As you probably know, fish oil has long been touted as an excellent source of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two marine-based omega-3 fats that are important for brain and heart health.
What may come as a surprise is that many (if not most) fish oil supplements on the market these days contain synthetic fish oil.
This little-known fact has been brought to the fore by a recent U.S. Supreme Court petition filed by Amarin Pharma Inc., the maker of a proprietary prescription formulation of fish oil called Vascepa (a highly-processed and concentrated form of EPA).
Amarin initially filed a complaint with the U.S. International Trade Commission (ITC) in 2017, charging certain fish oil manufacturers with unfair trade practices. According to Amarin:1
"… [C]ertain companies have violated the Lanham Act and other statutory provisions by importing synthetically produced omega-3 products that are falsely labeled, unlawfully marketed, and deceptively advertised as 'dietary supplements' when in fact the products are 'drugs' that have not been approved for sale in the United States."
ITC declined, ruling Amarin's claims were "not cognizable as a matter of law" because they're based solely on U.S. Food, Drug, and Cosmetic Act (FDCA) violations.2 An appeals court affirmed the ITC's decision, concluding that Amarin could not seek relief under the Tariff Act "unless and until FDA exercises its discretion to take action to enforce the FDCA."3
As reported by Natural Products Insider,4 the U.S. Food and Drug Administration claims it has not yet determined whether fish oils are dietary supplements or new drugs, thus it cannot determine whether FDCA violations have occurred.
Amarin has now filed a "petition5 for a writ of certiorari with the U.S. Supreme Court," Natural Product Insider reports,6 in an effort to clarify the ITC's authority to address complaints about products regulated by the FDA. As noted in the petition:7
"The Tariff Act of 1930 grants manufacturers the right to file a complaint with the International Trade Commission alleging Lanham Act violations when an importer engages in unfair trade practices … The Tariff Act mandates that the Commission must investigate a complaint and determine whether a violation has occurred …
This Court has held that 'Congress did not intend the' Food, Drug and Cosmetic Act to preclude Lanham Act claims alleging false and misleading advertising for products subject to regulation by the Food & Drug Administration …
The question presented is: When a manufacturer files a Lanham Act claim under the Tariff Act for competitive injuries caused by unfair trade practices, is the claim barred as a matter of law when the International Trade Commission would need to consider the meaning of terms used in the Food, Drug and Cosmetic Act in order to determine whether the claim has merit?"
Many fish oils are synthetic 'drugs,' Amarin says
In a nutshell, Amarin has taken issue with the fact that many fish oil supplements contain synthetic fish oil and not all-natural substances, and as such should fall under the category of "drugs," just like Vascepa. According to Amarin, since fish oils are marketed and sold as dietary supplements, they pose an unfair competition, and are mislabeled and mismarketed. As explained in Amarin's petition:8
"It is well established and understood that 'synthetic' substances derived from natural substances that qualify as 'dietary ingredients' under subsections 201(ff)(1)(C), (E), and (F) of the FDCA, or synthetic copies of such natural substances, are not themselves 'dietary ingredients' unless they were commonly or customarily used in the conventional food supply and in compliance with law."
According to Amarin, the FDA has failed to take action against supplement manufacturers that market fish oils that don't actually qualify as dietary ingredients, and asserts that the FDA's oversight was never meant to be the sole authority for ensuring proper labeling — which is why Amarin brought its complaint to the ITC. In its current petition to the Supreme Court, Amarin explains the cause for its complaint:9
"Amarin markets Vascepa®, a prescription drug that is synthetically derived from fish oil, with the active ingredient consisting of 1 gram of eicosapentaenoic acid …
Amarin has invested more than $500 million to develop this innovative product, including undertaking extensive clinical trials to support FDA-approved and planned uses of Vascepa® in the United States. Vascepa® has been hailed as a rare medical breakthrough.
Studies10,11 have demonstrated that the drug decreases triglyceride blood levels without raising bad cholesterol and reduces the risk of cardiovascular events, like cardiovascular death, heart attack, and stroke.
Unfortunately, there are large quantities of similar synthetic products derived from fish oil that meet the definition of 'new drug' that are not of the same manufacturing quality and have not been studied through clinical trials or approved by FDA as safe and effective.
Although the law is clear that these products are unapproved 'new drugs' that may not be marketed and sold as dietary supplements, FDA has failed to take uniform enforcement action under the FDCA.
Whatever the risks to public health might be, the domestic industry faces a serious threat of substantial competitive injury as these mislabeled and deceptively advertised products flood the market."
What makes most fish oils synthetic?
As structural elements, DHA and EPA are particularly important for proper cell division and function of cell receptors. They also play an important role in anti-inflammatory reactions. These fats are ideally obtained from the consumption of small fatty fish that are free of toxins.
Unfortunately, most people opt for fish oil supplements over eating fatty fish like sardines, anchovies and herring. While this has long been thought to be a perfectly viable option, it has now become clear that the processing of fish oil is deeply problematic, rendering the final product into something far from the natural oils you get from the whole fish.
As described in a 2018 paper12 in the Transformation and Agro-Industry journal, there are many different ways to extract, refine and concentrate the omega-3s in fish oil, and as noted in the 2017 white paper,13 "From Fish Waste to Omega-3 Concentrates in Biorefinery Concept," there are even methods by which omega-3 oils can be extracted from fish waste.
Former CEO of Twinlab, Naomi Whittel, described the crux of the problem with fish oils in my 2018 interview with her (see "processing of fish" link above):
"Even if you think the fish oil is coming from Norway or Europe, [the fish] is caught in Central and South America … The fish are then brought onto and thrown into the bottom of the boat …
By the time they get to Europe, the guts are so rancid that in order to get the omega-3s out, they have to go through a process of extracting these poisons and this rancidity. [In the end], you're left with something that has none of the cofactors [and] it's been heavily contaminated to clean out the rancidity …"
Whittel estimates about 98% of the omega-3 products on the market are inferior (and perhaps even toxic) due to the way the fish are caught and processed — a summary of which is provided in the graphic below.
In short, in order to render the rancid fish safe for human consumption, it must be cleaned, and what's left at the end of this process is a synthetic ethyl ester omega-3 oil. The reason why some brands are able to provide you with higher concentrations of DHA, for example, is also because of this deconstruction and reconstruction process, and this appears to be part and parcel of Amarin's complaint.
Triglyceride versus ethyl ester fish oils
The processing most fish oils undergo transforms the omega-3 fats from their triglyceride form into an ethyl ester form. In fish, the DHA and EPA occur in the form of triglycerides,14 which are the most bioavailable. In most commercial fish oil supplements, however, the DHA and EPA are delivered in the form of ethyl esters.15,16
As explained by Douglas MacKay17 N.D., senior vice president of scientific and regulatory affairs for the Council for Responsible Nutrition, in his paper18 "A Comparison of Synthetic Ethyl Ester Form Fish Oil vs. Natural Triglyceride Form," a triglyceride consists of a three-carbon molecule that forms a "backbone" for the fatty acids to latch onto.
Each carbon molecule is linked to a fatty acid, so in total, a triglyceride is composed of three carbons bonded to three fatty acids. Ethyl ester fish oil is most prevalent simply because it's far less expensive to produce than the triglyceride form.
Ethyl esters are also easier to work with during processing, as they have a higher boiling point. This becomes important during the molecular distillation phase (see above), during which the oils are heated and purified of harmful environmental pollutants.
The molecular distillation phase also concentrates the EPA and DHA. You can tell the concentration of these two fats in any given supplement by looking at the label. In fish, the oil consists of 20% to 30% EPA and DHA, whereas purified fish oil concentrate typically contains between 60% and 85% EPA and DHA.19
Ethyl esters are essentially a synthetic substrate, created through the micro distillation process of crude fish oil, in which ethanol and/or industrial alcohol is added. This mix is heat distilled in a vacuum chamber, resulting in a concentrated omega-3 ethyl ester condensate.
It is also important to note that this purifying molecular distillation process removes vital resolvins and protectins present in the raw material that are important in reducing inflammation.
The problem with ethyl esters
Ethyl esters, unfortunately, are the least bioavailable form of omega-3, and while manufacturers could convert them back into triglyceride form by detaching the ethyl alcohol molecule and reattaching a glycerol molecule in a process known as re-esterification,20 this process is a costly one.
The difference between triglyceride and ethyl ester forms become an issue when your body goes to metabolize them. Since the glycerol backbone is missing in the ethyl ester form, the EPA and DHA will scavenge for available triglycerides or steal a glycerol molecule from somewhere.
One way or another, the fatty acids need to be converted back into triglyceride form, or else your gut epithelium will not be able to process them. When the ethyl ester form of EPA/DHA ends up stealing glycerol molecules, the molecule that lost its glycerol will now go searching for a replacement, creating a negative domino effect. What's more, the fatty acids also cannot be transported through your blood unless they're in triglyceride form.
Now, when you consume omega-3s in triglyceride form, the fatty acids are first separated from the glycerol backbone. All of the individual parts are then absorbed by gut epithelial cells, where they're reattached to form triglyceride.
When you consume ethyl esters, they must be processed in your liver. There, the ethanol backbone is separated from the free fatty acids, and your body must then reattach the free fatty acids to glycerol to form triglyceride.
Your liver must also process the ethyl alcohol, which may release free radicals and cause oxidative stress — the complete opposite of what you're trying to achieve.
In fact, as suggested in an article21 by Short Hills Ophthalmology on this topic, many of the side effects of prescription strength fish oil such as Lovaza — a highly-concentrated ethyl ester form of fish oil — such as unpleasant body odor, vomiting, gastrointestinal dysfunction, pancreatitis and cardiac effects,22 may be due to the toxicity of ethanol, which must be separated out in your liver.
Ethyl esters more prone to rancidity and poorly absorbed
In summary, while triglycerides are the natural, more stable form, identical to human fatty acids and easily digestible and absorbed, ethyl esters lack molecular stability, your body cannot recognize them and because they take longer to digest, they may cause unpleasant reflux.
Molecular stability is important, as unstable molecules are more prone to oxidative damage and thus rancidity. As noted by MacKay:23
"The therapeutic action and safety of fish oil is in part related to its molecular stability and resistance to oxidative damage. Fish oil that has been subject to oxidative damage may do more harm to the body than good. EPA and DHA are long-chain polyunsaturated fatty acids (PUFAs), which means they contain several double bonds within their carbon-hydrogen chain.
In each location of a double bond, there is vulnerability for free radical attack, which results in an oxidized and rancid oil. The potential negative health effects of consuming rancid fish oils have not been fully elucidated. However, it has been shown that oxidized by-products of polyunsaturated fatty acids, including DHA, are elevated in patients with neurodegenerative conditions."
Poor absorption is also an issue with ethyl esters, as this will impair the effectiveness of the fish oil. Research24 has shown the free acids of fish oil have an absorption rate of at least 95%. In this study, ethyl ester EPA and DHA absorbed only 20% and 21% as well as the free acids respectively.
Taking them with a high-fat meal increased absorption to about 60%.25,26 Meanwhile, EPA in its natural triglyceride form had a 69% absorption rate from the start, and when taken with additional dietary fat, absorption increased to 90%.27
The take-home message here is that to really reap the benefits associated with omega-3 fats, you need to either eat omega-3-rich fish, or make sure the supplement you're taking contains DHA and EPA in their triglyceride form. Unfortunately, cold pressed, minimally processed fish oil with triglyceride DHA and EPA can be very hard to find, as it far costlier to produce.
A viable alternative would be to use krill oil, which research28 has shown to have greater bioavailability than triglyceride-based fish oil, allowing you to take lower doses while still reaping similar results.
Your best options for animal-based omega-3
Based on the evidence, it seems clear that to reap maximum health benefits, you really want a majority of your omega-3 to come from your diet. That means eating small fatty fish such as sardines, anchovies, mackerel and herring. Wild-caught Alaskan salmon is another good source.
If you opt for an omega-3 supplement, your choices become more complex. Many commercial fish oil supplements may not give you the benefits you're looking for, as they contain EPA and DHA in the form of synthetic ethyl esters rather than triglycerides.
If you are taking a fish oil supplement, find out if the fish oil is a synthetic ethyl ester. If this information is not on the label, contact the manufacturer and find out. ONLY use fish oil that is in the natural triglyceride formulation. Choosing otherwise could turn out to be problematic for your long-term health.
My preference, when it comes to omega-3 supplements, is krill oil, in part because of its superior absorbability, as mentioned above, but also because it's a vastly more sustainable source than fish.
Last but not least, don't rely on a set dosage. As with vitamin D, it's your serum (blood) level that counts. Your omega-3 level can easily be measured using an omega-3 index test. You'll want your index to be above 8% for optimal health and disease prevention.
Source: mercola rss