There’s this fad going around involving the popularity of the MTHFR genetic testing. Have you had your doctor recommend you test for it? Or have you been told you should take 5-MTHF or methylfolate? You might be thinking that its popularity is due to its importance. Just like anything in biology, that’s somewhat true, somewhat not. I’ll get to that in a second.
I’m writing this article because there’s an enormous amount of information out there that is being overly simplified (and it’s dangerous to over-simplify biochemistry), and is also out-of-context. There are some very key points that are being left out of this conversation and because the biochemistry is complicated, most people do not want to dig into this topic to see what’s accurate and what’s not, and who could blame them? It’s easier to believe the websites, the marketing, or the drug reps. What I’m going to do here is clarify this issue and put it into some context, since without this information, you might incorrectly prescribe or take a supplement, causing damage to someone’s genetic expression and/or increase their risk for cancer.
First, the basics.
First, a little primer on the MTHFR enzyme (with the risk of me also oversimplifying!). Methylene tetrahydrofolate reductase is one of multiple enzymes which help your body pass around the “hot potato” of a methyl group. Methyl groups are found in many, many foods and are the source to add a carbon to molecules like DNA, hormones, phospholipids, neurotransmitters, proteins, etc. In the case of MTHFR, the methyl group helps to convert homocysteine to methionine. You might have heard homocysteine is correlated with cardiovascular disease, which is accurate, but you also need homocysteine to make glutathione, which is the body’s homemade antioxidant and also deals with detoxification. So balance is key to remember here as well, since driving down homocysteine can also increase inflammation from insufficient glutathione.
A second area where MTHFR has some impact is in Recurrent Pregnancy Loss (RPL). It has been shown that have a polymorphism can increase chances of a pregnancy loss, especially the TT mutation (1,2,3,4) This, perhaps, begs several questions. Is the prevalence of miscarriage higher now than in the past? And if it’s higher now, why? One reason might be the different foods that were eaten. Nearly all traditional cultures prized liver, with one chicken liver providing 254 mcg of folate, versus a cup of raw spinach having only 58 mcg. Even with a polymorphism, eating a diet higher in folate would help mitigate issues.
How Did This Come About?
The pharmaceutical companies recently got really interested in the MTHFR gene (which codes for the actual enzyme) because when it has a variation, you don’t efficiently pass the methyl group around, effectively leaving you with too much homocysteine, potentially increasing your chances of cardiovascular disease. This would explain why the drug companies got interested in testing for the MTHFR gene and having cardiologists test for it — because this is the new cusp of medicine, the development of drugs specifically targeted to a specific gene type. That’s how the MTHFR gene got popular. It could have easily been another gene. It’s important to remember that we haven’t developed problems with this gene all of a sudden — genes take thousands of years to change. So how did we instantly seem to have problems with our lack of MTHFR function?
Primarily, because we are more nutrient deficient than we’ve been in the past, and one big common deficiency is folate, the naming of which comes from the word “foliage”. Of course, most of us are not eating enough vegetables, and who knows how nutrient-dense those vegetables are anyway? Eating enough folate “pushes” this reaction, regardless of if you have the variation (or which one). So any gene anomaly that you may have becomes apparent because you are deficient in folate. As I say to my patients, we waste valuable stomach space on things like bread, and then don’t eat enough vegetables.
There are two areas where the MTHFR gene has its SNP’s (single nucleotide polymorphism) — at the 677th location and the 1298th location. At the 677th location, the gene expression that is normal is the C,C amino acids (stands for cytosine-cytosine), which has 100% normal activity. The C,T SNP has one tyrosine substituted, which reduces its efficiency a bit, to 70%. The homozygous SNP is T, T and has about 35% function. In the last case, it’s distinctly possible that someone might have higher homocysteine if they don’t have enough folate or folic acid in their diet so in that case you might need to supplement. But you should be aware of the dangers involved when you don’t fully know or understand the issues in supplementation and the use of high-dose vitamins.
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What You Probably Don’t Know
Let me start dealing with the information that is either left out, or misrepresented or is simply inaccurate. The first issue is that there are people saying folic acid is poison and should be avoided at all costs and that people should only ingest folate (vs. folic acid). These people have not studied nutritional biochemistry. Folic acid is actually more bioavailable than folate.(5) In nutrition, folate is a family of eight compounds, of which folic acid is one of those (there’s even a receptor specific for it, called human folate receptor 1). Folic acid is found in food, just like the other folates are, it’s just that they ALSO make folic acid in a lab and add it to supplements, the same as vitamin E in a plant has eight parts which include alpha-tocopherol AND alpha-tocopherol is also made in labs and added to supplements. 80 years of the use of folic acid in supplements have shown it is safe BUT THE KEY IS THE DOSAGE AS WELL AS TIMING. Let me explain.
Folate is known to prevent cancer (6,7,8,9). Unfortunately, it can also cause cancer in two populations — people who were folate deficient for long lengths of time before they started supplementing, and in people who already have cancer. That’s right — if you already have cancer, folate will “feed” the cancer as folate is involved in DNA and replication.(10) In fact, that’s what the chemotherapy drug methotrexate does — it destroys folate pathways in an effort to slow the growth of cancer.(11)
And then there’s the amount ingested. It has been shown in research that too much folate supplementation will cause tumorigenesis. Basically, a consistent amount of 400 mcg per day is fine (800 mcg if you have the MTHFR 677 T,T variation), but more than that is problematic. Remember to calculate in the amount of folate you or someone might have in their diet as well, as that adds to this total. Additionally, check all supplements as it can be in other supplements besides just a multivitamin. High folate intake and cancer is the basis for a variety of research papers titled things like “Folate supplementation: too much of a good thing?”(12), “Folate and Cancer—Timing Is Everything”(13), and “Will mandatory folic acid fortification prevent or promote cancer?”(14)
Sometimes people will say “But what about unmetabolized folic acid found in the blood? That causes cancer!” It doesn’t actually — what it means is that your body is trying to clear excess folate, and that’s exactly what you want it to do. There is zero evidence that unmetabolized folic acid is a problem, despite what people might say. Zero.
Folic acid fortification has been in effect in the US since 1998, primarily to reduce the incidence of neural tube defects, for which it has been extremely effective. However, “In this regard, an emerging body of evidence suggests that folic acid supplementation may enhance the development and progression of already existing, undiagnosed premalignant and malignant lesions. Over the past few years, the US population has been exposed to a significant increase in folate intake, for which essentially no data on safety exist. The potential cancer-promoting effect of folic acid supplementation needs to be considered in carefully monitoring the long-term effect of folic acid fortification on the vast majority of the US population, who are not at risk of neural tube defects.” (15) The foods typically supplemented include breads, cereals, nutrition bars, etc. So if you’re not eating those things, and not taking a supplemental vitamin, and ALSO not eating enough vegetables, you may be folate deficient.
So the problem is two-fold — if you don’t eat enough vegetables, beans, or supplemented foods and have the MTHFR variation, then yes, you might notice some problems related to the MTHFR gene (and a possible increase in cancer). Or, not related to the gene, if you have too much folate or folic acid in your diet, it ALSO increases your chances of cancer.
Then there’s the issue of methylation and overmethylation. Methyl groups have effects on many, many different areas of the body, INCLUDING TURNING ON AND TURNING OFF GENES and this includes tumor suppressor genes. To prevent abnormal methylation, there are seven checkpoints to prevent hypermethylation, since hypermethylation often causes cancer. This is well known in oncology and there is plenty of research being done about this (16,17). So this is another reason that you not want to take large amounts folate (or any other methyl donor (ex: methyl-B12, SAMe), because you also do not want too much methylation to occur.
So then why in the world would you want to take a nutraceutical like methylfolate/5-MTHF? Methylfolate supplements can be as high as 10,000 mcg (over 10 times the considered safe amount) and Deplin, which is available only by prescription, is as high as 15,000 mcg. Not only that, but taking methylfolate bypasses the seven checkpoints that are there to prevent hypermethylation, You’ve got two issues going on — you’ve added in a gargantuan amount of folic acid, potentially feeding any cancers or pre-cancers you might have, and you’ve also added a large amount of methyl groups that have bypassed the safety mechanisms that your body has designed to prevent overmethylation.
Merck Pharmaceuticals designed 5-MTHF as an answer to the damage methotrexate does in its destruction of folate pathways in regards to treating cancer. In that particular case, taking 5-MTHF completely makes sense if you’re trying to rebuild those pathways. There can be isolated times where you might take it short term (like 4-6 weeks if you have high homocysteine, and are getting rechecked). But long term supplementation of methylfolate causes a list of side effects that rival a pharmaceutical drug: anxiety, irritability, insomnia (from changes in neurotransmitters), sore muscles and achy joints (from reduction in glutathione production), headaches and migraines (from increased nitric oxide production), nausea, palpitations, rashes and suicide, in addition to exacerbating B6 and B12 deficiencies, along with magnesium, zinc, copper, manganese and other mineral deficiencies. The advice from the website www.mthfr.net says to take more supplements to offset these side effects (sounding familiarly like taking more prescription drugs to offset side effects from other drugs) and actually says “Limit intake of leafy greens until side effects go away. This is because leafy green also contain methylfolate and nitrates.” Seriously? Instead of getting off this high-dose unnatural supplement, the advice is to limit vegetable intake?
Should I Ever Take Methylfolate?
People may feel better sometimes taking 5-MTHF for a short time simply because they’re nutritionally deficient — don’t let that mean that it’s appropriate to prescribe or take, especially long-term. I prescribe a higher dose for people with high homocysteine (typically 1200-2400 mcg/day) but I retest to see when I can put them on a lower, more normal maintenance dose. A practitioner once said to me in protest, “But it’s safe!” to which I replied, “How do you know that for certain? How long have we used this?” Not nearly long enough — a mere handful of years as a nutraceutical. You cannot figure out cause-and-effect by simply watching a handful of your patients — figuring out risk tasks years and large populations.
In preparing this article, I interviewed five biochemistry and nutrition PhD’s, all of whom categorically said that they would not take methyl folate as a supplement and considered the amounts typically prescribed as unsafe. In fact, one of them, who had a PhD in nutrition and cancer biology, and had worked as a clinical dietician in an oncology suite said that the last thing he would ever put in his mouth was a methylated form of folate supplement, simply because of his concerns for the cancer risks.
For Practitioners: Are you willing to put your health or the health of your patients in jeopardy just because some nutraceutical rep told you 5-MTHF was safe? Or your colleagues, who typically haven’t done the research involved to see the whole picture? Are you willing to believe some websites without really delving into their references (if they even have any?) or understanding the biochemistry? I certainly am not. History has proven that high-dose vitamins, never found naturally in foods, often cause harm — witness the studies on synthesized Vitamin A, C, E, beta-carotene and now folate. You’ll never go wrong sticking to low-dose supplements or better yet, eating real food.
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References:
1.Sah, Anil Kumar, et al. “Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss.” BMC research notes 11.1 (2018): 1-5.
2. Rai, Vandana. “Methylenetetrahydrofolate reductase C677T polymorphism and recurrent pregnancy loss risk in Asian population: a meta-analysis.” Indian Journal of Clinical Biochemistry 31.4 (2016): 402-413.
3. Grandone, Elvira, et al. “Homocysteine metabolism in families from southern Italy with neural tube defects: role of genetic and nutritional determinants.” Prenatal Diagnosis: Published in Affiliation With the International Society for Prenatal Diagnosis 26.1 (2006): 1-5.
4. Raziel, A., et al. “Hypercoagulable thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss.” American Journal of Reproductive Immunology 45.2 (2001): 65-71.
5. Winkels, Renate M., et al. “Bioavailability of food folates is 80% of that of folic acid.” The American journal of clinical nutrition 85.2 (2007): 465-473.
6. Giovannucci, E.Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr. 2002;132(suppl):2350S-2355S.
7. Kim YI. Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environ Mol Mutagen. 2004;44:10-25.
8. M. F. Fenech, “Dietary reference values of individual micronutrients and nutriomes for genome damage prevention: current status and a road map to the future,” American Journal of Clinical Nutrition, vol. 91, no. 5, pp. 1438S–1454S, 2010
9. B. N. Ames and P. Wakimoto, “Are vitamin and mineral deficiencies a major cancer risk?” Nature Reviews Cancer, vol. 2, no. 9, pp. 694–704, 2002.
10. Cole BF, Baron JA, Sandler RS, et al; for the Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007; 297:2351-2359.
11. Ulrich CM, Robien K, Sparks R. Pharmacogenetics and folate metabolism—a promising direction. Pharmacogenomics 2002;3:299 – 313.
12. Ulrich, Cornelia M., and John D. Potter. “Folate supplementation: too much of a good thing?.” Cancer Epidemiology Biomarkers & Prevention 15.2 (2006): 189-193.
13. Ulrich, Cornelia M., and John D. Potter. “Folate and cancer—timing is everything.” JAMA 297.21 (2007): 2408-2409.
14. Kim, Young-In. “Will mandatory folic acid fortification prevent or promote cancer?.” The American Journal of Clinical Nutrition 80.5 (2004): 1123-1128.
15. Kim, Young-In. “Will mandatory folic acid fortification prevent or promote cancer?.” The American Journal of Clinical Nutrition 80.5 (2004): 1123-1128.
16. Crider, Krista S., et al. “Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role.” Advances in Nutrition: An International Review Journal 3.1 (2012): 21-38.
17. Ulrich, Cornelia M. “Folate and cancer prevention: a closer look at a complex picture.” The American Journal of Clinical Nutrition 86.2 (2007): 271-273.
