Undermethylation Myths, MTHFR & The Great Folate Debate
70% of those with a mental health condition have a methylation imbalance. Of those, most are undermethylated (as opposed to overmethylated).
In case you haven’t yet met ….methylation….it’s an important biochemical process, in which methyl is added to particular molecules. Our ability to methylate impacts the expression of our genes, our ability to detoxify and our vulnerability to inflammation.
A methylation imbalance can contribute to chronic health issues like cardiovascular disease, autoimmunity, cancer and psychiatric condition.
70% of those with a mental health condition have a methylation imbalance. Of those most are undermethylated, as opposed to overmethylated.
The Incidence of Undermethylation:
98% of those on the Autism Spectrum
95% of those with Antisocial Personality Disorder
90% of those with Schizoaffective Disorder
85% of those with Oppositional - Defiance
82% of those with Anorexia
50% of those with Depression
Undermethylation is the most common biochemical imbalance in depression
MTHFR (Methylenetetrahydrofolate Reductase) is considered the most important enzyme in the process of methylation. A variant on the gene for this enzyme COULD mean a less effective enzyme and thus undermethylation (not methylating well).
The most commonly prescribed supplement for those with a MTHFR variant is folate in one of it’s various forms (listed below).
MYTH #1 - Having a variant on the MTHFR gene is unusual. It is estimated that 30 to 40 percent of the American population has a variant at position C677T of this gene.
MYTH #2 - Having a MTHFR variant means you are undermethylated (UM). As the star player in methylation, MTHFR gets a lot of attention. BUT, there are other genes which can also have variants that decrease or increase methylation and can even off-set the impact of MTHFR. Separately, having a variant doesn’t mean that that gene won’t do it’s job. Trauma, toxicity, chronic stress, and/or our microbiome can impact genetic expression…and thus methylation….and thus the expression of other genes…As you can see, it gets complicated. Those of us trained through the Walsh Research Institute assess methylation by looking at symptoms and traits, with a whole blood histamine/WBH (methlyation breaks down histamine), or a methylation panel (as certain medications can lower the WBH ).
MYTH #3 - Everyone who has an MTHFR variant needs folate . While folate helps the methlyation cycle, which is fabulous, it ALSO can unfortunately lower serotonin activity by way of an epigenetic (think “turning on and off of genes) mechanism. To oversimplify, folate impacts how tightly wound DNA is, which impacts the expression of certain genes. One of those genes encodes for serotonin re-uptake receptors. Dr. William Walsh (a pioneer in the field of methylation and brain disorders) found that most individuals with UM and brain symptoms have excess folate. Folate for someone already low in serotonin activity, could further decrease serotonin activity and thus worsen depression and anxiety. UM - from this perspective - is a methyl folate imbalance (too little methyl and too much folate). Those with Overmethylation (and thus high methyl and low folate) will thrive on additional folate.
This does run counter to the practice of many conventionally trained psychiatrists, who give folate (usually at very high doses) to those with a MTHFR variant on Gene Sight Testing. Similarly, many functional medicine doctors/practitioners use folate in those with MTHFR variants, independent of low serotonin symptoms, such as depression. All this to say, this impact of folate on serotonin activity, is not well known.
MYTH #4 - Those with low serotonin undermethylation should NEVER have folate. IF someone has a high homocysteine, we MIGHT use folate briefly to bring it down. This often isn’t necessary, as we have other tools such as B12, B6, Serine and TMG. If we have to, we’ll use folate, just long enough to bring that homocysteine down, before treating UM with targeted nutrients. Separately, children with autism (though not necessarily those on the high functioning end of the spectrum), do seem to benefit from folate.
MYTH #5 - Multivitamins, including B Complex vitamins are good for everyone. Almost all multivitamin or B complex vitamins contain some form of folate:
folic acid (a synthetic form of folate)
folinic acid
methylfolate dihydrofolate (DHF)
tetrahydrofolate (THF)
5, 10-methylenetetrahydrofolate (5, 10-MTHF)
5-methyltetrahydrofolate (5-MTHF).
Most of the adults and children that I see are UM with low serotonin symptoms. I am frequently taking people off multivitamins because of the folate. There are a very few multivitamins and B-Complex vitamins that have removed folate.
MYTH #6 - Everyone should eat a lot of leafy greens. A diet high in folate for someone with low serotonin UM (and thus most likely having too much folate already), isn't necessarily a good thing. Methyl, which we get from protein sources, is the priority, though, supplements are typically needed as well. I have seen a number of UM people, who because of their UM traits - their strong will and restricted eating patterns - were able to sustain a strict vegetarian diet that was low in protein (and thus low in methyl), which was making them more rigid in their thinking, excessively disciplined and lacking enjoyment. Spinach, asparagus and brussels sprouts are also high. Avocado is up there too.
MYTH #7 - Cereal is the breakfast of champions. Most cereals, “healthy” ones included, are fortified with folate (often in the form of folic acid) and therefore could worsen low serotonin symptoms for someone who is undermethlyated. I’m sure my pairing of a large glass of orange juice (also high in folate), with a bowl of flakes (back in the day), only added to my seeming need for lists with perfectly perfect boxes waiting eagerly to be checked off. Aside from cereal, many bread products, pastas and rice are enriched with folic acid. This will be indicated on the labels, though not necessarily like this
MYTH #8 - What’s good for the goose is good for the gander. I hope it it is clear, that we differ in our biochemical needs, despite the blanket dietary and supplement recommendations out there.
MYTH #9 - If taking folate for the first 3 months of pregnancy is important, then taking it the entire pregnancy must be even better. The reason for the first 3 months (and prior if anticipating pregnancy), is to prevent neural tube defects - things like spina bifida. That’s really important and recommended for all women (independent of methylation status). But after those first 3 months, are we needlessly exposing a fetus to high folate. We don’t know the methylation status of a fetus, but we do know that folate can impact the expression of certain genes. In 2016, Research from John’s Hopkins was able to, at least momentarily, bring this concern to public attention.
“The researchers found that if a new mother has a very high level of folate right after giving birth – more than four times what is considered adequate – the risk that her child will develop an autism spectrum disorder doubles.”
More, …for a low serotonin UM mother, being on all that folate beyond that important first 3 months, could be unnecessarily worsening or causing depression.
MYTH #10 - The incidence of UM is relatively constant. In an upcoming newsletter, I’ll share updates from the Dr. Walsh and the Walsh Research Institute, including the finding of a significant increase in UM (and decrease in overmethlyation) in the population and the role of the NMDA receptor in methylation imbalances.
Until Next Time,
Medical Disclaimer:
This newsletter is for educational purposes and not intended or implied to be a substitute for professional medical advice, diagnosis or treatment for either yourself or others, including but not limited to patients that you are treating (if you are a practitioner). Consult your own physician for any medical issues that you may be having.
Additional Resources
Nutrient Power - Heal Your Biochemistry and Heal Your Brain by William Walsh, PhD
Walsh Research Institute - Walsh trained practioners
Lunch with Dr. William Walsh - His Story, Discoveries & the Future of Nutrient-Based Psychiatry
Epigenetics, Methylation, MTHFR & the Brain, Made Easy...er
Undermethylation & Strengthening the Right Brain in a Left Brain World
Hi, I couldn’t find the blog post about “the role of the NMDA receptor in methylation imbalances” as you referred in this article, would it be possible to share the link?
I’m not sure which way to go in order to help my son. He is a 22 year old varsity athlete, and university student. He has been struggling greatly over this past year. It started with a major break up and the death of his grandmother. He has a lot of physical and mental stress from being a high level athlete. He is a 4th year university student who has never liked school and really struggles to apply himself academically. If it wasn’t for football, I doubt he would be in university. He has always been quiet and somewhat antisocial. He is extremely driven in sports and is also very sensitive to criticism. He is has never been a pleaser which certainly didn’t help him going through school. He has always been kind and likes to help the underdog.
This past year he started getting Ds and even failed a course. Normally he gets Cs and Bs. He seems very depressed. He has one more year of university to complete his degree but wants to drop out. He has even said he wants to take a break from football which has been his passion since he was a little boy.
I have done all of our family’s genetics. Owen is homozygous for the variants in COMT, MTHFR, DRD2, NBPF3, SLC23A1(B6), SLC30A8(zinc), GC(vitamin D) FUT2(B12), heterozygous for MAOA, ANKK1, and Homozygous for the normal allele of TPH2 and 5-HTTLPR.
He is the only one in our family with the slow version of COMT. My other 3 children have been diagnosed with ADHD. We tested Owen and he didn’t get a diagnosis, I’m assuming because of the slow COMT. However he struggled to focus and get motivated for school even though I know he has the intelligence. This past year he started using his siblings Vyvanse occasionally to help him get through his studies. I have also noticed that he started using cannabis as well, which is odd for him because he is so tuned into health and nutrition because of football. I now realize how detrimental Vyvanse is for him because of slow COMT and I am making an assumption that this along with the breakup and death has put him in a very bad place mentally and emotionally.
I desperately want to help him, he is struggling so much. But I am so confused as to the path to take because of his undermethylation, slow COMT, low dopamine and normal serotonin.
He has agreed to stop taking and I am hoping this will alleviate his need for cannabis. Should I try SAMe or TMG and stay away from methyfolate because of his very low mood? If it was just a slow COMT, that would be one thing, but add in undermethylation and low production of dopamine and fewer dopamaine receptors, and depressed mood….I am having a hard time trying to figure the hierarchy. I don’t want to give folate because of his depressed mood. I’m now even concerned about the amount of protein he consumes. But he needs to eat a lot of protein to preform in football.
I’m sorry this is so long, but I am just looking for some guidance in which is the most important gene to support first. I’m now thinking that because of how well we eat (tons of leafy greens, grassfed beef, chicken etc) this may have actually been detrimental for him as well. Any direction would be greatly appreciated. ❤️