Fish Oil

• Cardiovascular health
• Anti-inflammatory
• Cognitive function support
• Metabolic health

• Joint health
• Mood regulation
• Eye health
• Skin health
• Immune system modulation

Fish oil exerts its biological effects primarily through its two main bioactive omega-3 polyunsaturated fatty acids (PUFAs): eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids operate through multiple interconnected mechanisms that influence cellular function, inflammation, and physiological processes throughout the body. Upon consumption, EPA and DHA are incorporated into cell membranes, partially replacing omega-6 fatty acids, particularly arachidonic acid (AA). This membrane remodeling alters membrane fluidity, organization of lipid rafts, and function of membrane proteins, including receptors, ion channels, and enzymes.

DHA, with its highly flexible structure containing six double bonds, is particularly effective at increasing membrane fluidity and altering lipid raft composition. A primary anti-inflammatory mechanism involves the competitive inhibition of AA metabolism. EPA and DHA compete with AA for the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, reducing the production of pro-inflammatory eicosanoids derived from AA (such as prostaglandin E2 and leukotriene B4) while promoting the synthesis of less inflammatory or actively anti-inflammatory eicosanoids. Additionally, EPA and DHA serve as precursors for specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins.

These potent lipid mediators actively resolve inflammation by inhibiting neutrophil infiltration, promoting phagocytosis of cellular debris, and enhancing tissue repair. Fish oil omega-3s modulate gene expression through interaction with transcription factors, particularly peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). This affects genes involved in lipid metabolism, inflammation, and cellular differentiation. EPA and DHA also inhibit the activation of nuclear factor-kappa B (NF-κB), a key transcription factor that regulates the expression of pro-inflammatory cytokines and adhesion molecules.

In cardiovascular health, fish oil reduces triglyceride synthesis in the liver by decreasing the expression of lipogenic genes and increasing fatty acid oxidation. It also improves endothelial function, reduces platelet aggregation, lowers blood pressure through effects on vascular tone, and stabilizes atherosclerotic plaques. For brain function, DHA is particularly important as it constitutes a significant portion of neuronal membranes and influences neurotransmission, synaptic plasticity, and neurogenesis. DHA also supports the structural integrity of the blood-brain barrier and modulates neuroinflammation.

EPA and DHA exhibit distinct but complementary mechanisms of action. EPA tends to have stronger anti-inflammatory effects through eicosanoid modulation and cytokine reduction, while DHA has more pronounced effects on membrane structure, neurological function, and the resolution of inflammation through specialized pro-resolving mediators. The relative importance of these mechanisms varies by tissue type, health condition, and the specific ratio of EPA to DHA in the fish oil supplement.

The optimal dosage of fish oil is typically expressed in terms of the combined EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) content rather than the total oil amount. For general health maintenance, 250-500 mg of combined EPA and DHA daily is recommended. For therapeutic purposes, higher doses ranging from 1,000-4,000 mg (1-4 grams) of EPA+DHA daily are often used, depending on the specific condition being addressed.

It ‘s important to note that a 1,000 mg fish oil capsule typically contains only 300-500 mg of combined EPA and DHA, so multiple capsules may be needed to reach therapeutic doses.

The bioavailability of fish oil varies significantly depending on its molecular form, with absorption rates ranging from 60-90%. The chemical form of the omega-3 fatty acids is the primary determinant of absorption efficiency. Natural triglyceride forms (found in fish) have absorption rates of approximately 70-80%. Ethyl ester forms (common in many concentrated supplements) have lower absorption rates of 60-70% when taken without food.

Re-esterified triglyceride forms (created by converting ethyl esters back to triglycerides) have the highest absorption rates at 80-90%. Phospholipid-bound omega-3s (as found in krill oil) may have comparable or slightly higher bioavailability than triglyceride forms, particularly for brain uptake.

Taking with a fat-containing meal increases absorption by 50-60% for ethyl ester forms and by 20-30% for triglyceride forms by stimulating bile release and pancreatic lipase activity, Choosing re-esterified triglyceride forms over ethyl ester forms can improve bioavailability by 20-50%, Emulsified fish oil products (liquid or soft gel) increase surface area for enzymatic action, potentially improving absorption by 30-40%, Enteric-coated capsules protect the oil from stomach acid degradation and deliver more intact oil to the small intestine, Consuming with lipase-containing foods (like avocados) or digestive enzyme supplements may enhance breakdown and absorption, Phospholipid-bound omega-3s (as in krill oil) may offer improved bioavailability for certain tissues, particularly the brain, Dividing larger doses throughout the day improves absorption compared to a single large dose, Liposomal delivery systems encapsulate omega-3s in phospholipid vesicles, potentially enhancing cellular uptake, Consuming with antioxidants (vitamin E, astaxanthin) may protect the unsaturated fatty acids from oxidation during digestion

Fish oil supplements are best taken with meals, particularly those containing fat, to maximize absorption. This is especially important for ethyl ester forms, which show significantly reduced bioavailability when taken on an empty stomach. For larger therapeutic doses (>2 grams EPA+DHA), dividing the dose between two or three meals throughout the day may improve overall absorption and reduce potential gastrointestinal side effects compared to a single large dose. Morning or midday administration is often preferred over evening dosing, as some individuals report sleep disturbances or vivid dreams when taking fish oil before bed, though this effect varies between individuals.

For cardiovascular benefits, consistent daily dosing is more important than specific timing. For inflammatory conditions, maintaining steady blood levels through consistent daily dosing with meals is recommended. If using fish oil to improve exercise recovery, taking with a post-workout meal may be beneficial, though research on timing-specific effects is limited. If taking multiple supplements, separating fish oil from iron supplements by at least 2 hours may be prudent, as iron can potentially promote oxidation of the omega-3 fatty acids.

• Gastrointestinal discomfort (nausea, indigestion, diarrhea, abdominal pain)
• Fishy aftertaste or burping
• Mild allergic reactions in individuals with fish allergies
• Increased risk of bleeding at high doses (>3g EPA+DHA daily)
• Potential for increased LDL cholesterol in some individuals
• Vitamin A and D toxicity (rare, only with certain fish liver oil products)
• Mild skin reactions (rare)
• Halitosis (bad breath)

• Severe fish or shellfish allergies
• Bleeding disorders or hemophilia
• Scheduled surgery (discontinue 1-2 weeks prior)
• Uncontrolled hypotension (low blood pressure)
• Atrial fibrillation (high doses may increase risk in certain populations)
• Severe liver disease (for cod liver oil or high-dose supplements)
• Bipolar disorder manic phase (may potentially worsen manic symptoms)
• Implanted defibrillators (theoretical concern with high doses)

• Anticoagulant and antiplatelet medications (warfarin, aspirin, clopidogrel) – may increase bleeding risk
• Blood pressure medications – may enhance hypotensive effects
• Orlistat and other lipase inhibitors – may reduce absorption of fat-soluble vitamins in fish oil
• Vitamin E supplements – potential additive anticoagulant effects
• Glucocorticoids – may reduce the immunomodulatory effects of fish oil
• Contraceptive drugs – theoretical interaction affecting hormone levels
• Diabetes medications – may enhance glucose-lowering effects, requiring monitoring
• Cyclosporine – may affect blood levels of this immunosuppressant

The FDA considers doses up to 3 grams of EPA and DHA combined per day from supplements to be generally safe. The European Food Safety Authority (EFSA) has established a supplemental intake of up to 5 grams of EPA and DHA combined per day as safe for adults. For specific therapeutic applications, higher doses (up to 4-5 grams EPA+DHA daily) are sometimes used under medical supervision, particularly for severe hypertriglyceridemia. At these higher doses, increased risk of bleeding and potential immunosuppressive effects become more significant concerns.

Individuals with specific health conditions (particularly bleeding disorders, compromised immune function, or uncontrolled hypotension) should use lower doses and consult healthcare providers. For cod liver oil specifically, upper limits are lower due to potential vitamin A and D toxicity concerns. Quality is a critical safety consideration, as oxidized (rancid) fish oil may have pro-inflammatory rather than anti-inflammatory effects. Products should be tested for environmental contaminants including mercury, PCBs, and dioxins, with levels below established safety thresholds.

In the United States, fish oil has a complex regulatory status that spans both dietary supplement and pharmaceutical categories. As a dietary supplement, fish oil is regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this framework, manufacturers cannot make specific claims about treating, curing, or preventing diseases, but can make structure/function claims about effects on normal body functions (e.g., ‘supports heart health’). These claims must be accompanied by a disclaimer stating they have not been evaluated by the FDA.

The FDA has established a qualified health claim for conventional foods and dietary supplements containing EPA and DHA, stating that ‘supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.’ The FDA considers doses up to 3 grams of EPA and DHA combined per day from supplements to be generally safe. In addition to the supplement category, the FDA has approved several prescription fish oil products as pharmaceuticals for specific medical conditions. These include Lovaza (omega-3-acid ethyl esters), Vascepa (icosapent ethyl), and Epanova (omega-3-carboxylic acids), which are approved for the treatment of severe hypertriglyceridemia (≥500 mg/dL). In 2019, the FDA expanded the approval of Vascepa (purified EPA ethyl ester) to include reducing cardiovascular risk in certain high-risk patients with elevated triglycerides who are on maximally tolerated statin therapy.

These prescription products undergo the rigorous FDA approval process required for all pharmaceuticals, including clinical trials demonstrating safety and efficacy.

Eu: In the European Union, fish oil is primarily regulated as a food supplement under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has approved several health claims for EPA and DHA under Regulation (EC) No 1924/2006, including claims related to normal heart function, blood pressure, triglyceride levels, and brain development. Specifically, foods providing at least 250 mg of EPA and DHA per day can claim to contribute to ‘normal heart function,’ and foods with 250 mg DHA can claim to contribute to ‘normal brain function’ and ‘normal vision.’ The EU has established a tolerable upper intake level of 5 grams of combined EPA and DHA per day from all sources. Like the US, the EU also has approved prescription omega-3 fatty acid medications for treating hypertriglyceridemia, including Omacor/Lovaza and Vascepa.

Canada: Health Canada regulates fish oil both as a Natural Health Product (NHP) and as a prescription drug. As an NHP, fish oil products must have a Natural Product Number (NPN) on the label, indicating they have been assessed by Health Canada for safety, efficacy, and quality. Health Canada has approved specific claims for omega-3 fatty acids, including supporting cardiovascular health and reducing serum triglycerides. The recommended intake for general health is 500 mg of combined EPA and DHA per day. Prescription omega-3 products like Lovaza (marketed as Omacor in Canada) are approved for treating very high triglyceride levels.

Australia: The Therapeutic Goods Administration (TGA) regulates fish oil as a listed complementary medicine. Products must be included in the Australian Register of Therapeutic Goods (ARTG) and comply with quality and safety standards. The TGA allows certain health claims for omega-3 supplements based on evidence levels, including claims related to cardiovascular health, anti-inflammatory effects, and brain function. The National Health and Medical Research Council (NHMRC) suggests an adequate intake of 160 mg/day of combined DHA and EPA for men and 90 mg/day for women, with higher intakes recommended for specific health conditions.

Japan: In Japan, fish oil is regulated under the Foods with Function Claims (FFC) system, which allows for certain health claims based on scientific evidence without the strict approval process required for Foods for Specified Health Uses (FOSHU). Omega-3 fatty acids are widely recognized for their health benefits in Japan, and products can make claims related to triglyceride reduction and cardiovascular health if they provide sufficient scientific evidence. Japan also has pharmaceutical-grade omega-3 products approved as medications for hyperlipidemia.

China: The China Food and Drug Administration (CFDA) regulates fish oil primarily as a health food ingredient rather than a drug. Products containing fish oil must be registered with specific approved health functions, and the registration process includes safety assessments and quality control requirements. Health claims are strictly regulated, and only those specifically approved during the registration process can be used in marketing. China has also approved some high-concentration omega-3 products as prescription medications for treating hyperlipidemia.

Low to High (depending on quality, concentration, and form)

The cost of fish oil supplements varies dramatically based on several factors, primarily concentration, form, purity, and brand positioning. For standard fish oil supplements (30% EPA+DHA concentration), the cost ranges from $0.05-$0.15 per gram of oil, or approximately $0.15-$0.50 per day for a maintenance dose of 1,000 mg EPA+DHA. For higher-concentration products (60-90% EPA+DHA), the cost increases to $0.15-$0.40 per gram of oil, or approximately $0.25-$0.80 per day for a 1,000 mg EPA+DHA dose. Premium forms (re-esterified triglycerides, pharmaceutical grade) can cost $0.30-$0.80 per gram of oil, or $0.50-$1.50 per day for a 1,000 mg EPA+DHA dose.

Prescription omega-3 medications are significantly more expensive, ranging from $3-$12 per day for a therapeutic dose, though insurance coverage may reduce out-of-pocket costs. When calculated based on the actual EPA+DHA content (rather than total oil), the cost ranges from $0.15-$1.50 per gram of EPA+DHA for supplements and $3-$12 per gram for prescription products.

Fish oil offers excellent value for general health maintenance and primary prevention, with basic supplements providing adequate EPA+DHA for daily maintenance at $5-$15 per month. For specific therapeutic applications, the value proposition varies significantly by condition and required dosage. For hypertriglyceridemia, fish oil is highly cost-effective compared to many pharmaceutical alternatives, providing similar triglyceride-lowering effects at a fraction of the cost (except for prescription omega-3s, which are comparable in price to other lipid-lowering medications). For cardiovascular disease secondary prevention, the value is moderate, with some studies showing benefit while others show minimal effect.

Higher doses and higher-quality formulations may be necessary for meaningful benefits, increasing the cost. For inflammatory conditions like rheumatoid arthritis, fish oil may allow for reduced NSAID or other anti-inflammatory medication use, potentially offering cost savings and reduced side effects from those medications. For cognitive health, the evidence is mixed, making the value proposition less clear. The form of omega-3s significantly impacts value: ethyl ester forms are less expensive but have lower bioavailability, especially when taken without food, while re-esterified triglyceride forms cost more but offer superior absorption.

Krill oil (phospholipid-bound omega-3s) is typically the most expensive form per gram of EPA+DHA but may offer advantages for certain applications. Generic prescription omega-3 products offer better value than brand-name versions but are still substantially more expensive than supplements. For most consumers seeking general health benefits, mid-range products offering 1,000 mg of EPA+DHA daily in a triglyceride form with verified purity represent the optimal balance of cost and benefit. Those with specific health conditions may find higher doses and premium forms more cost-effective despite the higher upfront cost, particularly if they reduce the need for other medications or treatments.

Properly manufactured and stored fish oil typically has a shelf life of 18-24 months from the date of manufacture when in softgel form. Liquid fish oil generally has a shorter shelf life of 6-12 months after opening due to increased exposure to oxygen. Products with added antioxidants like vitamin E (tocopherols) or astaxanthin may have extended shelf life. The actual stability period varies significantly based on the specific formulation, processing methods, packaging, and storage conditions.

Higher concentrations of EPA and DHA generally correlate with decreased stability due to the greater number of double bonds susceptible to oxidation. Re-esterified triglyceride forms may have slightly better stability than ethyl ester forms under identical conditions.

Store fish oil supplements in their original, airtight container away from direct sunlight, heat sources, and moisture. Refrigeration is strongly recommended, particularly for liquid fish oil products and after opening, as lower temperatures significantly slow oxidation reactions. Even unopened softgel products benefit from refrigeration, though room temperature storage in a cool, dark place is generally acceptable if the temperature remains below 25°C (77°F). Freezing fish oil is acceptable and may further extend shelf life without damaging the oil, though it may affect the integrity of some softgel capsules.

Minimize exposure to air by keeping containers tightly closed when not in use. For liquid fish oil, consider transferring to smaller containers as you use it to minimize the air space in the bottle. Avoid storing near strong-smelling substances as fish oil can absorb odors. If capsules develop a strong, unpleasant smell (resembling rancid fish) or taste extremely bitter or ‘off,’ this indicates oxidation and they should be discarded.

Dark, opaque bottles with nitrogen-flushed headspace provide the best protection for liquid fish oil products.

Oxygen exposure (primary degradation pathway through oxidation of unsaturated fatty acids), Heat (accelerates oxidation reactions; each 10°C increase approximately doubles the rate of degradation), Light exposure (particularly UV light, which promotes photo-oxidation of unsaturated fatty acids), Transition metal ions (especially iron and copper, which catalyze oxidation reactions), Moisture (can promote hydrolytic rancidity and microbial growth in liquid products), Repeated opening of containers (increases oxygen exposure), Fluctuating temperatures (can cause condensation inside containers, promoting degradation), Extended storage beyond expiration date (natural antioxidants in the oil deplete over time), Improper packaging materials (some plastics may allow oxygen permeation), Pre-existing oxidation products (oxidation is autocatalytic, so products with initial oxidation degrade faster), Higher EPA and DHA concentration (more polyunsaturated fatty acids means more sites for oxidation), Absence of antioxidants (natural or added antioxidants like tocopherols or astaxanthin slow oxidation), Exposure to environmental pollutants or strong odors (oil can absorb contaminants), Enzymatic degradation (more relevant in liquid products without proper preservatives)

Synthesis Methods

Natural Sources

Quality Considerations

The medicinal use of fish oil has deep historical roots across multiple cultures, particularly those with strong maritime traditions. The earliest documented medicinal use dates back to ancient coastal civilizations, including the Greeks and Romans, who recognized the health benefits of consuming fatty fish and fish liver oils. Hippocrates, the father of Western medicine, recommended fresh fish for various ailments in the 4th century BCE. However, the most well-documented traditional use comes from Nordic coastal populations, particularly in Norway, Iceland, and the British Isles, where cod liver oil became a folk remedy by the late 18th century.

These communities used cod liver oil to treat rickets (now known to be caused by vitamin D deficiency), rheumatism, and general aches and pains. By the 1830s, cod liver oil had gained recognition in European medical literature for treating rickets, and it became one of the first widely accepted ‘scientific’ remedies of the modern medical era. The traditional Inuit diet, exceptionally high in marine-derived omega-3 fatty acids from seal, whale, and fish, drew scientific attention in the 1970s when researchers observed remarkably low rates of cardiovascular disease in these populations despite their high-fat diet. This observation, published by Danish researchers Bang and Dyerberg, launched the modern scientific investigation into omega-3 fatty acids and cardiovascular health.

In Japan, another culture with high fish consumption, traditional dietary patterns rich in marine foods have been associated with longevity and lower rates of certain chronic diseases. The specific isolation and identification of EPA and DHA as the bioactive components in fish oil occurred in the late 20th century, transforming fish oil from a traditional remedy to a targeted nutritional supplement with specific mechanisms of action. The American Heart Association issued its first recommendation for fish consumption for heart health in 1996, and by the early 2000s, concentrated fish oil supplements had become one of the most popular dietary supplements globally. The development of pharmaceutical-grade, highly purified omega-3 fatty acid products (such as Lovaza and Vascepa) in the early 21st century represents the evolution of this traditional remedy into modern evidence-based medicine.

Throughout this historical progression, fish oil has maintained its primary association with inflammatory conditions, pain management, and cardiovascular health, showing remarkable consistency between traditional uses and modern clinical applications.

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STRENGTH-2: Outcomes Study to Assess Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia II (NCT03698162), OMEMI: Omega-3 Fatty Acids in Elderly Patients With Acute Myocardial Infarction (NCT01841944), EVAPORATE: Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy (NCT02926027), ASCEND-MEMORY: A Study of Cardiovascular Events in Diabetes – Memory and Cognition in Diabetes (NCT04263155), OCEAN-DHA: Omega-3 for Cancer Prevention and Epigenetics – DHA (NCT03482401)