Vegetarian In Boston

N−3 fatty acids (popularly referred to as ω−3 fatty acids or omega-3 fatty acids) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain.

Essential fatty acids are molecules that cannot be synthesized by the human body but are vital for normal metabolism. One of the two families of these essential fatty acids is the omega-3 fatty acids.

The carbon chain has two ends—the acid (COOH) end and the methyl (CH₃) end. The location of the first double bond is counted from the methyl end, which is also known as the omega (ω) end or the n end.

Nutritionally important n−3 fatty acids include α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated.

Common sources of n–3 fatty acids include fish oils and some plant oils such as flaxseed oil and algal oil.

Mammals cannot synthesize n−3 fatty acids, but have a limited ability to form the "long-chain" n−3 fatty acids EPA (20-carbon atoms) and DHA (22-carbon atoms) from the "short-chain" eighteen-carbon n−3 fatty acid ALA.

N−3 fatty acids that are important in human physiology 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. As with most naturally-produced fatty acids, all double bonds are in the cis-configuration; in other words, the two hydrogen atoms are on the same side of the double bond.

Like free oxygen radicals, iodine can add to double bonds of docosahexaenoic acid and arachidonic acid forming iodolipids.^[1][2][3][4]

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

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 since the 1990s.^[5] 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 and European Union, these novel versions are often sold as prescription medications, such as Lovaza. Elsewhere 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 meat, 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.^[6]

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."^[7] This updated and modified their health risk advice letter of 2001 (see below). As of this writing, regulatory agencies^[who?] do not accept that there is sufficient evidence for any of the 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."^[8]

A 1992 article by biochemist William E.M. Lands^[9] 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 are 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 is only in recent decades that n−3 has become of interest.

In 1964, it was discovered that enzymes found in sheep tissues convert n−6 arachidonic acid into the inflammatory agent called prostaglandin E₂,^[10] which both causes the sensation of pain and expedites healing and immune response in traumatized and infected tissues.^{[citation needed]} By 1979, more of what are now known as eicosanoids were discovered: thromboxanes, prostacyclins, and the leukotrienes.^[9] 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.^[9]Researchers found that certain n−3 fatty acids are also converted into eicosanoids, but at a much slower rate. Eicosanoids made from n−3 fatty acids are often referred to as anti-inflammatory, but in fact they are just less inflammatory than those made from n−6 fats. If both n−3 and n−6 fatty acids are present, they will "compete" to be transformed,^[9] so the ratio of long-chain n−3:n−6 fatty acids directly affects the type of eicosanoids that are produced^{[citation needed]}.

This competition was recognized as important when it was found that thromboxane is a factor in the clumping of platelets, which can both cause death by thrombosis and cause death by bleeding. Likewise, the leukotrienes were found to be important in immune/inflammatory-system response, and therefore relevant to arthritis, lupus, asthma, and recovery from infections. 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.^[9]

When administered as the ethyl ester, the omega-3 fatty acid EPA appears to form potent anti-inflammatory molecules, called resolvins and omega-3-oxylipins,^[11] which may partly explain the positive effects of fish oil.^{[citation needed]}

The n-3 fatty acids DHA and EPA may act as direct ligands to a cell surface G-protein receptor, affecting anti-inflammatory and insulin sensitization in mice.^[12]

The short-chain n−3 fatty acids are converted to long-chain forms (EPA, DHA) with an efficiency below 5%^[13][14] in men, and at a greater percentage in women which may be due to the importance for meeting the demands of the fetus and neonate for DHA.^[15]

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 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.^{[citation needed]}

The conversion of ALA to EPA and further to DHA in humans has been reported to be limited, but varies with individuals.^[16] Women have higher ALA conversion efficiency than men, it is presumed due to the lower rate of use of dietary ALA for beta-oxidation. This suggests that biological engineering of ALA conversion efficiency is possible. Goyens et al. argue that it the absolute amount of ALA, rather than the ratio of n−3 and n−6 fatty acids, controls the conversion efficiency.^[17]

Some clinical studies^[9][18][19] 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 that while n−3 polyunsaturated fatty acids are extremely beneficial in preventing heart disease in humans, the levels of n−6 polyunsaturated fatty acids (and therefore the ratios) were insignificant.^[20][21]

Both n−3 and n−6 fatty acids are essential; i.e., humans must consume them in the diets. N−3 and n−6 eighteen-carbon polyunsaturated fatty acids 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.^[22] In general, grass-fed animals accumulate more n−3 than do grain-fed animals, which accumulate relatively more n−6.^[23] Metabolites of n−6 are 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 1:4 (an individual needs more n−3 than n−6.)^[24][25] Studies suggest the evolutionary human diet, rich in game animals, seafood, and other sources of n−3, may have provided such a ratio.^[26][27]

Typical Western diets provide ratios of between 10:1 and 30:1 (i.e., dramatically higher levels of n−6 than n-3).^[28] The ratios of n−6 to n−3 fatty acids in some common vegetable oils are: canola 2:1, soybean 7:1, olive 3–13:1, sunflower (non−3), flax 1:3,^[29] cottonseed (almost no n−3), peanut (no n−3), grapeseed oil (almost no n−3) and corn oil 46:1 ratio of n−6 to n−3.^[30]

As a Harvard expert explains, n-6 fatty acids also reduce inflammation and protect against heart disease, so the n-3 to n-6 ratio "is of no value in evaluating diet quality or predicting disease".^[31]

The 18 carbon α-linolenic acid (ALA) has not been shown to have the same cardiovascular benefits that DHA or EPA may have.^[32] Currently, there are many products on the market that claim to contain health-promoting "omega 3", but contain only ALA, not EPA or DHA. These products contain mainly plant oils and must be converted by the body to create DHA. DHA and EPA are made by marine microalgae. These are then consumed by fish and accumulate to high levels in their internal organs. The United States Environmental Protection Agency issues fish consumption advisories to empower Americans to avoid toxic mercury levels in certain fish and shellfish while still reaping the possible health benefits of consuming fish and shellfish.^[33]

Some evidence suggests that people with certain circulatory problems, such as varicose veins, may benefit from the consumption of EPA and DHA, which may stimulate blood circulation, increase the breakdown of fibrin, a compound involved in clot and scar formation, and, in addition, may reduce blood pressure.^[34][35] Evidently, n−3 fatty acids reduce blood triglyceride levels,^{[36][37][38][39]} and regular intake may reduce the risk of secondary and primary heart attack.^{[40][41][42][43]} A systematic review of studies prior to 2005 showed that ALA does not confer the cardiovascular health benefits of EPA and DHA.^[44]

Some potential benefits have been reported in conditions such as rheumatoid arthritis^[45][46] and cardiac arrhythmias.^[47][48][49]

There is preliminary evidence that EPA supplementation, either with DPA or medication, is helpful in cases of depression^[50][51][52] There is also limited evidence that supplementation with n-3 fatty acids, alone or in combination with n-6 fatty acids, may reduce anxiety,^[53] however, the only live study to suggest an anxiety reducing effect involved α-Linolenic acid (as opposed to EPA or DPA).^[54] The New York Times,^[55] however, reports that at least one study^[56] has not found a connection between depression in heart patients taking Sertraline and daily supplements containing two grams total of EPA and DHA during a ten-week period.

Some research suggests that fish oil intake may reduce the risk of ischemic and thrombotic stroke,^[57][58][59] although large amounts may actually increase the risk of hemorrhagic stroke (see below): Lower amounts are not related to this risk;^[59] 3 grams of total EPA/DHA daily are generally recognized as safe (GRAS) with no increased risk of bleeding involved^[60] and many studies used substantially higher doses without major side effects (for example: 4.4 grams EPA/2.2 grams DHA in 2003 study).^[50]

Several studies report possible anti-cancer effects of n−3 fatty acids (in particular, breast, colon, and prostate cancer).^[61][62][63] Omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival in mice.^[64] 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 in erythrocyte membranes, were associated with a reduced risk of breast cancer.^[65] Conversely, a 2011 study, the largest ever done involving 3,400 men, examined the association of dietary fats and prostate cancer risk, found that men with the highest blood percentages of docosahexaenoic acid, or DHA, an inflammation-lowering omega-3 fatty acid commonly found in fatty fish, have two-and-a-half-times the risk of developing aggressive, high-grade prostate cancer compared to men with the lowest DHA levels.^[66][67]

A 2006 report in the Journal of the American Medical Association, in their review of literature covering cohorts from many countries with a wide variety of demographics, concluded that there was no link between n−3 fatty acids and cancer.^[68]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.^[69]

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.^[70] A 2009 trial found that a supplement of eicosapentaenoic acid helped cancer patients retain muscle mass.^[71]

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.^[72] These beneficial effects were seen from three months onwards.^[73]

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 of n−3 fatty acids found in abundance in oily fish. It concluded that they do not have a significant protective effect against cardiovascular disease.^[74] 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^[75] and a second JAMAreview;^[76] both indicated decreases in total mortality and cardiovascular incidents (i.e., myocardial infarctions) associated with the regular consumption of fish and fish oil supplements.

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 improved the thickness of carotid arteries and improved blood flow in patients with unhealthy blood sugar levels.^[77]

In a 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 elevatedtriglycerides can also be deleterious for cardiovascular health.^[78]

A study on the benefits of EPA published in The Lancet in March 2007 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 lasted five years. At the end of the study, those patients in the E-EPA group had superior cardiovascular function and nonfatal coronary events were also significantly reduced. The authors concluded that EPA is a promising treatment for prevention of major coronary events, especially nonfatal coronary events.^[79]

Similar to those following 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−6 to n−3 is circa 4:1^[80]) was reported to lower total cholesterol by 4% relative to controls when people also ate 27% less cholesterol.^[81]

A study of 465 women showed that serum levels of EPA are inversely related to levels of anti-oxidized-LDL antibodies. Oxidative modification of LDL is thought to play an important role in the development of atherosclerosis.^[82]

Survivors of past myocardial infarctions are less likely to die from an arrhythmic event if they are consuming high levels of n-3.^[83] These antiarrhythmic effects are thought to be due to n-3 fatty acids' ability to increase the fibrillation threshold of the heart tissue.^[84]

N-3 fatty acids also have mild antihypertensive effects. When subjects consumed n-3 from oily fish on a regular basis, their systolic blood pressure was lowered by about 3.5-5.5 mmHg.^[85]

In a study regarding fish oil 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. Those infants supplemented with fish oil were found to have improvement in immune function maturation, with no apparent reduction in immune activation.^[86]  Were these studies ever repeated for flaxseed only, or comparing flaxseed with fish oil?

Limited evidence suggests that long-chain n-3 fatty acids may delay or prevent the progression of certain psychotic disorders in high-risk children and adolescents.^[87] The individuals diagnosed with schizophrenia exhibited reduced levels of bothn-6 and n-3 polyunsaturated fatty acids, and the results of a study in which the treatment of high-risk children with a dietary supplement containing both eicosapentaenoate and docosahexaenoate produced a statistically significant (95% confidence, but not 97.5% confidence) decrease in progression to schizophrenia.

Consumption of ethyl eicosapentaenoate (E-EPA) partially countered memory impairment in a rat model of Alzheimer's disease^[88] and produced a statistically insignificant decrease in human depression.^[89]

Fish oil has been shown to have no effect on cognitive performance in individuals 65 years of age or older without dementia.^[90]

Although not confirmed as an approved health claim, current research suggests that the anti-inflammatory activity of long-chain n−3 fatty acids may translate into clinical effects.^[91] For example, there is evidence that rheumatoid arthritissufferers taking long-chain n−3 fatty acids from sources such as fish have reduced pain compared to those receiving standard NSAIDs.^[92]

In a letter published October 31, 2000,^[93] 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 consumed in excess of 3 grams per day may include the possibility of:

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

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 doctors before taking n−3 fatty acids.^[94] 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.^[95]

In congestive heart failure, cells that only barely receive enough blood flow become electrically hyperexcitable. This can lead to increased risk of irregular heartbeats, which, in turn, can cause sudden cardiac death. Certain 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 sudden cardiac death. For most people, this is beneficial and could 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, rather than decreased, risk of cardiac death.^[94]

Although not supported by current scientific evidence as a primary treatment for ADHD, autism spectrum disorders, and other developmental differences,^[96][97] omega-3 fatty acids have gained popularity for children with these conditions.^[96] A 2004 Internet survey found that 29% of surveyed parents used essential fatty acid supplements to treat children with autistic spectrum disorders.^[98]

Omega-3 fatty acids offer a promising complementary approach to standard treatments for ADHD and developmental coordination disorder.^[97] Fish oils appear to reduce ADHD-related symptoms in some children.^[97] Double blind studies have shown "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.^{[99][100][101]}

A 2009 survey concluded that there is not enough scientific evidence to support the effectiveness of 'n-3 fatty acids for autism spectrum disorders.^[102] One randomized controlled trial (RCT) found that n-3 fatty acids did not significantly affect aberrant behavior in autistic children, and although the investigators noted reduced hyperactivity,^[103] their later reanalysis reported that the reduction was not statistically significant.^[104]

In a study of nearly 9,000 pregnant women, researchers found that women that ate fish once a week during their first trimester had 27% less risk of low birth weight and premature birth than those that ate no fish. Low consumption of fish was a strong risk factor for preterm delivery and low birth weight,^[105][106] but attempts by other groups to reverse this increased risk by encouraging increased prenatal consumption of fish were unsuccessful.^[107]  Were these studies ever repeated for flaxseed only, or comparing flaxseed with fish oil?

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. It is no coincidence that 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 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.^[74] 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.^[108]

In the prefrontal cortex (PFC) of the brain, low brain n−3 fatty acids are thought to lower the dopaminergic neurotransmission, possibly contributing to the negative and neurocognitive symptoms in schizophrenia. This reduction in dopaminesystem 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 cognitive symptoms in schizophrenia.

As a consequence, 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. A 2011 report of preliminary research on mice found that omega-3 deficiency is linked to depression and mood disorders.^[109]

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.^[110] 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.^[111]

"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."^[112] 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.^[113]

In a recent study, low levels of DHA were associated with an increased risk of suicide for members of the U.S. military.^[114]

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."^[115]http://article.psychiatrist.com/dao_1-login.asp?ID=10007556&RSID=69755683854317

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".^[116] A small American trial, published in 2009, concluded that E-EPA, as monotherapy, demonstrated a statistically insignificant advantage over placebo, thought to be due to study limitations.^[117] However, a 2011 longitudinal study of over 50,000 women, conducted at Harvard University, found no association between intake of EPA and DPA and a reduction in depression, over a period of ten years. The study did, on the other hand, find that intake of α-Linolenic acid was positively associated with a significant reduction in depression in the same group.^[118]

As macronutrients, fats are not assigned recommended daily allowances. Macronutrients have acceptable intake (AI) levels and acceptable macronutrient distribution ranges (AMDRs) instead of RDAs. The AI for n−3 is 1.6 grams/day for men and 1.1 grams/day for women,^{[119][citation needed]}, while the AMDR is 0.6% to 1.2% of total energy.^{[120][citation needed]}

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 of ALA, 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."^[120] There was insufficient evidence as of 2005 to set an upper tolerable limit for n−3 fatty acids.^[119]

Heavy metal poisoning by the body's accumulation of traces of heavy metals, in particular mercury, lead, nickel, arsenic, and cadmium, is a possible risk from consuming fish oil supplements. Also, other contaminants (PCBs, furans, dioxins, and PBDEs) might be found, especially in less-refined fish oil supplements. In reality, however, heavy metal toxicity from consuming fish oil supplements is highly unlikely, 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 all of the products passed safety standards for potential contaminants.^[121] The FDA recommends that the total dietary intake of n−3 fatty acids from fish not exceed 3 grams per day, with no more than 2 grams per day from nutritional supplements.^[7]

A recent trend has been to fortify food with n−3 fatty acid supplements. Global food companies have launched n−3 fatty acid fortified bread, orange juice, children's pasta, popcorn, confections, and infant formula.

These tables are incomplete (not the n-3).

Table 1. ALA content as the percentage of the seed oil.^[133]

Table 2. ALA content as the percentage of the whole food.^[134][135]

Flaxseed (or linseed) (Linum usitatissimum) and its oil are perhaps the most widely available botanical source of the n−3 fatty acid ALA. Flaxseed oil consists of approximately 55% ALA, which makes it six times richer than most fish oils inn−3 fatty acids,^[136] although it contains negligible amounts of EPA and DHA, the n-3 fatty acids that FDA considers healthful."^[137]

Purslane contains more ALA^[138] than any other leafy vegetable plant. Purslane also contains .01 mg/g^{[citation needed]} (0.001%) of EPA, which is an extraordinary amount for a vegetable source.^{[citation needed]}

The microalgae Crypthecodinium cohnii and Schizochytrium are rich sources of DHA, and can be produced commercially in bioreactors.^{[citation needed]} This is the only source of DHA acceptable to vegans.^{[citation needed]}

Oil from brown algae (kelp) is a source of EPA.^{[citation needed]}

Acai palm fruit contains an unspecified quantity of unspecified n−3 fatty acids.^{[citation needed]}