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Treating Methylation: Are We Over-supplementing?

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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.

17 Comments

  1. just wanted to say thank you so much for the level-headed tone of this article.
    due to a host of chronic inflammation problems i suffered from in early adulthood, i took MSM for the better part of 3 years. initially, it worked like a miracle drug. i felt the best i’d ever felt in my entire life. towards the end of the 3 years though, i developed significant kidney issues from the MSM. my oxalate levels went through the roof, my adrenals got all messed up, everything out of wack. doctors haven’t been able to help much or find any cause, and a decade later i still haven’t been able to fix whatever the heck it was i imbalanced by taking MSM for too long. i *highly* recommend people exercise caution with methyl donors or sulphur based supplements and i wish i could have read your article 15 years ago!

  2. Based on my methylation panel, I am an under-methylator. I also have high histamine (with major histamine intolerance), high unbound copper (but optimal serum copper). I have started feeling significant bouts of depression for the first time in my entire life (I am 48). It is almost debilitating for hours at a time…and then it lifts suddenly, only to come back later for a few more hours. It seems to happen within an hour or so after every meal I eat. Yesterday, I could barely function until it lifted around 1pm, before I ate lunch. What can I do to help ease this depression and high levels of histamine? I am taking B6 (P5P), C, low dose Zinc, and I just started methionine (My SAMe was low, as was my methionine on my mthylation panel). Thank you for ANY help. Not sure if this adds to the story, but I was also exposed to very toxic levels of mold and just moved out of my home about a month ago (It is being demolished and rebuilt). Again, I SO appreciate any ideas or support. I have a functional doc but now have no resources to continue going so I am doing this all on my own.
    My email is missymaiorano2@gmail.com