Supplement Summary: Omega 3’s

In order to render a verdict on the utility of omega 3 supplements, we need to understand their biochemistry, explore their physiological effects, and critically appraise their impact on human health outcomes.

A Primer on Fatty Acids

Fatty acids are the building blocks of fat in our bodies and in the food we eat. During digestion the body breaks down fats into fatty acids, which can then be absorbed in the blood. Fatty acid molecules usually come attached in a package of three, forming a molecule known as a triglyceride.

Fatty acids can be divided into four general categories—saturated, monosaturated, polyunsaturated, and trans fats—based on the structure of their long-chain hydrocarbons. More than 20 types pf fatty acids are found in food sources including fruits, vegetables, seeds, nuts, animal fats, and fish oil.

Some of these fatty acids are known as essential fatty acids, meaning that the body has no biochemical pathway to produce these molecules on its own; you can only get them by eating certain foods. These essential fatty acids are essential indeed. They form integral part of cell membranes throughout the body and affect the function of the cell receptors in these membranes. They provide the starting point for making hormones that regulate blood clotting, contraction and relaxation of blood vessels, and the inflammatory response. They also bind to receptors in cells that regulate genetic function. 

Omega 3 fatty acids, an essential type of polyunsaturated fatty acids (PUFA, for short), have received widespread scientific attention and press coverage as a potential therapy for a variety of medical conditions—cardiovascular disease, in particular—due to their anti-inflammatory properties.

The three main omega-3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is the most common omega-3 fatty acid in most Western diets and is found in vegetable oils and nuts, flax seeds and flaxseed oil, leafy vegetables, and grass-fed animals. The main sources EPA and DHA are fatty cold-water fish. Hence, EPA and DHA are also commonly referred to as “marine fatty acids.”

Your body can convert some ALA into small amount of EPA and then to DHA.

ALA⇒ EPA⇒ DHA

But conversion of ALA into EPA and DHA is quite limited. Therefore, getting EPA and DHA from foods, and potentially dietary supplements, is the only practical way to increase levels of these omega-3 fatty acids in your body.

The Physiological Effects of Omega 3 Fatty Acids

1)    Lowering of plasma triglycerides

It is well recognized and broadly accepted that omega 3’s reduce the number of triglycerides, a type of fat (or lipid), found in the blood. High triglycerides can cause hardening of the arteries which is part of the pathophysiology underlying cardiovascular disease. High triglycerides are often a sign of other conditions that increase the risk of heart disease and stroke, including obesity and metabolic syndrome.

The proposed mechanisms by which omega 3’s lower plasma triglycerides include: reduced fatty acid availability for triglyceride synthesis due to decreased de novo lipogenesis (the process of converting carbohydrates into fat), increased fatty acid breakdown; reduced delivery of fatty acids to the liver; reduced hepatic enzyme activity for triglyceride synthesis; and increased hepatic synthesis of phospholipids rather than triglycerides.

The magnitude of triglyceride-lowering effect of omega 3s is linearly dose-dependent across a wide range of consumption. However, individual responses vary.

Whereas the impact on triglyceride lowering is widely accepted, the effects of omega 3’s on cholesterol levels are not fully understood due to conflicting research.

2)    Reduction of heart rate and blood pressure

Omega 3 consumption reduces resting heart rate and blood pressure due to effects on the cardiac electrophysiological pathways and increase in vagal tone, nitric oxide production, vasodilation, and arterial compliance.

3)    Reduced formation of blood clots (Anti-thrombosis)

Omega 3’s are commonly considered to have anti-thrombotic effects. However, this appears to take effect only at very high doses (e.g., 15 g/day) based on increased bleeding times at very high doses.

4)    Improved endothelial health

The endothelium is a thin layer of cells that lines the inside of the heart and blood vessels. Endothelial cells release substances that control the relaxation and contraction of the blood vessels as well as enzymes that control blood clotting, immune function, and platelet adhesion. Endothelial injury and subsequent dysfunction is widely considered to be an early event in pathogenesis of cardiovascular disease. Studies have shown that omega 3’s improve flow mediated arterial dilation and lower markers of endothelial dysfunction.

5)    Increased cardiac filling and myocardial efficiency

Some studies suggest that omega 3’s improve the function and efficiency of the heart muscle (myocardium) itself by improving contractile function and reducing the oxygen demand during exercise.  In patients with diagnosed heart failure, omega 3s improved the squeezing function and cardiac output of the heart.

6)    Anti-inflammatory effects

Excessive and unabated inflammation is at the root of cardiometabolic disease. Similar to nonsteroidal anti-inflammatory medications, EPA and DHA inhibit the production of pro-inflammatory eicosanoids, signaling molecules that trigger the body’s inflammatory responses. There are multiple subfamilies of eicosanoids, some of which are pro-inflammatory while others are anti-inflammatory. Omega 3’s appear to reduce plasma and urine levels of pro-inflammatory eicosanoids such as leukotrienes and thromboxanes while increasing levels of resolvins, protectins, and other mediators that help to resolve inflammation.

Omega 3’s & Cardiovascular Risk

All of the physiological effects of omega 3’s--lowering plasma triglycerides, resting heart rate, and blood pressure, improving myocardial efficiency and vascular function, and reducing inflammation—provide a plausible (and strong) hypothesis that omega 3’s contribute to improved cardiovascular health.

However, this direct effect is not so clear. Some trials show a benefit of omega 3 fatty acids on cardiovascular outcomes while others do not.

In the GISSI Prevention Trial, heart attack survivors who took 1 gram of omega-3 fats every day for three years were less likely to have a repeat heart attack, stroke, or die of sudden death than those who took a placebo. In the Japan EPA Lipid Intervention Study (JELIS), participants who took EPA plus a cholesterol-lowering statin were less likely to have a major coronary event (sudden cardiac death, fatal or nonfatal heart attack, unstable angina, or a procedure to open or bypass a narrowed or blocked coronary artery) than those who took a statin alone.

More recently, the VITAL primary prevention trial reported that the use of omega-3 fatty acids (at a dose of 1 g per day) was not effective in preventing the combined end point of myocardial infarction, stroke, or death from cardiovascular causes in unselected patients. These findings concur with prior studies (see HERE, HERE, and HERE) that show no consistent effect of supplemental omega 3’s to reduce the incidence of cardiovascular events in populations at high risk for coronary heart disease.

That same week in January 2019, results from the REDUCE-IT Trial were published. In this study, a prescription medication containing EPA alone was given at a dose of 2 grams twice daily to participants, 70% of whom had established cardiovascular disease. Compared to a placebo pill containing mineral oil, the EPA formulation significantly reduced heart attacks and strokes, as well as deaths from those causes, in people who already had cardiovascular disease or were at high risk for it.

And then, in November 2020, results of the STRENGTH trial were published. In this study, half of the participants received a 4-gram daily dose of a carboxylic acid formulation of omega-3 while the other half received a corn oil placebo. The participants in this study, similar to VITAL and in contrast to REDUCE-IT, had a high risk of—but not yet diagnosed--cardiovascular disease (based on diabetes, cholesterol levels, triglyceride levels, etc.). The results showed no statistically significant reduction in major cardiovascular events for those who received the daily omega 3 supplement.

Each of these randomized control trials involved slightly different variables—different formulations of fish oil (EPA alone vs. combined EPA and DHA), different placebo formulations (mineral oil, corn oil, etc.), and slightly different study populations (those with diagnosed vs. high risk of cardiovascular disease). With different variables and divergent outcomes, we are still grappling with more controversy than clarity as it pertains to the impact of omega 3’s on cardiovascular outcomes.

 Omega 3’s & Other Health Conditions

Insulin resistance

Despite plausible mechanistic models and evidence from in vitro and animal studies, it remains unclear whether omega 3 fatty acids have any clinically relevant effects on insulin resistance or diabetes risk in humans. Two large meta-analyses of 18 and 23 RCTs found no overall effects of omega 3 fish oils (0.9 to 18 g/day) on fasting glucose or hemoglobin A1c in patients with non–insulin-dependent diabetes.

Weight loss

There is no consistency in the literature that omega-3 has benefits in weight loss or body fat mass in humans. This was recently confirmed by a meta-analysis looking at 20 different studies on the topic.

Cancer prevention

Both EPA and DHA have been found to have antitumor action in breast cancer. And according to case control studies, men whose diets are rich in EPA and DHA (mainly from fish and seafood) are less likely to develop advanced prostate cancer as compared to those with low intake of EPA and DHA. Recently scientists discovered a plausible cellular mechanism called ferroptosis, a type of cell death linked to the peroxidation of certain fatty acids. But the few adequately powered primary prevention trials, including the VITAL trial, found no benefit from a 1-g daily dosage of omega 3’s for the primary prevention of cancer. A recent umbrella analysis analyzed the results of 57 meta-analyses and found “no convincing evidence related to the effects of omega-3 fatty acids on cancer risk.”

Cognitive function, depression, & dementia

EPA and DHA are a core component of the brain’s development and structure. There is ample correlational data that more fish in the diet confers a favorable effect on the brain. Some longitudinal observation studies show that those who consume more fish have lower levels of cognitive impairment. However, it is hard to attribute the benefit to EPA and DHA directly, versus another component of fish. Or perhaps not eating as much meat. Or maybe the people who ate lots of fish lived healthier lifestyles overall. Intervention studies have yet to demonstrate that the benefit is produced by DHA and/or EPA specifically.

Some studies have shown that adults suffering from depression and who are taking prescription meds seem to experience a mood boost from taking omega-3 supplements—particularly ones high in EPA. Currently, there are no published studies demonstrating that omega-3 fatty acids can help reverse Alzheimer’s or dementia.

The Balance between Omega 3 & Omega 6 Fatty Acids

Omega-6 fatty acids, like omega 3 fatty acids, are a group of essential, polyunsaturated fatty acids. Linoleic acid (LA) is the predominant omega 6 fatty acid in the Western diet and we obtain it from vegetable oils such as sunflower, safflower, soybean, corn, and canola oils as well as nuts and seeds.

Our bodies process linoleic acid into arachidonic acid, the precursor molecule to a variety of pro-inflammatory eicosanoids. For this reason, some specify omega 6’s as pro-inflammatory (versus anti-inflammatory omega 3’s). But this speculation is not necessarily supported by randomized controlled feeding studies, in which dietary intake of linoleic acid was not found to increase plasma levels of arachidonic acid or inflammatory markers. On the contrary, some studies have found anti-inflammatory effects of diets higher in linoleic acid compared to those higher in saturated fat. And a large meta-analysis suggests that a reduction in dietary saturated fat and carbohydrates, replaced with foods rich in linoleic acid actually lowers the risk of heart disease.

In reality, we need both the pro-inflammatory signaling molecules derived from omega 6’s and the anti-inflammatory derivatives of omega 3’s. Proper physiology is a precarious balance. And so it seems that what really matters is the balance between omega 3’s and omega 6’s. Before the industrialization of food in the last century, scientists estimate that the ratio of omega-6 to omega-3 fats in the human diet averaged closer to 1:1. Substituting animal fats in the standard US diet with vegetable oils (particularly soybean oil) in margarines, salad dressings, and other processed foods has resulted in a drastic increase in omega-6 consumption. Consequently, the current omega-6 to omega-3 ratio has reached an all-time high, estimated at between 10:1 and 15:1.

Omega-3’s and omega-6’s are processed by the same enzymes.  Therefore, a more balanced ratio would plausibly produce a more adaptive level of inflammation—the needed amount to fight infectious diseases, but not so much as to cause autoimmune disorders or metabolic disarray. And since we likely cannot reverse engineer omega 6’s out of our modern food supply, perhaps the most practical remedy may actually be to increase our omega-3 intake.

The Verdict

In general, it is hard to determine the direct, causal impact of one particular nutrient on health outcomes that are most certainly driven by a multitude of complex inputs. And the current discrepancies in the research on omega 3 fatty acids further obfuscates any clear conclusions. These inconsistencies include the specific dose of omega 3, the placebo used as a comparator, the duration of administration, the type of intervention (primary vs secondary prevention trial), the specific compound (DHA vs EPA vs their metabolites), the ratio of omega 6 to omega 3 fatty acids, and the target population tested (high vs average risk).

Current research posits a host of plausible biochemical mechanisms by which omega 3 fatty acids confer physiologic benefits. Many animal model and observational studies suggest the possibility that diets rich in fish oils provide cardiovascular, metabolic, and cognitive benefits. However, the research is still inconclusive when it comes to DHA and EPA formulations specifically, and their impact on health outcomes. The most rigorous and adequately powered intervention trials to date have produced mixed results.

With this context, here is some actionable advice:

Eat a fish-rich diet.

The data is clear that 2+ servings of fish weekly is part of a healthy dietary pattern. Fatty (dark meat) fish are particularly rich in EPA and DHA. Here is a helpful list of common fish and seafood products and their omega-3 fatty acid content.

The recommended amount of omega-3s varies by age and condition, according to the National Institutes for Health. Adult males between the ages of 19 and 50, for example, need 1.6 grams a day, while females of the same age require only 1.1 grams. Clearly, a fish-rich diet alone can provide the recommended amount of omega-3s.

For those who are worried about contaminants in fish, the health benefits from a fish-rich diet far outweigh the risks from contaminants. For more, see HERE.

Rebalance your omega 6 to omega 3 ratio.

 As we discussed, most of us are currently consuming far more omega 6’s than omega 3’s. To be clear, the idea that omega 6’s cause pro-inflammatory health problems is still a hypothesis that lacks substantive evidence. That said, there is no question that we could all benefit from rebalancing this ratio by boosting our omega 3 intake.

In addition to fish sources identified above, we can also boost our omega 3 intake by eating ALA-rich vegetables, nuts, and seeds. For specific vegetarian and vegan sources of omega 3’s, see HERE.

But remember, ALA alone is inadequate; we need ample EPA and DHA.

Supplementing seem to be a safe strategy.

The health benefits of most supplements are often controversial. And the data is often murky.  It seems, therefore, that the more pertinent question pertains to the supplement’s safety profile.

Even if this may not be reducing my disease risk or enhancing my long-term health, is this supplement at least safe to take?

Even though the direct impact on health outcomes remains unclear, supplementing with omega 3 is safe. Your body regulates how many omega 3 molecules are incorporated into cell membranes. So as far as we know, there is minimal risk of excess omega 3’s (other than the potential blood thinning effect at excessively high doses). And given the robust evidence surrounding their cardiovascular benefit, boosting your omega 3 levels with supplements and fortified foods seems to be a perfectly prudent option.

 Especially for those who either hate fish or adhere to a vegetarian/vegan dietary pattern, you are not getting a meaningful amount of EPA or DHA from ingesting ALA alone. For you, omega 3 supplements are a principal prescription.

Not all omega 3 supplements are created equally, so choose wisely.

OK, you are on board for taking an omega 3 supplement. But with dozens of brands on the shelves, you have to be a savvy consumer to choose an appropriate formulation in an unregulated supplement market.  A recent analysis of over 50 top selling fish oil supplements found that many of the products contained less DHA and EPA than what was stated on the label.

When choosing the best omega 3 supplement, select:

• A reputable brand that has a 3rd part certification that confirms that the product contents match the label

• A formulation with high levels of EPA and DHA in particular (at least 400 to 500 milligrams of combined EPA and DHA fish oil, or 1000 mg if you have known coronary artery disease)

• A product that it is free from any significant amounts of heavy metals, as independently verified.

For some of the most reputable brands and formulations, see the LabDoor rankings HERE.