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Supporting Methylation Indirectly with Downstream Nutrients

Supporting Methylation Indirectly with Downstream Nutrients

  • Have trouble supporting methylation? Pre-methylated compounds may help avoid the bad reactions in some with methyl donors like B12, methylfolate, and betaine.
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The human body relies on methylation to drive some of its most fundamental processes. The biochemical process of adding and removing methyl groups is involved in everything from DNA repair to the removal of toxic metals and biotoxins.

This article discusses supplementing premethylated nutrients to reduce the overall burden on the methylation pathways—resulting in a functional increase of methyl donors. Such downstream methylation support may offer novel therapeutic options for cases where supplementation with methylated compounds directly is not well-tolerated.


  • Methylation is an essential biochemical process that serves a myriad of essential roles in the body.
  • Methylation can be supported directly via foods and certain supplements that are methyl donors
  • Methylation can also be supported indirectly by supplementing with nutrients that require methylation—lessening the total methylation burden.
  • Such methyl-receiving compounds include creatine, phosphatidylcholine, and carnitine.


Supporting methylation directly is the subject of many nutritional frameworks targeting outcomes ranging from athletic performance to healing chronic illness. These approaches generally outline supplementation with methyl-donating or pre-methylated compounds, often poorly tolerated by more sensitive individuals.

Methylation can be supported nutritionally by eating foods rich in compounds like betaine or supplementing with compounds such as SAMe, methionine, or even methylcobalamin. One other possible approach is to supplement with nutrients that require methylation to produce.

These nutrients may help lessen the total methylation burden on the body and offer a functional alternative for those sensitive to methyl-donating compounds like methylcobalamin (B12). There are a handful of compounds that fit this bill and keeping them on one’s radar is likely to prove beneficial.

Methyl Donors

Methylation is an essential biochemical process by which small compounds, known as methyl groups, are utilized throughout our bodies. These modest compounds facilitate a range of biochemical interactions between enzymes, DNA, amino acids, and a myriad of other biologic targets (6).

Animal studies hint that conditions like non-alcoholic fatty liver disease (NAFLD) may be characterized by altered states of methylation within liver cell DNA (7).

The primary dietary sources of methyl donors include choline, methionine, betaine, and folate (indirectly) (2). These are essential nutrients, meaning a daily intake from dietary sources—our bodies don’t make them on their own!

As such, the dietary requirements of one or more of these nutrients may change based on the availability of others. Given the methyl-donor status of these compounds, dietary flux may increase or decrease the requirement for other methyl donors. Otherwise, metabolic processes requiring methylation may be compromised.

Complex Considerations

Sounds simple enough, right? Support your methylation pathways by ensuring adequate dietary intake of methyl-donors like choline and betaine (eggs and beets, for example.)

Things are not always so simple among those with dietary restrictions, food sensitivities, nutrient absorption issues, or other outstanding health concerns. Supporting methylation via increased dietary intake of supportive foods may not be timely.

Additionally, methylation is involved in so many processes throughout our bodies that it may have unforeseen downstream effects, even among those without explicit dietary restrictions (3). As such, pushing methylation directly may cause undesired results (4).

In simple terms: supplementing with pre-methylated compounds may reduce the need for dietary intake of methyl donors while maintaining functional adequacy (1).

Methyl Receivers

One possible alternative is to reduce the burden of methyl donors by supplementing with pre-methylated compounds. Think of it as the dietary equivalent of building a modular home instead of building from scratch. Less mixing of concrete, less cutting of boards, etc.

Supplementing with nutrients such as phosphatidylcholine, creatine, and carnitine (among others) can reduce the upstream dietary need for methyl donors like choline, betaine, and methionine (1).

The applications are broad; one example would be vegan diets that are low-methionine being able to supplement with plant-derived PC to reduce methyl donor burden. Another application would be the sparing of methionine to protein-building processes in which it plays a prominent role (5).


Our bodies make creatine via the guanidinoacetate methyltransferase (GAMT) enzyme. Genetic issues can result in drastic issues with GAMT efficiency resulting in creatine deficiencies that affect the brain and muscle (9). The human body uses SAMe as a methyl donor during GAMT’s conversion of guanidinoacetate into creatine.

This process consumes more methyl groups than any other methylation process in the human body (8). As such, providing the body with supplemental creatine may help “free up” methyl groups for other processes such as the recycling of homocysteine back into methionine.


Phosphatidylcholine (PC) is a fatty compound used throughout the body to support cellular health, among other things. It is made of a phosphorus compound attached to a choline compound and can be found naturally in foods with notable lecithin content.

For example, many PC supplements are sourced from sunflower lecithin. However, it is important to note that lecithin is not the same as PC—though the two often get confused (10). Sources of PC can also greatly influence their role within human nutrition and nutrient utilization (11). In other words, PC quality is of great concern.

Phosphatidylcholine is synthesized in the body through a multi-stage process that requires, in part, methylation to facilitate (12). Supplementation with PC could represent a novel way to reduce the burden on the pool of available methyl donors representing a functional increase in methylation capacity. In other words, boosting methylation by removing some of the existing burdens.

Kind of like ensuring a refrigerator doesn’t run down your generator as fast by unplugging the tv. I recommend listening to this interview with Dr. Johnathan Bortz for a much deeper dive into this subject.


Carnitine is essential in the production of energy on a cellular level. It transports fatty acids into the mitochondria where they are then converted into energy. Carnitine supplements, such as Acetyl L-Carnitine (ALCAR) are often recommended for both support of fatty acid digestion and overall energy “boosting,” for lack of a better term (13).

Various studies and reviews have shown that supplementing with methyl-donors (or increasing them) such as S-Adenosylmethionine (SAMe), methylcobalamin (B12), or similar increase available Carnitine levels (14)(15). Carnitine is synthesized in the body via methylation of Lysine into Trimethyllysine (TML) (13)(16). As the name implies, this is a fairly methyl-heavy process.

Final Thoughts

Methylation is a fundamental process but very complex. It involves many biochemical pathways deeply integrated into fundamental processes like DNA repair, the generation of cellular energy, and the detoxification of toxins. The complexity of methylation is a bit like that of functional genomics—so eloquently described by Bob Miller, ND as a “3d chess game underwater.”

The support of methylation through supplementation is a common approach among integrative and nutritionally-oriented practitioners, at least in my experience. These approaches tend to focus on direct support via compounds like B12, SAMe, Trimethylglycine (TMG), and maybe even L-Theanine given the circumstance.

The concept of supporting methylation via compounds like creatine to remove downstream methylation burdens represents a novel approach and possible alternative to direct methylation support. As always, only use the highest quality vitamins & supplements to ensure the most beneficial support.