Balance Is The Key to Methylation
I regularly hear from customers that have learned they are MTHFR (methylenetetrahydrofolate reductase) mutated and rush out and start supplementing with large doses of what would be considered a ‘megadose’ of both methyl folate and methyl B12 and—much to their surprise—their symptoms become worse, with some becoming convinced that they can’t handle a ‘methyl’ vitamin. All this is based on a very limited gene test, and without running a comprehensive methylation assessment to identify what is happening with their individual chemistry. So what is happening with these people?
Dr. Lynch, author of Dirty Genes, writes that adverse responses to Methyl Folate (MTHF) supplementation is the #1 reason for entries on his MTHFR blog. He answers that this is due to increased cell division as a result of effective MTHF supplementation. He posits that cell division re-doubles demand for magnesium and other minerals. He advises mineral supplementation as a rational treatment in these cases.
My comment is necessarily complex because methylation is a multi-factorial system, regulated by enzymes, nutrients and hormones and modified also by environmental factors, including a variety of common toxic substances, many of which are undiagnosed in the individual patients seen by doctors. My comments are necessarily incomplete and open to discussion.
Let’s start with the fact that many patients complain that methyl folate causes unpleasant physical and mental effects: e.g. anxiety, dizziness, torpor, mental dullness and mood depression. These reactions pose a much greater immediate problem than has been reported in the medical literature regarding folic acid, or in my dad’s 50+ year experience in active practice of orthomolecular medicine.
In fact, the number of mood and mental complaints with folic acid supplementation is so few that the world medical literature has failed to mention adverse reactions due to folic acid supplements other than a concern that folic acid and methyl folate supplementation might promote—but not cause—cancer and leukemia. The present consensus is that both folic acid and methyl folate can be tumor growth promoters but not carcinogens. In fact, Dr. Bruce Ames, emeritus professor of biochemistry, University of California at Berkeley, classifies deficiency of folic acid as a carcinogen. Low blood folic acid levels are known to be a biomarker for susceptibility to colon cancer!
Both folic acid and especially methyl folate are catalysts for nucleoside synthesis, i.e. DNA, required for cell growth and mitosis. On the other hand, treatment of cancer with so-called anti-folates, that bind and inactivate the DHFR enzyme mechanism, seems to work by lowering availability of TetraHydro Folate (THF). The fact is many patients do benefit from treatment with methotrexate or 5-fluorouracil, which are used to retard cancer growth by interrupting the role of methylation in nucleoside synthesis which inhibits the growth of cancerous cells.
But adverse reports, as mentioned by Dr. Lynch, are common with regards to mood and mental changes after intake of methyl-folate supplements, particularly with large doses. In his discussion, the first advice is to stop methylfolate. He explains this in terms of overdose, similar to symptoms from over-eating or over-drinking water. As mentioned, methyl folate leads to increased cell division and the adverse effect may improve with magnesium, glutathione or antioxidant supplements.
But Dr. Lynch goes on to discuss the fact that methylfolate can lower methionine! I disagree, for the primary role of metylfolate is to provide intracellular methyl to recycle homocysteine to methionine, thus restoring methionine to higher levels, not lower. Ingestion of protein from almost any plant or animal tissue, can also restore methionine. Animal tissues generally are higher than plants in methionine. So I disagree with his explanation, which he claims is ‘complicated.’
A more likely explanation for the adverse effect of methyl-folate is that it causes increase in a liver protein, GNMT, which absorbs (binds) to methyl groups from methylfolate and also from methionine, after it is activated into SAM. If the methylfolate levels are high, the amount of GNMT increases. This increase is due to induction of the GNMT enzymes in the liver. Induction is a common biochemical adaptation, similar to the increase in size of muscles after exercise. However, the increased activity of GNMT caused by induction can also bind and deplete SAM, converting it to methylglycine, which is also called sarcosine, and which is lost in the urine. This event lowers SAM and increases SAH, also called adenosyl homoysteine, which adds an additional requirement for methyl from SAM, thus further depleting SAM and causing inadequate methyl to maintain the hundreds of ESSENTIAL biochemical reactions required for moment to moment HEALTH and WELLNESS.
In short, overdose of methylfolate can deplete methyl and cause an imbalance and/or deficiency in hundreds of essential products that are part of our body chemistry. This imbalance is perceived by the nervous system as a variety of nervous symptoms. If the imbalance is prolonged, it may lead to disturbed choline and other membrane essentials as well as deficient myelin synthesis, thus causing damage to nerve tracts. This is especially likely to occur in cases of co-esisting vitamin B12 deficiency.
It is important, to know that methylfolate normally transfers its methyl group to homocysteine ONLY via hydroxycobalamin (vitamin B12). This is Mother Nature’s master plan in every cell in your body—so as to regulate the biochemical methylation pathway and prevent overproduction of methionine and its activation into SAMe (S-Adenosyl-Methionine).
Balance is a key to health. Mother Nature knows how to do it. Mankind is still in search of knowledge and better answers. Excess Methyl-folate works well for some of us but not all of us. The point is that 5-methylfolate (5MTHF) is a natural folate and is naturally present in leafy vegetables, such as to generate dietary intake of about half a milligram or less per day. However the medical food supplements and ‘natural’ vitamin products and supplements may contain up to 7 milligrams a day. That amount of methylfolate is found in 3 pounds of spinach, which is about ten servings! It is unlikely to overdose on methylfolate by eating salad but easy to overdose on methylfolate by taking high quality supplements.
Dr. Lynch also recommends that increased glutathione can correct overdose of methylfolate. However it is more likely to worsen the problem because glutathione supports the conversion of methionine to SAMe (adenosylmethionine), the active methyl donor, which then is converted to homocysteine, raising circulating levels, which can cause vascular symptoms, including-arterial spasm, hypertension, headache and, in susceptible people, pro-coagulant effects sufficient to cause low blood flow (ischemia), angina and even strokes.
The answer is simply to lower the dose of methylfolate or switch to folic acid—even if you have MTHFR.
It’s because of these insights that we do not provide a megadose of Methyl Folate in our OLA LOA Vitamin B12 lozenges, and prefer to provide a physiologic dose (what the body would normally produce in a day), that if necessary, can be increased in a sensible manner.
