I get asked questions about methylfolate all the time. Everyone is concerned about their MTHFR gene mutation.

Many migraineurs are convinced they need methylfolate. Just last month a woman wrote to me:

I have the MTHFR mutation, and MUST have my B vitamins methylated, else they will not absorb at all! They were specifically prescribed by my metabolic disease specialist. I must have my B vitamins methylated.

Yet, I am not a big fan of methylfolate supplementation in migraineurs for one simple and extremely good reason: I regularly hear (and also personally experienced), that people with migraine and MTHFR gene mutations are often triggered by methylfolate, despite their doctors telling them they need it.

I’m not out to be a contrarian on principle. I’m not a doctor and methylation is an extremely complex topic, one that I don’t have a deep theoretical grasp on. What I do have a grasp on is perhaps even more valuable, however: the willingness to recognize that no matter what a doctor tells you you need to supplement with, if it makes you feel shitty, you might want to stop.

If supporting methylation were really as simple as supplementing with methylfolate, we would see that people with migraine (ie, glutamate toxicity) and MTHFR gene mutations would feel better on it — and yet, they usually they don’t.

Why is this?

For one thing, folate increases free glutamate in the body and brain, which is one major cause of excitotoxicity and migraines.

Folates are comprised of numerous glutamic acids conjugates. The higher the dose of folates, the greater the propensity towards an increase in the pool of free glutamate. Hence, the “excitatory” and neurological types of adverse effects of folate in certain individuals. (Source)

That’s the primary reason to avoid them. But there are other reasons too. Here are a few examples for why caution is warranted, from the experts.

Marlene Merritt, LAc, DOM, MS Nutrition:

[L]ong 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. . . .(Source)

Dr. Carolyn Ledowsky

[F] or anyone dealing with allergies, inflammation, poor detoxification, hormonal imbalances or mood/ neurotransmitter imbalances – methyfolate could amplify these issues if they have not been addressed prior to engaging the methylation cycle once more. (Source)

Dr. Albert Mensah

Much discussion surrounding methylated folate comes from genetic testing and the MTHFR paradigm, which is neither an accurate assessment nor an appropriate guide for true methylation disorders. People who are truly undermethylated do not do well on methylated folate after two to three months. In fact, on quite the contrary, many people report worsening of symptoms. (Source)

Although we are used to thinking in stark binary terms – ie, overmethlated or undermethylated – the body can actually cycle between those two states throughout the day. If you happen to take methylated vitamins when you are overmethylated, or even manage to shift yourself from undermethylation to methylation, it’s important to consider the risks of overmethylation.

Marlene Merritt, LAc, DOM, MS Nutrition:

To prevent abnormal methylation, there are seven checkpoints to prevent hypermethylation, since hypermethylation often causes cancer. So this is another reason that you do 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? . . .(Source)

Dr. Ben Lynch is arguably one of the top worldwide experts on methylation. Despite this expertise, he says that he mistakenly used to just give people methylfolate if they were found to have the MTHFR mutation. “If they had homozygous MTHFR C677T, I gave them more methylfolate than if they were heterozygous MTHFR A1298C. Boy did that fail.”

So, even the top experts have made mistakes in suggesting methylfolate supplementation.

And finally, even if methylfolate were beneficial for migraineurs, it is doubtful that the amounts people are taking as a supplement would do the job.

Chris Masterjohn:

The RDA for folate is 400 mcg depending on your sex and life stage, and that assumes you’re going to absorb 200mcg of folate. Each molecule of folate you consume is recycled 18,00 times per day. If you consume a molecule of methylfolate the methyl group on that folate is available once, and then it has to be recycled 17,999 times. Where does that recycling come from? The carbons come from serine or glycine, but the part that MTHFR is catalyzing, the part that’s defective in someone with an MTHFR mutation, they’re coming from glucose. . . One glucose molecule, if you’re burning it for energy, supplies enough NADPH to recycle one molecule of folate one time. You’re going to need 3,00 to 6,000 molecules of glucose for every molecule of folate to get your daily methyl flux out of it. . . . But if you wanted to make up for that process by adding individual methyl groups . . . . from methylfolate that you got out of a capsule, in order to make up for that process you would have to consume an incomprehensible amount of folate: 4.5 grams of folate. You would have to consume 18,000 times the RDA of folate. . . I would never advise anyone to eat 4.5 grams of folate. . . .If anyone thinks that by eating super high doses of folate like several milligrams that they’re getting anywhere near inching their way towards making up for the normal flux of methyl groups through that pathway, that’s delusional. (Source).

Your Body Needs Certain Nutrients in Place in Order to Handle Supplemental Methyl Donors

The challenges with the question of how best to support the body’s ability to methylate property may come down to understanding how nutrients work in dynamic concert with one another. Supplements need to be taken with those dynamics in mind. These relationships are very complex and taking a supplement as a singular agent is part of the “silver bullet” approach to nutrition which is being borrowed from the pharmaceutical approach to disease.

When someone is not methylating properly, it is likely because there are probably deficiencies in other nutrients involved in methylation besides methylfolate that will not allow methylation to be carried out in their absence — ie, glycine, betaine, choline, etc. Many minerals involved in methylation like zinc, magnesium, etc need to be present in adequate quantities for these enzyme processes to work.

Dr. Lynch confirms the necessity of keeping these nutrient relationships in mind:

If you know or suspect that you may be deficient in various minerals or vitamins, then it is important that you replenish many of them prior to supporting with methylfolate or methylcobalamin. Why? Because if you support with these two powerful methyl donor nutrients, it can cause a ‘clog’ in your biochemistry. This ‘clog’ may occur in how your brain chemicals (neurotransmitters) get formed and/or eliminated. Obviously, this can cause some significant issues. (Source)

He explains in this article that because methylation speeds up cell growth and division, methylation depletes magnesium, potassium, and glutathione.

If any of these are deficient, then the cell does not function properly, gets sick and dies. . . . As the cells malfunction, you malfunction. As the cells die, you experience greater side effects and a flare of your immune system – especially if your cells die a necrotic death which is what happens when the cells are very weak. This form of cell death triggers autoimmunity. Not good. Solution: Take electrolytes BEFORE taking any form of methylfolate OR methylcobalamin.

Here is a prime example of how a deficiency in one area can affect the benefits of taking another nutrient like methylfolate.

[F]olate and vitamin B12 are intimately interlinked within the folate/methionine cycles, and increasing the level of folate can mask the accrual of permanent neurological damage associated with a specific vitamin B12 deficiency. A striking illustration of this was provided by an epidemiological study by Morris et al. who reported that high folate status was associated with protected cognitive function, but only in those with normal vitamin B12 status, with this relationship reversed in participants with low vitamin B12 status. For this group, high folate status exacerbated the detrimental effect of vitamin B12 deficiency, increasing the risk of cognitive impairment and anaemia by a factor of five, compared to those with normal vitamin status. A further study also demonstrated that low vitamin B12 status was associated with a significantly increased decline in cognitive performance over the subsequent eight years, with this effect exacerbated in those having high levels of folate, or those taking folic acid supplements. Alongside these observations it is interesting to note that in one study supplementation with folic acid also significantly increased the proportion of participants with riboflavin deficiency. (Source)

This information is especially important for clients that I see showing a high cobalt level on their HTMA tests. Cobalt is part of the B12 molecule and an elevated level on a test usually represents a loss. This loss of cobalt and its effect on B12 is often a result of NSAID use, especially ibuprofen. So those who rely on ibuprofen for pain relief and who have a loss of B12 and cobalt may have a worse response to folate or methylfolate.

Folic acid and folate lower riboflavin, which can be valuable for some migraineurs (while it is not supportive for others, especially those with high iron).

It’s also interesting to note, as far as nutrient dynamics are concerned, that niacin lowers folate, and almost all migraineurs benefit from niacin, for reasons explained here.

It may be that the gut flora imbalances in those with migraine lend them towards higher amounts of folate produced by gut bacteria:

For example, bifidobacteria can make folate, whereas other types of gut bacteria may not contribute to the same degree. An overabundance of bifidobacteria or other gut flora imbalances may actually elevate your blood levels of folate beyond what is considered normal or beyond supplemental intake levels. This means that gut health must be restored. Other bacteria imbalances may alter SAMe and choline which affect methylation function. (Source)


Evolutionarily, we have never relied on food alone for our b vitamins. Our gut bacteria, instead, has always been a primary source of them. And, for those with imbalanced gut flora, it may be a source of an overabundance of some b vitamins like folate at the expense of others that would be available to us if we had healthier and more diverse gut flora.

So How to Support Methylation?

Choline, rosemary, betaine and trimethylgylcine all support methylation, but should, like all supplements, be used gently to nudge the body in the right direction. We should always take supplements as additives to foods rich in the nutrients we’re after. In this case, bitter leafy lettuces like romaine or mesclun greens are great for migraineurs as a source of folate, and many other common foods like eggs, liver, and beans also contain it.

To Summarize

Call it citizen science or just common sense, but I will continue to state the obvious that people with MTHFR gene mutations who feel like crap on methylfolate aren’t supported by methylfolate.

Seems simple enough, especially given the other ways out there to support methylation that won’t raise glutamate levels.

Common sense is an invaluable tool in the healing journey. When we are healing, our ability to test things out, see how we feel, and observe cause and effect are all infinitely more useful than intellectual knowledge or expertise. I can’t tell you how many times I’ve been excited about a nutrient’s properties, only to hear my body say a resounding, “No thank you, not for me.”

Over the years, I’ve learned to listen to that signal. It’s also very important to reduce the amount of supps you are on to a low enough level that you know what is causing what, so it’s not all a mashup of mixed signals – either that, or sequence out when you test and try supps so you can get a clearer message from your bodymind.

While methylation is complex, eating healthy foods high in naturally-occuring folate is not.

And doing simple experiments on oneself is relatively straightforward: just try going on and off a supplement like methylfolate, while acutely observing symptoms and taking notes, and decide for yourself whether it feels good for you.

Most migraineurs I talk to who have done this experiment have found and confirmed that methylfolate is not supportive to them. You may be different. Or, if you have so many migraines that you can’t notice a difference between how you feel off and on methylfolate, you may want to consider opting out, just to be on the safe side. Methylfolate supplements for migraine are a risk for more excitotoxicity in the brain.