NB: This article was modified March 2024. I am offering two new courses about this. The short course covers the specifics of folate, what to do, how to figure out if there’s an issue, and a decision tree to determine what to do if you have trouble with folate. The longer course goes into other problems related to anxiety and other mental health issues

I get a lot of questions about the methylation cycle and taking methylated folate. In articles and podcasts, I go into great detail about undermethylation. This causes a lot of confusion amongst patients because most providers don’t understand the full impact of methylated folates. Folate is a wonderful vitamin for many people. But for undermethylators, folate can cause problems. Why is that? To understand the issue, we have to first understand more about the methylation cycle, DNA, and why genetic tests may not be the right approach.

Undermethylators are one of the primary subtypes described by the Walsh Protocol. To understand why folate is a problem for them, we should discuss undermethylation.

Methylation is the process where DNA gets “tagged” by a small hydrocarbon group. Methyl is one carbon and three hydrogens. Carbon can bond to four different atoms, so a methyl group has one spot that allows it to attach somewhere else. The body uses methyl in many reactions and one of them is to turn off DNA.

How does it do this?

Though we are not exactly sure, methyl groups change the charge of chromatin, making it bind tighter to histones. What does this mean? The DNA is less accessible for transcription, so turning off those genes. Acetylation has the opposite effect. Here DNA becomes more available and turns genes on. Folate appears to increase acetylation of chromatin, though the mechanism is unknown.

One gene methyl turns off is the serotonin reuptake gene. Folate or folic acid appears to turn this gene on. If you have too much serotonin reuptake happening, serotonin levels will be low. If you have too little reuptake, serotonin will be too high. (Yes, you can have too much serotonin in your body and some people do.)

Undermethylators with anxiety or depression are vulnerable to folates. The folates turn on the serotonin reuptake gene that is already not downregulated because of the lack of methyl. For some people, they find that a sudden intake of folic acid causes a precipitous drop in mood or exacerbation of symptoms.

This gets further complicated when you add in high S-Adenyl-Homocysteine (SAH) a substance that regulates the enzyme methyltransferase. (This is a topic beyond the scope of this article for the moment. But the plasma methylation test is a wonderful way to determine if one is an undermethylator and the best treatment approach.)

NOTE: If you are a pregnant woman, it is advisable to have your folate levels measured to determine the amount of folate to take.

What about Methylated Folate?

What about methylated folate? Isn’t that supposed to help undermethylators? Many providers prescribe it because folate is intimately involved with recycling homocysteine into methionine. This drives the production of methyl in the 1-carbon cycle in the body. But Dr. Walsh has shown something odd about this. All folates turn on the serotonin reuptake gene so that serotonin levels drop and you have a recipe for problems. Likely, this happens because the DNA responsible for the production of the SERT gene has greater exposure to transcription factors. Increasing methyl causes this to reverse so there is less transcription of the gene.

Having said that, many undermethylators show temporary improvement because of taking methyl folate. After two to three months, the person devolves again. The methyl donation from the methyl folate gets overshadowed by the effects of folate on the body. So the person gets worse.

This is when patients call me. Fortunately, it’s not too late to feel better under this circumstance. A proper treatment plan can benefit everyone. Undermethylators respond slowly; some people may not get a benefit for almost a year after treatment starts.

To learn more about methylation, I’m planning a course that goes into greater detail about the topic and how to recognize the differences between overmethylation, undermethylation, and another underlying issue. A deeper course covers more information  Or if you think you may be an undermethylator or overmethylator, call today to schedule an appointment. Let me review your medications and supplements to ensure you are taking what is right for your healing process.