Omega-3 fatty acid

n−3 fatty acids (popularly referred to as ω−3 fatty acids or omega-3 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−3 position; that is, the third bond from the methyl end of the fatty acid.

Nutritionally important n−3 fatty acids include α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated. The human body cannot synthesize n−3 fatty acids de novo, but it can form "long chain" 20-carbon unsaturated n−3 fatty acids (like EPA) and 22-carbon unsaturated n−3 fatty acids (like DHA) from the "short chain" eighteen-carbon n−3 fatty acid α-linolenic acid. The short chain n−3 fatty acids are converted to long chain forms (EPA, DHA) with an efficiency of approximately 5%^[1][2] in men, and at a greater percentage in women.^[3]

These conversions occur competitively with n−6 fatty acids, which are essential closely related chemical analogues that are derived from linoleic acid. Both the n−3 α-linolenic acid and n−6 linoleic acid are essential nutrients which must be obtained from food. Synthesis of the longer n−3 fatty acids from linolenic acid within the body is competitively slowed by the n−6 analogues. Thus accumulation of long-chain n−3 fatty acids in tissues is more effective when they are obtained directly from food or when competing amounts of n−6 analogs do not greatly exceed the amounts of n−3.

History

Although omega-3 fatty acids have been known as essential to normal growth and health since the 1930s, awareness of their health benefits has dramatically increased in the past few years.^[4] New versions of ethyl esterized omega-3 fatty acids, such as E-EPA and combinations of E-EPA and E-DHA, have drawn attention as highly purified and more effective products than the traditional ones. In the United States, these novel versions are often sold as prescription medications, such as Lovaza. In the European Union, they are available as dietary supplements.

The health benefits of the long-chain omega-3 fatty acids — DHA and EPA omega-3 — are the best known. These benefits were discovered in the 1970s by researchers studying the Greenland Inuit Tribe. The Greenland Inuit people consumed large amounts of fat from seafood, but displayed virtually no cardiovascular disease. The high level of omega-3 fatty acids consumed by the Inuit reduced triglycerides, heart rate, blood pressure, and atherosclerosis.

On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to EPA and DHA n−3 fatty acids, stating that "supportive but not conclusive research shows that consumption of EPA and DHA [n−3] fatty acids may reduce the risk of coronary heart disease."^[5] This updated and modified their health risk advice letter of 2001 (see below). Currently, regulatory agencies do not accept that there is sufficient evidence for any of the other suggested benefits of DHA and EPA other than for cardiovascular health, and further claims should be treated with caution.

The Canadian Government has recognized the importance of DHA omega-3 and permits the following biological role claim for DHA: "DHA, an omega-3 fatty acid, supports the normal development of the brain, eyes and nerves."^[6]

Chemistry

Chemical structure of alpha-linolenic acid (ALA), an essential n−3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12 and 15). Although chemists count from the carbonyl carbon (Blue Numbering), physiologists count from the n (ω) carbon (red numbering). Note that from the n end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "n−3". This is explained by the fact that the n end is almost never changed during physiologic transformations in the human body, as it is more stable energetically, and other carbohydrates compounds can be synthesized from the other carbonyl end, for example in glycerides, or from double bonds in the middle of the chain.

Chemical structure of eicosapentaenoic acid (EPA).

Chemical structure of docosahexaenoic acid (DHA).

The term n−3 (also called ω−3 or omega-3) signifies that the first double bond exists as the third carbon-carbon bond from the terminal methyl end (n) of the carbon chain.

n−3 fatty acids which are important in human nutrition are: α-linolenic acid (18:3, n−3; ALA), eicosapentaenoic acid (20:5, n−3; EPA), and docosahexaenoic acid (22:6, n−3; DHA). These three polyunsaturates have either 3, 5 or 6 double bonds in a carbon chain of 18, 20 or 22 carbon atoms, respectively. All double bonds are in the cis-configuration; in other words, the two hydrogen atoms are on the same side of the double bond.

Most naturally-produced fatty acids (created or transformed in animalia or plant cells with an even number of carbon in chains) are in cis-configuration where they are more easily transformable. The trans-configuration results in much more stable chains that are very difficult to further break or transform, forming longer chains that aggregate in tissues and lacking the necessary hydrophilic properties. This trans-configuration can be the result of the transformation in alkaline solutions, or of the action of some bacterias that are shortening the carbonic chains. Natural transforms in plant or animal cells more rarely affect the last n−3 group itself. However, n−3 compounds are still more fragile than n−6 because the last double bond is geometrically and electrically more exposed, notably in the natural cis configuration.

Iodine can add to double bonds of docosahexaenoic acid and arachidonic acid forming iodolipids and making them less reactive to free oxygen radicals.^{[7][8][9][10]}

List of n−3 fatty acids

This table lists several different names for the most common n−3 fatty acids found in nature.

Biological significance

The biological effects of the n−3 are largely mediated by their interactions with the n−6 fatty acids; see Essential fatty acid interactions for detail.

A 1992 article by biochemist William E.M. Lands^[11] provides an overview of the research into n−3 fatty acids, and is the basis of this section.

The 'essential' fatty acids were given their name when researchers found that they were essential to normal growth in young children and animals. (Note that the modern definition of 'essential' is more strict.) A small amount of n−3 in the diet (~1% of total calories) enabled normal growth, and increasing the amount had little to no additional effect on growth.

Likewise, researchers found that n−6 fatty acids (such as γ-linolenic acid and arachidonic acid) play a similar role in normal growth. However, they also found that n−6 was "better" at supporting dermal integrity, renal function, and parturition. These preliminary findings led researchers to concentrate their studies on n−6, and it was only in recent decades that n−3 has become of interest.

In 1963 it was discovered that the n−6 arachidonic acid was converted by the body into pro-inflammatory agents called prostaglandins. By 1979 more of what are now known as eicosanoids were discovered: thromboxanes, prostacyclins and the leukotrienes. The eicosanoids, which have important biological functions, typically have a short active lifetime in the body, starting with synthesis from fatty acids and ending with metabolism by enzymes. However, if the rate of synthesis exceeds the rate of metabolism, the excess eicosanoids may have deleterious effects. Researchers found that n−3 is also converted into eicosanoids, but at a much slower rate. Eicosanoids made from n−3 fats are often referred to as anti-inflammatory, but in fact they are just less pro-inflammatory than those made from n−6 fats. If both n−3 and n−6 are present, they will "compete" to be transformed, so the ratio of n−3:n−6 directly affects the type of eicosanoids that are produced.

This competition was recognized as important when it was found that thromboxane is a factor in the clumping of platelets, which leads to thrombosis. The leukotrienes were similarly found to be important in immune/inflammatory-system response, and therefore relevant to arthritis, lupus, and asthma. These discoveries led to greater interest in finding ways to control the synthesis of n−6 eicosanoids. The simplest way would be by consuming more n−3 and fewer n−6 fatty acids.

In 1982 Dr. Charles Serhan's group at Harvard discovered that the omega-3 fatty acid EPA forms in the body potent antiinflamatory nanomolecules, called resolvins. Later another team found that omega-3s also turn into other antiinflammatory molecules called omega-3-oxylipins, which partly explain the versatile health effects of fish oil.^[12]

Health benefits

The 18 carbon α-linolenic acid has not been shown to have the same cardiovascular benefits as DHA or EPA.^[13] Currently there are many products on the market which claim to contain health promoting 'omega 3', but contain only α-linolenic acid (ALA), not EPA or DHA. These products contain mainly higher plant oils and must be converted by the body to create DHA and therefore considered less efficient. DHA and EPA are made by microalgae that live in seawater. These are then consumed by fish and accumulate to high levels in their internal organs. If a person has ethical concerns about killing fish, or is concerned about mercury and oceanborne contaminants in fish, DHA can be produced directly from microalgae as a vegetarian source. People with certain circulatory problems, such as varicose veins, benefit from such supplements containing EPA and DHA which stimulate blood circulation, increase the breakdown of fibrin, a compound involved in clot and scar formation, and additionally have been shown to reduce blood pressure.^[14][15] There is strong scientific evidence that n−3 fatty acids reduce blood triglyceride levels^{[16][17][18][19]} and regular intake reduces the risk of secondary and primary heart attack.^{[20][21][22][23]}

Some benefits have been reported in conditions such as rheumatoid arthritis^[24][25] and cardiac arrhythmias.^[26][27][28]

There is preliminary evidence that n-3 fatty acids supplementation might be helpful in cases of depression^[29][30] and anxiety.^[31][32] Studies report highly significant improvement from n-3 fatty acids supplementation alone and in conjunction with medication.^[33] The New York Times reports that at least one study, however, has found no connection between depression in heart patients and supplements containing n-3 fatty acids.^[34]

Some research suggests that fish oil intake may reduce the risk of ischemic and thrombotic stroke.^[35][36][37] However, very large amounts may actually increase the risk of hemorrhagic stroke (see below). Lower amounts are not related to this risk,^[37] 3 grams of total EPA/DHA daily are considered safe with no increased risk of bleeding involved^[38] and many studies used substantially higher doses without major side effects (for example: 4.4 grams EPA/2.2 grams DHA in 2003 study).^[29] There is evidence that the botanical sources of n−3 do not result in the health benefits derived from wild fish sources.^[39]

Cancer prevention

Several studies report possible anti-cancer effects of n−3 fatty acids (particularly breast, colon, and prostate cancer).^[40][41][42] Omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival.^[43] Among n-3 fatty acids [omega-3], neither long-chain nor short-chain forms were consistently associated with breast cancer risk. High levels of docosahexaenoic acid, however, the most abundant n-3 PUFA [omega-3] in erythrocyte membranes, were associated with a reduced risk of breast cancer.^[44] A 2006 report in the Journal of the American Medical Association concluded that their review of literature covering cohorts from many countries with a wide variety of demographic concluded that there was no link between n−3 fatty acids and cancer.^[45] This is similar to the findings of a review by the British Medical Journal of studies up to February 2002 that failed to find clear effects of long and shorter chain n−3 fats on total mortality, combined cardiovascular events and cancer.^[46]

A 2007 systematic review of n-3 fatty acids and cachexia found evidence that oral n-3 fatty acid supplements benefit cancer patients, improving appetite, weight and quality of life.^[47] A 2009 trial found that a supplement of eicosapentaenoic acid helped cancer patients retain muscle mass.^[48]

Cardiovascular disease prevention

In 1999, the GISSI-Prevenzione Investigators reported in the Lancet, the results of major clinical study in 11,324 patients with a recent myocardial infarction. Treatment 1 gram per day of n−3 fatty acids reduced the occurrence of death, cardiovascular death and sudden cardiac death by 20%, 30% and 45% respectively.^[49] These beneficial effects were seen already from three months onwards.^[50]

In April 2006, a team led by Lee Hooper at the University of East Anglia in Norwich, UK, published a review of almost 100 separate studies into n−3 fatty acids, found in abundance in oily fish. It concluded that they do not have a significant protective effect against cardiovascular disease.^[51] This meta-analysis was controversial and stands in stark contrast with two different reviews also performed in 2006 by the American Journal of Clinical Nutrition^[52] and a second JAMA review^[53] that both indicated decreases in total mortality and cardiovascular incidents (i.e. myocardial infarctions) associated with the regular consumption of fish and fish oil supplements.

Several studies published in 2007 have been more positive. In the March 2007 edition of the journal Atherosclerosis, 81 Japanese men with unhealthy blood sugar levels were randomly assigned to receive 1800 mg daily of eicosapentaenoic acid (EPA) with the other half being a control group. The thickness of the carotid arteries and certain measures of blood flow were measured before and after supplementation. This went on for approximately two years. A total of 60 patients (30 in the E-EPA group and 30 in the control group) completed the study. Those given the EPA had a statistically significant decrease in the thickness of the carotid arteries along with improvement in blood flow. The authors indicated that this was the first demonstration that administration of purified EPA improves the thickness of carotid arteries along with improving blood flow in patients with unhealthy blood sugar levels.^[54]

In another study published in the American Journal of Health System Pharmacy March 2007, patients with high triglycerides and poor coronary artery health were given 4 grams a day of a combination of EPA and DHA along with some monounsaturated fatty acids. Those patients with very unhealthy triglyceride levels (above 500 mg/dl) reduced their triglycerides on average 45% and their VLDL cholesterol by more than 50%. VLDL is a bad type of cholesterol and elevated triglycerides can also be deleterious for cardiovascular health.^[55]

Another study on the benefits of EPA was published in The Lancet in March 2007. This study involved over 18,000 patients with unhealthy cholesterol levels. The patients were randomly assigned to receive either 1,800 mg a day of E-EPA with a statin drug or a statin drug alone. The trial went on for a total of five years. It was found at the end of the study those patients in the E-EPA group had superior cardiovascular function. Non-fatal coronary events were also significantly reduced in the E-EPA group. The authors concluded that EPA is a promising treatment for prevention of major coronary events, especially non-fatal coronary events.^[56]

Similar to those who follow a Mediterranean diet, Arctic-dwelling Inuit - who consume high amounts of n−3 fatty acids from fatty fish - also tend to have higher proportions of n−3, increased HDL cholesterol and decreased triglycerides (fatty material that circulates in the blood) and less heart disease. Eating walnuts (the ratio of n−3 to n−6 is circa 1:4 respectively^[57]) was reported to lower total cholesterol by 4% relative to controls when people also ate 27% less cholesterol.^[58]

A study carried out involving 465 women showed serum levels of eicosapentaenoic acid is inversely related to the levels of anti-oxidized-LDL antibodies. Oxidative modification of LDL is thought to play an important role in the development of atherosclerosis.^[59]

Immune function

Another study regarding fish oil was published in the Journal of Nutrition in April 2007. Sixty four healthy Danish infants from nine to twelve months of age received either cow's milk or infant formula alone or with fish oil. It was found that those infants supplemented with fish oil had improvement in immune function maturation with no apparent reduction in immune activation.^[60]

Brain health

Fish oil may help prevent psychotic disorders in high-risk children and adolescents.^[61] A novel fish oil known as E-EPA may prevent memory impairment^[62] and speed up recovery from major depression^[63] There was yet another study on n−3 fatty acids published in the April 2007 Journal of Neuroscience. A group of mice were genetically modified to develop accumulation of amyloid and tau proteins in the brain similar to that seen in people with poor memory. The mice were divided into four groups with one group receiving a typical American diet (with high ratio of n−6 to n−3 fatty acids being 10 to 1). The other three groups were given food with a balanced 1 to 1 n−6 to n−3 ratio and two additional groups supplemented with DHA plus long chain n−6 fatty acids. After three months of feeding, all the DHA supplemented groups were noted to have a lower accumulation of beta amyloid and tau protein. Some research suggests that these abnormal proteins may contribute to the development of memory loss in later years.^[64]

There is also a study published regarding n−3 supplementation in children with learning and behavioral problems. This study was published in the April 2007 edition of the Journal of the Developmental and Behavioral Pediatrics (5), where 132 children, between the ages of seven to twelve years old, with poor learning, participated in a randomized, placebo-controlled, double-blinded interventional trial. A total of 104 children completed the trial. For the first fifteen weeks of this study, the children were given polyunsaturated fatty acids (n−3 and n−6, 3000 mg a day), polyunsaturated fatty acids plus multi-vitamins and minerals or placebo. After fifteen weeks, all groups crossed over to the polyunsaturated fatty acids (PUFA) plus vitamins and mineral supplement. Parents were asked to rate their children's condition after fifteen and thirty weeks. After thirty weeks, parental ratings of behavior improved significantly in nine out of fourteen scales. The lead author of the study, Dr. Sinn, indicated the present study is the largest PUFA trial to date with children falling in the poor learning and focus range. The results support those of other studies that have found improvement in poor developmental health with essential fatty acid supplementation.^{[55][56][60][64][65][66]} After completion of Dr. Nathalie Sinn's study, positive results still continued and children's behaviors improved.^[67]

A study^[68] examining whether omega-3 exerts neuroprotective action in Parkinson's disease found that it did, using an experimental model, exhibit a protective effect (much like it did for Alzheimer's disease as well). The scientists exposed mice to either a control or a high omega-3 diet from two to twelve months of age and then treated them with a neurotoxin commonly used as an experimental model for Parkinson's. The scientists found that high doses of omega-3 given to the experimental group completely prevented the neurotoxin-induced decrease of dopamine that ordinarily occurs. Since Parkinson's is a disease caused by disruption of the dopamine system, this protective effect exhibited could show promise for future research in the prevention of Parkinson's disease.

However, fish oil has been shown to have no effect on cognitive performance in older individuals without dementia.^[69]

Anti-inflammatory

Research in 2005 and 2006 has suggested that the in-vitro anti-inflammatory activity of n−3 acids translates into clinical benefits. Cohorts of neck pain patients and of rheumatoid arthritis sufferers have demonstrated benefits comparable to those receiving standard NSAIDs.

Risks

Health risks

Non-cardiac health risks

In a letter published October 31, 2000,^[70] the United States Food and Drug Administration Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements noted that known or suspected risks of EPA and DHA n−3 fatty acids consumed in excess of 3 grams per day may include the possibility of:

• Increased incidence of bleeding.
• Hemorrhagic stroke.
• Oxidation of omega-3 fatty acids forming biologically active oxidation products.
• Increased levels of low density lipoproteins (LDL) cholesterol or apoproteins associated with LDL cholesterol among diabetics and hyperlipidemics.
• Reduced glycemic control among diabetics.

Subsequent advice from the FDA and national counterparts have permitted health claims associated with heart health.

Cardiac risk

Persons with congestive heart failure, chronic recurrent angina pectoris or evidence that their heart is receiving insufficient blood flow are advised to talk to their doctor before taking n−3 fatty acids. There have been concerns if such persons take n−3 fatty acids or eating foods that contain them in substantial amounts.^[71] In a recent large study, n−3 fatty acids on top of standard heart failure therapy produced a small but statistically significant benefit in terms of mortality and hospitalization.^[72]

In congestive heart failure, cells that are only barely receiving enough blood flow become electrically hyperexcitable. This, in turn, can lead to increased risk of irregular heartbeats, which, in turn, can cause sudden cardiac death. n−3 fatty acids seem to stabilize the rhythm of the heart by effectively preventing these hyperexcitable cells from functioning, thereby reducing the likelihood of irregular heartbeats and sudden cardiac death. For most people, this is obviously beneficial and would account for most of the large reduction in the likelihood of sudden cardiac death. Nevertheless, for people with congestive heart failure, the heart is barely pumping blood well enough to keep them alive. In these patients, n−3 fatty acids may eliminate enough of these few pumping cells that the heart would no longer be able to pump sufficient blood to live, causing an increased risk of cardiac death.^[71]

Research frontiers

Developmental differences

Although not supported by current scientific evidence as a primary treatment for ADHD, autism, and other developmental differences,^[73][74] omega-3 fatty acids have gained popularity for children with these conditions.^[73] A 2004 Internet survey found that 29% of surveyed parents used essential fatty acid supplements to treat children with autism spectrum disorders.^[75]

Omega-3 fatty acids offer a promising complementary approach to standard treatments for ADHD and developmental coordination disorder.^[74] Fish oils appear to reduce ADHD-related symptoms in some children.^[74] Double blind studies have showed "medium to strong treatment effects of omega 3 fatty acids on symptoms of ADHD" after administering amounts around 1 gram for three to six months.^[65][76][77]

There is very little scientific evidence supporting the effectiveness of omega-3 fatty acids for autism spectrum disorders.^[78] One randomized controlled trial found that omega-3 fatty acids did not significantly affect aberrant behavior in autistic children, and although the investigators noted reduced hyperactivity,^[79] their later reanalysis reported that the reduction was not statistically significant.^[80]

Low birth weight

In a study of nearly 9,000 pregnant women, researchers found women who ate fish once a week during their first trimester had 3.6 times less risk of low birth weight and premature birth than those who ate no fish. Low consumption of fish was a strong risk factor for preterm delivery and low birth weight.^[81][82] However, attempts by other groups to reverse this increased risk by encouraging increased pre-natal consumption of fish were unsuccessful.^[83]

Psychiatric disorders

n−3 fatty acids are thought by some to have membrane-enhancing capabilities in brain cells. One medical explanation is that n−3 fatty acids play a role in the fortification of the myelin sheaths. Not coincidentally, n−3 fatty acids comprise approximately eight percent of the average human brain according to Dr. David Horrobin, a pioneer in fatty acid research. Ralph Holman of the University of Minnesota, another major researcher in studying essential fatty acids, who gave Omega-3 its name, surmised how n−3 components are analogous to the human brain by stating that "DHA is structure, EPA is function."

A benefit of n−3 fatty acids is helping the brain to repair damage by promoting neuronal growth.^[51] In a six-month study involving people with schizophrenia and Huntington's disease who were treated with E-EPA or a placebo, the placebo group had clearly lost cerebral tissue, while the patients given the supplements had a significant increase of grey and white matter.^[84]

In the prefrontal cortex (PFC) of the brain, low brain n−3 fatty acids are thought to lower the dopaminergic neurotransmission in this brain area, possibly contributing to the negative and neurocognitive symptoms in schizophrenia. This reduction in dopamine system function in the PFC may lead to an overactivity in dopaminergic function in the limbic system of the brain which is suppressively controlled by the PFC dopamine system, causing the positive symptoms of schizophrenia. This is called the n−3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia (Ohara, 2007). This mechanism may explain why n−3 supplementation shows effects against both positive, negative and neurocognitive symptoms in schizophrenia.

Consequently, the past decade of n−3 fatty acid research has procured some Western interest in n−3 fatty acids as being a legitimate 'brain food.' Still, recent claims that one's intelligence quotient, psychological tests measuring certain cognitive skills, including numerical and verbal reasoning skills, are increased on account of n−3 fatty acids consumed by pregnant mothers remain unreliable and controversial. An even more significant focus of research, however, lies in the role of n−3 fatty acids as a non-prescription treatment for certain psychiatric and mental diagnoses and has become a topic of much research and speculation.

In 1998, Andrew L. Stoll, MD and his colleagues at Harvard University conducted a small double-blind placebo-controlled study in thirty patients diagnosed with bipolar disorder. Most subjects in this study were already undergoing psychopharmacological treatment (e.g. 12 out of the 30 were taking lithium). Over the course of four months, he gave 15 subjects capsules containing olive oil, and another 15 subjects capsules containing nine grams of pharmaceutical-quality EPA and DHA. The study showed that subjects in the n−3 group were less likely to experience a relapse of symptoms in the four months of the study. Moreover, the n−3 group experienced significantly more recovery than the placebo group. However, a commentary on the Stoll study notes that the improvement in the n−3 group was too small to be clinically significant.^[85] Though Stoll believes that the 1999 experiment was not as optimal as it could have been and has accordingly pursued further research, the foundation has been laid for more researchers to explore the theoretical association between absorbed n−3 fatty acids and signal transduction inhibition in the brain.^[86]

"Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega−3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression. Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach."^[87] In 2004, a study found that 100 suicide attempt patients on average had significantly lower levels of EPA in their blood as compared to controls.^[88]

In 2006 the Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association (APA) stated the following: "The preponderance of epidemiologic and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mood disorders. Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p=.02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry. Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications." ^[89]

Another meta-analysis published in the Journal of Clinical Psychiatry in 2007, based on 10 clinical trials, found that Omega-3 polyunsaturated fatty acids significantly improved depression in patients with both unipolar and bipolar disorder. However, based upon the heterogeneity of the trials, the authors concluded that "more large-scale, well-controlled trials are needed to find out the favorable target subjects, therapeutic dose of EPA and the composition of omega-3 PUFAs in treating depression".^[90] A small American trial, published in 2009, suggests that E-EPA, as monotherapy, has an advantage over placebo in major depressive disorder.^[91]

Dietary sources

Daily values

As macronutrients, fats are not assigned recommended daily allowances. Macronutrients have AI (acceptable intake) and AMDR (acceptable macronutrient distribution range) instead of RDAs. The AI for n−3 is 1.6 grams/day for men and 1.1 grams/day for women^[92] while the AMDR is 0.6% to 1.2% of total energy.^[93]

A growing body of literature suggests that higher intakes of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) may afford some degree of protection against coronary heart disease. Because the physiological potency of EPA and DHA is much greater than that for α-linolenic acid, it is not possible to estimate one AMDR for all n−3 fatty acids. Approximately 10 percent of the AMDR can be consumed as EPA and/or DHA."^[93] There was insufficient evidence as of 2005 to set a UL (upper tolerable limit) for n−3 fatty acids.^[92]

A perceived risk of fish oil n−3 supplementation has been heavy metal poisoning by the body's accumulation of traces of heavy metals, in particular mercury, lead, nickel, arsenic and cadmium as well as other contaminants (PCBs, furans, dioxins, PBDEs), which potentially might be found especially in less-refined fish oil supplements. However, in reality, heavy metal toxicity from consuming fish oil supplements is highly unlikely. This is because heavy metals selectively bind with protein in the fish flesh rather than accumulate in the oil. An independent test in 2006 of 44 fish oils on the US market found that all of the products passed safety standards for potential contaminants.^[94] The FDA recommends that total dietary intake of n−3 fatty acids from fish not exceed 3 grams per day, of which no more than 2 grams per day are from nutritional supplements.^[5]

Historically, the Council for Responsible Nutrition (CRN) and the World Health Organization (WHO) have published acceptable standards regarding contaminants in fish oil. The most stringent current standard is the International Fish Oils Standard (IFOS). The Global Organization for EPA and DHA Omega-3 (GOED)^[95] has also published standards for omega-3 products. Fish oils that typically make this highest grade are those that are molecularly distilled under vacuum, and have virtually no measurable level of contaminants (measured parts per billion and parts per trillion).

n−3 supplementation in food has been a significant recent trend in food fortification, with global food companies launching n−3 fortified bread, mayonnaise, pizza, yogurt, orange juice, children's pasta, milk, eggs, confections and infant formula.

Fish

The most widely available source of EPA and DHA is cold water oily fish such as salmon, herring, mackerel, anchovies and sardines. Oils from these fish have a profile of around seven times as much n−3 as n−6. Other oily fish such as tuna also contain n−3 in somewhat lesser amounts. Consumers of oily fish should be aware of the potential presence of heavy metals and fat-soluble pollutants like PCBs and dioxin which may accumulate up the food chain. After extensive review, researchers from Harvard's School of Public Health reported in the Journal of the American Medical Association (2006) that the benefits of fish intake generally far outweigh the potential risks. As fish oil supplements are bought for their healthful Omega-3 fatty acid content, it is therefore vital that manufacturers and suppliers of these products ensure that they do not contain high levels of dioxins and other toxins.^[96]

Even some forms of fish oil may not be optimally digestible. Of four studies that compare bioavailability of the triglyceride form of fish oil vs. the ester form, two have concluded that the natural triglyceride form is better, and the other two studies did not find a significant difference. No studies have shown the ester form to be superior although it is cheaper to manufacture.^[97][98]

Although fish is a dietary source of n−3 fatty acids, fish do not synthesize them; they obtain them from the algae (microalgae in particular) or plankton in their diet.^[99]

Krill

Krill oil is a relatively new source of n−3 fatty acids. Various claims are made in support of krill oil as a superior source of n−3 fatty acids, such as that krill are not susceptible to contamination like fish and contain a special antioxidant called astaxanthin. However, numerous studies have found krill is often contaminated by pollution and astaxanthin hasn't been demonstrated to have a very potent antioxidant capacity.^[101][102]

Green-lipped mussel

Green-lipped mussel from New Zealand also known as Perna canaliculus is another source of n-3 fatty acids. Research suggests that green-lipped mussels contain a distinct blend of n-3 fatty acids in comparison to other sources of n-3s. Most published studies report green-lipped mussels’ health benefits with inflammation. The book The Inflammation Revolution by George Halpern, MD., PhD., professor at Hong Kong Polytechnic University discusses the effects of green-lipped mussels in comparison to NSAIDs in the treatment of inflammatory conditions, particularly arthritis.^[103] Lyprinol is a patented New Zealand mussel oil extract.^[104]

Botanical sources

Flax seeds produce linseed oil, which has a very high n−3 content

Six times richer than most fish oils in n−3,^[105] albeit in the short chain form lacking EPA and DHA, flax (or linseed) (Linum usitatissimum) and its oil are perhaps the most widely available botanical source of n−3. Flaxseed oil consists of approximately 55% ALA (alpha-linolenic acid). Flax, like chia, contains approximately three times as much n−3 as n−6.

Purslane contains more Omega-3 fatty acids (alpha-linolenic acid in particular^[106]) than any other leafy vegetable plant. Purslane has .01 mg/g of Eicosapentaenoic acid (EPA); this is an extraordinary amount of EPA for vegetable sources.

Table 1. ALA content as the percentage of n−3 in the seed oil.^[107]

Table 2. ALA content as the percentage of n−3 in the whole food.^[108][109]

Eggs

Eggs produced by chicken fed a diet of greens and insects produce higher levels of n−3 fatty acids (mostly ALA) than chicken fed corn or soybeans.^[110] In addition to feeding chickens insects and greens, fish oils may be added to their diet to increase the amount of fatty acid concentrations in eggs.^[111] The addition of flax and canola seeds to the diet of chickens, both good sources of alpha-linolenic acid, increases the omega-3 content of the eggs.^[112] However, the Center for Science in the Public Interest reports that "the omega-3s that FDA considers healthful (DHA and EPA) are not found in plants such as flax seed." It also reports that "Eggs contain too much saturated fat and cholesterol to meet FDA’s definition of healthy."^[113] The addition of green algae or seaweed to the diet boosts the content of DHA and EPA omega-3 content, which are the forms of omega-3 that are approved by the FDA for medical claims.

Meat

The n−6 to n−3 ratio of grass-fed beef is about 2:1, making it a more useful source of n−3 than grain-fed beef, which usually has a ratio of 4:1.^[114]

In most countries, commercially available lamb is typically grass-fed, and thus higher in n−3 than other grain-fed or grain-finished meat sources. In the United States, lamb is often finished (i.e. fattened before slaughter) with grain, resulting in lower n−3.^[115]

The omega-3 content of chicken meat may be enhanced by increasing the animals' dietary intake of grains that are high in n−3, such as flax, chia, and canola.^[116]

Kangaroo meat is also a source of n−3 with fillet and steak containing 74mg per 100g of raw meat.^[117]

Seal oil

Seal oil is a source of EPA, DPH, and DPA. According to Health Canada, it helps to support the development of the brain, eyes and nerves in children up to 12 years of age.^[118] However, like all seal products, it is not allowed for import into the European Union^[119]

Other sources

A marine oil softgel

Milk and cheese from grass-fed cows may also be good sources of n−3. One UK study showed that half a pint of milk provides 10% of the recommended daily intake (RDI) of ALA, while a piece of organic cheese the size of a matchbox may provide up to 88%".^[120]

The microalgae Crypthecodinium cohnii and Schizochytrium are rich sources of DHA (22:6 n−3) and can be produced commercially in bioreactors. This is the only source of DHA acceptable to vegans. Oil from brown algae (kelp) is a source of EPA. Walnuts are one of few nuts that contain appreciable n−3 fat, with approximately a 1:4 ratio of n−3 to n−6.^[57] Acai palm fruit also contains n−3 fatty acids.

Omega-3 is also found in softgels in pharmacies and nowadays it is also found in combination with omega-6, omega-9 and shark liver oil ^[121]

The n−6 to n−3 ratio

Clinical studies^{[11][122][123]} indicate that the ingested ratio of n−6 to n−3 (especially Linoleic vs Alpha Linolenic) fatty acids is important to maintaining cardiovascular health. However, two studies published in 2005 and 2007 found no such correlations in humans.^[124][125]

Both n−3 and n−6 fatty acids are essential, i.e. humans must consume them in the diet. n−3 and n−6 compete for the same metabolic enzymes, thus the n−6:n−3 ratio will significantly influence the ratio of the ensuing eicosanoids (hormones), (e.g. prostaglandins, leukotrienes, thromboxanes etc.), and will alter the body's metabolic function.^[126] Generally, grass-fed animals accumulate more n−3 than do grain-fed animals which accumulate relatively more n−6. Metabolites of n−6 are significantly more inflammatory (esp. arachidonic acid) than those of n−3. This necessitates that n−3 and n−6 be consumed in a balanced proportion; healthy ratios of n−6:n−3 range from 1:1 to 4:1.^[127][128] Studies suggest that the evolutionary human diet, rich in game animals, seafood and other sources of n−3, may have provided such a ratio.^[129][130]

Typical Western diets provide ratios of between 10:1 and 30:1 - i.e., dramatically skewed toward n−6.^[131] Here are the ratios of n−6 to n−3 fatty acids in some common oils: canola 2:1, soybean 7:1, olive 3–13:1, sunflower (no n−3), flax 1:3,^[132] cottonseed (almost no n−3), peanut (no n−3), grapeseed oil (almost no n−3) and corn oil 46 to 1 ratio of n−6 to n−3.^[133]

Conversion efficiency of ALA to EPA and DHA

It has been reported that conversion of ALA to EPA and further to DHA in humans is limited, but varies with individuals.^[134] Women have higher ALA conversion efficiency than men, probably due to the lower rate of utilization of dietary ALA for beta-oxidation. This suggests that biological engineering of ALA conversion efficiency is possible. Goyens et al. argue that it is the absolute amount of ALA, rather than the ratio of n−3 and n−6 fatty acids, which affects the conversion.^[135]

See also

Notes and references

Additional sources

Further reading

External links