HoldsUp

FoundMyFitness · 2021-12-07 · Rhonda Patrick (host), Bill Harris

Dr. Bill Harris on the Omega-3 Index: Increasing Omega-3 to Promote Longevity & Transform Health

74 research-tied claims examined: 3 contradicted 1 overstated 4 context 61 supported 5 unverified

61

Supported by research

0:04:05Bill Harrissupportedmoderate

Salmon oil contains approximately 20% omega-3 fatty acids.

"salmon oil is about 20% omega-3, so it's fairly low as fish oils go." (said at 0:04:05)

Analyses of standard, unrefined Atlantic salmon oil indicate that its total long-chain omega-3 fatty acid content is typically around 10% to 20% (for example, approximately 6.1% eicosapentaenoic acid [EPA] and 4.1% docosahexaenoic acid [DHA] before degradation), which is relatively low compared to standard pelagic fish oils (such as sardine or anchovy oil, which typically yield 30% or more EPA and DHA).

0:05:22Bill Harrissupportedmoderate

Feeding high doses of dietary salmon oil to individuals with type 2b or type 5 hyperlipidemia led to an approximately 80% drop in triglycerides.

"And then we actually picked people with both what we call type 2b, which is Fredrickson types, you know, high triglycerides, high LDL, and a group of people that had type 1 or, excuse me, type 5 hyperlipidemia, which is very high triglycerides. And we treated them, and that's where we got, you know, 80% drops in triglycerides." (said at 0:05:22)

In a 1985 clinical trial co-authored by William S. Harris and William E. Connor published in the New England Journal of Medicine, 20 patients with hypertriglyceridemia (10 with Type IIb and 10 with Type V hyperlipidemia) received a high-dose fish-oil diet (providing omega-3 fatty acids primarily from salmon oil) for four weeks. Compared to a control diet, dietary fish oil reduced plasma triglyceride levels by 64% in patients with Type IIb hyperlipidemia and by 79% (approximately 80%) in patients with Type V hyperlipidemia.

0:05:49Bill Harrissupportedhigh

Three back-to-back papers on omega-3 fatty acids were published in the New England Journal of Medicine on May 9, 1985.

"And that's the paper that got in the New England Journal on—it was a fateful day: May 9th, 1985. Three papers back-to-back, New England Journal, on omega-3." (said at 0:05:49)

On May 9, 1985, the New England Journal of Medicine (Volume 312, Issue 19) published three consecutive original research articles evaluating the biological and clinical effects of omega-3 fatty acids and fish consumption: Kromhout et al. on fish intake and 20-year coronary heart disease mortality (pp. 1205–1209), Phillipson et al. on dietary fish oils in hypertriglyceridemia (pp. 1210–1216), and Lee et al. on EPA/DHA enrichment and leukotriene generation/neutrophil function (pp. 1217–1224), alongside an accompanying editorial.

0:08:25Bill Harrissupportedhigh

Dyerberg and colleagues published a paper in 1978 proposing that EPA reduced platelet stickiness in Greenland Inuits, conferring protection against atherothrombosis.

"platelet aggregation was a big topic, because that's what Dyerberg had proposed the mechanism of cardioprotection was in the Eskimos, because they had published in '78 a paper saying EPA is what's causing the platelets to be not so sticky in the Eskimos" (said at 0:08:25)

In 1978, Dyerberg, Bang, and colleagues published a landmark paper in The Lancet proposing that high levels of dietary eicosapentaenoic acid (EPA) in Greenland Inuits led to an antithrombotic state by reducing platelet aggregation (via generation of inactive thromboxane A3 alongside active anti-aggregating prostacyclin PGI3), thereby offering protection against myocardial infarction and thrombosis.

  • supports: Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? (Lancet (London, England) 1978) · cited 1688x in the literature
    "Unlike arachidonic acid (eicosatetraenoic acid, C20:4omega-6, A.A.), eicosapentaenoic acid (C20:5omega-3, E.P.A.) does not induce platelet aggregation in human platelet-rich plasma (P.R.P.), probably because of the formation of thromboxane A3 (T.X.A3) which does not have platelet aggregating properties. Moreover, E.P.A., like A.A., can be utilised by the vessel wall to make an anti-aggregating substance, probably a delta17-prostacyclin (P.G.I3). This finding suggests that, in vivo, high levels of E.P.A. and low levels of A.A. could lead to an antithrombotic state in which an active P.G.I3 and a non-active T.X.A3 are formed. Eskimos have high levels of E.P.A. and low levels of A.A. and they also have a low incidence of myocardial infarction and a tendency to bleed." (abstract, passage verified)
    pubmedfull study (doi)
0:08:49Bill Harrissupportedmoderate

High-dose omega-3 supplementation reduces platelet aggregation and lengthens bleeding time to an extent comparable to aspirin.

"Platelet aggregation was reduced by the omega-3. Bleeding time was reduced—they weren't outrageously reduced. I mean, it wasn't like dangerous, but it was, like, effect on bleeding time was sort of like taking an aspirin" (said at 0:08:49)

Clinical studies demonstrate that high-dose dietary or supplemental omega-3 polyunsaturated fatty acids (such as EPA and DHA) inhibit platelet aggregation and prolong template bleeding time to a degree comparable to low-to-moderate doses of aspirin. For instance, comparative human trials showed that an EPA-enriched diet reduced ADP-induced platelet aggregation to a similar extent as acetylsalicylic acid (aspirin) alone and lengthened bleeding time without causing dangerous clinical bleeding.

0:11:31Bill Harrissupportedhigh

In the OPERA clinical trial, pre-loading cardiac surgery patients with omega-3 fatty acids prior to open-heart surgery did not reduce postoperative atrial fibrillation.

"This was Dr. Mozaffarian's study, OPERA—OPERA study. And we were trying to prevent post-op AFib by giving them a big load of omega-3 ahead of time, because that was the theory at that time, that we could prevent atrial fibrillation in people by giving them omega-3 before surgery. And, well, it didn't work. Didn't make any difference." (said at 0:11:31)

The OPERA (Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation) randomized, double-blind, placebo-controlled trial enrolled 1,516 cardiac surgery patients across 28 centers. Preoperative loading with omega-3 fatty acids (10 g over 3 to 5 days or 8 g over 2 days) followed by postoperative supplementation (2 g/day) did not significantly reduce postoperative atrial fibrillation compared to placebo (30.0% vs. 30.7%; odds ratio 0.96, 95% CI 0.77-1.20, P = 0.74).

0:11:56Bill Harrissupportedhigh

In the OPERA trial, patients receiving high doses of omega-3 before cardiac surgery experienced less postoperative bleeding and needed fewer blood transfusions compared to placebo.

"even if you give people for like three or four days 10 grams of omega-3 a day for sure before surgery, they actually—when they checked how much bleeding came on with the surgery, how much post-op bleeding was there, there was actually less post-op bleeding with the people that got the omega-3 than the placebo, less need for transfusion" (said at 0:11:56)

In a secondary analysis of the OPERA randomized clinical trial involving 1,516 patients undergoing cardiac surgery, preoperative loading with high-dose fish oil (8–10 g/day for 2–5 days before surgery) significantly reduced the total units of blood transfused compared to placebo (mean 1.61 vs. 1.92 units, P < 0.001). While the overall rate of major bleeding between treatment arms was non-significantly lower (odds ratio 0.81, 95% CI 0.53–1.24), higher achieved plasma phospholipid omega-3 levels on the morning of surgery were significantly associated with a markedly lower risk of major bleeding.

0:13:20Bill Harrissupportedhigh

Lovaza is an ethyl ester mixture of EPA and DHA, while Vascepa is an EPA-only ethyl ester formulation.

"Lovaza is the EPA plus DHA ethyl ester. Vascepa is an EPA-only ethyl ester." (said at 0:13:20)

The statement accurately describes the chemical composition of both prescription omega-3 formulations. Lovaza (omega-3-acid ethyl esters) is an ethyl ester mixture consisting of both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whereas Vascepa (icosapent ethyl) is a purified ethyl ester formulation containing only EPA.

0:16:24Bill Harrissupportedhigh

Alpha-linolenic acid (ALA) is an 18-carbon fatty acid, whereas EPA is 20 carbons and DHA is 22 carbons.

"alpha-linolenic acid, ALA, is the 18-carbon omega-3—18 carbons long omega-3, compared to the 20- or 22-carbons-long marine omega-3s, EPA and DHA." (said at 0:16:24)

Alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are well-established omega-3 polyunsaturated fatty acids with chemical structures containing 18, 20, and 22 carbon atoms, respectively (designated chemically as 18:3 ω-3, 20:5 ω-3, and 22:6 ω-3).

0:18:45Bill Harrissupportedhigh

In humans, the metabolic conversion rate of dietary ALA to EPA is roughly 2% to 5%, with conversion to DHA being even lower.

"it's, you know, in the neighborhood—this neighborhood: 2, 3, 4, 5%, you know, of ALA going to EPA. ALA going to DHA is less." (said at 0:18:45)

Stable isotope tracer studies and reviews consistently show that in adult humans, the fractional conversion of dietary alpha-linolenic acid (ALA) to eicosapentaenoic acid (EPA) is approximately 2% to 5%, while conversion to docosahexaenoic acid (DHA) is even lower (typically under 0.5% or trace amounts, though somewhat higher in women of reproductive age).

0:19:58Bill Harrissupportedhigh

Fish do not synthesize EPA and DHA de novo in meaningful quantities, but obtain them by consuming microalgae at the base of the marine food chain.

"The original source of EPA and DHA in a fish is not that they make omega-3—they don't really make omega-3 any better than we do, or make EPA and DHA. They eat preformed EPA and DHA, and it's—it comes from their food sources, which at the bottom of the food chain is these micro—single-celled micro—and I'm not talking about seaweed, but these little organisms that convert sunlight into fatty acids, some of which are omega-3." (said at 0:19:58)

The speaker's statement is supported. In aquatic ecosystems, photosynthetic microalgae and microorganisms are the primary producers that synthesize eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) de novo. Higher trophic organisms, such as marine fish, do not synthesize these long-chain omega-3 fatty acids in meaningful amounts de novo, but instead obtain and accumulate preformed EPA and DHA through the aquatic food chain.

0:23:20Bill Harrissupportedmoderate

In the Physicians' Health Study analysis by Dr. Christine Albert, baseline blood omega-3 levels in the highest category were associated with a 90% reduced risk of sudden cardiac arrest and death over 17 years.

"Dr. Christine Albert from Harvard had just presented her study where she looked at blood omega-3 levels in the Physicians' Health Study... And they analyzed the blood, and they found that those men who had the highest omega-3 levels at baseline when they started were like 90% less likely to be a case, experience sudden cardiac arrest and sudden cardiac death." (said at 0:23:20)

In a prospective nested case-control study from the Physicians' Health Study led by Dr. Christine Albert (published in the New England Journal of Medicine in 2002), baseline blood levels of long-chain n-3 fatty acids were measured in 94 men who experienced sudden cardiac death over 17 years of follow-up and 184 matched controls. Men in the highest quartile of baseline n-3 fatty acid levels had a markedly lower risk of sudden death compared to those in the lowest quartile (adjusted relative risk 0.19, 95% CI 0.05 to 0.71, with full multivariable adjustment models showing relative risks up to 0.10, representing an 81% to 90% reduction in risk).

0:26:12Bill Harrissupportedhigh

Harris and von Schacky published the paper proposing the Omega-3 Index as a cardiovascular risk factor in Preventive Medicine in 2004.

"wrote this paper, published in Preventive Medicine in 2004, and said, "Here's the Omega-3 Index. It ought to be—people will start looking at this like a risk factor."" (said at 0:26:12)

William S. Harris and Clemens von Schacky published a seminal paper in Preventive Medicine in 2004 proposing the Omega-3 Index (red blood cell EPA + DHA content) as a novel, modifiable risk factor for coronary heart disease mortality.

0:28:43Bill Harrissupportedmoderate

Typical normal plasma EPA and DHA level is around 2% of total fatty acids, compared to around 5% to 6% in red blood cell membranes.

"normal might be 2% for plasma EPA DHA, whereas for red blood cell EPA DHA, which is just the red cell membrane, it might be 5 or 6% would be normal." (said at 0:28:43)

The speaker's statement accurately reflects typical omega-3 fatty acid levels observed across blood compartments. In broad population cohorts, red blood cell (erythrocyte) membrane EPA+DHA (the Omega-3 Index) typically averages between 5% and 6% (e.g., 5.58% in 117,108 UK Biobank participants), while total plasma fatty acid EPA+DHA levels are substantially lower, typically averaging around 2%.

0:29:34Bill Harrissupportedmoderate

Plasma omega-3 percentages fluctuate acutely after meals due to postprandial triglyceride influx, whereas red blood cell membrane omega-3 levels remain stable.

"One problem that I have with the plasma is this is more noisy day to day. It varies because especially if you're in a non-fasting state, if you've just eaten, you've got now triglycerides coming with fatty acids coming into the blood, changing the denominator, because it's the percent of total fatty acids. And if you've just had a big meal, that's going to change your plasma percent EPA, where it won't affect your red blood cell." (said at 0:29:34)

Published studies evaluating the biological and postprandial variability of omega-3 fatty acid biomarkers confirm that plasma fatty acid percentages exhibit significantly higher within-subject variability and are sensitive to recent dietary intake (due to the influx of postprandial lipids altering the total fatty acid pool), whereas red blood cell (RBC) membrane fatty acid percentages remain stable and are not acutely altered by meal consumption.

0:20:15Bill Harrissupportedhigh

Land-based crops including Camelina and soybeans have been genetically engineered to synthesize the marine omega-3 fatty acids EPA and DHA.

"there are two or three groups that have found ways to put genes into plant or land—plant-animal—land plants that can be grown, you know, as long as you've got ground, you can grow them. Camelina is one. Even soybean oil, which starts with ALA, you can get up to a fair amount of DHA—EPA and DHA with genetic engineering of these plants." (said at 0:20:15)

Multiple research groups have successfully engineered terrestrial oilseed crops, notably Camelina sativa, soybean, and canola, to synthesize the long-chain marine omega-3 polyunsaturated fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). By introducing multi-gene biosynthetic pathways encoding fatty acid desaturases and elongases sourced from algae and other microorganisms into these plants, researchers have demonstrated stable seed-specific accumulation of EPA and DHA at levels comparable to marine fish oil across both greenhouse and multi-territory field trials.

0:30:44Bill Harrissupportedhigh

Brain tissue contains a substantial amount of DHA but almost no EPA.

"The brain has got a huge amount of DHA, almost no EPA in brain tissue. I mean, obviously in the blood flowing through the brain, that's there." (said at 0:30:44)

Published biochemical and lipidomic studies confirm that brain tissue contains large amounts of docosahexaenoic acid (DHA) but very low, near-negligible levels of eicosapentaenoic acid (EPA). In mammalian brain tissue phospholipids, DHA is highly enriched while EPA levels are typically 250- to 300-fold lower (several orders of magnitude lower), largely due to rapid beta-oxidation, decreased incorporation, and elongation/desaturation of EPA upon entry into the brain.

0:31:14Bill Harrissupportedvery low

Red blood cell omega-3 levels correlate much better with internal organ tissue levels (such as heart, liver, and muscle) than with brain tissue.

"the correlation between the red blood cell and brain tissue is not nearly as good in brain as it is in heart, liver, muscle, every other internal organ, where the red cell does reflect much better." (said at 0:31:14)

Animal studies examining the relationship between blood fractions and tissue fatty acid levels show that erythrocyte (red blood cell) phospholipid omega-3 long-chain polyunsaturated fatty acid levels correlate strongly and consistently with levels in peripheral internal organs (including the heart, liver, kidney, and skeletal muscle), but do not correlate well with brain tissue levels. Direct multi-organ tissue validation is primarily derived from animal models due to the invasive nature of organ biopsies in humans.

0:31:45Bill Harrissupportedhigh

Human red blood cells turn over in approximately 120 days.

"red cells turn over in 120 days." (said at 0:31:45)

Human red blood cells (erythrocytes) have a well-established average circulatory lifespan of approximately 120 days (about 4 months) under normal physiological conditions, after which senescent cells are cleared from circulation and recycled by macrophages.

0:32:45Bill Harrissupportedhigh

Mutations in the fatty acid desaturase (FADS) genes substantially affect omega-6 arachidonic acid levels but explain only 2 to 3% of the variability in omega-3 levels.

"like the standard fatty acid desaturase, the FADS gene, have very little effect. Mutations in that gene have very little effect on omega—they affect omega-6 arachidonic acid levels pretty substantially, those mutations in fatty acid desaturase, but they don't affect the omega-3s very much at all: 2 or 3% variability explained by that." (said at 0:32:45)

Genome-wide association studies (GWAS) confirm that common single-nucleotide polymorphisms in the fatty acid desaturase (FADS1/FADS2) gene cluster exert a major effect on circulating omega-6 arachidonic acid (AA) concentrations (explaining roughly 18% to 28% of the variance), whereas their effect on omega-3 fatty acid levels (such as EPA and DHA) is much smaller, accounting for only about 1% to 3% of the variance.

0:33:46Bill Harrissupportedhigh

In response to 1,800 mg of EPA and DHA supplementation, some individuals only increase their Omega-3 Index from 4% to 4.3%, while others increase from 4% to 8%.

"some people on 1,800 milligrams of EPA DHA, that might go up from an Omega-3 Index of 4 to 4.3. Others might go up from 4 to 8. I mean, it's just huge variability, and we don't—we don't think it's compliance all the time." (said at 0:33:46)

Randomized dose-response trial and pooled meta-analytic data support marked inter-individual variability in the Omega-3 Index (O3I) response to supplemental EPA and DHA. In a randomized controlled dose-response trial testing 0, 300, 600, 900, and 1,800 mg/day of EPA+DHA for approximately 5 months (PMID 24252845), supplemental dose accounted for 68% of the variability in O3I response, with baseline O3I, body weight, age, sex, and physical activity further influencing response heterogeneity. A pooled analysis of 14 intervention trials encompassing 1,422 individuals (PMID 31396625) similarly confirmed wide response variation (O3I increasing overall from 4.9% ± 1.7% to 8.1% ± 2.7%), with dose, baseline index, and chemical formulation explaining 62% of variance while individual changes varied widely.

0:39:20Bill Harrissupportedmoderate

Cardiovascular disease mortality has dropped from approximately half of all deaths in the 1950s to approximately one-third of deaths currently.

"We're way below what 1950s heart disease rates—now we're like a third of people die of heart disease now instead of half. And so the incidence of heart disease is down" (said at 0:39:20)

Long-term epidemiological tracking and prospective cohort data confirm that cardiovascular and coronary heart disease mortality rates have experienced substantial declines since the 1950s. Data from the Framingham Heart Study demonstrate that age-adjusted coronary heart disease mortality rates fell by approximately 59% between 1950–1969 and the 1990s, with concurrent reductions in disease incidence and risk factors. Vital statistics and population cohorts document that cardiovascular diseases accounted for roughly half of all deaths in mid-20th-century mortality tracking and have declined to approximately one-third (or fewer) of total deaths in recent decades.

0:41:29Rhonda Patrick (host)supportedhigh

In the REDUCE-IT trial, 4 grams of EPA reduced cardiovascular events and mortality by approximately 25%.

"And, you know, the REDUCE-IT trial, you said it was four grams of EPA, so they were using the Vascepa. And is this the trial where there was like a 25% reduction in mortality—cardiovascular-related mortality? GUEST1: Cardiovascular events, mortality, right." (said at 0:41:29)

In the REDUCE-IT trial (PMID: 30415628), 8,179 statin-treated patients with elevated triglycerides and high cardiovascular risk were randomized to receive 4 g daily of icosapent ethyl (a purified EPA ethyl ester, Vascepa) or placebo. Over a median follow-up of 4.9 years, the primary composite endpoint of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) was reduced by 25% (hazard ratio 0.75; 95% CI, 0.68 to 0.83). The risk of cardiovascular death alone was reduced by 20% (hazard ratio 0.80; 95% CI, 0.66 to 0.98).

0:45:06Bill Harrissupportedmoderate

The average American has an Omega-3 Index of approximately 5% of total red blood cell membrane fatty acids.

"Average American is roughly 5% Omega-3 Index, which is EPA and DHA in red cells as a percent of the total fatty acids in the red cells. So 5% of the fatty acids in the red cell membrane EPA and DHA." (said at 0:45:06)

Large observational cohort studies in the United States report mean Omega-3 Index levels (defined as erythrocyte EPA plus DHA as a percentage of total fatty acids) clustering around 4.5% to 5.5%. For example, in the Framingham Heart Study Offspring and Omni cohorts (n = 3,196), the mean Omega-3 Index was 5.6% (and 5.3% in matched subanalyses), while a survey of US adults in high cardiovascular risk regions reported a mean of 4.4%.

0:45:35Bill Harrissupportedhigh

The average Omega-3 Index in Japan is approximately 8% to 10%.

"Japan, it's on average 9%—8, 9, 10%—because they eat so much more omega-3 than we do." (said at 0:45:35)

Multi-country observational analyses measuring red blood cell fatty acid composition show that the population average Omega-3 Index in Japan falls in the desirable range (>8%), typical of high fish-consuming nations. In a global analysis evaluating red blood cell fatty acid patterns across 167,347 individuals, Japanese cohorts fell into the highest categorization of >8%, whereas populations in the US, Canada, Italy, and Germany were classified as low (>4% to 6%).

0:45:50Bill Harrissupportedmoderate

Vegans and US military personnel have an average Omega-3 Index of around 3.5%.

"vegans are down around 3.5%, as are U.S. military personnel, I'm sorry to say. When we've studied the soldiers, that's about the same as a vegan, and you know they're not vegans, um, so they're not getting enough omega-3." (said at 0:45:50)

Observational studies directly confirm that both vegans and U.S. military personnel have average Omega-3 Index levels of approximately 3.5% to 3.7%. A study of deployed U.S. service members found a mean HS-Omega-3 Index of 3.5%, while studies in vegans recorded average levels of 3.7% overall (and 3.5% specifically among male vegans). Both populations fall well below the recommended targets for blood EPA and DHA concentrations.

0:47:05Bill Harrissupportedhigh

Captive dolphins at SeaWorld eating exclusively fish have an Omega-3 Index of approximately 18% to 19%.

"a dolphin here at SeaWorld, which we studied, and that's all they eat is fish, right? And they weigh about 200 kilograms. I mean, they're big mammals like us and they only eat fish. Their Omega-3 Index is around 18 or 19%." (said at 0:47:05)

A comparative study analyzing red blood cell (RBC) fatty acid levels in 35 healthy captive bottlenose dolphins (Tursiops truncatus) on a diet of fish found that their mean Omega-3 Index (RBC EPA + DHA) was 19.9% (comprising 15.3% EPA and 4.6% DHA). This directly matches the speaker's statement that captive dolphins eating exclusively fish have an Omega-3 Index around 18% to 19%.

0:47:18Bill Harrissupportedmoderate

In normal human red blood cells and most other tissues, DHA is naturally present at approximately four times the concentration of EPA.

"DHA is always there in like four times the amount of EPA. I mean, unless you're just taking pure EPA, then they'll be one to one roughly. But in normal—the normal situation, um, there's a lot more DHA than EPA." (said at 0:47:18)

Human physiological studies confirm that under normal baseline conditions, docosahexaenoic acid (DHA) is naturally present in red blood cells, plasma lipid fractions, and tissue phospholipids at substantially higher concentrations than eicosapentaenoic acid (EPA), typically in a ratio around 4:1 to 5:1. For instance, controlled human dietary studies measuring baseline plasma fatty acid profiles observed DHA levels of 1.83 wt% compared to EPA levels of 0.38 wt%, reflecting a ratio of approximately 4.8 to 1.

0:50:00Bill Harrissupportedmoderate

A pooled analysis of 17 prospective cohorts with 40,000 to 45,000 participants found that individuals with the highest omega-3 levels had approximately a 15% lower risk of all-cause mortality compared to those with the lowest levels.

"it was a collaboration among 17 different cohorts, like, like the Framingham Study cohort, Women's Health Initiative, MESA, EPIC... And so we had 17 of those pooled together and around 40,000 to 45,000 people altogether where we had omega-3 levels at the beginning... And we found that the people who had the highest omega-3 levels compared to the lowest were 15% or so less likely to die over that time." (said at 0:50:00)

A 2021 de novo pooled analysis of 17 prospective cohort studies including 42,466 participants followed for a median of 16 years evaluated the relationship between baseline circulating omega-3 fatty acid levels and mortality. After multivariable adjustment, individuals in the highest quintile of circulating marine long-chain omega-3 fatty acids (EPA, DPA, and DHA) had a statistically significant 15% to 18% lower risk of all-cause mortality compared to those in the lowest quintile.

0:51:46Bill Harrissupportedmoderate

In the pooled 17-cohort analysis, higher omega-3 levels were associated with significantly lower risk of cardiovascular mortality, cancer mortality, and non-cardiovascular/non-cancer mortality.

"We then looked at cardiovascular mortality, cancer mortality, and then everything else, kitchen sink... And we saw the same thing in all. It wasn't as strong in cancer; it wasn't as stair-steppy like it was in cardiovascular. But the highest group in omega-3s did have a significantly lower risk of death in cancer. But interesting to me is the non-cardiovascular, non-cancer, all these other causes of death from electrocution to suicide to car accidents to kidney failure... the higher the omega-3, just like cardiovascular, lower risk." (said at 0:51:46)

A 2021 de novo pooled analysis of 17 prospective cohort studies (Harris et al., Nature Communications) examined 42,466 individuals over a median of 16 years of follow-up (15,720 deaths). After multivariable adjustment, individuals in the highest versus lowest quintile of circulating long-chain marine omega-3 fatty acids (EPA, DPA, and DHA) had significantly lower risk of all-cause mortality, cardiovascular mortality, cancer mortality, and non-cardiovascular/non-cancer mortality (other causes).

0:53:18Bill Harrissupportedlow

A study published from the Framingham cohort found that individuals with the lowest omega-3 levels had an odds of dying approximately five years earlier than those with the highest levels.

"in another study we published from Framingham, just one cohort, we did see that there's roughly a five-year difference. If you're at the very lowest omega-3 versus the highest, your your odds of dying are about five years earlier." (said at 0:53:18)

Analysis of the Framingham Offspring Cohort supports the claim that lower red blood cell omega-3 levels are associated with significantly higher all-cause mortality risk. In a prospective study of 2,500 participants followed over a median of 7.3 years, individuals in the lowest Omega-3 Index quintile (<4.2%) had a 34% higher risk of death from any cause compared to those in the highest quintile (>6.8%) (PMID: 29559306). A subsequent analysis of the cohort over 11 years of follow-up demonstrated that red blood cell fatty acid profiles, including the Omega-3 Index, predicted all-cause mortality risk as effectively as traditional cardiovascular risk factors (PMID: 34134132). Because these findings are derived from prospective observational cohort data, certainty is low regarding direct causality.

0:54:40Bill Harrissupportedhigh

A serving of salmon provides about 1.5 grams of omega-3 fatty acids.

"salmon itself, which is the one of the highest omega-3 fish, it's only the most—one of the highest that people actually eat. Um, you know, that's that provides about one and a half grams per serving of omega-3." (said at 0:54:40)

A typical serving (approximately 3 to 4 ounces, or ~85–115 g) of salmon provides roughly 1.0 to 2.0 grams of long-chain omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), consistent with the claim that a serving provides about 1.5 grams. Dietary intervention trials testing oily fish intake report that consuming two standard fish servings (including salmon) per week delivers approximately 3.4 g of total EPA and DHA (averaging ~1.7 g per serving), and clinical salmon feeding protocols similarly reflect this omega-3 density.

0:55:17Bill Harrissupportedmoderate

Average daily intake of EPA and DHA in Japan is roughly 900 mg per day.

"In Japan, it's roughly 900 milligrams a day." (said at 0:55:17)

Population-based dietary studies in Japanese adults support the claim that daily combined intake of long-chain n-3 polyunsaturated fatty acids (EPA and DHA) averages roughly 800–1,000 mg/day (approximately 900 mg/day). In Japanese population cohorts, high habitual fish intake yields dietary EPA intake alone of around 300 mg/day alongside higher accompanying DHA levels, with intake varying by age group.

0:56:23Bill Harrissupportedlow

In the Framingham study, 10-year mortality risk was approximately 50% for smokers with low omega-3, 30% for non-smokers with low omega-3 or smokers with high omega-3, and 10% for non-smokers with high omega-3.

"if you're a smoker and you have a low omega-3, you you're 50—you know, over the 10 years of study, you're 50-50 chance of living. You're going to die, a 50% chance of dying. If you have a low omega-3 and you're a non-smoker, it's not so bad. Your your risk of death maybe is 30%... if you're a smoker and you have a high omega-3... your risk is kind of like having a low omega-3, being a non-smoker. And then if you best case, you don't smoke and you have a high omega-3, your odds of dying are like 10%." (said at 0:56:23)

In a 2021 analysis of 2,240 Framingham Offspring Cohort participants followed over 11 years (McBurney et al., published in The American Journal of Clinical Nutrition), researchers evaluated red blood cell fatty acid profiles alongside standard cardiovascular risk factors, including smoking. The study found that red blood cell omega-3 index and smoking status had comparable predictive values for all-cause mortality, with survival curves showing that smokers with a low omega-3 index had the highest mortality risk (~50%), while non-smokers with low omega-3 and smokers with high omega-3 had similar intermediate mortality risks (~30%), and non-smokers with high omega-3 had the lowest mortality risk (~10%). Because this evidence comes from an observational cohort analysis, GRADE certainty is low due to potential residual confounding.

0:57:36Bill Harrissupportedmoderate

Smokers have a lower Omega-3 Index than non-smokers.

"Smokers have lower Omega-3 Index than non-smokers from other studies. And it could be because of the hyperoxidative state of a smoker's blood, that could actually destroy omega-3s, potentially, or they just don't eat fish oil, they don't eat fish." (said at 0:57:36)

Multiple large population-based and cohort studies consistently show that cigarette smoking is inversely associated with the Omega-3 Index (the percentage of EPA and DHA in red blood cell membranes). Data from national surveys and large biobanks (such as the Canadian Health Measures Survey and the UK Biobank) demonstrate that smokers have significantly lower Omega-3 Index levels and a higher prevalence of suboptimal omega-3 status compared to non-smokers.

0:55:22Rhonda Patrick (host)supportedhigh

Average life expectancy in Japan is approximately four to five years longer than in the United States.

"And there, they, if I remember correctly, their average lifespan is about five years longer than the United States average, right? Despite the fact they smoke more, despite the fact they have more hypertension, despite the fact they have a higher stress life, they still live four or five years longer." (said at 0:55:22)

Population-level demographic and health systems analyses confirm that life expectancy at birth in Japan is approximately 4 to 5 years longer than in the United States. International comparative data (e.g., from the OECD and national vital statistics) show US life expectancy typically between 76 and 79 years in recent years compared to approximately 84 to 85 years in Japan.

1:00:30Bill Harrissupportedlow

In a Framingham Study analysis of 10 distinct plasma inflammatory biomarkers against the Omega-3 Index, all 10 markers were inversely correlated with omega-3 levels.

"We looked at, uh, 10 different, very different inflammatory biomarkers, uh, that in the plasma in patients in Framingham and correlated it with the Omega-3 Index, and all 10 of them, the higher the omega-3, the lower the marker." (said at 1:00:30)

In a cross-sectional study of 2,724 participants from the Framingham Offspring and Omni Cohorts (Block et al., Atherosclerosis 2015, PMID 25897795), researchers evaluated the correlation between red blood cell omega-3 fatty acid levels (EPA + DHA, representative of the Omega-3 Index) and 10 specific biomarkers of inflammation: urinary isoprostanes, soluble interleukin-6, C-reactive protein, tumor necrosis factor receptor 2, intercellular adhesion molecule-1, P-selectin, lipoprotein-associated phospholipase-A2 mass, lipoprotein-associated phospholipase-A2 activity, monocyte chemoattractant protein-1, and osteoprotegerin. All 10 inflammatory biomarkers demonstrated inverse (negative) correlations with red blood cell omega-3 levels. Because the underlying study design is cross-sectional and observational, the overall certainty for the body of evidence is low.

  • supports: Red blood cell fatty acids and biomarkers of inflammation: a cross-sectional study in a co… (Atherosclerosis 2015) · cited 73x in the literature
    "We examined the cross-sectional association of red blood cell (RBC) fatty acids, representative of body membrane fatty acid composition, with 10 biomarkers active in multiple inflammatory pathways in 2724 participants (mean age 66 ± 9 years, 54% women, 8% minorities) from the Framingham Offspring and minority Omni Cohorts. After multivariable adjustment, the RBC EPA and DHA content was inversely correlated (all P ≤ 0.001) with 8 biomarkers: urinary isoprostanes (r = -0.16); and soluble interleukin-6 (r = -0.10); C-reactive protein (r = -0.08); tumor necrosis factor receptor 2 (r = -0.08); intercellular adhesion molecule-1 (r = -0.08); P-selectin (r = -0.06); lipoprotein-associated phospholipase-A2 mass (r = -0.11) and activity (r = -0.08). The correlations for monocyte chemoattractant protein-1 was -0.05, P = 0.006 and osteoprotegerin (r = -0.06, P = 0.002) were only nominally significant." (abstract, results, passage verified)
    pubmedfull study (doi)
1:02:42Bill Harrissupportedhigh

Lipoxin A is an anti-inflammatory specialized pro-resolving mediator synthesized from arachidonic acid.

"and some that are made from arachidonic that are also suppressive, uh, lipoxin A, this is the one from arachidonic." (said at 1:02:42)

Lipoxin A (including lipoxin A4) is an established specialized pro-resolving mediator (SPM) derived from arachidonic acid through lipoxygenase enzymatic pathways. Unlike classical pro-inflammatory arachidonic acid metabolites (such as leukotrienes and prostaglandins), lipoxins act to resolve inflammation, suppress neutrophil recruitment, and stimulate non-phlogistic macrophage phagocytosis.

1:05:36Bill Harrissupportedhigh

In the REDUCE-IT cardiovascular trial, the high-dose EPA intervention reduced triglyceride levels by approximately 15%.

"No, no, that wasn't the REDUCE-IT trial. We didn't lower triglycerides very much, I mean, it was 15%." (said at 1:05:36)

In the REDUCE-IT phase 3 randomized controlled trial (NCT01492361), patients with elevated baseline triglycerides (135 to 499 mg/dL) on statin therapy who were treated with high-dose icosapent ethyl (a highly purified EPA ethyl ester, 4 g daily) experienced a modest reduction in triglyceride levels (approximately 18% to 20% relative to baseline/placebo, around 15-20%), demonstrating that the clinical cardiovascular benefit observed in the trial occurred alongside only a modest decrease in circulating triglycerides.

1:07:43Bill Harrissupportedmoderate

Red cell distribution width (RDW) is an independent predictor of adverse clinical outcomes and mortality.

"That's the red cell distribution width, so it's expressed as a percent. If you have a high percent distribution, you've got—it's it's a remarkable predictor of all kinds of adverse outcomes, independent of everything else." (said at 1:07:43)

Red cell distribution width (RDW), a measure of erythrocyte size variability expressed as a percentage on standard complete blood counts, is well-established as a robust and independent predictor of all-cause mortality, cardiovascular mortality, and adverse clinical outcomes across numerous patient populations. Systematic reviews and meta-analyses involving tens of thousands of individuals demonstrate that higher baseline RDW levels correlate with significantly elevated risk for all-cause mortality (e.g., RR 2.20; 95% CI 1.42–3.39 in coronary artery disease cohorts) and cardiovascular events, maintaining independent prognostic significance even after multivariable adjustment for traditional risk factors, inflammatory markers, and anemia status.

1:08:40Bill Harrissupportedlow

In a dataset of over 40,000 individuals, higher Omega-3 Index levels strongly correlate with lower, healthier red cell distribution width (RDW).

"We've seen that we've got a dataset of 40-some thousand people. We see the very strong correlation between high omega-3 and lower, healthier RDW, and we're getting ready to submit that now." (said at 1:08:40)

The claim accurately reflects published findings from a clinical laboratory dataset of over 45,000 individuals (PMID 34839221). In an analysis of 25,485 healthy adults without inflammation or anemia selected from that dataset, higher Omega-3 Index levels were significantly associated with lower red cell distribution width (RDW) in both sexes (p < 0.00001), after adjusting for age, BMI, sex, and C-reactive protein. Because the evidence is derived from cross-sectional observational data, certainty is low and causality cannot be established without randomized intervention trials.

1:12:20Bill Harrissupportedvery low

A pilot study of 100 COVID-19 patients admitted to Cedars-Sinai found that patients in the highest quartile of Omega-3 Index had approximately half the mortality risk of those in lower quartiles (p = 0.07).

"pilot study because we only had access to data from 100 people... we did have Omega-3 Index levels in 100 people that had been admitted to Cedars-Sinai in LA with COVID... the people who had the highest quartile of omega-3 levels, the 25% highest compared to everybody else who was lower, and those people were really half as likely to die as people who had—but yeah, and it was 0.07 p-value" (said at 1:12:20)

A 2021 pilot study of 100 COVID-19 patients admitted to Cedars-Sinai Medical Center analyzed the Omega-3 Index in banked admission blood samples. In that cohort, 1 of 25 patients (4%) died in the highest quartile of Omega-3 Index (≥5.7%) compared to 13 of 75 (17.3%) in quartiles 1–3 (adjusted odds ratio 0.25, p = 0.07). The speaker accurately describes the pilot study's sample size, design, and reported p-value of 0.07. As an observational pilot study with only 14 total events, the certainty of evidence for clinical efficacy is very low.

1:15:45Bill Harrissupportedvery low

In silico molecular modeling demonstrated that DHA and linoleic acid can bind to the SARS-CoV-2 spike protein and stabilize it in a closed conformation, preventing receptor interaction.

"They were doing in silico experiments looking at the the spike protein on COVID, and they found that there's two conformations, an open and closed conformation... They found that DHA, again in silico experiments, if it's present, will hold that thing in a closed position... because it also showed that linoleic acid did the same thing." (said at 1:15:45)

Published structural biology and in silico molecular modeling studies confirm that linoleic acid and omega-3 polyunsaturated fatty acids such as DHA bind to a specific pocket on the SARS-CoV-2 spike glycoprotein. This binding stabilizes the spike protein in a locked/closed conformation, which impedes its interaction with host cell ACE2 receptors. Because this finding is based strictly on computational docking/molecular dynamics and in vitro structural data, clinical efficacy remains unproven, corresponding to very low GRADE certainty.

1:21:30Bill Harrissupportedmoderate

In a pooled cohort consortium study, higher blood biomarker levels of linoleic acid were associated with a lower risk of cardiovascular disease.

"And one of them looked at linoleic acid levels in the blood and cardiovascular outcomes, and found that the higher the linoleic acid, the lower the risk for cardiovascular disease." (said at 1:21:30)

A pooled individual-level meta-analysis from a global consortium of 30 prospective cohort studies (68,659 participants) evaluated circulating and tissue biomarker levels of linoleic acid (LA) in relation to incident cardiovascular outcomes. The study found that higher biomarker levels of LA were significantly associated with lower risks of total cardiovascular disease (hazard ratio [HR] per interquintile range 0.93, 95% CI 0.88–0.99), cardiovascular mortality (HR 0.78, 95% CI 0.70–0.85), and ischemic stroke (HR 0.88, 95% CI 0.79–0.98).

1:21:45Bill Harrissupportedmoderate

In a pooled cohort consortium study, higher blood biomarker levels of linoleic acid were associated with a lower risk of developing type 2 diabetes.

"And another paper looked at linoleic acid levels and risk for developing diabetes: higher omega-3—excuse me, higher omega-6 linoleic, lower risk for developing diabetes." (said at 1:21:45)

A large pooled analysis of individual participant data from 20 prospective cohort studies across 10 countries (39,740 participants, 4,347 incident cases of type 2 diabetes) found that higher proportions of linoleic acid biomarkers were significantly associated with a lower risk of developing type 2 diabetes (relative risk 0.65 per interquintile range, 95% CI 0.60–0.72). This association remained consistent across multiple lipid compartments, including plasma, phospholipids, cholesterol esters, and adipose tissue.

1:22:58Rhonda Patrick (host)supportedmoderate

The 2013 Brasky study nested within the SELECT trial found a statistically significant positive association between plasma phospholipid omega-3 fatty acid levels and prostate cancer risk.

"this 2013 paper that was published by—... Brasky... Plasma phospholipids, yeah... and the incidence of prostate cancer in a trial of people—it was called the SELECT trial... Statistically significant, yes, it was." (said at 1:22:58)

The 2013 study by Brasky and colleagues nested within the Selenium and Vitamin E Cancer Prevention Trial (SELECT) evaluated plasma phospholipid fatty acids and prostate cancer incidence among 834 case subjects and a subcohort of 1,393 men. Men in the highest quartile of long-chain omega-3 polyunsaturated fatty acids (LCω-3PUFA) had a statistically significant increased risk of total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88), low-grade prostate cancer (HR = 1.44, 95% CI = 1.08 to 1.93), and high-grade prostate cancer (HR = 1.71, 95% CI = 1.00 to 2.94) compared with men in the lowest quartile.

1:26:10Rhonda Patrick (host)supportedhigh

High-dose alpha-tocopherol supplementation (e.g., 400 IU) depletes serum gamma-tocopherol levels.

"400 IU of alpha-tocopherol, my mentor Bruce Ames and his one of his postdocs had shown that when you give like a high dose of alpha-tocopherol... that you basically deplete another tocopherol, gamma-tocopherol, which is anti-inflammatory." (said at 1:26:10)

High-dose alpha-tocopherol supplementation significantly reduces circulating plasma/serum concentrations of gamma-tocopherol in human trials. Research originating from Bruce Ames's laboratory (e.g., Jiang et al.) and subsequent clinical pharmacokinetic studies demonstrated that alpha-tocopherol displaces gamma-tocopherol and accelerates its degradation (increasing gamma-CEHC excretion). Furthermore, laboratory and animal investigations confirmed that gamma-tocopherol possesses distinct anti-inflammatory properties—such as inhibiting cyclooxygenase-2 (COX-2) activity—that alpha-tocopherol lacks.

1:28:46Bill Harrissupportedhigh

The STRENGTH trial tested Epanova (a free fatty acid EPA/DHA formulation) against corn/olive oil placebo in over 13,000 statin-treated cardiovascular risk patients and was halted early for futility.

"They used a thing called Epanova... which is a EPA plus DHA... except they're free fatty acids, not ethyl esters... STRENGTH, which was a bigger study than REDUCE-IT, but in virtually the same kind of patient—high cardiovascular risk, high triglycerides, on statins, everybody had to be in there, 13,000 people worldwide... they found no effect at all. They stopped the study early, as a matter of fact, for futility." (said at 1:28:46)

The STRENGTH randomized clinical trial (Nicholls et al., 2020) evaluated a high-dose carboxylic acid / free fatty acid formulation of EPA and DHA (4 g/day) compared to corn oil placebo in 13,078 statin-treated patients with high cardiovascular risk and hypertriglyceridemia across 22 countries. The trial found no significant difference in the primary composite cardiovascular outcome between groups (12.0% vs 12.2%, hazard ratio 0.99, P = .84) and was prematurely halted following an interim analysis showing a low probability of clinical benefit (futility).

  • supports: Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events… (JAMA 2020) · cited 1014x in the literature
    "When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84)." (abstract, results, passage verified)
    pubmedfull study (doi)
1:16:40Rhonda Patrick (host)supportedhigh

The mRNA and Johnson & Johnson COVID-19 vaccines incorporate two proline amino acid substitutions into the SARS-CoV-2 spike protein sequence to stabilize it in a closed, prefusion conformation.

"the vaccines, at least mRNA vaccines and Johnson & Johnson, keep it in the closed conformation spike protein. They inserted two proline amino acids to keep it in a closed—" (said at 1:16:40)

Both major mRNA COVID-19 vaccines (Pfizer-BioNTech's BNT162b2 and Moderna's mRNA-1273) as well as Johnson & Johnson's viral-vector vaccine (Ad26.COV2.S) were engineered with two proline substitutions (the 2P mutation, K986P and V987P) in the S2 subunit of the SARS-CoV-2 spike glycoprotein. This modification prevents the structural transition to the postfusion state and locks the spike protein in its prefusion conformation, preserving the key antigenic epitopes targeted by neutralizing antibodies.

1:14:50Bill Harrissupportedlow

A study from Chile confirmed an association between higher omega-3 fatty acid levels and reduced mortality in COVID-19 patients.

"Another paper's come out from Chile just confirming the same thing. They saw the same thing." (said at 1:14:50)

A cross-sectional study from Chile (Zapata et al., 2021) evaluated the Omega-3 Index (O3I) in hospitalized patients with severe COVID-19 and analyzed its relationship with clinical outcomes. The authors reported that a higher Omega-3 Index was inversely associated with mechanical ventilation and in-hospital death, even after adjusting for age, sex, and other established risk factors. The certainty of evidence is low given the observational, cross-sectional design and small sample size (n = 74 severe cases).

1:31:58Bill Harrissupportedhigh

In the REDUCE-IT trial, the event rate in the treated group was 25% lower than placebo, while event rates in both placebo and active arms of the STRENGTH trial were lower than the treated group in REDUCE-IT.

"the event rate in REDUCE-IT in the placebo group, which is like this, and the event rate in the treated group, which is lower, 25% lower. And then you look at the event rate in STRENGTH, and both placebo and active were even lower than the event rates in the treated group in REDUCE-IT." (said at 1:31:58)

The speaker's claims accurately reflect the primary results of the REDUCE-IT and STRENGTH randomized controlled trials. In REDUCE-IT (Bhatt et al., 2019), the primary composite cardiovascular event rate was 17.2% in the icosapent ethyl (treated) group versus 22.0% in the placebo group, representing a 25% relative risk reduction (hazard ratio, 0.75; 95% CI, 0.68 to 0.83; P<0.001). In the STRENGTH trial (Nicholls et al., 2020), which evaluated an identical 5-point major adverse cardiovascular event primary composite outcome, the event rates were 12.0% in the active treatment arm (omega-3 CA) and 12.2% in the corn oil placebo arm, both of which were lower than the 17.2% observed in the treated group of REDUCE-IT.

1:34:09Rhonda Patrick (host)supportedhigh

In the VITAL trial, omega-3 supplementation resulted in a major reduction in the risk of heart attack, and participants with low baseline fish intake experienced a significant reduction in the primary composite cardiovascular endpoint.

"There was reduced—major reduction risk of heart attack, and even in people who didn't who were ate little fish, or half, the lower half of the fish intake, they got a significant reduction in the primary endpoint, right?" (said at 1:34:09)

In the VITAL randomized controlled trial (N=25,871), marine omega-3 fatty acid supplementation (1 g/day) did not significantly reduce the primary composite cardiovascular endpoint overall, but did produce a statistically significant 28% reduction in total myocardial infarction (HR 0.72; 95% CI, 0.59 to 0.90) and a 50% reduction in fatal myocardial infarction (HR 0.50; 95% CI, 0.26 to 0.97). Furthermore, in subgroup analyses by baseline fish intake, participants consuming less than the cohort median (1.5 servings/week) experienced a statistically significant 19% reduction in the primary composite cardiovascular endpoint (HR 0.81; 95% CI, 0.67 to 0.98; P for interaction = 0.045).

1:34:21Bill Harrissupportedhigh

The VITAL trial administered 840 milligrams per day of omega-3, which equals one capsule of Lovaza.

"So there was there was good outcomes in that study from from taking 840 milligrams, that's a one capsule Lovaza, and that's not much." (said at 1:34:21)

The VITamin D and OmegA-3 TriaL (VITAL) evaluated daily supplementation with 1 gram of marine omega-3 fatty acid fish-oil concentrate (Omacor/Lovaza formulation), which provides approximately 840 mg of active eicosapentaenoic acid (EPA, ~460 mg) and docosahexaenoic acid (DHA, ~380 mg) in a single capsule. Standard prescription omega-3-acid ethyl esters (Lovaza/Omacor) contain exactly 840 mg of EPA and DHA per 1-gram capsule.

1:34:46Bill Harrissupportedhigh

The REDUCE-IT trial tested a dose of 4 grams per day of omega-3 (EPA), which is five times higher than doses commonly used in previous omega-3 trials.

"The 4 grams of—what was important with REDUCE-IT is 4 grams a day, which is really five times higher than anybody's ever used before for omega-3 dosing, and that that showed a benefit." (said at 1:34:46)

The REDUCE-IT trial evaluated icosapent ethyl (a highly purified EPA ethyl ester) at a dose of 4 grams daily (2 g twice daily) versus placebo in statin-treated patients with elevated triglycerides and high cardiovascular risk. The trial showed a significant 25% reduction in major adverse cardiovascular events (hazard ratio 0.75; 95% CI, 0.68 to 0.83). Most earlier major omega-3 cardiovascular outcome trials (such as GISSI-Prevenzione, GISSI-HF, ORIGIN, and ASCEND) had tested standard doses of approximately 1 gram per day (typically ~840 mg of combined EPA/DHA), making the 4 g/day regimen roughly 4 to 5 times higher than previous standard outcome trial dosing (though JELIS previously evaluated 1.8 g/day of EPA).

1:39:33Bill Harrissupportedhigh

A Cochrane systematic review by Middleton et al. examining 70 trials in pregnant women showed that omega-3 supplementation reduces the risk of premature birth, particularly early premature birth before 34 weeks.

"a Cochrane report from a couple years ago reporting that looking at 70 trials in pregnant women given omega-3, that the giving omega-3 reduces risk for premature birth, especially early premature birth before 34 weeks." (said at 1:39:33)

A 2018 Cochrane Systematic Review led by Philippa Middleton examined 70 randomized controlled trials involving 19,927 women to evaluate omega-3 supplementation during pregnancy. The meta-analysis found high-quality evidence that omega-3 supplementation reduces the risk of preterm birth before 37 weeks (RR 0.89, 95% CI 0.81 to 0.97) and leads to an even greater reduction in early preterm birth before 34 weeks (RR 0.58, 95% CI 0.44 to 0.77).

  • supports: Omega-3 fatty acid addition during pregnancy. (The Cochrane database of systematic reviews 2018) · cited 446x in the literature
    "In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3... Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3." (abstract, results, passage verified)
    pubmedfull study (doi)
1:42:38Bill Harrissupportedhigh

Susan Carlson's trial from the University of Kansas found that DHA supplementation in pregnancy reduced preterm birth and decreased the risk of other adverse delivery outcomes.

"ADORE was the name of it, from Kansas University, Susan Carlson. They published it and they found a benefit in preterm birth, but they also found benefits in other adverse outcomes, reduced risk for adverse outcomes in the delivery." (said at 1:42:38)

The Assessment of DHA On Reducing Early preterm birth (ADORE) trial, led by Dr. Susan Carlson at the University of Kansas Medical Center and published in 2021, evaluated high-dose (1000 mg/day) versus standard-dose (200 mg/day) DHA supplementation in 1,100 pregnant women. The trial found that the higher DHA dose reduced rates of early preterm birth (<34 weeks gestation), especially among women with low baseline DHA status (2.0% vs 4.1%, Bayesian posterior probability = 0.93). The trial also observed significant reductions in serious adverse maternal and delivery-related events (including premature rupture of membranes, chorioamnionitis, and pyelonephritis) as well as neonatal complications (feeding, genitourinary, and neurological issues; all posterior probabilities > 0.90).

1:34:39Bill Harrissupportedmoderate

Dose-response studies submitted to the FDA for Lovaza (Omacor) demonstrated that an 8-gram daily dose produced greater triglyceride reduction than a 4-gram daily dose.

"they did dose-response studies, on triglyceride reduction, and they got good enough at four capsules a day of triglyceride reduction, so they said, "Let's use that." But they got better at 8 grams, better triglyceride reduction." (said at 1:34:39)

Evidence evaluating dose escalation of Lovaza (omega-3-acid ethyl esters) demonstrates that an 8 g/day dose produces greater triglyceride lowering than the standard 4 g/day dose. In a clinical trial assessing dose titration in patients with primary severe hypertriglyceridemia, triglyceride levels were reduced by 37% at 4 g/day and further reduced by 46% at 8 g/day (with additional reduction at 12 g/day), confirming a dose-dependent decrease in triglycerides beyond the conventional 4-capsule (4 g) daily regimen.

1:35:54Rhonda Patrick (host)supportedhigh

Both the REDUCE-IT and STRENGTH clinical trials demonstrated a small but statistically significant increase in atrial fibrillation.

"And this was something that was found as a, I guess you'd call, an adverse side effect in the in the clinical trials. I believe it was both in the REDUCE-IT and STRENGTH, right? Where there was a small but statistically significant increase in atrial fibrillation." (said at 1:35:54)

The host's statement is accurate. Both the REDUCE-IT (NCT01492361) and STRENGTH (NCT02104817) clinical trials evaluated high-dose prescription omega-3 fatty acids and found a small but statistically significant increase in atrial fibrillation (or atrial flutter) in the treatment arms compared to the control arms. In REDUCE-IT, hospitalization for atrial fibrillation or flutter occurred in 3.1% of patients receiving icosapent ethyl compared to 2.1% receiving placebo (P = 0.004). Subsequent sub-analyses and clinical trial results across both large-scale randomized controlled trials confirmed this adverse effect.

1:36:18Bill Harrissupportedhigh

In the VITAL trial, which tested an 800 mg dose of omega-3, there was a slight increase in atrial fibrillation that was not statistically significant.

"And yeah, and then they looked in VITAL, and there was a slight increase, but not statistically significant, in AFib, and that was a lower dose; it was 800 milligrams instead of 4,000 milligrams." (said at 1:36:18)

In the large-scale, randomized Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, participants were randomized to receive 1 g/day of marine omega-3 fatty acids (providing approximately 840 mg/day of EPA and DHA) or placebo. Over a median follow-up of 5.3 years, the omega-3 intervention resulted in a slight, non-statistically significant increase in incident atrial fibrillation (hazard ratio 1.09, 95% CI 0.96–1.24), confirming that lower-dose omega-3 supplementation did not significantly alter atrial fibrillation risk compared to higher-dose trials.

1:38:01Bill Harrissupportedmoderate

Two cohort studies following participants over time have found that higher baseline omega-3 levels are associated with a lower risk of developing atrial fibrillation.

"Two studies have been published already looking at that question. We're looking at two individual cohorts have followed people out and said higher omega-3 at baseline, lower risk for AFib." (said at 1:38:01)

Prospective cohort evidence supports the claim that higher baseline blood levels of long-chain omega-3 fatty acids (specifically DHA, DPA, and combined EPA+DHA) are associated with a lower risk of developing atrial fibrillation (AF). A 2023 pooled meta-analysis of participant-level data from 17 prospective cohort studies (comprising 54,799 participants and 7,720 incident AF cases) found that higher baseline levels of docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and combined EPA+DHA were significantly associated with a lower hazard of incident AF (HR for DPA: 0.89, 95% CI: 0.83–0.95; HR for DHA: 0.90, 95% CI: 0.85–0.96; HR for EPA+DHA: 0.93, 95% CI: 0.87–0.99) (PMID: 37468189). Individual cohorts such as the Multi-Ethnic Study of Atherosclerosis (MESA) (PMID: 33693794) and the Atherosclerosis Risk in Communities (ARIC) study (PMID: 22570739) have also shown lower AF risk specifically associated with higher plasma concentrations of DHA in sub-analyses.

1:33:29Bill Harrissupportedhigh

The VITAL trial enrolled approximately 25,000 participants in a four-arm study design.

"VITAL had 25,000 people, four arms in vitamin D." (said at 1:33:29)

The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, double-blind, placebo-controlled clinical trial testing vitamin D3 (2000 IU/day) and marine omega-3 fatty acids (1 g/day). It utilized a 2-by-2 factorial design, resulting in four intervention arms (vitamin D + omega-3, vitamin D + placebo, omega-3 + placebo, and double placebo), and enrolled a total of 25,871 participants.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.