Folic acid is dangerous, but folates found in foods are healthy.
For many years, public health officials have advocated the consumption of folic acid. Folic acid is a synthetic substance that was developed in the 20th century. Folic acid is chemically known as pteroylglutamic acid and is a crystalline substance. Folates were once also known as vitamin B9. Folates exist in foods, yet crystalline folic acid does not. Research suggests that folic acid consumption may worsen, or even cause, some types of cancer and contribute to the worsening of certain neurological conditions. Folates in food, however, have not been shown to be dangerous. Instead folates found in foods are believed to help build and maintain health. Humans should rely primarily on natural whole foods for their folate needs, and if more is needed, take nutritional supplements that supply folates, not synthetic folic acid.
Vitamin B9, Folate
In the 1930s, it was discovered that there was a substance in liver that reversed megablastic anemia that was independent of cobalamin (sometimes called vitamin B12). (1) Once called vitamin B9, it is more commonly referred to as folate (though there are multiple folates) or folacin. Early on, food folate was given for people with a pregnancy-related anemia in the form of autolyzed yeast; later the synthetic form, folic acid, was developed. (2)
Folate functions as a co-enzyme. Different folate forms are important for the synthesis of thymidine for DNA and purines for RNA. (1) MethylTHF is the predominant form of folate found in human plasma. (1)
USDA reports show that broccoli and alfalfa sprouts contain food folate (3,4) and they are considered to be the best food supplement source by some. Furthermore, "folates are ubiquitous in nature, being present in nearly all natural foods...50 to 95% of folate in food may be destroyed by protracted cooking or other processing." (2) Yeast, dark green leafy vegetables, and oranges have the highest folate content. (2,5) Those with the highest amount by caloric density include brewers' yeast, spinach, Romaine lettuce, turnip greens, parsley, asparagus, collards, cabbage, broccoli, lima beans, and beef liver. (6)
A JAMA study concluded that "studies have suggested that folate intake decreases risk of cardiovascular diseases. However... folic acid supplementation has not been shown to reduce risk of cardiovascular diseases." (7) This is because studies using folate (the natural form) show it works, yet folic acid (the synthetic form) does not. Food folate is clearly superior.
Folic Acid is Synthetic and Unnatural
Folic acid accumulations may be problematic. (8) Since food folate is natural and is absorbed through a different pathway than folic acid, (2) long-term consumption of folate does not result in an accumulation of a foreign substance in the body, but instead has many benefits.
Folate is an important nutrient for healthy blood; the absence of any of it can trigger various forms of anemia (especially pernicious anemia). (2,6) Subclinical deficiencies of folate may impair cognitive function. (9) Folate deficiency is the most important determinant in high homocysteine levels, (8) and supplemental folate is effective in reducing homocysteine. (10-11) Homocysteine is highly implicated in vascular diseases such as cardiovascular and other vascular disorders. "The major forms of folates found in food are methylTHF and formylTHF." (12)
For many years, public health officials have advocated the consumption of folic acid. There are many reports that folic acid should be taken by pregnant women and may prevent birth defects. Folic acid has also been claimed to help prevent cardio- and cerebral-vascular diseases. Yet few reports have mentioned that folic acid is unnatural, folic acid is synthetic, and that the body cannot properly convert much folic acid into a usable folate form. Furthermore, concerns about folic acid feeding cancer are now a real concern in the 21st century, too much folic acid may kill you.
"Folic acid is a synthetic folate form" (5) and was not developed until the 20th century. (2) Folic acid is chemically known as pteroylglutamic acid (PGA) and is a crystalline substance (no food vitamins are naturally crystalline in structure). (2,13) Folate, once also known as vitamin B9, exists in foods, yet crystalline folic acid does not. (2,5,8,13) Folates also differ from folic acid "in the extent of the reduction state of the pteroyl group, the nature of the substituents on the pteridine ring and the number of glutamyl residues attached to the pteroyl group." (5)
An Irish study found that the body has trouble converting more than 266 mcg of folic acid per day. (2) "Consumption of more than 266 mcg of synthetic folic acid (PGA) results in absorption of unreduced PGA, which may interfere with folate metabolism for a period of years" (2) A 2004 paper from the British Medical Journal confirmed what many natural health professional have known all along: since folic acid is unnatural and the body cannot fully convert large amounts of it into usable folate, this artificial substance can be absorbed and may have unknown negative consequences in the human body. (8)
One of the biggest scientific concerns about folic acid is that even in amounts close to official daily recommendations, some of it is absorbed in unreduced form into the bloodstream with potentially dangerous results. (2,8) Also, "in vitro studies do show that PGA derivatives act to inhibit certain enzymes, including those associated with nucleotide biosynthesis." (8) In spite of this, the U.S. Food and Drug Administration has required that uncooked cereal grains and flour products be fortified with folic acid. (8)
While insufficient folate can result in fatigue, depression, confusion, anemia, reduced immune function, loss of intestinal villi, and an increase in infections, (2,5,6) it is not totally clear what dangers long-term consumption of folic acid will cause. (2,8) Certain scientists believe that excessive consumption of folic acid may actually interfere with folate metabolism (2)--this could be expected to worsen conditions that would have otherwise benefited from real food folate. Furthermore, "very large amounts of folic acid in its pharmacological oxidized (PGA) form may be noxious to the nervous system...and have provoked seizures in patients otherwise under control on anticonvulsant therapy" (2)
Folic acid is placed in certain refined grain products to help "fortify" the vitamin content. However, as the refining process tends to reduce fiber, protein, and natural B vitamin levels, it would seem wiser to consume foods that have not been as refined.
Excessive Folic Acid is Becoming a Health Concern
A 2010 report states, "The more we learn about folic acid, the more it's clear that giving it to everyone has very real risks," says folic acid researcher David Smith, PhD, a professor of pharmacology at the University of Oxford in England...the risk experts worry about most: colon cancer. Last year, health officials in Chile reported that hospitalization rates for colon cancer among men and women age 45 and older more than doubled in their country since fortification was introduced in 2000. In 2007, Joel Mason, MD, director of the Vitamins and Carcinogenesis Laboratory at the Tufts University School of Medicine, described a study of the United States and Canada suggesting that rates of colon cancer rose--following years of steady decline--in the late 1990s (around the time our food was being fortified)." (14)
The same report also states, "Other research links high doses to lung and prostate cancers. In one study conducted in Norway, which doesn't fortify foods, supplementation with 800 mcg of folic acid (plus B12 and B6) daily for more than 3 years raised the risk of developing lung cancer by 21 percent. Another, in which men took either folic acid or a placebo, showed those consuming 1,000 mcg of folic acid daily had more than twice the risk of prostate cancer. And a new worry recently came to light when scientists discovered the liver has limited ability to metabolize folic acid into folate--which means any excess continues circulating in the bloodstream. "Unlike folate, folic acid isn't found in nature, so we don't know the effect of the excess," says Smith. Indeed, many scientists have grown increasingly concerned about mounting research--including a study published last winter in the Journal of the American Medical Association --suggesting that all the extra folic acid might increase your odds of developing cancer." (14)
A major placebo controlled trial found that men who took folic acid were about three times as likely to develop prostate cancer as men who did not. (15) That same trial suggested that folates in food helped reduce the risk for prostate cancer.
At least one study involving breast cancer was even less conclusive, but had findings that hinted that reduction in folic acid consumption may possibly reduce the risk. (16) While "higher dietary folate intake may be associated with a lower risk" of breast cancer, (17) the same is not the case with folic acid. One study, for cancer survivors, found that "Folic acid supplement use was associated with higher risk of death, only among survivors reporting low-quality diets." (18)
"Some studies showed a higher risk of breast cancer in populations exposed to high folate intake post fortification, especially when folic acid is used. The results support the need to be cautious and to limit the exposure of women to high intakes of folic acid, especially in countries with mandatory food fortification." (19) (Countries like the USA have mandatory fortification.)
A study involving 38,772 women in the USA who took synthetic multi-vitamin formulas found that, on average, women died several years earlier than those who did not take them, and folic acid was identified as a possible reason. (20) Synthetic vitamins are dangerous. Yet, 100% food vitamins and minerals are essential to human health and promote longevity.
Foods "fortified" with folic acid may cause serious neurological problems in patients deficient in vitamin B12. (12) Furthermore, "no folic acid dose can be considered as truly safe in the presence of untreated cobalamin deficiency" (12) Although synthetic folic acid is considered to be more bioavailable than natural sources, it also seems to be much less safe. (15)
Now, this is not to say that folic acid uniformly causes neurological problems or increases cancer rates for everyone, (21) but since it will take a long time to determine the effects of lifelong consumption of foods fortified with folic acid, it would seem to be better not to take additional folic acid in the form of nutritional supplements for most people
Researchers R. Iyer and S. Tomar rightly concluded, "A number of studies have shown that high intakes of folic acid, the chemically synthesized form, but not natural folates, can cause adverse effects in some individuals such as the masking of the hematological manifestations of vitamin B12 deficiency, leukemia, arthritis, bowel cancer, and ectopic pregnancies." (22) They also concluded that food forms were preferred for pregnant women. (22)
In 2016, Johns Hopkins said that it appears that too much folic acid can possibly cause (or at least contribute to) autism. (23) While causes for autism can be debated, this researcher's view is that toxicity plays a role and it may be that excessively high intakes of folic acid increase that risk.
While there may be forms of folate or folic acid that may help better deliver anti-cancer agents, (24) it seems that many people would be better off not intentionally taking folic acid in supplements.
"Folate over-supplementation and deficiency causes prophase DNA damage." (25) So obviously humans need folate, but over-supplementation with folic acid can be a problem.
Laura Bell correctly stated, "We all need the natural folate found in leafy greens, orange juice, and other foods, and diets high in these foods are perfectly healthy; many researchers, though, believe that folic acid may be both friend and foe. When cells in the body are healthy, folate helps shepherd along the normal replication of DNA. But when cells are malignant or in danger of becoming so- and as many as half of adults older than 60 could already have precancerous colon polyps, while most middle-aged men have precancerous cells in their prostates--animal studies suggest excess folate in the form of folic acid may act like gas on the fire... lowering your intake to 400 mcg won't hurt- and might help save your life." (14)
It is clear that since folic acid is unnatural, synthetic, chemically different, structurally different, and is not absorbed in the same pathways as folate, long-term folic acid consumption may be hazardous to human health. Folate in foods is what is safe and is the preferred form of folate for human consumption. Excessive folic acid may make cancer worse. And unlike folic acid, humans have been safely consuming food folate for thousands of years.
Some have been warning people against possible folic acid dangers for many years. (2,8,13,26,27) Now perhaps it is becoming more evident that those warnings should have been heeded by more people. Everyone should be concerned about taking synthetic/isolated USP vitamins like those containing folic acid. And if folate is needed, it should be taken in one of its highly beneficial food forms.
About the Author
Dr. Thiel, Ph.D. is a nutrition scientist and president of Doctors' Research, Inc. www.doctorsresearch.com. He also runs a holistic health clinic in Grover Beach, California www.healthresearch.com.
(1.) Carmel R. Folic Acid. In Modern Nutrition in Health and Disease, 10th ed. Lippincott Williams & Wilkins, Philadelphia, 2006:47-481
(2.) Shils ME, Olson JA, Shike M. Modern Nutrition in Health and Disease, 9th ed. Williams & Wilkins, Balt., 1999
(3.) Broccoli, raw. USDA National Nutrient Database for Standard Reference, Release 18 (2005)
(4.) Alfalfa seeds, sprouted raw. USDA National Nutrient Database for Standard Reference, Release 16-1, 2004
(5.) Hendler SS, Rorvik D, eds. PDR for Nutritional Supplements. Medical Economics, Montvale (NJ), 2001
(6.) Whitney EN, Hamilton EMN. Understanding Nutrition, 4th ed. West Publishing, NY, 1987
(7.) Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006;296(22):2720-2726
(8.) Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ, 2004;328:211-214
(9.) Gonzalez-Gross M, Marcos A, Pietrzik K. Nutrition and cognitive impairment in the elderly. Br J Nutr 2001;86:313-321
(10.) Verhoef P. Homocysteine metabolism and risk of myocardial infarction: Relation with vitamin B6, B12, and Folate. Am J Epidemiol 1996;143(9):845-859
(11.) Brattstrom L. Vitamins as homocysteine-lowering agents: A mini review. Presentation at The Experimental Biology 1995 AIN Colloquium, April 13, 1995, Atlanta Georgia
(12.) Carmel R. Folic Acid. In Modern Nutrition in Health and Disease, 10th ed. Lippincott Williams & Wilkins, Baltimore, 2006:470-481
(13.) Thiel R. Natural vitamins may be superior to synthetic ones. Med Hypo, 2000;55(6):461-469
(14.) Bell L. Is your breakfast giving you cancer? Research links too much folic acid to certain cancers. Prevention. March. 29, 2010. http://www.msnbc.msn.com/id/35874922/ns/health-diet_and_nutrition//
(15.) Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009 Mar 18; 101(6):432-5
(16.) Stevens VL, McCullough ML, Sun J, Gapstur SM. Folate and other one-carbon metabolism-related nutrients and risk of postmenopausal breast cancer in the Cancer Prevention Study II Nutrition Cohort. Am J Clin Nutr. 2010 Jun;91(6):1708-15
(17.) de Balle J, et al. Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition. J Natl Cancer Inst. 2014 Dec 12; 107(1):367
(18.) Inoue-Choi M, Greenlee H, Oppeneer SJ, Robien K. The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors. Cancer Epidemiol Biomarkers Prev. 2014 May;23(5):865-75
(19.) Castillo-L C1, Tur JA, Uauy R. [Folate and breast cancer risk: a systematic review; original article in Spanish] Rev Med Chil. 2012 Feb;140(2):251-60
(20.) Mursu J., et al. Dietary Supplements and Mortality Rate in Older Women: The Iowa Women's Health Study. Arch Intern Med. 2011;171 (18):1625-1633
(21.) Grupp SG, Greenberg ML, Ray JG, Busto U, Lanctot KL, Nulman I, Koren G Pediatric cancer rates after universal folic acid flour fortification in Ontario. J Clin Pharmacol. 2010 May 10
(22.) Iyer R, Tomar SK. Folate: a functional food constituent. J Food Sci. 2009 Nov-Dec;74(9):R114-22
(23.) Stobbe M. A Study Asks: Too Much Folic Acid a Cause of Autism? ABC News, May 11, 2016
(24.) Li H, Lu Y, Piao L, Wu J, Yang X, Kondadasula SV, Carson WE, Lee RJ. Folate-immunoglobulin G as an anticancer therapeutic antibody. Bioconjug Chem. 2010 May 19;21(5):961-8
(25.) Ortbauer M, Ripper D, Fuhrmann T, Lassi M, Auernigg-Haselmaier S, Stiegler C, Konig J. Folate deficiency and over-supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in Caenorhabditis elegans. Mol Nutr Food Res. 2016 Apr;60(4):949-56
(26.) Thiel R. Is Folic Acid Hazardous to Your Health? The Original Internist, 2004;11(2):39-40
(27.) Thiel R. Folic Acid is Hazardous to Your Health. The Original Internist, 2010;17(2):88-90
(by: Robert Thiel, Ph.D., Nutrition Scientist and Clinician
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