Methylfolate versus folic acid for MTHFR polymorphisms

Methylfolate is a very expensive pharma-patented ingredient in a supplemental form that is not generally required by people. Even those with genetic polymorphisms can convert folic acid to methylfolate, though less efficiently due to their genetic differences, and still benefit from folic acid supplementation. 

Since a main concern with MTHFR polymorphisms is the production of less active forms of the MTHFR enzyme due to genetically driven variations in its composition (such as the substitution of alanine with valine), the polymorphisms are most noted for increasing the need for folates (of any form, rather than a particular form). This is because higher quantities of these weaker MTHFR enzymes are needed to compensate for their lower activity levels and methylfolate is a cofactor in the enzyme production, so more dietary folic acid or folates are also needed. 

The medical literature on folic acid has been misrepresented on the Internet to falsely imply that folic acid will not work in individuals with MTHFR polymorphisms. But even people with the most severe polymorphisms can still convert folic acid to methylfolate and eliminate signs of folate insufficiency, particularly high homocysteine levels, according to clinical trials. Here is one example where increasing folic acid intake for individuals with these polymorphisms resolved the problem of high homocysteine levels caused by their weaker MTHFR enzymes:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601299

The folic acid was converted to methylfolate and utilized by these study subjects to make more of these enzymes, which is needed to resolve the health concerns over high homocysteine levels, despite the subjects having polymorphisms that cause weaker versions of the enzymes to be produced. 

The CDC is even more direct, reporting, “You might have read or heard that folic acid is not safe if you have one or two copies of the MTHFR C677T variant. This is not true. Even if you have one or two copies of the MTHFR C677T variant, your body can safely and effectively process the different types of folate, including folic acid.” 

https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.htm

So the widespread myth that people with MTHFR polymorphisms cannot process folic acid has been disproven in authoritative research showing that they actually need to increase folic acid intake (or methylfolate intake) to produce enough of the weaker enzymes to resolve the health concerns, including elevated homocysteine levels and potential neural tube defects in their offspring. 

Folic Acid: Risks or Myths?

There are theoretical risks for isolated folic acid in high doses. But these supposed risks fly in the face of established science and are controversial, not at all conclusive. There is also confusion over the significance of the supposed risks of high dose isolated folic acid in test tube and animal studies which do not identify a danger for moderate level supplementation - or even higher dose supplementation if combined with multivitamins or vitamin B-12. In other words, if the theoretical risks do not reflect real world human activities and the way that people actually obtain essential vitamins from their diet, including supplementation, aren’t these improbable risks really irrelevant to us? On the other hand, these negative reports may stop people from taking essential vitamins in quite reasonable amounts even though they are known to promote human health. Published human clinical science has determined that folic acid can reduce birth defects and has been proven to do so. Clinical science has also found mechanisms by which folic acid can prevent cancers, as well as the theoretical possibility that very high doses given in isolation can stimulate colorectal cancers including prostate cancer. There is stronger evidence that taking B-12 or a multivitamin along with high folic acid actually reduces rates of prostate and colon cancers. For example, in one human clinical trial where food intake, blood and plasma levels of folic acid were considered, Multivitamin users had about 2/3 the risk of subsequent prostate cancer as Non-Multivitamin users; only the independent use of folic acid was considered a risk factor. The report concluded, “…on the whole, the biological and epidemiological evidence supports the potential for folate supplementation to prevent colorectal neoplasia in humans.” (Cole) This shows that single nutrient studies, especially if unpublished and not peer reviewed or subjected to subsequent comments by experts in the field, should not be given overinflated importance when they are merely preliminary studies that may conflict with more relevant published human clinical studies. In the case of such conflicts, the human clinicals should bear more weight and be seen as more convincing, especially those that mimic the full range of variables (nutrients) in the human diet. Folic acid itself is considered non-toxic. Also, “data from in vitro and in vivo studies indicate that folic acid is not genotoxic [damaging to genetic material]”. (UK Food Standards Agency) There have been reports of levels as high as 50,000 micrograms per day given with no signs of toxicity in humans. There are accepted problems associated with levels exceeding 5,000 micrograms a day, which resulted in a far more conservative Upper Limit of 1,000 micrograms daily being set. This effect has been demonstrated in patients suffering from pernicious anemia taken off of their successful medicine (vitamin B-12), which was replaced by 5,000 mcg/day of folic acid. The substitution of one vitamin for another was unsuccessful in treating pernicious anemia, but did mask some symptoms. This test – and a large safety margin - provided the rationale given for the current Upper Limit. But it does not logically imply danger to those who are not severely anemic and who obtain B-12 in adequate amounts. (Oakley) It is very uncommon for people to take folic acid singly in doses of thousands of micrograms daily, but this is the method which test tube and animal studies often use. Overemphasizing unproven cancer risks requires ignoring valid studies showing reductions of cancers by taking folic acid and multivitamins. Needlessly scaring people from taking their vitamins, which have in human clinical trials shown significant improvements in birth defect and cancer rates, is not helpful to our common goal of protecting public health. Neil E. Levin, CCN, DANLA QUOTES & REFERENCES: Dr. Gideon Koren, director of the Motherisk Program at the Hospital for Sick Children in Toronto , note that rates of birth defects such as spina bifida and cancers such as neuroblastoma have plummeted since folic acid supplementation was begun. He believes that the known benefits outweigh theoretical risks. "I think it is very important to remember that the scares about cancer are mostly from animal studies and laboratory studies, not from human experience," he says. "We are still awaiting to see such human experience." http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20090417/folic_acid_090418/20090419?hub=SciTech Health Canada recommends all women of childbearing age take 0.4 mg of folic acid a day, but says taking more than 1 mg a day of folic acid without the advice of a doctor is not recommended. "We continue to encourage all women who could become pregnant to take a daily supplement," the agency says on its website. "We caution against taking more than one multivitamin tablet a day, as excess amounts of certain vitamins can be toxic." http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20090417/folic_acid_090418/20090419?hub=SciTech “All women who could become pregnant should take a multivitamin containing 0.4 mg of Folic Acid every day. To help reduce the risk of NTDs, you should start taking the vitamin supplement at least three months before you get pregnant and continue through the first three months of your pregnancy. Talk to your health professional to find the supplement best for you…If you have had a previous pregnancy affected by an NTD or have a family history of this problem, see your doctor. You may be advised to take a higher dosage of Folic Acid. If you have diabetes, obesity or epilepsy, you may be at higher risk of having a baby with an NTD, and you should see your doctor before planning pregnancy… Do not take more than one daily dose of vitamin supplement as indicated on the product label. Increasing your dose of Folic Acid beyond 1 mg per day without the advice of a doctor is not recommended.” (Public Health Agency of Canada , 2/27/08; http://www.phac-aspc.gc.ca/fa-af/index-eng.php) The NIH’s Office of Dietary Supplement reports on the prevention of cancer with the use of supplemental folic acid as part of a multivitamin: “Over 88,000 women enrolled in the Nurses' Health Study who were free of cancer in 1980 were followed from 1980 through 1994. Researchers found that women ages 55 to 69 years in this study who took multivitamins containing folic acid for more than 15 years had a markedly lower risk of developing colon cancer.” (Giovannucci E, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129:517-24; http://ods.od.nih.gov/factsheets/folate.asp) Cole BF, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. Polyp Prevention Study Group. JAMA. 2007 Jun 6;297(21):2351-9. PMID: 17551129 Figueiredo JC, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009 Mar 18;101(6):432-5. Epub 2009 Mar 10. PMID: 19276452 Folic Acid, CASRN: 59-30-3. NLM TOXNET Hazardous Substances Database accessed online 28 March, 2009. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@na+folic+acid Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. N Engl J Med. 2006 Apr 13;354(15):1567-77. Epub 2006 Mar 12. Erratum in: N Engl J Med. 2006 Aug 17;355(7):746. PMID: 16531613 Oakley GP Jr. When will we eliminate folic acid-preventable spina bifida? Epidemiology. 2007 May;18(3):367-8. PMID: 17435446 http://www.food.gov.uk/multimedia/pdfs/evm_folicacid.pdf

Natural Health: Ten Predictions for the Year 2008

Natural Health: Ten Predictions for the Year 2008 By Neil E. Levin, CCN, DANLA 12/10/2007 The New Year will bring more proof of antioxidant benefits for human health. Recent research shows that antioxidants help to maintain healthy brain functions during aging, protect brain and nerve cells, and prevent hormones and cholesterol fractions from oxidizing to become more harmful forms. Look for an expanded understanding of the benefits of these synergistic nutrients in 2008. 2008 will provide more proof of omega-3 fatty acids’ benefits. For example, DHA helps to maintain healthy balances of cholesterol fractions and protects the brain and nerves. EPA helps normalize cell membranes and cellular health. These essential fats are typically very low in the American diet, so dramatic results could occur in clinical trials providing these nutrients to participants. There will be more safety scares regarding popular prescription and Over-The-Counter drugs, creating new safety warnings and label cautions. Since the most popular medications are typically blocking or inhibiting natural body functions (calcium channel blockers, cholesterol production inhibitors, serotonin re-uptake inhibitors, stomach acid production inhibitors, etc.) rather than dealing holistically with the causes of problems that create body imbalances (lack of optimal levels of nutrients, environmental chemicals and metals, chronic stress - lack of deep sleep, low fiber - high carbohydrate diets, etc.), major side effects from such drugs are inevitable. Side effects from pain medications will become more evident, increasing the number of people looking for safer alternatives. Herbs and spices are the major natural alternatives with some scientific evidence of efficacy. The market for organic and local foods will continue to grow at amazing levels. This will put pressure on the regulatory, farm and grocery industries to manage these products and segregate them to maintain their integrity. That contrasts with the increased reliance on genetically engineered corn to produce ethanol that raises food costs and increases the use of farm chemicals. And there is much evidence that non-genetically engineered foods are both environmentally and nutritionally superior to their modified cousins, while natural farming techniques are proving superior to chemical and genetically engineered farming in terms of managing fuel and seed costs, water use, improving both crop yields and selling prices, etc. Millions of farmers around the world have already weaned themselves from the chemical-genetic “green revolution” to use appropriate local farming techniques and have actually been more successful as a direct result of truly “green” practices. America has begun to awaken to the benefits of local and organic foods in terms of freshness, reducing the use of fossil fuels for transportation and demonstrable benefits to local economies. Watch for these trends to accelerate in 2008. Blood pressure and blood sugar concerns will continue to grow, along with a medical backlash attacking natural strategies to manage these concerns. However, science will also continue to amass evidencing the positive health benefits of natural products to help people maintain already healthy blood levels, in contrast with the poor symptom management that is a characteristic of pharmaceutical or surgical interventions used to “correct” chronic biological imbalances. These issues dovetail with current obesity and cardiovascular concerns and are part of the same syndrome related to chronic stress and poor diets. Positive reports of the benefits of higher levels of vitamin D will continue to proliferate, though with some bias against the synthesized vegetarian/vegan form of vitamin D2 versus D3 from fish oil or sheep lanolin. Health authorities will be pressured to raise both the recommended Daily Value and the Upper Limit of vitamin D to five times the current levels. Research will continue to accumulate regarding the health benefits of whole grains and whole foods, as will reports of people allergic or sensitive to gluten, corn, and other grains. More mainstream processed groceries will have whole food options in 2008. This is a good trend, though with cautions for the sensitive minority. There will be continuing claims that “dietary supplements” are illegally contaminated with steroids or other pharmaceutical drugs. These claims will typically be self-serving and defensive, made primarily by athletes accused of cheating by using banned substances. Beyond the obvious fact that legitimate supplement manufacturers do not have illegal substances on hand and that GMP (Good Manufacturing Practices certification) quality manufacturing protocols would avoid inadvertent contamination, these accusations are a barometer of how “unregulated” the mainstream media and the public thinks dietary supplements are. While there are plenty of regulations written specifically to regulate supplements, and even the FDA claims that it has adequate regulatory authority, somehow certain medical authorities and journalists like to pretend otherwise; perhaps to have a handy punching bag to deflect attention from the well-documented hundreds of thousands of deaths caused annually from pharmaceuticals and medical errors. In any case, expect more of this blame game in 2008. With a presidential election campaign under full swing, no meaningful legislation regarding health care or Medicare will be passed in 2008. There will be a narrow window of opportunity for such measures in 2009 with a new Congress and Administration. Natural health advocates will continue to press for meaningful use of nutrition to combat the major causes of disease and illness in America, with probably little impact against the lobbying might of the medical and pharmaceutical interests. The wild card is if, by some miracle, the insurance industry finally notices that their costs could be contained by the use of targeted nutrition such as the use of calcium and vitamin D to prevent osteoporosis, antioxidants to prevent age-related macular degeneration and oxidative-related glaucoma that affect vision and impact seniors’ independence, omega-3 fats to prevent coronary heart disease, the use of fiber to manage healthy cholesterol levels, etc. That could swing the pendulum towards the use of natural products to control healthcare costs. But I’m not betting on it happening in 2008, though I hope that they wise up soon enough to manage the recently overactive increases in medical costs. There will be additional, unjustified health scares about essential nutrients in 2008. Especially beware of “meta-analyses” that mix unrelated studies and magnify the number of variables using often-flawed statistical models. Some probable targets: · Kava (a few unrelated, anecdotal reports of liver problems) · Folic acid (a few reports of higher cancer levels despite a lot of cellular data indicating the opposite, creating a backlash against re-fortification of refined foods) · Vitamin E (continued championing/publicity of questionable meta-analyses over more rigorous blood-level studies will continue the inexplicable controversy over the safety of this essential nutrient that most Americans are reportedly deficient in.) · Beta-Carotene (again, blood level studies and total antioxidant studies repeatedly show its safety, but studies measuring only administration of certain doses to sick populations that may be deficient in antioxidants create a conflicting picture.) · DHEA (this adrenal hormone has been vilified as a “steroid”, but is no more so than vitamin D. No less an authority than physician and US Senator Tom Coburn has sent a letter to his colleagues informing them that he has reviewed the issues and urging them to avoid a ban of this natural product, which is useful in anti-aging strategies but not for bodybuilders. Efforts by leading senators (including presidential candidates Clinton and McCain) to ban DHEA are ongoing.

Multiple Vitamins - Waste or Wise?

Multiple Vitamins - Waste or Wise? The information in this presentation is for educational purposes only. It is not intended to serve as a replacement for the advice of a medical professional. Amid the current confusion about whether or not to take multivitamins, here are some facts you should consider: There are widespread nutrient deficiencies in America: According to dietary data from the National Health and Nutrition Examination Survey 1999-2000, ninety percent or more of the adults studied had their usual intakes below the current Estimated Average Requirement. 9-11 A report published in the medical journal JAMA made this strong statement: “Most people do not consume an optimal amount of all vitamins by diet alone. Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements.” 2 There is strong evidence that multivitamins may improve immune functions in adults: A so-called “gold standard” randomized, double-blind, placebo-controlled trial looked at adults age 45+ during a one-year study, with results of diabetic and non-diabetic subjects reported separately. 1 73% of those receiving the placebo reported getting infections over the year versus 43% of those taking multivitamins, a 30% difference. Infection-related absenteeism was also found to be much higher in the placebo group (57%) than in the treatment group (21%). But the most striking results were found among the diabetic subjects. A whopping 93% of diabetics receiving the placebo reported getting infections versus only 17% of those taking vitamins, an amazing 76% difference! In other words, the diabetics that did not take multivitamins were over five times as likely to report infections as those in the group that did take the vitamins. Multivitamins reduce birth defects: A meta-analysis of published studies reviewing women’s use of prenatal multivitamins was published by the Journal of Obstetrics and Gynaecology of Canada (JOGC). Researchers found that taking prenatal multivitamins may reduce the risk of a wide range of serious birth defects, including: cardiovascular and limb defects, cleft palate and oral cleft, congenital hydrocephalus, and urinary tract anomalies. Their conclusion was that, “Maternal consumption of folic acid-containing prenatal multivitamins is associated with decreased risk for several congenital anomalies, not only neural tube defects. These data have major public health implications, because until now fortification of only folic acid has been encouraged. This approach should be reconsidered.” 3 The data indicated that the possible benefits to infants of their mothers taking prenatal multivitamins went far beyond the well-known prevention of neural tube defects in the children. That known benefit has already led to widespread fortification of folic acid in processed foods, especially refined flour. Multivitamins protect pregnant women and their fetuses: Another possible benefit of multivitamin use is to prevent potentially fatal complications in pregnant women. This finding was reported by researchers at the University of Pittsburgh: “Women who are considering becoming pregnant may significantly reduce their risk of developing a common life-threatening complication called pre-eclampsia by taking a multivitamin supplement regularly three months before conception and during the first trimester of pregnancy.” 8 Multivitamins reduce infertility: Harvard scientists found that women who took multivitamins at least six times a week were over 40% less likely to have fertility problems linked to ovulation than other women. Dr Jorge Chavarro, from the Harvard School of Public Health, presented his findings to delegates at the American Society for Reproductive Medicine conference in New Orleans in October, 2006. 4 Multivitamins and chronic conditions: Another scientific review published in JAMA noted that, “Although the clinical syndromes of vitamin deficiencies are unusual in Western societies, suboptimal vitamin status is not. Because suboptimal vitamin status is associated with many chronic diseases, including cardiovascular disease, cancer, and osteoporosis, it is important for physicians to identify patients with poor nutrition or other reasons for increased vitamin needs. The science of vitamin supplementation for chronic disease prevention is not well developed, and much of the evidence comes from observational studies.” 5 The report concluded, “Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis.” Multivitamins may reduce childhood tumors: In a case-control study of brain tumors and the mothers’ use of vitamin and mineral supplements early in pregnancy, the researchers confirmed earlier research indicating that mothers taking multivitamins had a reduced risk of their child developing brain tumors. “The results of the study add to the evidence of a protective role for multivitamins, suggest a possible role for micronutrients early in pregnancy...” 6 Vitamin-Mineral Deficiencies are Theoretically Linked to Increased Cancer Risks: Researchers writing in the scientific journal Nature Reviews Cancer have stated, “Diet is estimated to contribute to about one-third of preventable cancers -- about the same amount as smoking. Inadequate intake of essential vitamins and minerals might explain the epidemiological findings that people who eat only small amounts of fruits and vegetables have an increased risk of developing cancer. Recent experimental evidence indicates that vitamin and mineral deficiencies can lead to DNA damage. Optimizing vitamin and mineral intake by encouraging dietary change, multivitamin and mineral supplements, and fortifying foods might therefore prevent cancer and other chronic diseases.” 7 There is a wide range of published research on multivitamins and I have presented only a sampling to you today. I hope that this information intrigues you as to the potential benefits of the vitamins and minerals found in multivitamins, and the fact that some respected health authorities advocate that most Americans take a good multivitamin. Copyright 2007 Neil E. Levin REFERENCES: Barringer TA, et al. Effect of a multivitamin and mineral supplement on infection and quality of life. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003 Mar 4;138(5):365-71. PMID: 12614088 Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. 2002 Jun 19;287(23):3116-26. Review. Erratum in: JAMA 2002 Oct 9;288(14):1720. PMID: 12069675 Goh YI, et al. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. PMID: 17022907 Chavarro, J. (Harvard School of Public Health) American Society for Reproductive Medicine conference. New Orleans, LA. October 2006. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. 2002 Jun 19;287(23):3116-26. Review. Erratum in: JAMA 2002 Oct 9;288(14):1720. PMID: 12069675 Bunin GR, et al. Maternal supplement, micronutrient, and cured meat intake during pregnancy and risk of medulloblastoma during childhood: a children's oncology group study. Cancer Epidemiol Biomarkers Prev. 2006 Sep;15(9):1660-7. PMID: 16985028 Ames BN, Wakimoto P. Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer. 2002 Sep;2(9):694-704. Bodnar LM, et al. Periconceptional multivitamin use reduces the risk of preeclampsia. Am J Epidemiol. 2006 Sep 1;164(5):470-7. Epub 2006 Jun 13. PMID: 16772374 Dial S, Eitenmiller RR. 1995. Tocopherols and tocotrienols in key foods in the U.S. diet. In: Ong ASH, Niki E, Packer L, eds. Nutrition, Lipids, Health, and Disease. Champaign, IL: AOCS Press. Pp. 327–342. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000). Institute of Medicine, NIH Ahuja JK, et al. Current status of vitamin E nutriture. Ann N Y Acad Sci. 2004 Dec;1031:387-90. PMID: 15753177