Question: Is there a potential for adverse effects of 5-10 mg of folate for heterozygous MTHFR?

Is there a potential? Yeah. The tolerable upper intake level for folate was set at 1 milligram on the basis that there are rare hypersensitivity syndromes that have caused reactions to 1 milligram or higher. On the basis that in numerous case reports, supplementation of more folate than that has been the factor that appears to precipitate the neurological degeneration in B12 deficient patients. It seems like if you're B12-deficient and you add a megadose of folate, there might be something causal about adding the folate precipitating the B12 deficiency. That makes sense.

Folate and B12 participate together in methylation. The neurological degeneration specific to B12 deficiency is probably mostly due to the non-methylation functions of B12. That's why it doesn't happen in folate deficiency. If you add folate, you're going to probably redirect some of the B12 into the methylation pathway, rob it from the other pathway, which is metabolizing methylmalonic acid into the citric acid cycle. You do that and you provoke the specific neurological degeneration of B12 deficiency.The flipside of this is someone could say, well, there's no evidence that outside of these rare things that 50 milligrams of folate causes harm. That's true. There isn't a well-characterized harm from it. But I still think that it's stupid, it's stupid. Why would someone with a heterozygous MTHFR SNP need 10 milligrams of folic acid or methylfolate? That makes no sense biochemically at all. It makes no sense. First of all, are they compound heterozygous or are they just heterozygous for the SNP?

I don't know if it's harmful, but it's irrational to take high-dose methylfolate for this purpose or high-dose folic acid is irrational. It's on the basis that it's not effective. It is five to ten times the Institute of Medicine's tolerable upper intake level. It's not that I know it will cause harm. It's just that it's way into the territory of what has the possibility of harm in some people. Why for no benefit would you take yourself deep into the territory of possible harm?

This Q&A can also be found as part of a much longer episode, here: https://chrismasterjohnphd.com/podcast/2019/03/30/ask-anything-nutrition-march-4-2019

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