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Heart and Mind

January 2005

By William Davis, MD, FACC

The Omega-3 Connection

Fish oil, containing abundant quantities of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), is a dual-action supplement with compelling data to support its use for both depression and heart disease. Some have called omega-3 fatty acids the “missing link” between the two disorders.

The human brain contains an extraordinarily high concentration of omega-3 fatty acids. This simple fact has prompted extensive investigation of the role of essential fats in various brain functions and diseases. A deficiency of omega-3 fatty acids has been associated with conditions as diverse as hostility, cognitive decline with aging, and attention-deficit/hyperactivity disorder.24 Several studies have demonstrated that people suffering from major depression are measurably deficient in omega-3 fatty acids.25-27 Not surprisingly, these and other studies have highlighted the failure of conventional antidepressant medication to correct the omega-3 deficiency.28 From an epidemiological viewpoint, cultures marked by abundant fish consumption and omega-3 intake, such as Eskimos and some of the coastal natives of Japan and Canada, are far less likely to suffer from depression than Americans. Conversely, cultures consuming less fish than Americans, such as New Zealanders, suffer substantially higher rates of depression.29-31

An ultra low-fat diet (with less than 20% of calories derived from fat) may be contraindicated in individuals who suffer both heart disease and depression. Although low-fat diets have demonstrated benefits for some people with heart disease, such diets tend to be seriously deficient in omega-3 fatty acids. Some authorities have proposed that low-fat diets may even contribute to depression because of their low omega-3 content. All too often, low-fat diets are high in carbohydrates. For the 47 million Americans estimated to have metabolic syndrome, a high-carbohydrate diet may magnify heart disease risk.32 It can also result in most fat intake coming from omega-6 fatty acids, compounds that increase thromboxane A2, a pro-inflammatory and vessel-constrictive agent that contributes to heart disease and may promote the depressive syndrome.


Fish oil comes in various forms and dosages. Here is some guidance in the tricky business of determining how much you should take.
Most fish oil capsules contain 300 mg of total omega-3 fatty acids in each 1000-mg capsule. This is called a 30% preparation. A common proportion is 180 mg of EPA and 120 mg of DHA, for a total of 300 mg in each 1000-mg capsule.

The lipid benefits, including a substantial reduction of triglycerides and fibrinogen that is largely responsible for reducing the risk of heart attack, begin to be measurable when 1200 mg per day of total omega-3 fatty acids (EPA + DHA) are taken. You can obtain a dose of 1200 mg of the omega-3 fatty acids by taking 4000 mg of fish oil, or four capsules (4 x 300 mg = 1200 mg).

The dose of fish oil that seems to translate into benefits for mood may be somewhat higher, generally a minimum of 1500 mg of the EPA component.15 This dose would require eight capsules per day of the most common 30% preparation. For this reason, a more concentrated preparation might be more convenient; for example, taking four capsules per day of the new Super EPA/DHA with sesame lignans would achieve these kinds of dosing levels.

Avoid cod liver oil, as it is too diluted a preparation and contains undesirable ingredients such as saturated fats. You and your doctor may decide to use a higher dose of fish oil as you assess your results. Doses of 6000–10,000 mg per day have been used when triglycerides are above 400 mg/dL or VLDL is severely elevated. Even higher doses have been used in clinical trials of depression and bipolar illness without ill effects.

If you suffer an unpleasant aftertaste after consuming fish oil capsules, try refrigerating the capsules, as this usually eliminates that effect. Fish oil is also best taken with meals to minimize the occasional stomach upset some people experience.

When fish oil is given to people suffering from depression, mood is substantially improved. A small, placebo-controlled trial conducted by Lauren Marangell, MD, chief of psychopharmacology at the Baylor College of Medicine, demonstrated improved mood in depressed persons following six weeks of treatment with 2 grams per day of DHA in a trial of 36 patients.33 A similar study at the Taiwan Medical University in China compared higher doses of fish oil (9.6 grams per day) with placebo in 28 patients with major depression. Substantial improvement in mood using a standardized rating assessment was experienced only in the group receiving fish oil.34 In another study, Andrew Stoll, MD, of Harvard examined 30 patients suffering from difficult-to-treat bipolar disorder (manic depression). Daily consumption of 6.2 grams of EPA and 3.4 grams of DHA resulted in objective improvement in depression scores and longer periods of remission between relapses.35

Perhaps the most persuasive clinical evidence documenting the mood benefits of omega-3s was seen in people who already take conventional antidepressant medication. An Israeli study of 20 patients with major depression who were receiving maintenance antidepressant pharmaceutical therapy showed that mood markedly improved after only three weeks of EPA supplementation when compared to placebo.36 Dr. Malcolm Peet, head of the Omega-3 Mental Health Research Group at the University of Sheffield (England), reported a study of 70 patients on conventional antidepressant therapy. In this trial, dramatic improvement in measures of depression was seen when 1 gram of EPA per day was added to the treatment regimen. Curiously, doses of 2 and 4 grams did not show statistically significant benefits.37

Likewise, solid data demonstrate the benefits of omega-3 fatty acids in reducing risk for cardiovascular disease. The Italian GISSI Prevenzione Trial of more than 11,000 participants neatly showed that 850-882 mg of EPA and DHA resulted in a 30% reduction in death from cardiovascular disease and a 45% reduction in sudden cardiac death. These numbers equal or exceed the magnitude of benefits claimed by the cholesterol-reducing statin agents. The large number of participants in the GISSI study makes these observations virtually unassailable. Another study of 360 patients with symptoms of heart attack showed that patients given 1008 mg a day of EPA and 720 mg a day of DHA suffered 48% fewer cardiac deaths and 76% fewer sudden cardiac deaths, as well as a 54% reduction in dangerous heart rhythms.38

Fish oil likely achieves these benefits through a broad spectrum of mechanisms, including increased cell membrane fluidity (affecting signal transduction), suppression of abnormal heart rhythm-generating activity, and marked reductions of triglycerides and the very low-density fraction of lipoproteins that can lead to the formation of dangerous “small” LDL particles and a drop in beneficial HDL. Fish oil also reduces the blood-clotting protein fibrinogen and inhibits platelet aggregation, both of which can prevent blood-clot formation on active, ruptured coronary plaque that can contribute to a heart attack.

In the US, prevention of heart disease is an area of huge neglect. Treatment of major depression is likewise an imperfect practice, with less-than-optimal responses to antidepressant medication being an everyday phenomenon. Omega-3 fatty acids may indeed be a missing link that provides substantial benefits in both areas with virtually no downside. While the concomitant treatment of heart disease and depression with fish oil has never been formally examined in a clinical trial, it remains a compelling topic worthy of further examination.

Fish oil is the most concentrated source of the omega-3 fatty acids EPA and DHA. A secondary source is alpha-linolenic acid (ALA), which is found in flaxseed, walnuts, and canola oil. However, only 10% of ALA ingested from food is converted into active EPA or DHA; much of it is simply burned for calories. Fish oil thus remains the most potent source of omega-3 fatty acids.

Benefits of Folic Acid and SAMe

Depressed, hostile, or angry people have higher homocysteine levels. If homocysteine leads to coronary plaque growth and heart attack, will folic acid and B vitamins that lower homocysteine improve mood and reduce heart attack?

The data strongly suggest that folic acid supplementation elevates mood, both in people already taking antidepressant medication and in those who are not. Indeed, five clinical trials, though all relatively small (each with fewer than 100 patients), have consistently demonstrated improvements in depression measures when patients are given various doses of folic acid.39 For instance, in a 1993 study of 96 patients at the University of Parma, Italy, folic acid supplementation yielded improvements in mood similar to those of conventional antidepressants.22 Another study by Drs. Alec Coppen and John Bailey in Surrey, England, showed that response to prescription fluoxetine (Prozac®) was substantially improved by taking as little as 500 mcg of folic acid a day.21

Though few psychiatrists have added folic acid to their arsenal of antidepressant therapeutics, the data suggest that this simple, inexpensive treatment should be a part of every depressed person’s panel of therapies. Doses of only 1-5 mg would be required, generally along with 25-50 mg of vitamin B6. Vitamin B12 should always be taken with folic acid to help guard against a hidden B12 deficiency.

The growing experience with folic acid treatment in people at risk for cardiovascular disease includes three clinical trials suggesting that folic acid reduces the growth of plaque in the carotid arteries (a surrogate for coronary plaque growth) and reduces the likelihood of future heart attack. The Canadian group at the Stroke Prevention and Atherosclerosis Research Centre in Ontario reported an investigation in 101 patients showing that a homocysteine level greater than 14 µmol/L identified a group that showed much more rapid growth of carotid plaque. Daily treatment with 2.5 mg of folic acid, 25 mg of vitamin B6, and 250 mcg of vitamin B12 eliminated plaque growth. The Dutch group at Vrije Universiteit in Amsterdam has reported extensively on treating high homocysteine levels using folic acid and vitamin B6 in patients with peripheral arterial disease (usually of the leg arteries), demonstrating reduction of heart attack, slowed growth of carotid and leg artery plaque, and diminished likelihood of death.40-42

Folic acid supplementation increases levels of the homocysteine metabolite s-adenosyl-L-methionine, or SAMe. Some have speculated that the mood-elevating properties of folic acid may be at least partly due to an increase in endogenous SAMe, since SAMe has been shown in numerous studies to be an effective antidepressant supplement. Since 1973, over 40 clinical trials have demonstrated the effectiveness of SAMe in elevating mood in the depressed, including a total of 537 patients in 13 randomized, double-blind studies. In 18 trials pitting SAMe head to head against the conventional antidepressants imipramine, chlorimipramine, and others, SAMe proved equally effective, and it is essentially without side effects.43,44

SAMe has been available in the US as an over-the-counter supplement since 1997, though it has been available over the counter or by prescription in Europe for over 20 years. SAMe at a dose of 400 mg per day yields blood levels in the range believed to induce antidepressant benefits, though some clinicians have noted that doses up to 1600 mg daily are required for some individuals.44 It is interesting to speculate that the combination of folic acid and SAMe might yield even greater benefits and more powerfully improve mood and many of the downstream phenomena leading to coronary disease risk. This remains an area for further research.

Folic acid supplementation, therefore, likely improves mood while lowering homocysteine and thus the risk of heart attack. Along with fish oil and omega-3 fatty acids, folic acid represents another intriguing “missing link” between two disparate diseases with an exciting potential for common treatments.

Depression and Metabolic Syndrome

As the US population gets heavier and heavier, metabolic syndrome becomes increasingly more prevalent. One in every four American adults suffers from this common condition, which represents a combination of lifestyle and genetic factors.10 Because depressed people are more likely to develop metabolic syndrome, this disorder is another important mediator of the interplay between mood and heart disease.

Most of us have seen someone who, when struck with depression or impaired by other chronic negative emotions, burrows into a lifestyle of physical inactivity and overeating. The resulting weight gain activates all the latent characteristics of the tragically common metabolic syndrome (increased abdominal fat, hypertension, low HDL, resistance to insulin—dubbed “the deadly quartet” by Dr. Norman Kaplan in 1989). This familiar sequence can greatly magnify risk for heart disease.45

But can the reverse occur? Can a person become overweight through neglect or indulgence, develop metabolic syndrome, then trigger depression and the cascade of events leading to heart disease? If this flip-flop in the sequence of events were true, then efforts aiming squarely at managing weight and metabolic syndrome should be among our principal health concerns.

A fascinating study conducted by Drs. Katri Raikkonen of the University of Helsinki (Finland) and Lewis Kuller of the University of Pittsburgh attempted to untangle this question. Psychological and metabolic measures were obtained in 425 middle-aged females. Seven and a half years later, these same measures were repeated. Raikkonen and Kuller reported that women with emotional characteristics of anger, depression, and anxiety at initial enrollment were more likely to develop metabolic syndrome. Even more interestingly, women without these psychological traits but with metabolic syndrome at the start were more likely to develop anger, anxiety, and depression by the end of the study. In other words, in this second group, abdominal fat, high blood pressure, low HDL, and insulin resistance—all the features of metabolic syndrome—predicted a future of negative emotions.46 By either route, the result is a person with the physiological stage set for development of heart disease.