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Preventing Heart Disease and Depression with High-Dose Folic Acid

March 2005

By Debra Fulghum Bruce, PhD

While modern medicine has succeeded in developing powerful drugs to treat serious diseases, the myriad side effects of these treatments have provoked a renewed interest in preventive medicine. Growing evidence suggests that nutritional therapies can help prevent and manage many lethal diseases, and that their application may lessen the need for more invasive, risky medical interventions.

Folic acid was long ago demonstrated to exert a protective effect against cardiovascular diseases, some forms of cancer, and various neurological impairments. Scientists are now looking at what dose of folic acid might produce optimal effects. Findings from new studies are quite surprising. It turns out that some people may benefit from folic acid doses far exceeding what is found in today's dietary supplements.

Why We Need Folate

Folate is necessary for cell replication and growth, as well as the synthesis of DNA and RNA, the cell’s genetic blueprints. Folate helps prevent alterations to DNA that can lead to cancer.1 Both adults and children require folate to build normal red blood cells and prevent one type of anemia.2

Folic acid, also referred to as folate or vitamin B9, has been the subject of growing scientific interest in the past decade. Although not yet widely recognized by the medical community, folic acid may be an important addition to the disease-prevention arsenal, particularly against cardiovascular disease, neuropsychiatric disorders, and certain cancers.

Folic Acid and Cardiovascular Disease

Cardiovascular disease, the number-one killer of men and women, claims the lives of almost 40% of the more than 2.4 million Americans who die each year. Today, about 64 million Americans have some form of cardiovascular disease.3

Homocysteine, a nonessential, sulfur-containing amino acid, is an independent marker of risk for the development of cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease (fatty deposits in the peripheral arteries).4 Some researchers consider homocysteine as important a cardiovascular risk factor as low-density lipoprotein (LDL). Homocysteine can make blood clot more easily than normal, increasing the risk of both heart attack and death by heart attack. Inadequate levels of folic acid and vitamins B6 and B12 can lead to increased homocysteine levels.

Studies show that elevated levels of homocysteine may cause endothelial dysfunction of the arteries, an early step in the development of atherosclerosis, the underlying cause of most heart attacks.5 The endothelium is the inner layer of cells lining the arteries, and maintaining its integrity is crucial to preventing atherosclerosis. Aging, poor health habits, and biochemical stressors such as elevated homocysteine can weaken the endothelial barrier, allowing blood cells and toxic substances to infiltrate and enter the subendothelial compartment. Lipids such as LDL and triglycerides can accumulate in this area and oxidize. In an attempt to repair the area, smooth muscle cells infiltrate the site, causing an atherosclerotic lesion to form. As this process continues, atherosclerosis progresses, and chronic inflammation takes root in the area. As the body attempts to repair the injured site, calcium accumulation, or hardening of the arteries, can also occur.

Photomicrograph of folic acid, essential in the formation of red blood cells. A deficit of folic acid in the diet during the first two weeks of pregnancy causes birth defects such as spina bifida (incomplete development of the vertebral column).

In addition to atherosclerosis and thrombosis, endothelial dysfunction and impaired vascular reactivity—possibly representing early large vessel disease—are present in a variety of conditions such as hypertension, diabetes, hyper-cholesterolemia, heart failure, cigarette smoking, hyper-homocysteinemia, and aging.5 Infection and the resulting inflammatory response can produce endothelial dysfunction,6 as can a brief period of mental stress in healthy young adults with no evidence of vascular disease or risk factors for cardiovascular disease.7

In recent years, elevated homocysteine has emerged as an independent risk factor for heart disease.8 Overwhelming evidence suggests that folate and homocysteine metabolism are closely linked, and that folic acid supplementation lowers plasma total homocysteine substantially.9 Some new findings indicate that lowering homocysteine may improve endothelial function and thus dramatically reduce the risk of cardiovascular disease and heart attack.

The Importance of Supplementing

Undoubtedly, eating folate-rich green leafy vegetables, citrus, nuts, seeds, and meat will boost the body’s levels of this B vitamin. However, according to the Institute of Medicine, the body absorbs only about 50% of the folate in food, while absorbing approximately 100% of the folic acid in vitamin supplements.10


Supplementing with folic acid offers a wealth of benefits. Among other things, folic acid:

• can decrease homocysteinemia, a major risk factor for cardiovascular and other chronic diseases
• can improve endothelial function
• may contribute to the prevention of peripheral artery disease
• may improve lipid profile
• may reverse depression
• can boost the effectiveness of antidepressant therapy
• may help prevent dementia and other neuropsychiatric disorders
• prevents neural tube defects
• appears to reduce the risk of some cancers, such as colon, cervical, and breast cancer
• is safe and inexpensive.

Convinced that folate was crucial in preventing neural tube defects, the Food and Drug Administration in 1998 mandated that manufacturers fortify all cereal grains with folic acid, specifically with a concentration of 140 mcg of folic acid per 100 grams of cereal grain products. This amount provides the average woman with an extra 100 mcg per day of folic acid. While neural tube defects in the US declined significantly after these products were fortified with folic acid, a statistical decline in stroke and ischemic heart disease deaths was also recorded, according to data presented in March 2004 at the American Heart Association’s 44th annual Conference on Cardiovascular Disease Epidemiology and Prevention.11

High-Dose Folic Acid and the Heart

Around the beginning of the new millennium, Australian researchers speculated that if low-dose folic acid (200 mcg daily) has some therapeutic influence, then higher doses might be even more effective. Investigators from the Institute for International Health at the University of Sydney followed the rationale that lowering homocysteine with folic acid may in turn help reduce the risk of recurrent coronary heart disease. In the PACIFIC Study Group, a trial involving 723 subjects with a history of unstable angina or myocardial infarction, daily doses of both 200 mcg and 2000 mcg of folic acid reduced homocysteine, but the outcome of the higher dose was about one third greater than the lower dose.12

Taking the healing potential of folic acid to a new level, investigators at Wales Heart Research Institute in London found that high-dose folic acid (5000 mcg daily) lowered plasma homocysteine by 25% in clinical trials, while improving the bioavailability of nitric oxide.13 Nitric oxide is the primary mediator of endothelial function, capable of dilating blood vessels and inhibiting platelet aggregation.

It is common sense that quitting smoking, avoiding saturated and trans fats, and exercising regularly may reduce the risk of cardiovascular disease. For many people, however, these lifestyle changes are not easily attainable. Scientists thus search for any approach that might prevent early endothelial dysfunction and subsequent cardiovascular disease before too much damage occurs.

With this in mind, a team of investigators in Ireland used high-dose folic acid (5000 mcg daily) for four weeks to determine whether supplementation influenced endothelial function in otherwise healthy young cigarette smokers. While measured homocysteine levels stayed about the same in the smokers and the control group, the researchers reported that folic acid supplementation significantly improved endothelial function in healthy young smokers.14

About the same time, re-searchers in the Netherlands examined the effects of folic acid and vitamin B12 in patients with high homocysteine levels and coronary artery disease. Their findings showed that coronary endothelial function improved after just six months of treatment with high-dose folic acid (5000 mcg daily) and vitamin B12 (400 mcg daily).15