Vegans and Methylation

Methionine and SAMe

S-Adenosyl Methionine, SAM-e, (aka AdoMet) is the fuel for methylation. It provides the methyl group to all compounds that need one.

SAM-e is made from the amino acid methionine. Methionine is the amino acid of second most concern for vegans, after lysine (Norris 2016). Less methionine, as found in a vegan diet, may alone improve health and longevity (Lee 2016; Orgeron 2014). However, not all agree that less methionine is better. (Cohen 2017).

It is possible to add more fuel to the methylation fire by supplementing SAM-e. SAM-e often is taken first thing in the morning on an empty stomach, away from protein-containing food.

Adding more fuel with SAM-e may be one of the quickest and simplest ways to test whether more methylation would be helpful. When I started with SAM-e, before I tried many other supplements, I found improvements in mood and energy within days.

ATP and Magnesium

Energy in the form of adenosine triphosphate, ATP, is needed to activate methionine into SAMe. ATP also contains the same molecule, adenosine, which bonds to methionine in SAMe. ATP is the basic currency of energy which carries energy where it is needed in the body. However, ATP is only bioactive once bonded with magnesium. So we also need magnesium to build SAMe. (Masterjohn 2017).

Magnesium deficiency may affect most of the population. There just isn't as much magnesium in the soil as before. And processing food takes out even more magnesium. So does softening drinking water. Calcium and vitamin D supplements may deplete body magnesium further, which is unfortunate because magnesium is needed to experience the benefits of calcium and vitamin D. (Dean 2017; Dean 2011).

Dr. Dean has presented a persuasive case for magnesium deficiency as a primary cause of almost all modern health problems. Indeed, almost all body processes need energy as ATP, and ATP needs magnesium. The making of SAMe is one of those processes that needs ATP and magnesium. Since methylation and also hundreds of other processes will be impaired without enough magnesium, magnesium supplementation might be a good place to start for many people.

I've found magnesium gluconate powder to be an effective form of magnesium, which has a calming effect and makes muscle cramps and twitches go away, as well as boosting methylation. I take 1 to 3 teaspoons a day in divided doses (about 150 to 450 mg of elemental magnesium).

Magnesium oxide, though commonly found in many multivitamins, may be an ineffective form of magnesium supplement because it lacks bioavailability, with fractional absorption only 4 percent (Firoz 2001).

Recycling Pathway 1: Methyl B12, B2, and Methyl Folate

Recycling Pathway 2: Betaine and Choline

The second recycling pathway takes place in the liver. Betaine (aka trimethylglycine) acts as a methyl donor to recycle homocysteine back into methionine and then SAM-e. Betaine can be made from choline.

Beets, spinach, and quinoa are excellent dietary sources of betaine; grains and sweet potatoes are good sources too (Norris 2013; USDA 2008). It's possible some vegans or vegetarians might miss these high-betaine foods.

Betaine can be made from choline. The richest food sources of choline are egg yolks and liver (USDA 2008). Vegans and vegetarians might get enough choline from plant foods (Norris 2013). Still, the lesser amount of choline in plant foods might not provide enough to synthesize extra betaine.

Less choline in vegan and vegetarian diet might increase methylation demand to synthesize extra phosphatidylcholine, which otherwise might be made from dietary choline (Norris 2013). More about phosphatidylcholine below.

One easy way for vegans and vegetarians to support the betaine-choline recycling pathway is to eat some beets, spinach, quinoa, grains, and/or sweet potatoes from time to time.

Creatine

Creatine is critical to muscles and the brain, providing energy on demand. Creatine supplements are known for improving athletic performance.

Creatine may be the methylation nutrient aside from vitamin B12 where vegans and vegetarians are at the greatest disadvantage. In omnivores, almost half of the creatine that the muscles need comes from eating animal flesh, including fish. Even so, around 40% of methylation in omnivores goes to making the rest of the creatine the body needs (Brosnan 2011).

As the calculation below shows, vegans and vegetarians need around 20-31% additional total methylation just to compensate for the lack of one nutrient — creatine — in their diets:

Table 1. Calculation of Methylation Burden of Creatine Synthesis in Omnivores versus Vegans and Vegetarians.

Chris Masterjohn suggested that creatine supplement could support methylation by reducing demand for methyl groups. Tim Ferriss recommended creatine as a supplement for vegans.

When I first tried a creatine supplement, I was amazed by the result. It made a long bicycle ride seem easy — and I went faster and ate far less along the way than ever before. In fact, my athletic performance has exceeded my expectations in runs and bicycle rides ever since starting creatine supplement.

Almost instantly, I noticed that the creatine seemed to stop the between-meal crashes I've always experienced, which I have always attributed to hypoglycemia or "blood sugar crashes." For the first time in my life, I could comfortably skip meals. And I've even been trying intermittent fasting, which might never have been possible for me before creatine due to energy crashes between meals.

Creatine also seems to improve my testosterone level, sex drive, athleticism, stress response, body temperature, vivid sleep, positive outlook, and general feeling of well-being.

When I took the commonly recommended 1-week loading dose of 5 g (1 tsp) creatine 4 times daily, I had to stop on the second day because the creatine was causing a major energy disruption with body temperature below 96°F. Even a small dosage, 0.5 g (1/10 tsp), taken all at once, seemed at first to induce a later stress crash for me when the creatine runs out. I've experimented with trickle dosing, adding 0.5 g (1/10 tsp) to each liter of water and drinking 1-5 liters throughout the day and night, with the amount depending on exercise level. Now I am taking 1.25g (1/4 tsp) of creatine 2 to 3 times daily, plus trickle dosing especially during exercise. The physical and mental benefits of the creatine are remarkable!

The amount of creatine I've supplemented, 0.5-4g per day, of which 80% is absorbed, 0.4-3.2g, makes a large dent in the 14.6 mmol = 1.9g creatine that the body breaks down daily (Brosnan 2011). And the trickle dosing might supply the body with a steady supply so that it can downregulate creatine production without facing gaps in availability.

Creatine supplement, even with just trickle dosing, has taken a huge load off my body. Maybe creatine can do the same for you!

[UPDATE 12/6/2018: I was unable to maintain the remarkable benefits of creatine supplement, regardless of the many different dosages I tried. I concluded the creatine was only temporarily patching over energy metabolism impairments, without fixing the underlying causes. For a more recent update about creatine, please see the section in another article called Creatine Supplement as a Stimulant?.]

Phosphatidylcholine (PC) and Omega-3 DHA.

Phosphatidylcholine (aka PC) carries fatty acids for inclusion in membranes throughout the body.

PC synthesis by methylation has been hypothesized as a consumer of methyl groups as much or more than creatine — which means more than 40% of the total methylation flux. (Stead 2006). Aside from methylation, the body also makes PC from choline by a process called the Kennedy pathway.

PC includes fatty acids in its molecular structure. Unlike Kennedy pathway PC synthesis, methylation PC synthesis selectively favors attachment of long-chain polyunsaturated acids — including the beneficial omega-3 fatty acid DHA. So methylation product PC contains more DHA than Kennedy pathway PC does. (da Costa 2011; Pynn 2010).

Vegans consume less PC than omnivores. The richest food sources of PC are egg yolks and liver (USDA 2008).

Maybe choline, lecithin, or PC supplements might help vegans and vegetarians reduce the demand for methylation. In my minimal experience, however, neither CDP choline nor soy lecithin had any noticeable effect on me. I look forward to try sunflower lecithin soon.

PC might be a delicate place to intervene in the methylation cycle. The source of the PC will alter the balance of fatty acids included in PC. Plant-based PC sources, such as soy lecithin and sunflower lecithin, might be higher in short-chain omega-6 fatty acids and lower in long-chain omega-3 fatty acids. If food or supplement plant-based PC were to relieve the need for the body's methylation-made PC, we might lose the benefit of the DHA enrichment in the methylation-based PC.

The richest food source of omega-3 DHA is fish. Vegans and those who don't eat fish are at a disadvantage for DHA. Also, some or many people have low conversion rates making long-chain omega 3 EPA and DHA from the short-chain omega 3 ALA which is found in flax, chia, and walnuts. (Norris 2014). A regular amount of fish or fish oil, or a vegan DHA supplement, might help support the 40% or more of methylation that goes to make PC.

L-Carnitine.

L-carnitine helps the mitochondria transport fatty acids for energy. It has several roles in the Krebs energy metabolism cycle (Cerretelli 1990). It is found primarily in muscle.

Vegans and vegetarians consume little L-carnitine. L-carnitine is abundant in meat. For example, beef steak contains 65-66 mg carnitine per 100g (Seline 2007; Demarquoy 2004). Little L-carnitine has been found in plant foods. Avocado, however, may be a rich source of carnitine — though measurements vary by more than an order of magnitude, from 0.58 mg to 11 mg per medium avocado:

Table 2. Carnitine Content of Avocado.

Omnivores get 75% of their required carnitine from food. In contrast, vegans and vegetarians may need to make more than 90% of their carnitine. As a result of the low dietary carnitine, vegans and vegetarians show lower blood carnitine levels. (Vaz 2002). One study found 53% of vegans had low levels of free carnitine (Krajcovicová-Kudlácková 2000).

For the portion of L-carnitine which is made within the body, the biosynthesis starts with N-trimethyllysine. There are two theories of where this carnitine precursor comes from. N-trimethyllysine may come from plant foods in the diet including sweet peppers and fruit juices, which might give vegans and vegetarians a carnitine-making advantage. (Servillo 2014). However, many scientists seem to think that the N-trimethyllysine used for carnitine synthesis is made by triple-methylating the amino acid lysine (Al Temimi 2016; Vaz 2002).

Indeed, methylation seems to support carnitine synthesis. Vitamin B12 and SAM-e seem to increase carnitine synthesis by supporting methylation (Podlepa 1990 abstract). And in vegans and vegetarians, levels of methionine and lysine seem to correlate with carnitine levels (Krajcovicová-Kudlácková 2000).

The initial building block, lysine, is usually the limiting amino acid in vegan diets. Legumes and seitan are the richest vegan sources of lysine (Norris 2016).

A few avocados a day might go a long way toward giving vegans and vegetarians the carnitine they need, without needing to produce it by methylation. Alternatively, if vegans needed to triple-methylate lysine to make all their L-carnitine, the L-carnitine production might add an extra 3.6% of methylation demand for vegans. And this number might be a significant underestimate, given the powerful effect of carnitine supplements on methylation. Here's the calculation:

Table 2. Calculation of Methylation Burden of L-Carnitine Synthesis in Omnivores versus Vegans.

Those with methylation symptoms commonly respond to carnitine supplements, sometimes even at micro-doses 3 orders of magnitude lower than those commonly found in supplement capsules. (Freddd 2015). Many people (90%) report L-carnitine fumarate to be a more effective form of carnitine supplement than the more popular acetyl-L-carnitine (ALCAR). (Freddd 2017).

Mega-doses of carnitine, sold as the common supplement dose of 500 mg, drive some people totally nuts (including me). However, much smaller doses (<50 mg) helped me a lot in mood and energy. However, the amount I could tolerate kept getting smaller and smaller. I eventually gave up on taking tinier and tinier dots of L-carnitine fumarate powder. Now I rely on eating a few delicious avocados a day to get L-carnitine. L-carnitine supplements might help some people a lot — but watch out for intense anger, fear, worry, and/or panic if you take too much.

Glycine to Sarcosine: Methyl Group Overflow "Relief Valve"

Sarcosine is a significant methylation product — at least sometimes. Unlike other methylation products which are made for the product itself, sarcosine's production is an overflow for excess methyl groups from excess SAMe. Sarcosine production by methylation varies greatly depending on excess SAM-e availability. It has been proposed that the glycine to sarcosine GNMT pathway acts as an overflow path to catabolize excess methionine. (Mudd 2007; Martinov 2000).

Martinov et al proposed a mathematical model with two stable steady states of methylation in which SAM-e supply equals SAM-e consumption. In the low-methionine steady state, the methylation reactions regulate the flow of SAM-e, and there is little to no methylation of glycine to sarcosine. In the high methylation steady state, the levels of the other methylation reactions stay constant, SAM-e concentration increases by an order of magnitude (10x), while the methylation of glycine to sarcosine increases in flow to absorb the overabundance of SAM-e. (Martinov 2000).

Related Article Section: The Martinov Model of Two Steady States of Liver Methylation: For Plant Food and Animal Food?

Perhaps if methylation support supplements suddenly increased the supply of SAM-e, the sarcosine pathway could rapidly start up to absorb the excess SAM-e and could deplete glycine faster than the body's ability to eat or make more glycine. Perhaps temporary glycine deficiency could be responsible for some of the anxiety/ panic-type "overmethylation symptoms" and "side effects" of L-methylfolate and other methylation supplements. Glycine is an inhibitory neurotransmitter itself.

If "overmethylation" involves high activity of the glycine to sarcosine pathway, it's possible that "undermethylation" symptoms still could be present simultaneously — if the overflow pathway is overactive, leaving too little SAM-e around for needed methylation.

Collagen, found in connective tissue, is a particularly rich source of glycine. The body concentrates glycine in collagen. Bone broth made from bones, skin, and connective tissue would provide lots of glycine. Glycine is found in plant foods too, though not in as high a concentration as in collagen. (Masterjohn 2017).

I would like to try some experiments with glycine at times when methylation supplements seem to be overdone and causing anxiety and distractibility. It has been suggested that many people can't make enough glycine to meet demand (Brind 2015), and that vegans may be deficient in glycine (Cohen 2018). Maybe some vegans and vegetarians might be able to regulate the methylation cycle better, to prevent overmethylation, by taking a glycine supplement.

It might be critical to remember that, as discussed above in the section about L-methylfolate, L-methylfolate supplements are likely to have a major effect on GNMT. L-methylfolate regulates the methylation cycle by binding GNMT, the enzyme that methylates glycine to sarcosine. Each GNMT enzyme can bind two L-methylfolate molecules. The two L-methylfolate molecules inactivate the GNMT. (Reed 2015; Wagner 1985). Thus, large dosages of L-methylfolate, commonly taken as supplements, may be able to override the regulation mechanism of the GNMT overflow pathway. Then other methylation reactions aside from GNMT would be bombarded with excess SAMe, and methylation might increase to unnatural levels.

The vastly increased methylation might have major positive effects, at least temporarily. The volatility caused by L-methylfolate supplements may be due to its override of the GNMT overflow path, which causes much larger than normal fluctuations in all other methylation reactions. In fact, large doses of folate, together with supplemental creatine, have been proposed as a manual override to permit larger than physiological normal methylation levels. The proposal would apply to help people methylate arsenic in areas such as Bangladesh where detoxifying arsenic is a major methylation burden. (Reed 2015).

The GNMT pathway connects with the folate cycle to regulate methylation. Methylfolate supplementation might be a way to override the regulation and enhance methylation, at the risk of greater volatility due to loss of GNMT activity. In contrast, collagen or glycine supplementation might support the GNMT pathway and stabilize methylation.

GNMT contains heme iron. (Finkelstein 1998). Iron may be a nutrient of interest for some vegans and vegetarians. (Norris 2013).