Treating Methylation: Are We Over-supplementing?

on June 21, 2017 by Chris Kresser

Genetic testing for MTHFR variants has become increasingly popular in the alternative health community, and many patients begin supplementing with high-dose methyl donors based solely on their genetic results. But are we supplementing too much? Read on to learn how we should really be treating methylation issues.

Methylation is a process that is absolutely fundamental to the body. In this article, I’ll review what methylation is, talk about the perils of over-supplementation, and discuss how we should be treating methylation issues. (Hint: think diet and lifestyle.)

Methylation: what is it?

Methylation is a biochemical process involving the transfer of an active methyl group between molecules. Methylation is required for cell division, DNA and RNA synthesis, early CNS development, gene expression, immune cell differentiation, post-transcriptional modification, neurotransmitter synthesis and metabolism, histamine clearance, detoxification, hormone clearance, cellular energy metabolism, phospholipid synthesis, and myelination of peripheral nerves.

Methylation of DNA also plays a crucial part in epigenetics, determining which genes are turned on or off. For most genes, less methylation = ON; more methylation = OFF. These methylation patterns can be passed on and influence the gene expression of subsequent generations. Fortunately, they can also be influenced by diet and environmental factors.

Given the many crucial functions of methylation, it’s not surprising that methylation deficits can lead to a wide range of conditions. Impaired methylation can lead to depression, anxiety, histamine intolerance, increased risk of cancer, hormone imbalance, poor detox capacity, infertility, birth defects, fatigue, and low energy. (For more background on methylation, check out this podcast.)

Functional methylation testing: beyond MTHFR

The identification of the MTHFR SNP is perhaps what first put methylation “on the map.” Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme of the methyl cycle; it is responsible for the activation of folate for the subsequent reduction of homocysteine to methionine (1) . Certain single nucleotide polymorphisms (SNPs), or variants of this gene, result in the reduced capacity of this enzyme (2). Indeed, MTHFR variants are associated with increased risk for many diseases, including depression, fertility issues, insomnia, and thyroid conditions (3).

Because of this, many individuals, whether on their own, or at the recommendation of their healthcare practitioner, have sought genetic testing for MTHFR and other genes related to methylation and begun supplements to correct their supposed “methylation deficiency” based solely on their genetic results. This is a fundamentally flawed approach, since genes do not tell you about functional methylation capacity. Just because a patient has an SNP that might predispose them to impaired methylation does not mean they actually have impaired methylation. In fact, they could have completely normal methylation! On the other hand, a person who has no SNPs in their methylation genes could have severe methylation imbalance and require treatment.

Taking supplements for methylation? Be careful you don’t overdo it.

While genetic information can certainly be useful, it’s important to look at genetic results alongside functional methylation markers. Markers of impaired methylation on a typical functional blood chemistry panel include low serum folate, low serum B12, high serum MMA, and high serum homocysteine. Additional indicative markers include low RBC folate, high urine MMA, and high urine FIGLU.

The Health Diagnostics and Research Institute (HDRI) has a comprehensive test called the Methylation Pathways Panel that measures the many distinct folate derivatives in the methylation cycle, oxidized and reduced glutathione, and levels of methyl donor SAM-e and methylation inhibitor SAH. Doctor’s Data offers a similar panel with faster turnaround time, but it is not as complete as HDRI. These tests can help get an accurate picture of a patient’s actual methylation capacity.

The perils of over-supplementing

For several years, high-dose methyl donors have been viewed as the standard method for treating methylation issues. In the last several years, my viewpoint has evolved, and I now believe there is sufficient evidence to suggest that long-term high-dose methyl donor supplementation can be harmful. Like many nutrients, methylation appears to follow a U-shaped curve, where both deficiency and excess cause pathology. While hypomethylation is associated with many different problems, hypermethylation may be equally problematic. What we really need is methylation balance.

The truth is, we don’t yet have the knowledge to say that methylation needs to increase in area X and decrease in area Y. It’s also far too simplistic to assume that increasing methyl donors like folate and other B vitamins will inevitably lead to hypermethylation because the control of methylation is complex, involving DNA-methyltransferases, histones, and other regulatory proteins (4). In fact, several folate-requiring enzymes are actually inhibited by excess substrate (5); modest increases in cellular folate concentration activate these enzymes, whereas large cellular folate concentrations inhibit them.

Enzyme activity isn’t the only concern. In an animal model, both folate deficiency and over-supplementation were found to cause DNA damage (6). Excess folate intake has been linked to risk of nerve damage in older adults with B12 deficiency (7), and unmetabolized folic acid in plasma was associated with reduced natural killer cell cytotoxicity in postmenopausal women (8). It has even been hypothesized that excess folic acid supplementation could be a risk factor for autism (9).

Treating methylation imbalance

Clearly, high-dose methyl donors have some adverse effects, so let’s talk about what we should do to restore methylation balance instead.

Alleviate nutrient deficiencies

Nutrient deficiency is one of the primary causes of impaired methylation. The two most important nutrients in methylation pathways are B12 and folate, but other nutrients such as methionine, cysteine, taurine, DHA, zinc, magnesium, potassium, riboflavin, niacin, pyridoxine, betaine, choline, and sulfur also play a role (10). Inadequate intake of any of these nutrients can impair methylation. Foods high in these methylation-supporting nutrients include beets, spinach, mushrooms, eggs, organ meats, and shellfish.

Support gut health

You might be surprised to hear that bacteria play a role in the methylation cycle. Many Bifidobacteria are folate producers (11), while other bacterial genera, like Lactobacilli, are folate consumers (12). Gut dysbiosis can therefore lead to hypo- or hypermethylation, depending on which genera predominate. Restoring a healthy gut microbiota can help bring methylation back in balance.

Reduce competition for methyl donors

Competition for methyl donors is another reason for impaired methylation. If one particular function of methylation is in overdrive, it may use up available methyl donors at the expense of other methylation functions. This is most often caused by environmental toxins, high histamine intake, high estrogens, acute or chronic stress, and chronic infection or immune challenges.

Reduce exposure to methylation inhibitors

Methylation inhibitors can also interfere with methylation-dependent functions in the body. Drugs that interfere with methylation include valproic acid, cholestyramine, oral contraceptives, PPIs, and antibiotics. Nitrous oxide, which some patients take at the dentist, is a known oxidizer of cobalamin (B12) (13). Studies have shown that metabolites produced by beneficial bacteria serve as critical cofactors and allosteric regulators of epigenetic processes (14, 15).

Rebalance methylation with methylation adaptogens

An “adaptogen” is a plant-based compound that promotes the body’s natural balance within a biochemical pathway, bringing the body back into homeostasis. The term “methylation adaptogen” was first coined by Dr. Michael Stone in Oregon and describes any compound that helps to restore methylation balance, both promoting appropriate methylation and inhibiting aberrant methylation.

Examples of methylation adaptogens include curcumin, betanin, anthocyanins, quercetin, rosmarinic acid, lycopene, and sulforaphane. These phytonutrients are found in abundance in a nutrient-dense diet, but additional supplementation may be helpful in some patients.

Putting it all together

It’s clear that methylation is a very complex issue. Luckily, the treatment plan is fairly straightforward and circles right back to the idea that we need a diet and lifestyle that aligns more closely with our biology. To summarize:

  1. Methylation plays a crucial role in the body, both metabolically and epigenetically.
  2. Genetics aren’t everything. Regardless of what SNPs a patient might have, we need functional methylation testing to determine what is actually going on with methylation in the body.
  3. Methylation should first and foremost be addressed by making diet and lifestyle changes, addressing gut issues, and removing methylation competitors and inhibitors. You can also supplement with a bit of choline or creatine in patients that might need extra support.
  4. High-dose methyl donors can be helpful in some patients, but should not be continued long-term. The use of these supplements should be seen as an acute therapeutic phase to get patients back into a range that can be maintained with diet and lifestyle.
  5. Retest after 60 days to see whether the intervention is working.

For more on this topic, be sure to check out my recent podcast with methylation expert Dr. Kara Fitzgerald.

Now I’d like to hear from you. Have you seen patients with methylation issues? What do you think of using high-dose methyl donors? Start the discussion in the comments below!


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  1. Might want to fix your tweet worthy quote. It’s “overdo”.

    Also, great post. Lines up with a lot of my self experimentation. I’m homozygous c677t which means I need tons of supplements right? I can’t tolerate a low daily dose of methylcobalmin and methylfolate. I just eat raw leafy greens every other day and take a small amount of methylcobalmin a couple times a week and that’s good for me. I also take 750mg creatine daily and 500mg quercetin, and once every few days I take seeking health’s b-minus.

    As an aside, fish oil seems to make me feel sick, like I have a cold or something. Haven’t figured that one out yet. Even 500EPA/250DHA daily is enough to eventually bring on the effect. I try to just eat omega 3 eggs and sushi with salmon now.

    • Amy, they’re referencing the methylation testing you can do through Doctor’s Data or HDRI, mentioned in the article. The whole point is that the genetic testing doesn’t tell us enough, since clearly methylation changes with supplementation, dietary changes, etc.

  2. I am hetero for mthfr 677 and 1298 as is my daughter. I have shown some signs of RA (joint pain and burning. I can control it mostly with diet. Paleo is best for me. I had pretty good luck with metagenics ultrainflamax and probiotics. Have to supplement with b12, iron and D. Any testing recommendations. Also my daughter struggles with high cortisol. Wonder what your thoughts are on that?

  3. Thank you for this article. My personal experience is of scare mongering tactics by so called MTHFR Experts. I wasted a lot of time and money on supplements my body rejected – clearly didn’t want or need. Before I fired the expert, she told me it was all in my head, psychosomatic reactions to the supplements she prescribed. Very concerning that this was from one of Australia’s largest MTHFR clinics. Thankfully my naturopath who charges a quarter of the fee, provides me with the necessary information I need & acknowledges my sensitivity to supplements. Thank you for confirming that diet & lifestyle are key; over supplementation not advised.

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