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Ultimate Guide to Nootropics | Part 5 | Fish Oil



 Whether you’re just starting to dip your toes into nootropics, or have already taken the full plunge, fish oil is going to provide a very solid base to build a nootropics stack upon. This is because a significant portion of our brain is composed of fatty acids; in particular omega-3 polyunsaturated fatty acids (ω-3 PUFA). The most abundant ω-3 PUFAs in the brain are docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AA) which all play very diverse neurological roles. Luckily enough, fish oil is loaded with DHA and EPA, and is thus a great substance to support neurological functioning. Apart from its neurological benefits, fish oil also produces a host of positive effects on various biological systems throughout the body.

These effects include but are not limited to:

helping to prevent:

    - Type-2 diabetes

    - Alzheimer’s disease

    - Age related neurodegeneration

    - Cardiovascular disease

    - anti-depressant effects well as:

    - decreasing blood pressure

    - increasing HDL-C (good cholesterol)

    - enhancing memory and learning

    - reducing risk of stroke

While this a very impressive list of effects, keep in mind that fish oil is mainly going to exert a supportive role, rather than providing a direct stand-alone enhancement. That being said, fish oil is fantastic for supporting the healthy functioning of our bodies and brains.

There is one important question that we need to answer before diving into this article. Why supplement fish oil when I can just eat fish? There are a couple of answers to this question, with the most obvious answer being convenience and cost. It is much easier, cost effective, and calorie friendly to simply swallow a purified fish oil capsule rather than having to prepare and eat fish. For example, one capsule of triple strength fish oil clocks in at 9 calories, 750 mg of ω-3 PUFAs and 0.25 USD. Of this 750 mg: 325 mg is EPA, 325 mg is DHA and the remaining 100 mg is composed of unspecified ω-3 PUFAs. In terms of DHA this is equivalent to about 140 grams of light canned tuna (162 calories) and in terms of EPA, a whopping 690 grams of light canned tuna (800 calories). In terms of pricing, assuming an average cost of 0.25 USD per ounce of light canned tuna, the DHA equivalent would cost 1.23 USD and the EPA equivalent would cost 6.08 USD. However, the real cost of regularly eating canned light tuna extends much further than its financial and caloric cost. Since tuna is a large predatory fish, it tends to bioaccumulate various compounds, the most concerning of which is methylmercury, a potent neurotoxin. According to ‘Got Mercury?’ our canned light tuna EPA equivalent dose would put us well above the daily allowable methylmercury intake set by the US Environmental Protection Agency. The triple strength purified fish oil capsule on the other hand is lab tested for methylmercury, and is guaranteed to be well below the daily allowable methylmercury intake. To summarize, without taking into account the nutritional value of fish and solely focusing on DHA and EPA content, the triple strength purified fish oil is the clear winner; cheap, convenient and no risk of methylmercury poisoning.

 Now that we have the basics out of the way, lets start to add in some more variables. DHA and EPA in fish oil are present in a few different forms. In nature most DHA and EPA are bound in triacylglycerides (TAG) whereas in isolated fish oil capsule most EPA and DHA is bound in ethyl esters (EE) or re-esterified TAG (rTAG). In general it appears that rTAG is slightly more bioavailable than TAG and EE (Schuchard et al., 2011). Furthermore, DHA and EPA can also be bound in phospholipids (PL). It appears that PL fish oil, which is generally extracted from krill, is significantly more bioavailable than TAG, rTAG and EE fish oil (Ramprasath et al., 2015). In addition to PL fish oil having greater bioavailability, the phospholipids in PL fish oil produce unique effects that are not seen with TAG, rTAG and EE fish oils, but we’ll get into that a little further in to the article.

We’ve now formed a basic understanding of what fish oil is, so now it’s time to explore what it actually does. As discussed fairly briefly earlier in the article, fish oil has a supportive role in many biological systems throughout the body. This has been attributed to its potent anti-inflammatory effects. DHA in particular is a very comprehensive anti-inflammatory agent. It affects inflammation directly by inhibiting nuclear factor kappa B (NF-κB), which is a very important mediator of proinflammatory cytokines. NF-κB is also particularly sensitive to oxidative stress; this is because NF-κB is normally bound to an inhibitory protein called IκB, which is degraded by oxidative stress. Degradation of IκB thus leads to the activation of NF-κB, which subsequently leads to a proinflammatory signalling cascade. DHA increases levels of endogenous intracellular antioxidants, such as glutathione, and thus prevents NF-κB activation by preventing the degradation of IκB. DHA also activates peroxisome proliferator activated receptor (PPAR‐γ), activation of which directly decreases the induction of inflammatory cytokines whilst also interrupting NF-κB activation (Calder, 2013). Furthermore, a significant portion of our brain cells but also other cells throughout our bodies are made up of DHA. The DHA in these cells is bound to phospholipids, which get degraded during tissue stress. This causes a release of free DHA. DHA is subsequently oxidised to resolvins and protectins. Resolvins downregulate NF-κB expression and protectins prevent IL-1β mediated stimulation of the pro-inflammatory enzyme cyclooxygenase (COX)(Bradbury, 2011). The overall reduction of inflammation is the underlying mechanism for most of the positive effects associated with fish oil listed earlier in the article, since a lot of biological functions are mediated by inflammatory and oxidative mechanisms.

 We briefly mentioned above that DHA is released from phospholipids during periods of oxidative stress. This is a very important mechanism because oxidative stress is directly correlated to metabolic activity. Therefore, it is no surprise that DHA concentrations are highest in areas of the body that are very metabolically active; in particular the brain which uses an enormous amount of energy relative to its size (2.3% of bodyweight, 23% of total energy consumption). In the brain, DHA concentrations are highest in grey matter, which is the most metabolically active tissue in the brain. During oxidative stress in the brain, DHA is released from phospholipids and converted to neuroprotectin, which can regenerate nerves, reduce oxidative stress induced apoptosis and reduce oxidative stress induced inflammation. In addition to this, during activation of neurons small amounts of DHA are released into the cytosol of the cell; most of which is rapidly reincorporated into the cell, but a small portion can be converted to neuroprotectin (Green et al., 2008). In addition to this, higher brain DHA levels are correlated with higher BDNF levels (Miyazawa et al., 2010). BDNF is incredibly important for the maintenance of neuroplasticity and has various neuroprotective effects throughout the brain. DHA also appears to be a major component of vesicles, which are structures within the neuron that are filled with neurotransmitters, and thus an adequate amount of vesicles is needed for proper cognitive functioning. In particular DHA levels appear to directly influence vesicle density in an area of the brain called the hippocampus, a crucial hub for memory and proper cognitive functioning (Bradbury, 2011).

 As mentioned earlier in the article, fish oil is going to form a very solid base on which to build a nootropics stack. As we have seen so far, this is because DHA is crucial for proper neurological function; especially during periods of high metabolic activity. So what about EPA? The interesting thing about EPA is that it’s present at much lower concentration in the brain than DHA, about 250-300 times lower (Chen et al., 2013). This would hint at the fact that EPA is not as important for proper neurological functioning as DHA is. However, research is indicating that EPA possibly has more profound neurological effects than DHA does. In a study by Sublette et al., (2011), it was shown that EPA was effective at decreasing depression, whereas DHA was completely ineffective at decreasing depression. This could be due to the fact that EPA appears to be implicated in the production of myelin, which is a mixture of proteins and phospholipids that insulates neurons (Salvati et al., 2008). Myelin is essential for proper functioning of the nervous system and many neurodegenerative diseases are to a certain extent the result of a loss of myelin. Myelin also makes up the majority of white matter in the brain, and abnormalities in white matter have recently been correlated with depression. Furthermore, drugs that enhance myelin production, like the antihistamine clemastine are now being looked at as a potential treatment option for depression (Liu et al., 2016). Another fact to consider is that the reason why there is much less EPA in the brain is because EPA gets degraded by β-oxidation much more rapidly than DHA does, and it also has a much harder time getting incorporated into phospholipids (Chen et al., 2013). Considering these two facts, it could be theorized that EPA supplementation has a much more profound effect on depression because an EPA deficiency seems much more likely due to the high rate of degradation, which would in turn lead to abnormalities in white matter. This would also explain why not every test subject in the above-mentioned studies experienced significant depression relief, since it is highly likely that not all of the test subjects had an EPA deficiency.

 In terms of EPA’s effects on inflammation, it shares most of DHA’s effects, but it also has some unique and potent effects on inflammation that distinguish it from DHA. To start, EPA inhibits the enzyme delta-5-desaturase (D5D), which synthesizes the ω-6 PUFA arachidonic acid (AA) (Dias & Parsons, 1995). This is important in terms of inflammation because like DHA, AA also gets converted to biologically active metabolites but instead of being anti-inflammatory the AA metabolites are pro-inflammatory. Furthermore EPA, similar to DHA produces anti-inflammatory resolvins when it comes into contact with the enzymes COX and lipoxygenase (LOX), these are the same two enzymes that convert AA to its pro-inflammatory metabolites. This means that EPA and AA compete for this enzyme and thus, a higher EPA:AA ratio is going to result in the production of less pro-inflammatory AA metabolites and more anti-inflammatory EPA metabolites (Pilkington et al., 2014). Interestingly enough, AA concentrations are very high in the brains white matter and as discussed earlier, EPA can prevent white matter abnormalities. Taking into account that EPA counteracts AA’s pro-inflammatory actions, it could be theorized that EPA is controlling AA mediated inflammation in the brains white matter and that this is what is causing its anti-depressant effect in individuals who have a low EPA:AA ratio (EPA deficiency).

 To summarize fish oils main benefits are due to its DHA and EPA content which both play a role in our bodies inflammatory response and the maintenance of proper neurological functioning. DHA is a major component of the cells in our bodies and it could be said that DHA is the most important for younger individuals since increased DHA consumption could lead to enhanced cognitive functioning. On the other hand an EPA deficiency seems much more likely and appears to have some serious consequences, EPA consumption would likely be more suited to older individuals whom are interested in maintaining cognitive functioning. So based on this information what fish oil do you choose? We offer a  triple strength fish oil, which contains equal amount of EPA and DHA; this would be a fantastic choice for somebody looking to support their overall health. We also offer a  70% DHA fish oil, which would be a great choice for younger individuals whom are interested in increasing the DHA content in their brains, since increased DHA content in the brain could potentially increase cognitive functioning. We also offer a  krill oil, which as mentioned earlier contains EPA and DHA, which is already bound in phospholipids. This increases the bioavailability of EPA and DHA but also appears to significantly increase their anti-depressant and cognition enhancing activity, which could potentially be due to the phospholipid content (Wibrand et al., 2013). Based on this, krill oil would be a good choice for an individual looking to use fish oil for its anti-depressant and cognition enhancing activity. We also have a  blend of krill oil and wild Alaskan salmon oil, which boasts many of the same benefits as krill oil with the added benefit of containing more DHA, vitamin D and 8 other essential fatty acids.


Bradbury, J. (2011). Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern

Human Brain . Nutrients, 3(5), 529–554.

Calder, P. C. (2013). Omega‐3 polyunsaturated fatty acids and inflammatory processes:

nutrition or pharmacology? British Journal of Clinical Pharmacology, 75(3), 645–662.

Chen, C. T., Domenichiello, A. F., Trépanier, M.-O., Liu, Z., Masoodi, M., & Bazinet, R.

P. (2013). The low levels of eicosapentaenoic acid in rat brain phospholipids are maintained via multiple redundant mechanisms. Journal of Lipid Research, 54(9), 2410–2422.

Dias, V.C. and Parsons, H.G. (1995) Modulation in delta 9, delta 6, and delta 5 fatty acid

desaturase activity in the human intestinal CaCo-2 cell line.J. Lipid Res. 36:(3) 552-63.

Green, J. T., Orr, S. K., & Bazinet, R. P. (2008). The emerging role of group VI calcium-

independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids. Journal of Lipid Research, 49(5), 939-944.

Liu, J., Dupree, J. L., Gacias, M., Frawley, R., Sikder, T., Naik, P., & Casaccia, P.

(2016). Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice. The Journal of Neuroscience, 36(3), 957–962.

Miyazawa, D., Yasui, Y., Yamada, K., Ohara, N., & Okuyama, H. (2010). Regional

differences of the mouse brain in response to an α-linolenic acid-restricted diet: Neurotrophin content and protein kinase activity. Life Sciences, 87(15), 490-494.

Pilkington, S. M., Rhodes, L. E., Al-Aasswad, N. M. I., Massey, K. A., & Nicolaou, A.

(2014). Impact of EPA ingestion on COX- and LOX-mediated eicosanoid synthesis in skin with and without a pro-inflammatory UVR challenge – Report of a randomised controlled study in humans. Molecular Nutrition & Food Research, 58(3), 580–590.

Ramprasath, V. R., Eyal, I., Zchut, S., Shafat, I., & Jones, P. J. H. (2015).

Supplementation of krill oil with high phospholipid content increases sum of EPA and DHA in erythrocytes compared with low phospholipid krill oil. Lipids in Health and Disease, 14, 142.

Schuchardt, J. P., Schneider, I., Meyer, H., Neubronner, J., von Schacky, C., & Hahn, A.

(2011). Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations - a comparative bioavailability study of fish oil vs. krill oil. Lipids in Health and Disease, 10, 145.

Sublette, M. E., Ellis, S. P., Geant, A. L., & Mann, J. J. (2011). Meta-analysis: Effects of

Eicosapentaenoic Acid in Clinical Trials in Depression. The Journal of Clinical Psychiatry, 72(12), 1577–1584.

Wibrand, K., Berge, K., Messaoudi, M., Duffaud, A., Panja, D., Bramham, C. R., &

Burri, L. (2013). Enhanced cognitive function and antidepressant-like effects after krill oil supplementation in rats. Lipids in Health and Disease, 12, 6.






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