Folic acid supplement 400 mcg, food source, deficiency, health benefit for homocysteine, spina bifida, dosage
January 17 2017 by Ray Sahelian, M.D.


Folic acid generally functions in cooperation with vitamin B12 in many metabolic reactions, including the making of DNA. Itd helps reduce levels of homocysteine and functions as a methyl donor. Folic acid is found in almost all foods and the recommended daily intake is about 400 micrograms or 0.4 mg. A shortage of folic acid can lead to anemia, where not enough red blood cells are made. Folic acid is a synthetic compound of folate, and, for practical purposes the terms are often used interchangeably. Basically, folate is the form found in foods, and folic acid is the form available as a supplement.


FDA allows these two qualified health claims
A. Healthful diets with adequate folic acid may reduce a woman's risk of having a child with a brain or spinal cord defect. The Institute of Medicine of the National Academy of Sciences recommends that women capable of becoming pregnant consume 400 micrograms of folic aced daily from supplements, fortified foods, or both, in addition to consuming food folic acid from a varied diet."
B. 0.8 mg folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form. FDA does not endorse this claim. Public health authorities recommend that women consume 0.4 mg folic acid daily from fortified foods or dietary supplements or both to reduce the risk of neural tube defects."

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Dosage: I don't think it is necessary for most people to take a 400 mcg pill more than 3 or 4 times a week.



Folic acid benefit
This nutrient is essential for the health and function of DNA. Relative deficiency of folic acid may occur in  pregnancy and hyperproliferative or chronic inflammatory disorders. Folic acid supplementation could prevent neural tube defects and in limiting side effects of methotrexate. Supplements may reduce the risk of colon cancer (however it is possible that very high dosages, over 1,000 mcg a day, could increase the risk for colon cancer) and perhaps reduce cognitive decline. Folic acid is one of the vitamins that lower blood levels of homocysteine, which in turn is a thought to be a risk factor for cardiovascular diseases. Folic acid supplementation may be helpful in those who have chronic inflammatory skin diseases, such as moderate to severe psoriasis. For the time being, a supplement of 400 micrograms a few times a week appears to be sufficient.
   Women who take folic acid supplements for at least one year before they become pregnant reduce their risk of delivering prematurely.
   Older individuals may benefit from folic acid supplements as a way to reduce the risk of dementia.

Folic acid and food sources
You can get this B vitamin in beans and legumes; citrus fruits and juices; wheat bran and other whole grains; dark green leafy vegetables; and poultry, pork, shellfish, and liver.


Fortified cereals (1 cup) 25-100%
Spinach, boiled (1/2 cup) 33%
Navy beans, boiled (1/2 cup) 31%
Orange juice (1 cup) 28%
Asparagus, boiled (4 spears) 21%
Wheat germ (1/4 cup) 20%


Side effects, caution, danger, safety, adverse events, risk for increasing cancer? Risk during pregnancy.
Q. I was sent a newsletter in 2009 written by Dr. Joel Fuhrman, M.D. He writes in the newsletter, "DO NOT take multivitamins that contain folic acid and If you are pregnant, DO NOT take prenatal vitamins. Folic acid supplementation is dangerous - especially for pregnant women. In a 10-year study, scientists found that women who take multivitamins containing folic acid increase their breast cancer risk by 20-30%. Even more alarming are the associations between supplemental folic acid during pregnancy and death from breast cancer, and asthma and respiratory tract infections in children. Folic acid is the synthetic form of folate, a B vitamin. Folate protects against birth defects known as neural tube defects (NTDs). Pregnant women could safely increase their folate status and prevent NTDs by eating green vegetables, but instead they are instructed to take folic acid supplements, putting them and their children at risk. These supplements are not a substitute for folate-containing green vegetables - there are inverse associations between maternal vegetable intake and childhood cancers. Unlike synthetic folic acid, folate obtained from food sources - especially green vegetables - protects against breast and prostate cancer." What do you think of the claims made by Dr. Joel Fuhrman, M.D.?
    A. I agree that as much as possible vitamins and nutrients should be obtained from food. I await to see results of additional studies to determine whether the small amounts of folic acid in multivitamins, such as 400 mcg or less, taken 3 or 4 times a week, have significant negative effects. I doubt they would. High dosages could be harmful.


JAMA Pediatr. 2014 Nov. Folic acid supplements during pregnancy and child psychomotor development after the first year of life. Children whose mothers used FA supplement dosages higher than 5000 μg/d during pregnancy had a statistically significantly lower mean psychomotor scale score. To our knowledge, this is the first time a detrimental effect of high dosages of FA supplements during pregnancy on psychomotor development after the first year of life has been shown. Further research from longitudinal studies is warranted to confirm these results.



A suboptimal intake may play a role in the development of colorectal cancer, which points to a possible role for supplementation in colorectal cancer prevention. In individuals with colorectal adenomas -- polyps that can be precursors to bowel cancer -- supplementation reverses so-called DNA hypomethylation. However, too high a dose may also be counterproductive. Therefore it is best to take some but not a lot. Some of the trials have shown conflicting results.


Cancer Prev Res (Phila). 2013. Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial.


Does folic acid increase your chances of getting cancer? I've been taking the B vitamin product which has relieved my depression /anxiety / fatigue symptoms but I notice it contains 400 mcg of folic acid. Should I be concerned?
   I am not concerned that dosages 400 mcg or less a day will have a strong influence. I do not think it is necessary to take FA every day and with occasional breaks from use I am not concerned.


The Lancet, March 2013. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses that are, on average, an order of magnitude smaller than the doses used in these trials.

NPA Challenges Findings of JAMA Study on Health Risks Associated with Folic Acid and B12 Treatment
2009 - Natural Products Association
The Journal of the American Medical Association (JAMA) released a study that indicates an associated increased risk of cancer and death from any cause if the study subjects had received treatment with folic acid and vitamin B12. In response to the findings, the Natural Products Association issued the following statement from Daniel Fabricant, Ph.D., vice president of scientific and regulatory affairs: “This is an analysis of two studies -- the NORVIT [the Norwegian vitamin trial, a 2005 randomized trial of homocysteine-lowering with B-vitamins for secondary prevention of cardiovascular disease after acute myocardial infarction] and WENBIT [Western Norway B-vitamin intervention trial presented at the European Society of Cardiology Congress 2007]. “Despite the authors’ justification for the analysis, previous review has indicated the NORVIT might not have been adequately powered and the factorial design might have been too complex, thus rendering the trial incapable of isolating the effect of folate per se. Being combined with the WENBIT, which was terminated early, and which wasn’t without its design flaws, either, creates a scenario in which two flawed studies are combined to yield one larger flawed study. This does not seem to be in the best interest of medical science or public health.” Fabricant also states that most of the subjects in both trials were also being treated with beta-blockers and statins, and some were also being treated with ACE inhibitors and diuretics, “yet there are no numbers, no analysis on the effects these interventions may have on the incidence of cancer. There is no adjustment of the baseline effect for these interventions, yet the authors adjusted the baseline for smoking, age and sex, which are all factors in the development of cancer. We have no way of determining these factors’ impact on this study as they just decided to leave that out, like ordering off of an a la carte menu, “said Fabricant. The Natural Products Association has made these comments available to the media and is monitoring media coverage of the study. The association will continue to inform its members if new developments arise.


Heart patients in Norway -- where unlike many countries foods are not enriched with folic acid -- were more 25 percent likely to die from cancer if they took folic acid and vitamin B12 supplements compared with those who did not take them. Dr. Marta Ebbing of Haukeland University Hospital in Bergen, Norway says folic acid given over a period of more than three years may feed the growth of cancers that were too small to be detected otherwise. This raises new questions about the benefits of fortifying foods with folic acid. Dr. Marta Ebbing analyzed data from two large trials involving people with heart disease who took folic acid and vitamin B12 supplements to try to lower levels of the amino acid homocysteine. The three-year studies failed to show a heart benefit, but the team continued to follow patients for over three years to see if the supplements had any effect on cancer risk. When the findings from the two trials for a total of more than 6,800 patients were combined, those who got folic acid and vitamin B12 supplements had a higher risk of being diagnosed with cancer, of dying from cancer and of dying from any other cause. 2009.


Folic acid and hearing loss
Supplementation appears to slow the decline in hearing loss that commonly occurs with age, at least in people with high blood levels of the amino acid homocysteine. Dr. Jane Durga, from the Nestle Research Center in Lausanne, Switzerland, and colleagues assessed changes in hearing among 728 subjects, between 50 and 70 years of age, who were randomized to receive folic acid 800 micrograms or inactive placebo daily for 3 years. Because there is evidence that folic acid may improve hearing by lowering plasma homocysteine levels, the researchers excluded subjects who had low homocysteine levels at the start of the study. At 3 years, the threshold for low frequency hearing increased by 1.0 dB in the folic acid group, significantly less than the increase noted in the control group. By contrast, high frequency auditory acuity worsened by a similar extent in each group. Whether the current findings are applicable to subjects in the US is unclear since at the time of the study, folic acid fortification of foods was prohibited in the Netherlands and, as a result, the subjects had baseline folic acid levels that were about half of those typically seen in the US population. Archives of Internal Medicine January 2, 2007.


Folic acid helpful for mental decline
Among older adults with elevated blood  levels of homocysteine, three years of supplementation improves cognitive function to levels generally seen in people several years younger. Dr. Jane Durga, currently with the Nestle Research Centre in Lausanne, Switzerland has been conducting the Folic Acid and Carotid Intima-media Thickness FACIT trial. The FACIT trial included 818 subjects 50 to 70 years old who were likely to benefit from folic acid homocysteine lowering effect. Subjects with low blood levels of homocysteine and those with homocysteine levels caused by factors other than low folic acid were excluded. The participants were randomly assigned to folic acid at 800 micrograms per day or placebo. Blood folate levels at the beginning of the study averaged 12 nanomoles per liter, but by 2004, had risen to 76 nanomoles per liter, while in the placebo group, it remained at 13 nanomoles per liter. The average total plasma homocysteine level was 13 micromole per liter in the folic acid supplement group and 12.9 micromoles per liter in the placebo group. This declined to 10 micromoles per liter in the folic acid group and rose to 13 in the placebo group. Compared with the placebo group, the folic acid group had significantly less decline in sensorimotor speed, information-processing speed, and complex speed. The folic acid group also improved significantly more than their counterparts in memory and word fluency. The Lancet, 2007.


Lack of folic acid, also called vitamin B-9, increases the risk of developing dementia in old age. Researchers in South Korea measured naturally occurring folic acid levels in 518 elderly persons, none of whom showed any signs of dementia, and then tracked their development over the next few years. At the end of the period, 45 of the patients had developed dementia, including 34 diagnosed with Alzheimer's disease. When the researchers rechecked folic acid levels, they uncovered a strong link with the dementia.


Folic acid and memory
Folate deficiency inhibits proliferation of adult hippocampal progenitors.
Neuroreport. 2005.
Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. The perturbance of homocysteine / folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. Ddietary folic acid deficiency dramatically increases blood homocysteine levels and significantly reduces the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice. In vitro, the perturbance of one-carbon metabolism represses proliferation of cultured embryonic multipotent neuroepithelial progenitor cells and affects cell cycle distribution. Dietary folate deficiency inhibits proliferation of neuronal progenitor cells in the adult brain and thereby affects neurogenesis.
   Dr. Sahelian's comments: Folic acid could benefit those with deficiency, but it is unlikely those with normal levels would have a memory improvement by taking a supplement.


Homocysteine level reduction
Folic acid reduces plasma homocysteine levels and may be an important therapy for preventing cardiovascular disease. A key mechanism in the benefit of folic acid in heart disease may be the reduction of arterial stiffness. Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Folic acid and other B vitamins seem even more of a wonder drug than anyone suspected: Already known to prevent severe birth defects and heart attacks, they may also reduce the risk of osteoporosis.

Rheumatoid arthritis
Folic acid may be helpful in rheumatoid arthritis patients on methotrexate.

After folic acid fortification of enriched grain products was fully implemented in 1998, deaths due to strokes dropped rapidly in the US and Canada. The main reason for folic acid fortification was to reduce the number of babies born with neural tube defects such as spina bifida. There is "accumulating, controversial evidence" that homocysteine -- an amino acid in the blood -- is a risk factor for stroke and heart disease, Dr. Quanhe Yang, from the Centers for Disease Control and Prevention in Atlanta, said in a statement. Folate decreases homocysteine levels, which may help explain the drop in stroke deaths. Yang's team compared stroke mortality trends between 1990 and 2002 in the US and Canada with those in England and Wales, where folate fortification is not required. Stroke mortality was already falling in the US and Canada from 1990 to 1997, but in 1998 a precipitous drop began, the report indicates. In the US, the annual decrease in mortality during the earlier period was 0.3 percent, whereas starting in 1998 the reduction was 2.9 percent. Similar results were seen in Canada. By contrast, stroke mortality rates did not decline significantly in England and Wales between 1990 and 2002. Source: Circulation, March 14, 2006.

   Folic acid appears to lower the risk of hemorrhagic strokes, strokes caused by bleeding in the brain.


Benefit of folic acid in depression
Reduced plasma, serum, or red blood cell folic acid is commonly found in major depressive illnesses. Supplementing antidepressant medication with folic acid enhances the therapeutic effect. Although more work is required to confirm these beneficial results, it is suggested that, meanwhile, 0.4 to 0.8 mg of folic acid be given during the acute, continuation, and maintenance treatment of depression.


Folic acid and pregnancy, how much to supplement
Pregnant women with low levels of folic acid in their blood are more likely to have a baby with a low birth weight, Folate is essential for fetal growth and gene expression, helping produce and maintain new cells. Women are already advised to take folic acid supplements, a synthetic compound of folate, before conceiving and during the early months of pregnancy, to reduce the risk of defects such as spina bifida, a defect of the spinal column. Researchers from the University of Newcastle upon Tyne examined folate levels in red blood cells for nearly 1,000 pregnant women and looked at lifestyle data. They found higher folate levels in women were associated with increased birth weight for their babies -- a marker for good health in infancy and later in life.


2017 - USPSTF reaffirms need for folic acid supplements in pregnancy
The U.S. Preventive Services Task Force continues to recommend that all women planning or capable of pregnancy should take a daily supplement of 0.4-0.8 mg of folic acid to prevent neural tube defects in their offspring.


Pregnant women who get enough folic acid reduce their risk of having a baby with spina bifida and other neural tube defects. For this reason, several countries, including the United States and Canada, now require grain products to be fortified with folic acid.


J Clin Pharmacol. 2015. Folic acid supplementation for pregnant women and those planning pregnancy - 2015 update. In addition to fortification of dietary staples with folic acid, women of reproductive age should supplement before conception with 0.4-1.0 mg of folic acid daily as part of their multivitamins. In the United State, all enriched rice is also fortified with folic acid at 0.7 mg per pound of raw rice. However, this is not the case in many countries, and it has been estimated that only 1% of industrially milled rice is fortified with folic acid. In countries where rice is the main staple (e.g. China), this does not allow effective folate fortification. While the incidence of neural tube defect is around 1/1000 in the USA, it is 3-5 fold higher in Northern China, and 3 fold higher in India. We identified groups of women of reproductive age who may benefit from higher daily doses of folic acid and this should be considered in current practice. These include women who have had previous pregnancies with NTDs, those who did not plan their pregnancy and hence did not supplement, and women with low intake or impaired adherence to daily folic acid supplementation. In addition, women with known genetic variations in the folate metabolic cycle, those exposed to medications with antifolate effects, smokers, diabetics and the obese, may benefit from higher doses of folic acid daily during the first trimester.

Folic acid and neural tube defects
Researchers who reviewed birth-defect data from 21 states before and after the FDA mandated the fortification of grain products with folic acid have found that spina bifida and anencephaly decreased by about one third. However, since current fortification levels do not guarantee that pregnant women will consume the recommended amount of 400 micrograms a day, supplementation is still appropriate for women likely to get pregnant.

     Folic acid in the diet not only helps prevent birth defects but also improves the one-year survival rate of children who are born with defects.


Folic acid and cleft lip prevention
Women who take a folic acid supplement in early pregnancy can reduce the risk of cleft lip in their baby. Folic acid has been recommended to prevent neural tube disorders such as spina bifida. But its impact on cleft clip has been less clear. "Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third," according to Allen Wilcox of the National Institute of Environmental Health Sciences in Durham, North Carolina.


Fortification in Canada
In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. A review of the benefits completed in 2007 indicates food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.


Folic acid is a water-soluble B vitamin and enzymatic cofactor that is necessary for the synthesis of purine and thymidine nucleotides and for the synthesis of methionine from homocysteine. Impairment of folic acid -mediated one-carbon metabolic pathways can result from B-vitamin deficiencies and/or single nucleotide polymorphisms, and increases risk for pathologies, including cancer and cardiovascular disease, and developmental anomalies including neural tube defects. The coenzyme form of folate is called tetrahydrofolate.


What is the ideal dose of folic acid supplement to lower homocysteine levels?
   Each person has a different requirement and dietary intake, but it appears from most studies that 400 mcg of folic acid, or 0.4 mg, is adequate taken 3 times a week. Because of lower baseline homocysteine values due to consumption of folic acid fortified food, the degree of the homocysteine lowering response to supplementation would be expected to be less in North American countries than in countries without folic acid food fortification.


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