Any dietary or drug treatment with high doses of micronutrients may override the body's own control mechanisms; therefore, micronutrient therapies may be associated with potential side effects and toxicities. High-dosed micronutrients should not be used without medical supervision.
Dietary intervention trials
In male myocardial infarction (MI) survivors who were advised to increase their weekly intake of oily fish to 200–400 g (an amount estimated to provide an additional 500–800 mg/day of the long-chain omega-3 fatty acids EPA and DHA), total mortality and deadly (‘fatal’) MI decreased by 29% (114).
In another dietary intervention trial, patients who survived a first MI were randomly assigned to usual care or advised to adopt a Mediterranean diet that was higher in omega-3 fatty acids (especially alpha-linolenic acid, ALA) and lower in omega-6 fatty acids than the standard Western-style diet. After almost four years, those on the Mediterranean diet had a risk of cardiac death and non-fatal MI that was 38% lower than the group that was assigned to usual care (115).
Although higher blood plasma ALA levels were associated with better outcomes, the benefit of the Mediterranean diet cannot be entirely attributed entirely to increased ALA intakes since intakes of monounsaturated fatty acids and fruits and vegetables also increased.
In an intervention trial that compared survival in MI survivors who followed a Mediterranean-style diet or a low-fat diet for an average of 46 months, total mortality and cardiovascular-related mortality did not differ between the two groups (116).
In a large randomized controlled trial of supplemental omega-3 fatty acids, coronary heart disease (CHD) patients who received supplements providing 850 mg/day EPA + DHA for 3.5 years had a risk of sudden death that was 45% lower than those who did not take supplements. Supplement users also experienced a 20% lower risk of death from all causes compared to non-supplement users (117). It took only three months of supplementation to demonstrate a significant decrease in total mortality and four months to demonstrate a significant decrease in sudden death (118).
In another supplementation trial, patients admitted to the hospital with an acute myocardial infarction (MI) were randomized to receive capsules containing fish oil (1.8 g/day EPA + DHA), mustard oil (2.9 g/day ALA) or a placebo (119). After one year, total cardiac events, including non-fatal MI, were significantly lower in the groups that received fish or mustard oil compared to the groups that received a placebo.
The JELIS trial conducted in Japan found that 1800 mg/day of EPA reduced major coronary events during a five-year follow up of subjects with an elevated level of LDL. The benefit was primarily seen in patients with a history of coronary artery disease (282).
In a trial considering post MI subjects, 78% of men aged 60-80 years using a supplemented margarine containing placebo, 400 mg/day DHA plus EPA, 1.9 g/day ALA or 400mg/day of DHA plus EPA and ALA showed no difference in the rate of major cardiovascular events after 40 months of treatment (283). The amount of DHA plus EPA used in this trial was below the recommended amount for secondary prevention.
Another secondary prevention trial (284) used 600 mg/day of DHA plus EPA starting up to 12 months after the event. Unfortunately the study was underpowered and failed to show any benefit after four years of treatment. Delay of intervention may have also played a part in the null finding.
Acute MI patients did not realize any additional benefit from supplementation with 3.5 g/day EPA + DHA compared to corn oil in a region of Norway where fish intakes are relatively high (120).
The results of a meta-analysis that pooled the findings of 11 randomized controlled trials of dietary or supplementary omega-3 fatty acids indicated that increased omega-3 fatty acid intakes significantly decreased overall mortality, mortality due to MI, and sudden cardiac death in patients with CHD (121).
Although a randomized controlled trial in 59 patients with coronary artery atherosclerosis found no benefit after two years of supplementation with fish oil providing 6 g/day EPA + DHA compared to olive oil (122), a larger trial of 223 patients found that supplementation with 3.3 g/day EPA + DHA for three months and 1.65 g/day for an additional 21 months resulted in a modest decrease in the progression of coronary atherosclerosis compared to a placebo (123).
The results of randomized controlled trials in individuals with coronary heart disease (CHD) indicate a beneficial effect of dietary and supplemental omega-3 fatty acids DHA and EPA on progression of disease and mortality. For this reason, various expert panels have recommended using supplemental DHA and EPA in patients with coronary artery disease.
In individuals with diabetes mellitus, cardiovascular diseases are the leading causes of death. High bloodtriglyceride levels (greater than 200 mg/dL) are a common abnormality in individuals with type 2 diabetes.
A review that pooled the results of 18 randomized controlled trials, including more than 800 diabetic patients, found that fish oil supplementation significantly lowered serum triglycerides, especially in those with high blood triglyceride concentrations (124).
A meta-analysis that combined the results of 18 randomized controlled trials in individuals with type 2 diabetes found that fish oil supplementation decreased blood triglycerides by 31 mg/dL compared to the placebo, but had no effect on serum cholesterol, or fasting glucose concentrations (125).
A more recent meta-analysis of randomized controlled trials in type 2 diabetics found that omega-3 fatty acid supplementation lowered serum triglyceride levels by 25% (126).
Although few controlled trials have examined the effect of fish oil supplementation on cardiovascular diseaseoutcomes in diabetics, a prospective study that followed 5,103 women diagnosed with type 2 diabetes who did not have cardiovascular disease or cancer at the start of the study, found that higher fish intakes were associated with significantly decreased risks of coronary heart disease (CHD) over a 16-year follow-up period (128).
Rheumatoid arthritis is a chronic autoimmune disease characterized by inflammation of the lining of joints. Clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and therefore might be useful in the management of inflammatory and autoimmune diseases.
Three meta-analyses of randomized controlled trials of rheumatoid arthritis patients found that fish oil supplementation, at a minimum dose of 2.7 g/day EPA + DHA for at least 12 weeks, significantly decreased the number of painful and/or tender joints on physical examination and improved pain intensity and duration of morning stiffness (125, 131, 132).
Six out of seven studies that examined the effect of long-chain omega-3 fatty acid supplementation on anti-inflammatory drug or corticosteroid use in rheumatoid arthritis patients demonstrated a reduced requirement for anti-inflammatory medication (125).
Inflammatory bowel disease
Inflammatory bowel disease is a group of inflammatory conditions of the digestive tract (colon and ‘small intestine’). The major types are ‘Crohn's disease’ and ‘ulcerative colitis’.
Although two randomized controlled trials of fish oil supplementation in Crohn’s disease patients reported no benefit (133, 134), one randomized controlled trial found that a significantly higher proportion of Crohn’s disease patients supplemented with 2.7 g/day of the omega-3 fatty acids EPA + DHA remained in remission over a 12-month period than those given a placebo (135).
A randomized controlled trial in 38 children (5–16 years of age) with Crohn's disease found that supplementation with omega-3 PUFA (1.2 g/day EPA and 0.6 g/day DHA) in addition to standard therapy significantly reduced the one-year relapse rate (136).
Three randomized controlled trials of EPA + DHA supplementation (4.2–5.4 g/day for 3–12 months) in ulcerative colitis patients reported significant improvement in at least one outcome measure, including weight gain, decreased medication (corticosteroid) use, and improved disease activity scores (137, 138, 139).
In contrast, supplementation of ulcerative colitis patients in remission with 5.1 g/day EPA + DHA did not significantly alter the incidence of relapse over a 2-year period (140).
More research is necessary to determine whether long-chain omega-3 fatty acid supplementation has any therapeutic benefit in ulcerative colitis (141).
Inflammatory eicosanoids (‘leukotrienes’) derived from the long-chain omega-6 fatty acid, arachidonic acid (AA), are thought to play an important role as chemical messengers in the pathology of asthma, a chronic disorder of the airways characterized by airflow obstruction (8).
Although there is some evidence that omega-3 fatty acid supplementation can decrease the production of inflammatory mediators in asthmatic patients (142, 143), evidence that omega-3 fatty acid supplementation decreases the clinical severity of asthma in controlled trials has been inconsistent (144).
Three reviews of randomized controlled trials of long-chain omega-3 fatty acid supplementation in asthmatic adults and children found no consistent effects on clinical outcome measures, including pulmonary function tests, asthmatic symptoms, or medication use (145, 146, 147).
Regular supplementation with omega-3 supplements may have some benefit for patients with cystic fibrosis and may be burdened with relatively few side effects. According to a review by the Cochrane Collaboration, there are, however, not sufficient study results to draw any firm conclusions or to recommend a routine use of omega-3 fatty acid supplements (286). The authors note that a comprehensive, long-term, multicenter and randomized controlled trial is needed to determine whether a therapeutic effect is present and to assess the influence of the severity of the disease, the dosage and duration of treatment.
Immunoglobulin A nephropathy
Immunoglobulin A (IgA) nephropathy is a kidney disorder that results from the deposition of the antibody IgA in the filtering units (‘glomeruli’) of the kidney. Progressive kidney (‘renal’) failure may eventually develop in 15–40% of patients (148). Since IgA deposition results in increased production of inflammatory mediators, omega-3 fatty acid supplementation could potentially modulate the inflammatory response and preserve renal function.
In a randomized controlled trial, supplementing IgA nephropathy patients with fish oil (1.8 g/day EPA + 1.2 g/day DHA) for two years significantly slowed declines in renal function (149). These results were sustained over an average of six years of follow-up (150), but additional improvements were not observed with higher doses of fish oil (151).
In contrast, several studies have failed to find a significant benefit of omega-3 PUFA supplementation in IgA nephropathy patients (152, 153, 154, 155). Two meta-analyses of randomized controlled trials of fish oil supplementation did not find evidence of a statistically significant benefit in IgA nephropathy patients overall (156, 157).
Due to the inconsistent results of available randomized controlled trials, it is not clear whether fish oil supplementation will prevent the progression of IgA nephropathy in children or adults (125).
Omega-3 fatty acids are important components of nerve cell membranes. They help nerve cells communicate with each other: an essential step in maintaining good mental health. In particular, the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is involved in a variety of nerve cell processes, such as the modulation of signal transduction molecules and G-protein coupled receptors (287), synaptogenesis (288, 289), neuronal differentiation(290), and generation of active metabolites such as docosanoids (291).
Major depression and bipolar disorder
Data from ecological studies across different countries suggest an association between high seafood consumption and low national rates of major depression (158) and manic-depressive alterations in mood (‘bipolar disorder’)(159).
Several small studies have found omega-3 fatty acid concentrations to be lower in the blood (160, 161, 162) and fat (‘adipose’) tissue (163) of individuals suffering from depression compared to controls. Although it is not known how omega-3 fatty acid intake affects the incidence of depression, the modulation of neuronal signaling pathways and the production of chemical messengers (‘eicosanoids’), derived from polyunsaturated fatty acids, have been proposed as possible mechanisms (164).
The results of randomized controlled trials of supplementation with long-chain omega-3 fatty acids on depression have been mixed.
Adding fish oil supplements (8 g/day) to existing therapy in people who were being treated for depression was not significantly more effective than adding the same amount of olive oil for 12 weeks (165). In patients with diagnosed major depression, and in mild to moderately depressed individuals, fish oil supplementation for four months did not provide any therapeutic benefit beyond that associated with standard therapy (166, 167, 168).
However, a small randomized controlled trial in Chinese patients diagnosed with major depression found that supplementation with 6.6 g/day eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) for eight weeks improved depression compared to placebo (169).
Additionally, a small, randomized, double-blind, placebo-controlled trial demonstrated a trend of improvement of depressive symptoms (p<0.12) with 1g/day of EPA when administered over eight weeks to those with major depression (292).
Another small randomized controlled trial in 30 women diagnosed with borderline personality disorder found that the 20 women randomized to treatment with 1 g/day EPA for eight weeks experienced less severe depressive symptoms than the ten women randomized to treatment with a placebo (170).
A recent open-label trial of women with major depression and undergoing menopausal transition found a significant response rate (70%) and remission rate (45%) with 2 g/day DHA+EPA over eight weeks of treatment(293). However, a trial with 800 mg/day of DHA-enriched fish oil given during pregnancy did not provide benefit for women with post-partum depression (294). Another randomized, double-blind, placebo-controlled trial in elderly women with depression (295) found significant improvements in depressive symptoms and quality of life when administered 2.5 g/day DHA+EPA over eight weeks.
Additionally, results of a study suggest that omega-3 fatty acid supplementation may be useful in treating children with major depression (171).
A randomized controlled trial that assessed the effects of high doses of EPA (6.2 g/day) + DHA (3.4 g/day) in patients with bipolar disorder (‘manic-depressive illness’) found that those supplemented with EPA + DHA had a significantly longer period of remission than those on an olive oil placebo over a four-month period (172). Patients who took the EPA + DHA supplements also experienced less depression than those who took the placebo.
However, one study found that patients who took 6 g/day EPA for four months did not experience any relief from bipolar depression (173).
Lower doses of EPA may be more efficacious in treating bipolar disorder. One small study found that patients taking 1.5 g/day or 2 g/day EPA for six months had some relief of depression associated with bipolar disorder (174). A 12-week, double-blind, placebo-controlled trial of individuals with bipolar depression found those who took either 1 g/day or 2 g/day EPA experienced significant improvements in depressive symptoms, but measures of mania were not significantly different in either group compared to the placebo group (175).
Some meta-analyses of randomized controlled trials have concluded that omega-3 polyunsaturated fatty acid supplementation is beneficial in treating major depression and bipolar depressive disorders (176, 177). However, a Cochrane review (296) cited only one study that demonstrated a benefit from n-3 PUFAs in bipolar depression. A more recent meta-analysis concluded that that there was a significant benefit of n-3 PUFA supplementation in individuals with diagnosed depressive illness (178).
Large, long-term randomized controlled trials are required to determine the efficacy of long-chain omega-3 fatty acid supplementation on major depression and bipolar disorder.
Findings of decreased omega-3 fatty acid levels in the red blood cells (179, 180) and brains (181) of a limited number of schizophrenic patients, together with the results of uncontrolled supplementation studies (182), have created interest in the use of long-chain omega-3 fatty acid supplements as an additional treatment to conventional antipsychotic therapy regimens for schizophrenia.
Results of randomized controlled trials using the omega-3 fatty acid eicosapentaenoic acid (EPA) as an adjunct to standard antipsychotic therapy in schizophrenic patients have been somewhat contradictory. In one trial, the addition of 3 g/day EPA to standard antipsychotic treatment for 12 weeks improved schizophrenic symptoms and reduced impaired control of voluntary movement ('dyskinesia') (183), while a similar 12-week trial found that 2 g/day EPA did not benefit schizophrenic patients with tardive dyskinesia (184). In another trial, supplementation with 3 g/day EPA for 16 weeks was not different from the placebo in improving residual symptoms, mood, or cognition (185).
A recent randomized, double-blind, placebo controlled trial of adolescents and young adults (13-25 years old) with sub-threshold psychosis demonstrated significant decreases in the rate of progression to first-episode psychotic disorder when they were given 1.2 g/day of omega-3 PUFA over a 12-week period followed by a 40-week monitoring period (297). The omega-3 supplemented group also significantly reduced positive symptoms (p = .01), negative symptoms (p = .02), general symptoms (p = .01), and improved functioning (p = .002) compared with placebo. These results suggested a potential prevention strategy of using omega-3 PUFAs in young adults at risk of first-episode psychosis.
Although limited evidence suggests that EPA supplementation may be a useful additional treatment to antipsychotic therapy in schizophrenic patients, larger long-term studies addressing clinically relevant outcomes are needed (186).
Attention deficit/hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD)
Children with attention deficit/hyperactivity disorder (ADHD) may have low levels of certain essential fatty acids (including EPA and DHA) in their bodies (187). In a clinical study of nearly 100 boys, the boys with lower levels of omega-3 fatty acids demonstrated more learning and behavioral problems (such as temper tantrums and sleep disturbances) than boys with normal omega-3 fatty acid levels (188).
One clinical study used omega-3 and omega-6 fatty acid supplementation in 117 children with ADHD. The study found significant improvements in reading, spelling, and behavior in the children over the three months of therapy (189). Another clinical study found that omega-3 fatty acid supplementation helped to decrease physical aggression in school-aged girls with ADHD, but not school-aged boys (190).
A recent systematic review of fatty acid supplementation in ADHD concluded that despite success noted in open-label trials, results from randomized controlled trials did not demonstrate a similar benefit (299).
A recent systematic review evaluated the efficacy and safety of omega-3 fatty acids for treating autistic spectrum disorder (ASD) (300). The investigators noted that there were only limited data from uncontrolled studies and from only one randomized controlled trial. As a consequence, it was not possible to determine whether omega-3 fatty acids were safe and effective for ASD.
In a recent crossover study of children with ADHD, a sub-group of those with inattentiveness and neurodevelopment disorders responded with a 25% reduction of ADHD symptoms and improved functional impairment scores after three months of blinded omega-3 (558 mg EPA+ 174 mg DHA) supplementation; and 47% of the children receiving omega-3s after six months showed a reduction in symptoms of ADHD (301).
By contrast, a study of short-chain fatty acid (480 mg of linoleic acid and 120 mg of alpha-linolenic acid) supplementation for seven weeks showed no difference from the placebo in children with ADHD (299). However, EPA supplementation alone (0.5 g/day) was also recently shown to improve ADHD symptoms in sub-groups of oppositional and less hyperactive children (302).
Clinical studies suggest that men and women with the eating disorder ‘anorexia nervosa’ have lower than optimal levels of polyunsaturated fatty acids (including ALA and GLA) (191).
To prevent the complications associated with essential fatty acid deficiencies, some experts recommend that treatment programs for anorexia nervosa include PUFA-rich foods such as fish and organ meats, which include omega-6 fatty acids.
Studies suggest that long-chain omega-3 fatty acid eicosapentaenoic acid (EPA) may help increase calcium levels in the body, deposit calcium in the bones, and improve bone strength.
Studies also suggest that people who are deficient in certain essential fatty acids (particularly EPA and long-chain omega-6 fatty acid gamma-linolenic acid, GLA) are more likely to suffer from bone loss than those with normal levels (193).
In a study of women over 65 with osteoporosis, those given EPA and GLA supplements experienced significantly less bone loss over a three year period than those who were given a placebo (194). Many of these women also experienced an increase in bone density during that time.
Positive correlations between dietary intake of AA and ALA and reduced hip fracture rate in older men have also been recently reported. Benefits from PUFA intake related to bone health may vary depending upon age and gender.
Clinical studies suggest that overweight people who follow a weight loss program that includes exercise tend to achieve better control over their blood sugar and cholesterol levels when fish rich in omega-3 fatty acids (such as salmon, mackerel, and herring) is a staple in their low-fat diet (195).
While further research is needed, preliminary evidence suggests that omega-3 fatty acids may also prove helpful in protecting against some infections and treating a variety of additional conditions including burns (196), emphysema, glaucoma, menstrual pain (197), migraine headaches, multiple sclerosis (198), lupus, Lyme disease, panic attacks, preeclampsia, preterm delivery (199), psoriasis (200), stress, and ulcers (201).
Regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although the evidence is insufficient to draw firm conclusions or to recommend routine use of supplements of omega-3 fatty acids, according to a review by the Cochrane Collaboration (286). The authors note that a large, long-term, multicenter, randomized controlled study is needed in order to determine if there is a significant therapeutic effect and to assess the influence of disease severity, dosage, and duration of treatment.