The Potentially Dangerous Overemphasis on MTHFR
Have you ever worried about your MTHFR gene?
If so, have you been told to take methylfolate, or a B vitamin supplement that contains methylfolate?
And if you did take methylfolate, did you notice initial benefits and then maybe some strange symptoms after the first few weeks (or maybe even immediately)?
Maybe some anxiety? Maybe some depression? Maybe some insomnia?
If so, you are not alone.
People are often led to believe that their version of an MTHFR gene is the main factor affecting whether they have efficient or inefficient methylation processes in the body.
And if they have an inefficient MTHFR enzyme and/or signs of undermethylation (e.g. high blood histamine), they are also typically told that they need to take more methylfolate, sometimes a whole lot of it.
This is all part of a massive misconception, and it's potentially very dangerous. I'll explain why shortly.
Four Parts of the "Methylation Misconception"
This "methylation misconception" has at least four parts, including these ideas ...
- That how well you methylate folate is equivalent to which version(s) you have of one or two MTHFR genes. But there are over 100 MTHFR genes (not just the two MTHFR genes generally considered most important). And several other factors besides MTHFR genes affect the methylation of folate.
- That how well you methylate overall (your "methylation status") is equivalent to how well you methylate folate. But folate methylation is just one of many methylation reactions in the "methylation cycle".
- That how well you methylate overall is equivalent to how well your methylation cycle works to regenerate S-adenosyl methionine (SAM), the ultimate methyl donor in methyl transfer reactions throughout the body. But there are many other genes that affect how well methyl groups get transferred from SAM to other molecules.
- That the first step to improve methylation is usually to take more methylfolate, especially if you have an MTHFR gene variant.
None of this is accurate. All of it is potentially deadly.
Despite the fact that the MTHFR enzyme that methylates of folate is a very important step in the folate cycle and in the methylation cycle that regenerates SAM, there are other enzymatic steps before and after the MTHFR step that are also important and could be more important than the MTHFR step for any given person.
So we need to look at factors other than the MTHFR gene, including other genes, other B vitamins that act as cofactors for the various enzymes involved, and of course your actual symptoms and lab test results, both of which constitute the evidence of what the net result of all of this is in your body.
Can We Make MTHFR Irrelevant?
In fact, even with a gene variant for an inefficient version of MTHFR, you might have perfectly normal methylation. And how much riboflavin (B2) you ingest is probably more important than which version of MTHFR you have because riboflavin is the precursor for the cofactor for the MTHFR enzyme. The inefficient variant of the MTHFR enzyme simply has a reduced affinity for its cofactor, so supplying more of the cofactor via vitamin B2 solves the problem.
If you increase the supply of MTHFR's cofactor by ingesting more riboflavin, you can compensate for MTHFR's lower affinitiy for its cofactor. The cofactor is flavin adenine dinucleotide (FAD), which your body makes from riboflavin. The bottom line is that if you take enough riboflavin, it could make an inefficient MTHFR enzyme irrelevant.
And again, how well you recycle and re-methylate folate is just one factor in the methylation cycle that regenerates the main methyl donor in your body, SAM.
Looking at the Whole Methylation Cycle
The image below depicts the overall methylation cycle, with the folate cycle on the left and the rest of the methylation cyle that regenerates SAM on the right, plus a few other items below homocysteine that will not be covered here.
Don't try to understand the whole cycle right now. Just notice that there are multiple parts of the cycle and multiple enzymes and B vitamins in each part. In other words, it's not all about folate.
A Big Risk of Focusing on Folate
Here's where it gets dangerous to think of methylation as mainly a folate issue ...
People with an inefficient MTHFR gene could be an "undermethylator", or they could be an "overmethylator". You cannot diagnose methylation status based on one gene.
And people can "undermethylate" in some areas of their biochemistry and "overmethylate" in other areas of their biochemistry. So the terms "undermethylator" and "overmethylator" are oversimplifications yet can still be useful.
People who "undermethylate" overall are often low in methyl donors and consequently high in unmethylated folate. They are typically not deficient in folate, just in methylation! This is a very important distinction.
Although giving them methylfolate does give them functional methylfolate that can go through the cycle one time, that folate very quickly becomes unmethylated and ultimately adds to the pool of unmethylated folate if the body can't efficienctly re-methylate it. And having too much folate in the body can have some nasty consequences.
Folate exerts many effects in the body besides its role in the methylation cycle, and one of folate's effects is to increase the production of reuptake proteins that reuptake neurotransmitters like serotonin, dopamine, and norepinephrine, thereby reducing the amount of of these neurotransmitters in synapses.
When it comes to serotonin, serotonin reuptake is a larger influence on serotonin actvity than the amount of serotonin present. So in people with low serotonin, too much folate will lower their serotonin further, potentially deepening depression if it is related to low serotonin (depression is not always related to low serotonin) and increasing the risk of suicidal ideation.
Another potential effect of dumping too much folate into the system is that folate seems to have unpredictable effects on genetic processes that affect cancer.
So "undermethylators" that are not folate deficient should not add lots of folate to the system and should instead us other strategies for improving methylation. We need to optimize folate supply and methylation in the body rather than maximize the supply of folate, because with things like depression and cancer the stakes are obviously high.
Other Ways to Improve Methylation
One strategy to improve methylation that does not involve folate is to use methylcobalamin (methylated B12). But if the person has impaired detoxification pathways, this could stimulate detoxification more than they can handle and make them feel worse. These people might need to unmethylated forms of B12.
However, it's important to realize that as with folate, excess B12 has also been linked to certain cancers. And excess B12 can ironically cause some of the symptoms that are associated with B12 deficiency, including fatigue, anemia, and nerve damage. SO don't over supplement with B12 either!
It's also important to check for deficiencies of all of the cofactors for enzymes in the folate and methylation cycles, such as riboflavin (B2), niacin (B3), B6, B12, zinc, and magnesium.
A more direct way to improve methylation status would be to supplement with SAM, which is an expensive supplement. But SAM downregulates MTHFR, so supplementing with SAM could potentially further reduce folate recycling and create dependency on SAM supplementation. This may be an OK compromise in an "undermethylator" that is high in unmethylated folate and low in methyl groups.
But it is important to be sure that the person is an "undermethylator" before using SAM, which you cannot know for sure based only on the version of the MTHFR gene that they have.
If the person is actually an "overmethylator", then adding SAM can be disastrous because it could elevate already high levels of neurotransmitters (overmethylators often have high levels of neurotransmitters due to low folate and high methyl groups), and this can push them into a disorder like schizophrenia or another psychosis.
So remember that taking folate and SAM are high-powered interventions that should not be undertaken without full knowledge of the person's biochemical landscape, especially if there are mental health symptoms that could be related to neurotransmitter imbalances.
And remember that if you have an MTHFR gene variant for an inefficient MTHFR enzyme, just taking more riboflavin might be enough to improve the function of the MTHFR step in the overall the folate and methylation cycles.
If you have one of these MTHFR gene variants and have signs of undermethylation (e.g. high unmethylated folate, low methyl groups, low neurotransmitter levels, etc), there are other steps for improving the overall methylation cycle besides SAM supplementation, like consuming other methyl donors, such as betaine anhydrous / trimethylglycine (TMG) (not to be confused with betaine HCl). TMG is sold as a supplement and is high in some foods, most notably beets.
Taking TMG also spares phosphatidylcholine from getting converted to TMG to donate methyl groups to the methylation cycle. Phosphatidylcholine is a very scarce and valuable resource in the body that should not be wasted on conversion to TMG.
Ways to Reduce Methylation Demand in the Body
Phosphatidylcholine is essential for keeping bile fluid so that it can help digest our foods, carry toxins out of the liver, and does not form gallstones. Phosphatidylcholine is also essential to healthy cell membrane function, neurological function, and much more. It is an expensive nutrient to make (via methylation), constituting about 30% of the body's demand for methylation.
The synthesis of creatine constitutes an even bigger demand for methylation. About 45% of the body's methylation demand is for the production of creatine, which is essential for the recycling of ATP in brain and muscle tissue.
So increasing the supply of creatine and phosphatidylcholine through food and supplements could satisfy 75% (45% + 30%) of the body's methylation demand.
In other words, for undermethylators, the lowest-risk (and probably highest-reward) way to improve methylation is probably to get more riboflavin, phosphatidylcholine, and creatine from food and/or supplements.
First, Know Your Methylation Status
Before considering any more direct interventions in the folate and methylation cycles, first you need to know how your methylation cycle is actually functioning, using a methylation panel. A detailed methylation panel can show you exactly where your methylation cycle may be getting interrupted. When I run this test with clients, what we see is often different from what we expected.
Once you know how your methylation is owrking, your levels of B vitamins, and take into account other factors like small intestine bacterial overgrowth (SIBO), which can create issues with folate,, then you can more accurately choose the right foods and supplements to address methylation issues.
When it comes to diet, overall "undermethylators" with high folate and low neurotransmitters may need to limit high-folate vegetables and beef liver while consuming at least some animal products for methionine, choline, and zinc (among other things), all of which tend to be low in undermethylators.
In contrast, overall "overmethylators" tend to be low in folate and high in methyl groups and therefore should generally emphasize high-folate vegetables, probably avoid methyl donors like TMG, possibly use "methyl-burning" supplements (e.g. unmethylated folate or lysine) and can potentially do better on diets low in animal products in order to restrict methyl donors like methionine.
Normal methylators have far more flexibility in these matters.
Does This Sound Complicated?
If this sounds complicated, well, it kind of is. But it becomes more understandable once you learn a few new things about how it all works. If you re-read this post a few times, and if I've written it sufficiently clearly, you'll understand methylation better than many functional medicine doctors.
If you would like support with things like this, the Bio-Individual Blueprint system can help. It cuts through the contradictions, confusion, and chaos in the nutritional world that constantly gives you ever-changing, one-size-fits-all adivce.
If you have health challenges, bio-individualizing your nutrition can change everything, and it can be a psychological breath of fresh air if you've felt frustrated trying to discern food facts and food fiction.
But just as methylation is not only about MTHFR and folate, health is not only about nutrition. Other powerful factors affect regulation and dysregulation in the body. So a comprehensive, holistic process that goes beyond nutrition is often needed to resolve health challenges.
If you'd like to finally solve your health mysteries and get on a more effective healing path, I invite you to learn more about the Bio-Individual Blueprint system, a process of deep root-cause analysis of health issues through the lens of your bio-individuality.
Then, if appropriate, book a time to meet with us to ...
- Go over your situation
- Review what you've done so far
- Identify some potential next steps for you to take
- Discuss whether the Bio-Individual Blueprint might be a fit for you