I have written quite a bit recently about the methylation cycle and its relation to nutrient balance. At Wise Traditions this November in Anaheim, one of my three talks will expand these ideas to include targeting methylation nutrition to individual needs based on genetics and health status. Here, I’d like to chip away at one small piece of the puzzle that I have not written about yet: why benefits from SAMe supplementation should cause one to look not only at the most commonly discussed methylation nutrients (e.g., B12, folate, choline, betaine, methionine) and genetic polymorphisms (e.g., MTHFR) but also at issues that are more commonly neglected when discussing methylation: magnesium and the metabolic rate.
In my previous posts and articles, I have simplified the methylation cycle in order to make the nutritional topics I was discussing easier to understand. One thing I have left out (e.g., here and here) is that before methionine can be used for methylation it must be activated to S-adenosyl-methione, which is sold as a supplement and in the supplement market generally abbreviated as SAMe.
The Mayo Clinic has conveniently collected information on the doses of SAMe that treat a variety of conditions, as well as ratings of the evidence that SAMe is beneficial for a variety of conditions. SAMe is a very expensive supplement, so it makes sense to dig a little deeper and see why the supplementation may be necessary.
Joel Brind, a Baruch College professor of human biology and endocrinology whose research on methionine/glycine balance I have cited in the past has been blogging on Matt Stone’s site and recently addressed this topic himself. In the most recent post, he suggested that some people who have genetic difficulties recycling methionine from homocysteine may need small doses of methionine to hold them over between meals, which they can get from a small methionine-rich snack.
Indeed, any problems recycling methionine from homocysteine should be fully investigated because if these are the real problems then an expensive supplement like SAMe is a waste of money. These conditions would tend to be associated with elevated levels of homocysteine and they could include deficiencies of B12 or folate, especially in the context of a diet that is not rich in choline or betaine, or genetic polymorphisms in the pathways of these nutrients. They could also result from a deficient intake of methionine itself, which would be most likely on a very low-protein vegan diet or a diet that is outright deficient in protein, and this may not (necessarily) be associated with any elevation of homocysteine.
There is another possibility, however, that is strongly suggested by the biochemistry: some people may not be efficiently activating methionine to SAMe. In order for this activation to take place, the enzyme methionine adenosyltransferase (MAT, also known as S-adenosyl methionine synthetase) breaks apart ATP to harvest from it a molecule of adenosine and then activates methionine by sticking adenosine onto it.
People who have severe genetic deficiencies of the MAT enzyme are unable to use methionine, even when adequately present, for the methylation process. This is because that methionine is never activated to SAMe. Thus, they are deficient in methylation, they have little risk of depleting glycine by consuming excess methionine if the problem isn’t fixed (though they still may have inadequate glycine for other purposes, such as detoxification and synthesizing collagen), and since they never use up the methionine to make homocysteine, their methionine becomes elevated rather than their homocysteine, and their homocysteine is actually low.
The biochemistry suggests that people with a normally functioning MAT gene could have two other reasons for poor activation of methionine: poor magnesium status, or a low metabolic rate. Since ATP is the source of the activating molecule, the reaction is, quite clearly, ATP-dependent. Since ATP is always utilized as a chelate with magnesium, the reaction is also magnesium-dependent. The presence of a magnesium deficiency, a low metabolic rate, or both conditions together, could prevent methionine from being activated.
It is important to realize, however, that a low metabolic rate or a magnesium deficiency will compromise thousands of bodily processes, and that either condition would be likely to coexist with multiple nutrient deficiencies. Thus, such a person will not necessarily replicate the presentation of someone with a genetic deficiency of the MAT enzyme. They will not, for example, necessarily have low homocysteine. If the recycling of homocysteine is also being compromised, then homocysteine could be normal or elevated even while methionine is failing to be utilized properly and is thereby generating homocysteine at a much lower rate.
In my opinion, if someone benefits from SAMe supplementation or suffers from any of the conditions for which SAMe supplementation has shown to be beneficial, and it can be ruled out that simply ensuring adequacy of dietary methionine and relevant B vitamins would fix the problem, magnesium status and metabolic rate should be evaluated.
Magnesium concentrations in serum, plasma, red blood cells, and urine can be useful in assessing magnesium status, but probably should not be used to rule out the possibility that magnesium supplementation could be helpful. In addition to supplementation, proper stress and sleep management as well as eating a wide variety of unrefined plant foods can help with magnesium status.
Ensuring a normal basal body temperature is, in my current opinion, probably the most cost-effective and helpful way to address the metabolic rate. However, addressing why the metabolism may have slowed may be more complicated. Managing stress and sleep, ensuring adequacy of most nutrients, and eating enough total food and carbohydrate are probably the key factors to consider.