What is The Maximum Safe Dose of L-5MTHF?

L-5MTHF is the active form of folate, but ironically, it is far less studied than the synthetic (inactive) form folic acid. Because of that, the safe upper limit of L-5MTHF is not known precisely, but we can draw some conclusions from existing data about the risks of high-dose folic acid.

As we have discussed, there are many different types of folate, including the myriad of forms of natural folate that occur in food sources like beans and pulses, the synthetic crystalline form called folic acid that was discovered in 1941, folinic, acid, and L-5MTHF, the biologically active form. However, most of the research on folate has been conducted using folic acid, so we are left to conclude from this.

Risks of High Doses of Folic Acid

Masking of Vitamin B12 deficiency and Cognitive Decline

Folic Acid has been used in food fortification programs to prevent neural tube defects in North America for decades. The program has been overwhelmingly successful in preventing these birth defects. Folic acid, however, has a tolerable upper intake level (UL), set in the US by the Institue of Medicine, of 1,000 mcg daily. This is equivalent to 1 mg folic acid. This level was chosen because research showed that it is 1/5 of the dose where adverse events begin to happen (called the lowest-observed-adverse-effect level, or LOAEL). Most notably, the masking of vitamin B12 deficiencies.

Vitamin B 12 deficiencies appear in the blood as oversized red blood cells with symptoms of fatigue and other signs of anemia with eventual nerve damage and neuropathy. Taking high doses of folic acid, like the 5,000 mcg dose we just mentioned, shrinks the red blood cells back to a normal size, making it look like there is no anemia present, but then doesn’t correct the nerve damage and neuropathy. This risk is especially important for seniors. This was demonstrated in observational studies showing that, at doses higher than or equal to 5 mg/day folic acid there were more than 100 reported cases of neurological progression in patients with pernicious anemia, compared with fewer than eight cases in studies administering less than 5 mg/day oral folic acid. The UL for folic acid was set to 1,000 mcg with the reasoning that setting the UL lower would prevent people from getting to that 5,000 mcg daily dose.

Observational studies show that high folic acid in the form of high serum folate or high UMFA presents an increased risk for cognitive decline in the elderly with vitamin B12 deficiencies. Cognitive decline among the elderly is a rapidly increasing problem with limited solutions and must be taken seriously.

 “Among those with low vitamin B-12, high UMFA or high serum total folate was associated with higher risk of scoring low on the DSST [cognitive decline]”

Bailey RL, Jun S, Murphy L, Green R, Gahche JJ, Dwyer JT, Potischman N, McCabe GP, Miller JW. High folic acid or folate combined with low vitamin B-12 status: potential but inconsistent association with cognitive function in a nationally representative cross-sectional sample of US older adults participating in the NHANES. Am J Clin Nutr. 2020 Dec 10;112(6):1547-1557. doi: 10.1093/ajcn/nqaa239. PMID: 32860400; PMCID: PMC8184300.

Unmetabolized Folic Acid (UMFA)

Synthetic folic acid must go through an enzyme called dihydrofolate reducatase to be converted into the natural reduced form of folate, but this enzyme is both slow and easily saturated. Because of this, unmetabolized folic acid can remain in the blood, even after a single dose higher than 200 mcg and levels increase with increasing doses of folic acid. Also, a recent study of pregnant women in Canada showed that UMFA was detectable in more than 90% of pregnant women’s serum and cord blood samples, and nearly all blood samples from the US.

While the risks of UMFA haven’t been fully documented, we do know that it competes with receptor sites for folate, essentially blocking active folate from functioning. We also know that children with higher levels of UMFA in their cord blood at birth are at higher risk for autism spectrum disorders especially when they are black.

Cancer

The relationship between cancer and folate is a complicated one, and likely has more to do with the whole body folate status, than with particular forms so it is likely that this risk applies to L-5MTHF as well, although that is not verified by research.

“There is strong evidence that low folate status promotes cancer, especially colorectal cancer. […] Elevated folate status has been proposed to promote tumorigenesis from preexisting foci of neoplasia and accelerate the growth of established tumors.”

Field MS, Stover PJ. Safety of folic acid. Ann N Y Acad Sci. 2018 Feb;1414(1):59-71. doi: 10.1111/nyas.13499. Epub 2017 Nov 20. PMID: 29155442; PMCID: PMC5849489.

Essentially this indicates that both too little folate and too much folate are dangerous. Too little, because the lack of folate causes altered methylation patterns in the genes, thereby allowing cancer promotor genes to express and reducing the effectiveness of cancer supressor genes. Too much folate is dangerous here because it encourages cell growth and division and if there are cancerous or precancerous cells present, they divide and grow more rapidly in a folate-rich environment.

The receptor-blocking action of UMFA could be an additional risk factor for low folate activity with folic acid supplementation, which would be removed by supplementation with L-5MTHF. However, in terms of high folate activity, L-5MTHF could potentially be more dangerous because it is more biologically active.

Again, this research has not yet been conducted, so most of this is educated guess work.

At the end of the day, it is not safe to assume that L-5MTHF is not also cancer promoting so it is imperative to find a balance, especially for people taking therapeutic doses of L-5MTHF for symptoms related to MTHFR such as anxiety or depression. There is a beneficial effect to these supplements, but obviously a risk as well.

Metabolic Disease

The research is mixed on the relationship between high folate levels in pregnancy and metabolic disease in the offspring in later life.

One study, conducted on rats, fed pregnant dams a normal folate diet or a high folate diet which had 20 times the amount of folate relative to normal. Their offspring were fed regular food or food plus 10% fructose, which sounds like the lab rat equivalent of pop. The study found that the rats whose mothers were on the high folate diet were more likely to have high blood sugar, more visceral fat, and insulin resistance. Essentially, this study is saying that the high maternal folate diet effectively programmed long-term metabolic dysfunction in the offspring.

A review article of the current literature reiterates that there is strong evidence in rats, but very little research evidence in humans. Although, rising trends in metabolic disease since the 90s, when folic acid fortification came about, certainly do give one a pause for thought.

Lab Testing For Folate Levels

As we have discussed in other posts, the lab testing for folate is sadly inadequate because it doesn’t differentiate between active forms of folate and unmetabolized folic acid.

In the US, folate levels have no real range, just a minimum. In most labs, the minimum is set to 4 μg/L, but research from the European Journal of Hematology suggests that red blood cell changes can be seen in blood cell samples under 8 μg/L, so functionally that is likely a healthier lowest level. The problem here, is that a safe upper limit is not set and many people I have seen in my office come in with folate levels well above 20 μg/L. So how do we know how much is too much?

The Last Word on How much L-5MTHF is Too Much

Ultimately, we’re left with educated guessing. For myself, My diet is high in natural folates – probably hovering close to the 400 mcg RDA, and almost 100% free of folic acid fortified foods, and a few times a week I take a reasonable dose of L-5MTHF (usually between 1,400 and 3,400 mcg just depending on how much support I feel like I need that day). This works out for me in terms of symptom management, and hopefully keeps me below the danger zone.

I try to keep my folate levels between 8 μg/L and 16 μg/L, even though I only take the active forms. I do this for the arbitrary reason that double the lower limit sounds like it *could be* a safe upper limit. Of course, this is entirely guess work so stay skeptical, and I will update this post as more research on the subject comes to light.

At the end of the day, it is important to remember that every supplement, nutrient, and drug you take in is going to have effects on your body and your health and we don’t know what all of those are. There will be some very positive effects, but also some negative ones. There is so much to medicine and nutrition that we don’t know, the safest course of action is to always use supplements and medications sparingly and cautiously. Also, please remember that nothing on this site is intended to substitute for the care of a qualified physician who knows your medical history and can give you real medical guidance. This is for information purposes only.