We often hear about the health benefits of fish oil: enhanced cognitive performance, improved heart and blood health, potent anti-inflammatory activity, etc. Not all fish oils, however, will have the same physiological effects. Outside the realm of possible contamination, product rancidity, or even total fish oil content, the supplements levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—the omega-3 fatty acids primarily responsible for fish oil’s medicinal effects—are often overlooked. These molecules share similar chemical structures, and accordingly, share some similarities in their biological roles. Nevertheless, their structural differences give each molecule the unique ability to influence different biological systems.

Higher EPA plus DHA concentrations will necessarily provide greater benefits. But what is the key to tailoring a fish oil supplement to your needs? The answer is simple: check for the supplement’s ratio of EPA to DHA.

In this article, we will review the available clinical evidence on the effects of 1) EPA combined with DHA, 2) EPA alone, and 3) DHA alone on various neurological and cardiovascular conditions. As such, we will attempt to discern, with regard to physiology, where the fatty acids act similarly and where they differ. Note that this is a review of clinical literature and an effort to help you make the most appropriate supplement choice for your needs. It should not serve as a substitute for professional medical advice.

Cardiovascular Effects

Blood Lipids 101: Fish oil exerts its cardiovascular-protective benefits by mitigating the effects of high levels of circulating triglycerides and lipoproteins. Triglycerides are the most basic of blood lipids, known for carrying adipose fat and glucose produced in the liver to the rest of the body. But how does a fatty substance circulate in water-based blood? Triglycerides, along with cholesterol esters, are packaged into structures called lipoproteins. This class of blood lipids is responsible for the transfer of hydrophobic (water-repelling) triglycerides and cholesterol molecules throughout the body.

The clever structure of a lipoprotein–one that encloses the transported lipids (triglycerides and cholesterol) with water-soluble phospholipids and proteins–is responsible for its unique ability to carry fatty compounds in the blood. While all lipoproteins share similar general structures, the small structural differences that do exist can have major health implications. In this review, we focus on high-density lipoproteins (HDL) and low-density lipoproteins (LDL), as these blood lipids are widely studied in clinical science and are generally used to assess and predict cardiovascular health.

So what are the structural differences between HDL and LDL? And what are their health implications? HDL molecules have more protein in their coats and less triglyceride and cholesterol content in their interior. Meanwhile, LDL molecules are characterized by less protein in their coats and larger amounts of triglycerides/cholesterol in their hydrophobic cores. The result: HDL, due to more protein on its surface, is able to navigate the blood stream efficiently while LDL tends to move about in a “clumsy” manner, increasing its risk of collapsing on artery walls and causing plaque buildup.

It is important to note that LDL carries cholesterol and triglycerides from the liver to the body’s tissues. HDL, which is known to be a cholesterol scavenger, picks up excess cholesterol in the body and takes it back to the liver for breakdown. Therefore, while lowering LDL may slow down or prevent further plaque buildup, it may not reduce the risk of heart disease, according to the Mayo Clinic. On the other hand, increasing HDL levels will decrease levels of LDL and may reduce the risk of developing heart disease.

Clinical Perspective: How does fish oil mediate this process? Numerous clinical-efficacy trials and a recent meta-analysis have established that fish oil is able to potently reduce triglyceride levels in hyperlipidemic individuals (those suffering from high blood triglycerides) after several weeks of supplementation. Some studies have cited a 25-30% reduction in blood triglycerides (after supplementation with 4g of EPA ethyl ester). In a more conservative estimate, recent research suggests that the magnitude of reduction may be slightly less pronounced (in the range of 15-20%) depending on baseline triglyceride levels. This factor is somewhat determinative according to current medical opinion, which suggests that fish oil supplementation provides greater benefits for those with higher baseline triglyceride levels.

So what is the breakdown? Is EPA or DHA better for reducing triglyceride levels? According to a 2011 meta-analysis assessing the effects of EPA alone, DHA alone, or EPA plus DHA on serum lipids (in separate trials), DHA raised LDL cholesterol while EPA insignificantly reduced LDL levels. In clinical studies drawing direct comparisons between EPA and DHA, similar results concerning LDL were drawn. Although both EPA and DHA reduced triglycerides, the magnitude of reduction was greater after DHA supplementation. Additionally, DHA raised HDL (good) cholesterol whereas EPA did not have any effect on HDL levels.

The Takeaway: Both EPA and DHA reduce triglyceride levels—with DHA showing greater benefit—but they seem to have differing effects on HDL and LDL cholesterol. DHA increases both LDL (bad) and HDL (good) cholesterol while EPA insignificantly reduces LDL levels and does not seem to have any effect on HDL cholesterol. An important metric to note here is that although DHA raised both HDL and LDL, the magnitude of the increase differed drastically: LDL levels increased by nearly twice the amount of HDL, favoring the effects of LDL cholesterol.

Neurological Effects

A Clinical Perspective: When it comes down to dealing with blood triglyceride and cholesterol levels, current clinical research suggests that DHA may have a slight leg up on EPA. Outside the realm of cardiovascular disease, fish oil (sometimes referred to as “brain food”) has also shown some efficacy in improving cognitive function and in attenuating and preventing neurological disease.

Animal testing has revealed that DHA improves cognition—primarily affecting reference memory but with no effect on working memory—in otherwise healthy rats. In human testing, healthy young adults (aged 18 - 25) showed improvement in working memory after a 6-month regimen of 2g Lovaza (pharmaceutical grade fish oil). A separate study that tested youth with a low dietary intake of fish concluded that 1,160mg DHA for 6 months improved both memory retention and reaction time. In older humans, a higher serum concentration of DHA is positively correlated with improved verbal fluency, according to clinical study.

Research has also shown promising evidence supporting fish oil’s benefit on stress response. Current thinking suggests that both EPA and DHA offer advantages during times of stress, but for different reasons. Stress is a multi-faceted response affecting several bodily systems. EPA appears to help attenuate stress-induced immune activity while DHA has been linked to helping reduce aggressiveness during stress. Other studies noted that DHA significantly reduces adrenaline levels during stress but has no effect on cortisol, another prominent stress hormone.

Along with its other uses, fish oil has shown evidence of being able to reduce the risk of developing and attenuating depression. Furthermore, a meta-analysis assessing 28 studies on indications such as general depression, bipolar disorder, schizophrenia, Parkinson’s Disease, personality disorders, and other conditions, concluded that EPA—and not DHA—was responsible for fish oil’s anti-depressive effects. But the response depended heavily on dosage. In particular, 1g of EPA was shown to be most effective, with higher doses showing less efficacy.

In some research studies, fish oil has also shown some benefit in combating more severe cognitive disorders, such as dementia and Alzheimer’s disease (AD). Animal studies support the use of high doses of DHA against these diseases although human evidence has not shown any benefit in those with AD. Supplementation did, however, attenuate the rate of cognitive decline in older adults not suffering from AD.


EPA and DHA have been shown to provide a wide variety of clinical benefits. Choosing a fish oil supplement richer in one of the two primary omega-3 types may help tailor, however little, its medicinal properties to your needs. For example, Mayo Clinic Professor of Medicine Dr. Stephen Kopecky recommends a 3:2 ratio of either EPA to DHA or vice-versa. According to the research reviewed here, DHA outperforms EPA in reducing total triglyceride counts and increasing HDL (good) cholesterol. Alternatively, EPA has a more beneficial effect on lowering overall LDL (bad) cholesterol.

In the cognitive domain, DHA appears to offer greater mental benefits. DHA has been suggested to be more effective in improving overall cognition and preventing cognitive decline in healthy older adults. While both forms of omega-3 have beneficial effects on the stress response, DHA seems to quell the neurological response (aggression) while EPA modulates stress-affected immune activity. EPA also seems to have greater anti-depressive effects.


  1. Header Image: YumaNuma (Flickr)
  2. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis - International Journal of Cardiology
  3. n-3 fatty acids and serum lipoproteins: human studies - American Journal of Clinical Nutrition
  4. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis - Current Atherosclerosis Reports
  5. Serum Phospholipid Docosehexaenoic Acid is Associated with Cognitive Functioning during Middle Adulthood - The Journal of Nutrition
  6. Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats - Neuroscience
  7. Improved Working Memory but No Effect on Striatal Vesicular Monamine Transporter Type 2 after Omega-3 Polyunsaturated Fatty Acid Supplementation - PLOS One
  8. DHA Supplementation Improved Both Memory and Reaction Time in Healthy Young Adults: a Randomized Controlled Trial - The American Journal of Clinical Nutrition
  9. The Effect of Docosahexaenoic Acid on Aggression in Young Adults. A Placebo-Controlled Double-Blind Study - The Journal of Clinical Investigation
  10. Anti-Stress Effects of DHA - Biofactors
  11. The Effect of Docosahexaenoic Acid on Aggression in Elderly Thai Subjects – A Placebo-Controlled Double-Blind Study - Nutritional Neuroscience
  12. Effects of Dietary n-3 or n-6 Fatty Acids on Interleukin-1 beta-Induced Anxiety, Stress, and Inflammatory Responses in Rats - Journal of Lipid Research
  13. Possible Regulatory Mechanism of DHA-Induced Anti-Stress Reaction in Rats. Brain Research - Brain Research
  14. Administration of Docosahexaenoic Acid Influences Behavior and Plasma Catecholamine Levels at Times of Psychological Stress - Lipids
  15. The Effect of Docosahexaenoic Acid on Plasma Catecholamine Concentrations and Glucose Tolerance During Long-Lasting Psychological Stress: a Double-Blind Placebo-Controlled Study - J Nutr Sci Vitamino (Tokyo)
  16. EPA but not DHA Appears to be Responsible for the Efficacy of Omega-3 Long Chain Polyunsaturated Fatty Acid Supplementation in Depression: Evidence from a Meta-Analysis of Randomized Controlled Trials - Journal of the American College of Nutrition
  17. Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease: a Randomized Trial - The Journal of the American Medical Association
  18. Docosahexaenoic Acid Provides Protection from Impairment of Learning Ability in Alzheimer’s Disease Model Rats - Journal of Neurochemistry
  19. Beneficial Effects of Docosahexaenoic Acid on Cognition in Age-Related Cognitive Decline - The Journal of the Alzheimer's Association
  20. Blood Cholesterol - Mayo Clinic
  21. Triglycerides and Lipoproteins - Animal Health Diagnostic Center, Cornell University
  22. LDL and HDL - Discovery Health
  23. Fish Oil -

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