess what else can happen with high levels of Omega-6 fats in our diets? According to Dr. David Perlmutter and certain more recent studies (1,2), overconsumption can lead to increased appetite, increase lipogenesis, reduced lipolysis, and reduced mitochondrial biogenesis. Rodents fed diet rich in Omega-6 PUFAs saw 2-AG and AEA levels increase; DHEA, 2-DHG, and EPEA levels decrease; and impaired endocannabinoid plasticity and CBr1 receptor activity.(1) Luckily, phytocannabinoids can counteract this, and Omega-3 derived endocannabinoids compete for binding sites with AEA and 2-AG. It has been shown that a higher fat diet rich in w-3 can lead to weight loss, with a parallel decrease in AEA and 2-AG; whereas a low-fat diet high in w-6 increases weight gain.(1) We cannot conclude this is the only pathway for weight gain or normalization, but it is a contributing factor. A diet enriched in DHA for 2-4 months increased CB1 and CB2 receptors in musculoskeletal tissue and favored glucose uptake in that tissue over uptake in adipose tissue. Testis and Sperm are rich in DHA, and there are abundant EC receptors in the gonads, so there is definitely a role for ECs in fertility, but the mechanisms have yet to be elucidated.(1) We could posit, though, that a high Omega-6 imbalance might contribute to infertility by reducing the amount of DHA in the gonads and the optimal motility and fertility of germ cells.
What are the endocannabinoids which are derived from Omega-3 fatty acids? These come from alpha-linoleic acid, ALA, and are converted to DHA via the same pathways as AEA and 2-AG. DHA can also come directly from the diet and freely cross the BBB via passive diffusion and perhaps some transporters. Both ARA and DHA enter the neurons via esterification in the phospholipid bi-layer of the cell membranes. Once released into the cell, DHA can be converted to DHEA and 2-DHG. Residual DHA goes on to be enzymatically converted through LOX pathways to compounds we are just beginning to recognize as absolutely crucial. These are the SPMs (Special Pro-Resolving Mediators): Resolving D2, Neuroprotectin D1, and Maresin D1. NPD1 protects against neuronal death with an anti-apoptotic protein. Synaptamide, another DHA endocannabinoid derivative, plays an important role in neuronal development and cell differentiation. EPEA and DHEA endocannabinoids are present in the brain in twofold higher concentration than Omega-6 derived AEA, but the affinity for CB receptors is much weaker. They share almost exactly the same pathways and the same enzymes for synthesis and degradation as AEA, which makes it difficult to study them separately. Because current research shows that direct intervention on neuronal health and neuroglial activation with DHA has mixed results, we are realizing that the metabolites such as the SPMs may play the biggest role in balancing out the ECS activity and even reversing diseased states.(3) These SPMs are the true “resolvers” of inflammation. They balance out the “burn” from the fires of inflammation and put them out when the job is done. A deficiency on this side of the equation means that the inflammation burns unchecked like California wildfires. There is ongoing research into how the metabolites of Omega-3 derived endocannabinoids activate CB receptors throughout the whole body, to demonstrate the full body actions which the ECS may exert.(2) Rodents fed a diet rich in Omega-3s, especially EPA and DHA, saw Omega-3 derived endocannabinoids increase; 2-AG and AEA decrease, and positive impacts on synaptic plasticity.(1)
Also, although DHA and EPA can be synthesized in the liver from dietary ALA, the conversion is not very efficient in humans due to the shared delta-6 desaturase enzymatic pathways and higher conversion rates of LNA to ARA. Zinc deficiency can also impair the conversion. Thus the best way to see results and changes in health is to eat or supplement these two directly. Again, although the liver can convert EPA to DHA, Dietary DHA can easily cross the BBB as is, and has demonstrated effects on neuronal survival by triggering BDNF production (see more on BDNF in article on Ageing and the Brain, NP). (1)
What research seems to show, however, is that maintaining adequate Omega-3 intake is crucial. EPA and DHA are both important for different reasons. And now we are realizing that our Omega-3 supplements have been rendered devoid of the other nine Omega-3s that may actually be in whole seafood, as well as the SPMs that those fish create. Liver oil from Cod in the Pacific seems to be especially high in these SPMs as they are developed to protect the animal in a stressful environment. Human breast milk is not only high in DHA, but also the SPMs, and liver oil from certain species of cod can be as high in SPMs as human breast milk! Even our own microbiome and the diet we provide the organisms determines release of SPMs, as well as endocannabinoids. And phytocannabinoids? Much of this has been covered in previous articles in Natural Practitioner, but in short, they seem to be able to inhibit the re-uptake of endocannabinoids, they can modulate receptors other than the CB receptors throughout the body to mediate other beneficial effects, they can fine tune synaptic expression, and they seem to modulate overproduction of Omega-6 derived endocannabinoids and downregulate inflammatory effects of excess ARA. Many argue that CBD is, in fact, psychoactive because of the effect it can have on stress, anxiety, and depression. But it is not “euphoria inducing” like THC. While it does not bind CB receptors like THC does, it can change the shape of the receptors and displace THC.
We are so accustomed now to calling inflammation bad, but what if you injured yourself or faced a viral invader and needed that important immune-modulated inflammatory response to be initiated? This is exactly why we need a certain amount of the ESSENTIAL Omega-6 fatty acid in our diets. These become initiators of the inflammatory response and an important part of maintaining health and homeostasis. It would be preferable, however, that we all get them from nuts, seeds, other plants, and clean healthy animals. And so far research has shown that the best ratio to maintain is 4-5:1 Omega-6:Omega-3. This can be more accurately monitored through testing, but generally estimated through logging of dietary intake.
https://www.pnas.org/content/114/30/E6034
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656721/pdf/11745_2017_Article_4292.pdf
Amber Lynn Vitale, BA, CN
Amber Lynn Vitale practiced as a Certified Nutritionist, Ayurvedic Specialist, Advanced Bodyworker and Yoga Therapist since 1996. Much of her nutrition practice was in collaboration with Functional Medicine doctors and other Integrative Practitioners. Since 2008 she has also produced written and video educational content for many publications, as well as for her own clients and an interested public audience. By 2012 she had realized that raw materials sourcing, labeling transparency, legitimate certifications, and educational support were the criteria that would set quality natural products companies apart from others; and she made it her mission to educate the public on the importance of education before supplementation. In 2014 she became the NE Regional Educator for Garden of Life and continues to write, lecture, and produce online content on health and wellness topics important to the practitioner and the patient alike.