Fish Oil? Upgrade to Snake Oil!

Fish oil companies don’t sell snake oil. Perhaps they should… 

I have spoken to the management of some of the biggest fish oil companies and they acknowledge (off the record) that their products don’t do much. But hey – it’s great business. No matter that they are emptying the oceans, making false claims, and taking money from customers who get little more for their hard-earned cash than indigestion and a false sense of security.

And it certainly does seem to be largely false. 

Cochrane Collaboration methodology uses a powerful set of investigative tools. They are not particularly well-suited to measuring the effects of nutritional inputs but nonetheless, the Collaboration have published numerous meta-analyses showing that omega 3 HUFA’s have no effects in most indications (1-21); ranging from psoriasis and cognitive decline to gestational diabetes, retinopathy, chronic kidney disease, IBD and ADHD.

There is evidence of possible and slight effects (ie not reaching statistical significance) in a few other conditions such as muscle performance, cancer, pre-eclampsia, multiple sclerosis and non-alcoholic fatty liver disease (22-31), but there is nothing really substantial. And in the area of heart health, which is why most consumers swallow fish oil, the data is hopelessly conflicted. 

Two recent meta-analyses (32, 33) and one large population-based cohort study (34) generated data that suggests that fish oils do reduce various cardiovascular end-points, including atheroma progression. One of the meta-analyses (34) found that the protective effects were dose-related, which is always persuasive. In marked contrast, three recent powerful clinical trials found fish oil to have no effects on cardiovascular pathology in either primary or secondary prevention (35-37). Yet another meta-analysis found null results, except for a slight degree of protection in subjects who had gallantly taken fish oil supplements for over ten years (38).

These last seven studies are all well-powered, and designed and run by established scientists, but they cannot all be right. Or can they? I think they can … and that the riddle of the sands is based on secondary bioavailability.

Getting omega 3’s into the bloodstream (primary bio-availability) is relatively easy because humans are good at absorbing fats and oils, unless they have gall bladder or exocrine pancreatic problems. Despite shrill commercial claims from fish oil vendors for the superior nature of their triglycerides, esters or free fatty acids, they are all broadly similar; and it makes little difference whether they are sourced from algae, krill, fish, whale or Inuit.

None of this matters. Levels of omega 3’s in the bloodstream are irrelevant, except in terms of their calorie content. That is not where they do their anti-inflammatory thing.

They become precursors for the pro-resolving resolvins, maresins and protectins, and anti-inflammatory eicosanoids such as PGE3, TXA3 and LTA5, only after they have been incorporated into the host’s cell membranes. Getting them into the cell membranes is secondary bioavailability (or bio-efficacy), and this is a much more complicated procedure. Seafood does it, but fish oil doesn’t.

I know this because I was given access to a library of over 600,000 dried blood spot samples, generated by Vitas Analytical Services (39). This is the largest library of its kind in the world by far.

Membrane lipid profiling performed by Vitas shows that those who eschew fish oil have an average 6:3 ratio of 14.8:1 (40). This is a pro-inflammatory configuration. Consumers who had drunk fish oil for decades and in many cases from birth (forgive them, they are Scandinavian), have slightly higher omega indices and an average 6:3 ratio of 9.9:1 (40). This is marginally better than the first group, but it is still pro-inflammatory; both of these groups have a ‘normal’ (ie high) incidence of inflammatory disorders. 

In marked contrast, fish-eaters have excellent omega indices and 6:3 ratios that are typically between 2 and 3 (40). This is anti-inflammatory, and this group has far fewer inflammatory problems, showing that fish oil and oily fish are two very different things. Specifically, there is something in oily fish which enables secondary bioavailability, but which is missing in commercial fish oils. As I have long suspected, that something is a lipohillic polyphenol called phlorotannin (41). 

Phlorotannin, like many polyphenols, has a range of anti-inflammatory activities which occur down-stream from the omega 3’s in the inflammatory cascade (42-50), and are therefore additive or supra-additive. Produced by the same marine algae that produce the omega 3’s, they bind the omega 3’s tenaciously and act as fantastically effective antioxidants (51-55). They are also chaperones, vital in permitting the transfer of the fragile omega 3 HUFA’s through multiple trophic levels and over many months until they arrive intact in the apex consumer. They also inhibit MMP enzymes (56-58), thus amplifying the anti-inflammatory effects of the omega 3’s. 

The ability of the phlorotannins to transport omega 3’s through the marine food web demonstrates their role in delivering omega 3’s through the body of many different species; including us. This is why omega 3’s from algal oil achieve the same levels in erythrocyte membranes as they do when consumed in oily fish (59). 

Once we have consumed oily fish, the polyphenols continue to act as chaperones until the omega 3’s have arrived safely in the cell membranes. Once there, the omega 3’s and phlorotannins cooperate in a different way, generating effective anti-inflammatory cover.

This explains why commercial fish oils do not work. They mostly use versions of vitamin E to protect their oil, forgetting that vitamin E becomes a pro-oxidant in the presence of iron, haem and/or high partial pressures of oxygen (ie 60-62). That would explain why fish oil drinkers generally have low omega 3 indices and high 6:3 ratios in their cell membranes, and the poor outcomes of so many clinical trials of fish oil; the omega 3’s are largely failing to get to their target site intact.

This is particularly likely to occur in populations whose dietary intake of polyphenols is low, such as North America and Northern Europe. In areas where people eat a diet containing higher levels of polyphenols, however, fish oil supplements would be more likely to show a positive result, however small. This, I believe, is a major factor behind the scientific community’s current lack of consensus on the subject. Carotenoid intakes may also play a role, but do not appear to be as effective in maintaining omega 3 integrity (63).

Alternatively, consume your fish oil containing pre-dissolved lipid-soluble polyphenols, such as those from olive. There are an increasing number of these products, the first of which was Balance Oil.

The dried blood spot library I mentioned earlier shows that Balance Oil drinkers have cell membrane lipid profiles similar to those of sea-food eaters (40). This shows that Balance oil is not fish oil but effectively an oily fish in liquid form.

Back to the heart of the matter. The omega 3 HUFA’s undoubtedly have some ability to dampen endothelial dysfunction (64, 65), and so do the polyphenols (66, 67). I and many thousands of others have found that the combination of the two is highly synergistic, and consistently succeeds where fish oil fails. Furthermore, it does not need a prescription. The pharma product Vascepa also shows cardiovascular benefits (ie 68-70) but is in my view poorly formulated, potentially harmful and based on outdated science.

Postscript. When I accused fish oil manufacturers of selling snake oil, the sting was in the tail. Snake oil was originally a Chinese remedy derived from water snakes, which live in cool to cold waters. Their oil is approximately 30% EPA (71, 72), and as that EPA is derived from the base of the marine food web, snake oil will also contain phlorotannins. It was traditionally used to treat arthritides and other inflammatory conditions, and was almost certainly as effective as well-designed fish oil products are today.

When skeptics describe Balance oil as snake oil, they are more right than they know.

References

1. Alex A, Abbott KA, McEvoy M, Schofield PW, Garg ML. Long-chain omega-3 polyunsaturated fatty acids and cognitive decline in non-demented adults: a systematic review and meta-analysis. Nutr Rev. 2020 Jul 1;78(7):563-578.
2. Chen X, Hong S, Sun X, Xu W, Li H, Ma T, Zheng Q, Zhao H, Zhou Y, Qiang Y, Li B, Li X. Efficacy of fish oil and its components in the management of psoriasis: a systematic review of 18 randomized controlled trials. Nutr Rev. 2020 Oct 1;78(10):827-840.
3. Schwartz SG, Wang X, Chavis P, Kuriyan AE, Abariga SA. Vitamin A and fish oils for preventing the progression of retinitis pigmentosa. Cochrane Database Syst Rev. 2020 Jun 18;6(6):CD008428.
4. Griffith RJ, Alsweiler J, Moore AE, Brown S, Middleton P, Shepherd E, Crowther CA. Interventions to prevent women from developing gestational diabetes mellitus: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2020 Jun 11;6(6):CD012394.
5. Gao C, Liu Y, Gan Y, Bao W, Peng X, Xing Q, Gao H, Lai J, Liu L, Wang Z, Yang Y. Effects of fish oil supplementation on glucose control and lipid levels among patients with type 2 diabetes mellitus: a Meta-analysis of randomized controlled trials. Lipids Health Dis. 2020 May 8;19(1):87.
6. Watson H, Stackhouse C. Omega-3 fatty acid supplementation for cystic fibrosis. Cochrane Database Syst Rev. 2020 Apr 10;4(4):CD002201.
7. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KH, Summerbell CD, Worthington HV, Song F, Hooper L. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Feb 29;3(2):CD003177.
8. Chewcharat A, Chewcharat P, Rutirapong A, Papatheodorou S. The effects of omega-3 fatty acids on diabetic nephropathy: A meta-analysis of randomized controlled trials. PLoS One. 2020 Feb 11;15(2):e0228315.
9. Alvarez Campano CG, Macleod MJ, Aucott L, Thies F. Marine-derived n-3 fatty acids therapy for stroke. Cochrane Database Syst Rev. 2019 Jun 26;6(6):CD012815.
10. Popoff F, Balaciano G, Bardach A, Comandé D, Irazola V, Catalano HN, Izcovich A. Omega 3 fatty acid supplementation after myocardial infarction: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2019 Jun 4;19(1):136.
11. Saglimbene VM, Wong G, van Zwieten A, Palmer SC, Ruospo M, Natale P, Campbell K, Teixeira-Pinto A, Craig JC, Strippoli GFM. Effects of omega-3 polyunsaturated fatty acid intake in patients with chronic kidney disease: Systematic review and meta-analysis of randomized controlled trials. Clin Nutr. 2020 Feb;39(2):358-368.
12. Abdullah M, Jowett B, Whittaker PJ, Patterson L. The effectiveness of omega-3 supplementation in reducing ADHD associated symptoms in children as measured by the Conners’ rating scales: A systematic review of randomized controlled trials. J Psychiatr Res. 2019 Mar;110:64-73.
13. Mohammady M, Janani L, Jahanfar S, Mousavi MS. Effect of omega-3 supplements on vasomotor symptoms in menopausal women: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2018 Sep;228:295-302.
14. Ajabnoor SM, Thorpe G, Abdelhamid A, Hooper L. Long-term effects of increasing omega-3, omega-6 and total polyunsaturated fats on inflammatory bowel disease and markers of inflammation: a systematic review and meta-analysis of randomized controlled trials. Eur J Nutr. 2020 Oct 21. doi: 10.1007/s00394-020-02413-y. Epub ahead of print.
15. Sun L, Li Y, Xie W, Xue X. Association between omega-3 fatty acid supplementation and lower risk of preterm delivery: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2020 Sep 17:1-10. doi: 10.1080/14767058.2020.1785423. Epub ahead of print.
16. Kilchoer B, Vils A, Minder B, Muka T, Glisic M, Bally L. Efficacy of Dietary Supplements to Reduce Liver Fat. Nutrients. 2020 Jul 31;12(8):2302.
17. Parks NE, Jackson-Tarlton CS, Vacchi L, Merdad R, Johnston BC. Dietary interventions for multiple sclerosis-related outcomes. Cochrane Database Syst Rev. 2020 May 19;5(5):CD004192.
18. Brainard JS, Jimoh OF, Deane KHO, Biswas P, Donaldson D, Maas K, Abdelhamid AS, Hooper L; PUFAH group. Omega-3, Omega-6, and Polyunsaturated Fat for Cognition: Systematic Review and Meta-analysis of Randomized Trials. J Am Med Dir Assoc. 2020 Oct;21(10):1439-1450.e21.
19. Zhang Y, Lin J, Zhou R, Zheng X, Dai J. Effect of omega-3 fatty acids supplementation during childhood in preventing allergic disease: a systematic review and Meta-Analysis. J Asthma. 2020 Jan 10:1-14.
20. Yang SJ, Chi CC. Effects of fish oil supplement on psoriasis: a meta-analysis of randomized controlled trials. BMC Complement Altern Med. 2019 Dec 5;19(1):354.
21. Chewcharat A, Chewcharat P, Rutirapong A, Papatheodorou S. The effects of omega-3 fatty acids on diabetic nephropathy: A meta-analysis of randomized controlled trials. PLoS One. 2020 Feb 11;15(2):e0228315.
22. Huang YH, Chiu WC, Hsu YP, Lo YL, Wang YH. Effects of Omega-3 Fatty Acids on Muscle Mass, Muscle Strength and Muscle Performance among the Elderly: A Meta-Analysis. Nutrients. 2020 Dec 4;12(12):E3739.
23. Abdelhamid A, Hooper L, Sivakaran R, Hayhoe RPG, Welch A; PUFAH Group. The Relationship Between Omega-3, Omega-6 and Total Polyunsaturated Fat and Musculoskeletal Health and Functional Status in Adults: A Systematic Review and Meta-analysis of RCTs. Calcif Tissue Int. 2019 Oct;105(4):353-372.
24. Lee KH, Seong HJ, Kim G, Jeong GH, Kim JY, Park H, Jung E, Kronbichler A, Eisenhut M, Stubbs B, Solmi M, Koyanagi A, Hong SH, Dragioti E, de Rezende LFM, Jacob L, Keum N, van der Vliet HJ, Cho E, Veronese N, Grosso G, Ogino S, Song M, Radua J, Jung SJ, Thompson T, Jackson SE, Smith L, Yang L, Oh H, Choi EK, Shin JI, Giovannucci EL, Gamerith G. Consumption of Fish and ω-3 Fatty Acids and Cancer Risk: An Umbrella Review of Meta-Analyses of Observational Studies. Adv Nutr. 2020 Sep 1;11(5):1134-1149.
25. Yan JH, Guan BJ, Gao HY, Peng XE. Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018 Sep;97(37):e12271.
26. Bakouei F, Delavar MA, Mashayekh-Amiri S, Esmailzadeh S, Taheri Z. Efficacy of n-3 fatty acids supplementation on the prevention of pregnancy induced-hypertension or preeclampsia: A systematic review and meta-analysis. Taiwan J Obstet Gynecol. 2020 Jan;59(1):8-15.
27. AlAmmar WA, Albeesh FH, Ibrahim LM, Algindan YY, Yamani LZ, Khattab RY. Effect of omega-3 fatty acids and fish oil supplementation on multiple sclerosis: a systematic review. Nutr Neurosci. 2019 Aug 28:1-11.
28. Su KP, Tseng PT, Lin PY, Okubo R, Chen TY, Chen YW, Matsuoka YJ. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms: A Systematic Review and Meta-analysis. JAMA Netw Open. 2018 Sep 7;1(5):e182327.
29. Jiang L, Gao C, Yan P, Chen P, Jiang C, Xu Y, Chen M. Omega-3 fatty acids plus vitamin for women with gestational diabetes or prediabetes: a meta-analysis of randomized controlled studies. J Matern Fetal Neonatal Med. 2020 Sep 23:1-8.
30. Morvaridzadeh M, Sepidarkish M, Yavari M, Tahvilian N, Heydarian A, Khazdouz M, Farsi F, Persad E, Heshmati J. The effects of omega-3 fatty acid supplementation on inflammatory factors in HIV-infected patients: A systematic review and meta-analysis of randomized clinical trials. Cytokine. 2020 Dec;136:155298. 
31. Newberry SJ, Chung M, Booth M, Maglione MA, Tang AM, O’Hanlon CE, Wang DD, Okunogbe A, Huang C, Motala A, Trimmer M, Dudley W, Shanman R, Coker TR, Shekelle PG. Omega-3 Fatty Acids and Maternal and Child Health: An Updated Systematic Review. Evid Rep Technol Assess (Full Rep). 2016 Oct;(224):1-826.
32. Bernasconi AA, Wiest MM, Lavie CJ, Milani RV, Laukkanen JA. Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials. Mayo Clin Proc. 2020 Sep 17:S0025-6196(20)30985-X.
33. Sekikawa A, Cui C, Sugiyama D, Fabio A, Harris WS, Zhang X. Effect of High-Dose Marine Omega-3 Fatty Acids on Atherosclerosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Nutrients. 2019 Oct 30;11(11):2599.
34. Li ZH, Zhong WF, Liu S, Kraus VB, Zhang YJ, Gao X, Lv YB, Shen D, Zhang XR, Zhang PD, Huang QM, Chen Q, Wu XB, Shi XM, Wang D, Mao C. Associations of habitual fish oil supplementation with cardiovascular outcomes and all-cause mortality: evidence from a large population-based cohort study. BMJ. 2020 Mar 4;368:m456.
35. Nicholls SJ, Lincoff AM, Garcia M and 19 others. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020;324(22):2268–2280.
36. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D’Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019 Jan 3;380(1):23-32.
37. Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Fagerland MW, Solheim S, Seljeflot I, Arnesen H; OMEMI investigators. Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial. Circulation. 2020 Nov 15. doi: 10.1161/CIRCULATIONAHA.120.052209. Epub ahead of print. PMID: 33191772.
38. Zhu Y, Bo Y, Liu Y. Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies. Lipids Health Dis. 2019 Apr 6;18(1):91.
39. https://vitas.no/
40. In house data.Vitas Analytical Services and Zinzino AS
41. Clayton PR, Ladi S. From alga to omega; have we reached peak (fish) oil? J R Soc Med. 2015;108(9):351-357. 
42. Dutot M, Fagon R, Hemon M, Rat P. Antioxidant, anti-inflammatory, and anti-senescence activities of a phlorotannin-rich natural extract from brown seaweed Ascophyllum nodosum. Appl Biochem Biotechnol 2012; 167: 2234–2240. 
43. Jung HA, Jin SE, Ahn BR, Lee CM, Choi JS. Anti-inflammatory activity of edible brown alga Eisenia bicyclis and its constituents fucosterol and phlorotannins in LPS-stimulated RAW264.7 macrophages. Food Chem Toxicol 2013; 59: 199–206. 
44. Yang YI, Shin HC, Kim SH, Park WY, Lee KT, Choi JH. 6,6′-Bieckol, isolated from marine alga Ecklonia cava, suppressed LPS-induced nitric oxide and PGE₂ production and inflammatory cytokine expression in macrophages: the inhibition of NFκB. Int Immunopharmacol 2012; 12: 510–517. 
45. Wijesinghe WA, Jeon YJ. Exploiting biological activities of brown seaweed Ecklonia cava for potential industrial applications: a review. Int J Food Sci Nutr 2012; 63: 225–235. 
46. Thomas NV, Kim SK. Potential pharmacological applications of polyphenolic derivatives from marine brown algae. Environ Toxicol Pharmacol 2011; 32: 325–335. 
47. Wijesekara I, Yoon NY, Kim SK. Phlorotannins from Ecklonia cava (Phaeophyceae): biological activities and potential health benefits. Biofactors 2010; 36: 408–414. 
48. Vo TS, Ngo DH, Kim SK. Potential targets for anti-inflammatory and anti-allergic activities of marine algae: an overview. Inflamm Allergy Drug Targets 2012; 11: 90–101. 
49. Kim MM, Ta Q, Mendis E, Rajapakse N, Jung WK, Byun HG, et al. Phlorotannins in Ecklonia cava extract inhibit matrix metalloproteinase activity. Life Sci 2006; 79: 1436–1443. 
50. Kim SK, Lee DY, Jung WK, Kim JH, Choi I, Park SG, et al. Effects of Ecklonia cava ethanolic extracts on airway hyperresponsiveness and inflammation in a murine asthma model: role of suppressor of cytokine signaling. Biomed Pharmacother 2008; 62: 289–296.
51.  AOCS Official Method Cd12b-92. Data on antioxidants (astaxanthin, E, olive polyphenols) in fish oil. Average of 3 analysis at 70 C SINTEF – Fisheries and Aquaculture. August 2010.
52. Yan XJ, Li XC, Zhou CX, Fan X. Preservation of fish oil rancidity by phlorotannins from Sargassum kjelmaniamum. J Appl Phycol 1996; 8: 201–203.
53. Wang T. Industry Research Thesis, Open University, Iceland. ISBN 978-9979-9928-3-7, http://skemman.is/stream/get/1946/4139/11867/1/Final_fixed.pdf (2009).
54. Wijesinghe WA, Jeon YJ. Exploiting biological activities of brown seaweed Ecklonia cava for potential industrial applications: a review. Int J Food Sci Nutr 2012; 63: 225–235. 
55. Thomas NV, Kim SK. Potential pharmacological applications of polyphenolic derivatives from marine brown algae. Environ Toxicol Pharmacol 2011; 32: 325–335.
56. Li YX, Li Y, Je JY, Kim SK. Dieckol as a novel anti-proliferative and anti-angiogenic agent and computational anti-angiogenic activity evaluation. Environ Toxicol Pharmacol. 2015 Jan;39(1):259-70.
57. Kim EK, Tang Y, Kim YS, Hwang JW, Choi EJ, Lee JH, Lee SH, Jeon YJ, Park PJ. First evidence that Ecklonia cava-derived dieckol attenuates MCF-7 human breast carcinoma cell migration. Mar Drugs. 2015 Mar 30;13(4):1785-97.
58. Ryu B, Li Y, Qian ZJ, Kim MM, Kim SK. Differentiation of human osteosarcoma cells by isolated phlorotannins is subtly linked to COX-2, iNOS, MMPs, and MAPK signaling: implication for chronic articular disease. Chem Biol Interact. 2009 May 15;179(2-3):192-201.
59. Arterburn LM, Oken HA, Bailey Hall E, Hamersley J, Kuratko CN, Hoffman JP. Algal-oil capsules and cooked salmon: nutritionally equivalent sources of docosahexaenoic acid. J Am Diet Assoc. 2008 Jul;108(7):1204-9.
60. Allard JP, Kurian R, Aghdassi E, Muggli R, Royall D. Lipid peroxidation during n-3 fatty acid and vitamin E supplementation in humans. Lipids. 1997 May; 32(5):535-41.
61. Pearson P, Lewis SA, Britton J, Young IS, Fogarty A. The pro-oxidant activity of high-dose vitamin E supplements in vivo. BioDrugs. 2006;20(5):271-3.
62. Omaye ST. Vaping-Linked Lung Disease: Implication for Pro-oxidant Effect of Vitamin E. Biomed J Sci & Tech Res 23(5)-2019. 
63. 70 C SINTEF: Fisheries & Aquaculture, Norway (2010). AOCS Official Method Cd12b-92
64. Kris-Etherton PM, Harris WS, Appel LJ, American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002 Nov 19; 106(21):2747-57.
65. Robinson JG, Stone NJ. Review Antiatherosclerotic and antithrombotic effects of omega-3 fatty acids. Am J Cardiol. 2006 Aug 21; 98(4A):39i-49i.
66. Furuuchi R, Shimizu I, Yoshida Y, Hayashi Y, Ikegami R, Suda M, Katsuumi G, Wakasugi T, Nakao M, Minamino T. (2018). Boysenberry polyphenol inhibits endothelial dysfunction and improves vascular health. PloS one, 13(8), e0202051.
67. Di Pietro N, Baldassarre MPA, Cichelli A, Pandolfi A, Formoso G, Pipino C. Role of Polyphenols and Carotenoids in Endothelial Dysfunction: An Overview from Classic to Innovative Biomarkers. Oxid Med Cell Longev. 2020;2020:6381380. 
68. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM, REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3; 380(1):11-22.
69. Bays HE, Ballantyne CM, Doyle RT Jr, Juliano RA, Philip S. Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies. Prostaglandins Other Lipid Mediat. 2016 Sep; 125():57-64.
70. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22.
71. Kunin RA. Snake oil. West J Med. 1989 Aug;151(2):208.
72. Zhang G, Higuchi T, Shirai N, Suzuki H, Shimizu E. Effect of Erabu sea snake (Laticauda semifasciata) lipids on the swimming endurance of mice. Ann Nutr Metab. 2007;51(3):281-7.