Researchers at London’s Heart and Lung Institute reached the same conclusion: supplementation with folic acid and vitamin B12 improves vascular endothelial function in patients with coronary heart disease.16 Interestingly, the latest findings from Wales College of Medicine in London show conclusively that lowering homocysteine by methods other than high-dose folic acid—whether using trimethylglycine (TMG), a nutrient used to remove extra homocysteine from the body, or low-dose folic acid—does not improve endothelial function.17

This raises an obvious question: is supplementing with high-dose folic acid (5000 mcg daily) safe? In an exclusive interview with Life Extension, Malcolm J. Lewis, MD, professor of cardiovascular pharmacology and deputy head of the Department of Pharmacology, Therapeutics and Toxicology at Cardiff University, discussed the results of the most recent folic acid trials. Dr. Lewis leads one of the world’s premier team of scientists in investigating the role of this B vitamin and its relationship to cardiovascular disease.

Dr. Lewis confirmed the safety and effectiveness of high-dose folic acid, saying that findings reported at the May 2004 meeting of the British Cardiac Society “clearly demonstrated that although both 400 mcg and [5000 mcg] of folic acid can lower homocysteine levels to the same extent in patients with coronary disease, only the [5000- mcg daily dose] was effective at improving endothelial function (an excellent surrogate for cardiovascular health). None of the subjects in any of our studies has had adverse effects from taking [5000 mcg] of folic acid. Provided vitamin B12 deficiency has been excluded, this dose would seem safe to use.”18

Dr. Lewis added, “It is obvious, therefore, that ‘high’ doses of folate have pharmacological effects which are different from more conventionally used ‘low’ doses. We are currently investigating why this may be the case.”18

Some new studies speculate that folic acid’s ability to reverse endothelial dysfunction is independent of its ability to lower plasma homocysteine levels. Lewis and his team recently reported that reversing endothelial dysfunction with folic acid shows that this B vitamin has myriad effects on the vasculature besides lowering homocysteine. In-vitro evidence demonstrates that 5-methytetrahydrofolate, the main circulating metabolite of folic acid, can increase nitric oxide production and directly scavenge superoxide radicals. These properties may account for some of its cardioprotective effects.19

Folic Acid and Neuropsychiatric Disease

Researchers now believe that major depressive disorders and cardiovascular disease are mutually associated, sharing signs and symptoms of metabolic syndrome, usually caused by being overweight or obese, lack of physical exercise, and genetic factors (see “Heart and Mind: The Dangerous Link Between Heart Disease and Depression,” Life Extension, January 2005). Scientists in the Netherlands recently observed that in both major depressive disorders and cardiovascular disease, omega-3 polyunsaturated fatty acids are diminished while plasma homocysteine levels are elevated.20 While most folic acid studies have focused on heart health, some recent findings suggest that folic acid either has antidepressant properties or can act as an augmenting mediator for standard antidepressant treatment.

Although the link between folate deficiency and neuropsychiatric disorders is not well understood, several subjective cases have established an intriguing relationship. Dr. Victor Herbert, the late hematologist and nutritional scientist, experimented on himself 40 years ago to better understand folate deficiency, eating foods thrice boiled to extract folate.21 In the state of induced folate deficiency from diet restriction, Herbert noted that central nervous system effects, including irritability, poor memory, and increasing sleeplessness, appeared within four to five months. Interestingly, Herbert reported that all central nervous system symptoms disappeared within 48 hours after taking oral folate.22 (Victor Herbert, MD, died in 2002 at the age of 75. According to his family, the cause of death was melanocytoma, “a rare form of neurological cancer.”23)

How Does It Work?

In the body, folate is crucial to the production of S-adenosyl-L-methionine (SAMe), the methyl-group donor involved in the biosynthesis of DNA, RNA, phospholipids, proteins, and other molecules. SAMe is also involved in the synthesis of catecholamine neurotransmitters, such as epi-nephrine, that appear to play a role in determining mood.24 Depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency. Borderline low or deficient serum or red blood cell folate levels are seen in 15-38% of adults diagnosed with depressive disorders.25 Doctors now believe that patients with low plasma folate levels do not respond to antidepressant treatment as well as those with adequate folate levels.25 Consequently, folate is believed to play an important role in regulating mood.

According to a report published in 2003, some people with depression appear to have problems metabolizing folate. This is consistent with the idea that folic acid supplements might help reverse or even prevent depression. In this study of 5,948 people aged 46 to 49, Norwegian scientists found that people with high blood levels of homocysteine were almost twice as likely to be depressed as those with normal levels.26

Scientists from Finland have continued to unravel the connection between folate and depression. Analyzing the diets of 2,682 men aged 42 to 60, they found that men with the lowest dietary folate intake had a 67% greater risk of having elevated depressive symptoms than those with the highest intake. The authors concluded that nutrition may play an important role in mental health and in preventing depression.27

Folic Acid and Antidepressants

In a study of patients previously unresponsive to selective serotonin re-uptake inhibitors (SSRIs), folic acid boosted the response rate, even in those who had normal folate levels at the trial’s onset.28 Emerging evidence from randomized trials shows that the combination of folate and conventional antidepressant treatments may improve outcomes.29 In a study published last year, Harvard researchers noted that depressed people with low serum folate levels had poorer responses to antidepressant therapy.30 Evidence suggests that elderly depressed patients have lower levels of folate than their non-depressed cohorts. Supplementing with folate may thus reduce the incidence of depression in the elderly.31

The Alzheimer’s Connection

A study published in the New England Journal of Medicine in 2002 reported that people with high blood levels of homocysteine (greater than 14 mmol/L) have twice the normal risk of developing Alzheimer’s disease.32 Alzheimer’s destroys brain cells and the important neurotransmitter acetylcholine, the chemical messenger responsible for memory and other cognitive skills. High homocysteine levels have also been associated with impairment in verbal memory, fine motor skills, and cognition,33 as well as with stroke.34

Low folate levels are associated with increased levels of homocysteine. With research still in the early stages, scientists theorize that high homocysteine levels may cause brain injury and neuropsychiatric disorders. Increased intake of folic acid and other B vitamins may help to prevent cognitive impairment, dementia, and Alzheimer’s disease in people with elevated homocysteine levels.

Conclusion

High-dose folic acid—up to 5000 mcg daily—is a scientifically substantiated and safe nutritional approach to achieving optimal health in men and women who want to prevent or reverse chronic illness. With demonstrated benefits in reducing cardiovascular risk factors, preventing and enhancing treatment outcomes in depression, and preventing cancer, folic acid is highly indicated as a therapeutic ally for men and women of all ages. The US recommended dietary allowance (RDA) of 400 mcg of folic acid, established by the National Academy of Sciences and National Research Council, is the minimal amount necessary to prevent gross deficiency syndromes. This nominal level is not at all adequate for preventing chronic disease.

Much remains unknown about chronic and degenerative ailments such as cardiovascular disease and neuropsychiatric disorders. Ground-breaking findings continue to be published. Only in the past decade have scientists begun to unravel how nutrients help the human body prevent, manage, and treat disease. Inexpensive and readily available to most people, high-dose folic acid has the potential to positively influence the health of people throughout the world.