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Vegans and Methylation

by Jon Sasmor

Last Updated May 30, 2018

Hypothesis: Some Vegans and Vegetarians Need Methylation Supplements to Thrive

Certain helpful substances for methylation are found mainly in meat. Vegans and vegetarians may be at a disadvantage for methylation in several respects (more details below).

Methylation is a key body chemical process. It involves addition of a CH3 group. That means a group of a carbon atom and three hydrogen atoms are added to various body chemicals. Methylation makes hundreds of vital substances.

People with low methylation status generally seem to benefit from methylation supplements. If they go vegan or vegetarian, they might especially need methylation supplements to make the plant-based diet work.

Summary of Recommendations

Methylation is a critical biochemical process. Vegans are at a methylation disadvantage. But they can favor methylation with choices of food and supplements.

Top recommendation: take a supplement of the methyl and/or adenosyl forms of vitamin B12. These are the coenzyme forms that the body uses. B12 might have been present in the soil before and in plant foods, but the soil is just too sterile now. No B12 is dangerous!

The B12 supplement brand matters a lot in effectiveness. The following have helped many people sensitive to B12's effects:

  • Enzymatic Therapy B12 Infusion (Methyl B12)
  • Anabol Naturals Dibencozide (Adenosyl B12)
  • B12 Oils Adenosyl Methyl Oil (both Adenosyl and Methyl B12).

Other suggestions which might help a lot for vegans, near-vegans, vegetarians, and others who are sensitive to methylation:

  • For more SAM-e methylation fuel
    • Magnesium supplement
    • SAM-e supplement
    • Try eating more protein
  • For improved recycling of SAM-e
    • Supplement methyl B12 and/or adenosyl B12! See top recommendation above in bold!
    • Vitamin B2 supplement or Methyl Life multivitamin (which is helpful because its balance is high in B2)
    • Eat some beets, spinach, quinoa, grains, and/or sweet potatoes from time to time for the betaine
    • Avoid synthetic cyanocobalamin ("vitamin B12") and folic acid ("folate") supplements and fortified foods
    • Eat veggies for folate.
    • There might be a "too much" for folate from veggies.
    • Try methyl folate supplements, if you dare.
  • For premade methylation products, to reduce methylation need
    • Creatine supplement. Try trickle dosing.
    • Sunflower lecithin or soy lecithin
    • Eat avocados for carnitine.
    • Try carnitine supplements, if you dare, especially carnitine fumarate; try micro-dosing
  • Try glycine supplement to stabilize fluctuations in methylation.

My Own Experience

I keep hearing about methylation. In fact many of my characteristics keep showing up on symptom lists related to methylation.

Often when I try out a supplement related to methylation, it seems to help a lot. Sometimes there are life-changing positive effects, and within minutes! Like lights turning on for the first time! The wonderful effects may last only a few days, but with hard work balancing the methylation supplements and delicious plant foods, the improvements persist.

On a vegan diet for the last 3 years, I feel much healthier and more fit than before. However, I think that learning about methylation has made all the difference.

My lifelong undermethylation traits were getting worse on a vegan diet without methylation supplements. I'm very grateful that initial trouble going vegan pointed me toward methylation!

Who Might Need Methylation Supplements, Especially for a Vegan or Vegetarian Diet?

  • You have some undermethylation traits (Walsh 2017; Walsh 2014), including:
    • allergies
    • calm on the outside, tense on the inside
    • chronic depression which may be seasonal
    • high achievement at a young age
    • perfectionism
    • competitiveness
    • obsessive-compulsive tendencies
    • oppositional-defiant tendencies
    • addictive tendencies
    • ritualistic behaviors
    • sparse arm/leg/chest hair
    • high fluidity (tears, saliva, [etc.])
    • phobias
    • high sex drive
    • low pain threshold
    • high lab test level of whole blood histamine (>70 ng/mL)
    • positive response to SSRI antidepressant drugs or SAMe or methionine supplements
  • You have some of hundreds of symptoms of active B12 and active folate deficiency (Freddd 2014), including:
    • neurological symptoms
    • joint symptoms
    • muscle symptoms
    • skin symptoms
    • reproductive symptoms
    • endocrine symptoms
    • digestive symptoms
    • sleep disorders
    • macrocytic anemia (with high MCV level)
    • fatigue
    • hypersensitivities
    • mood and personality changes
    • high lab test levels of MCV, homocysteine, and/or MMA
  • You have "sticky thoughts" characteristic of high background levels of dopamine (Masterjohn 2017):
    • stable, intense focus on specific thoughts—which could be anxiety or depression-producing thoughts or could be productive work
    • low distractibility (but intense focus on distraction once distracted)
    • slow or minimal response to new stimuli
    • difficult to redirect attention and motivation
    • tired muscles
    • mental rigidity
    • what's caught in your mind stays there
    • OCD tendency
    • if severe undermethylation, difficult to attach motivation or attention to anything
    • even stickier thoughts several hours after eating, possibly caused by dip in methionine; may be helpful to productivity, but if severe may be misidentified as "blood sugar crash"
  • You have persistent nonspecific symptoms that medicine is unable to treat
  • Before becoming vegan or vegetarian, eating organ meats made you feel good, especially liver

For Which Methylation Substances Are Vegans and Vegetarians at a Disadvantage?

Vegans and vegetarians might need extra foods or supplements to help with the nutrients in red. More about each below.

Figure 1.  The methylation cycle, highlighting in red
substances of interest to vegans and vegetarians.

Figure 1. The methylation cycle, highlighting in red substances of interest to vegans and vegetarians. Click for larger image. Sources: Kennedy 2016; Mudd 2007; Wanders 2002.

The Fuel for Methylation: S-Adenosyl Methionine (SAMe)

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).

The Recyclers of SAM-e

There are 2 pathways to recycle homocysteine back into methionine and then SAM-e to allow for another iteration of methylation. Both are of interest to vegans and vegetarians.

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

Methyl B12.

Vitamin B12 consists of a complex molecule surrounding a cobalt atom. The methylcobalamin form of B12 (methyl B12) is critical to methylation and the hundreds of associated reactions. The adenosylcobalamin form of B12 (adenosyl B12) is involved in the inter-related krebs energy cycle, and is concentrated and stored in mitochondria.

Vegans and vegetarians need vitamin B12 because meat is the main dietary source of B12. (Rotter 2016; Obersby 2013.) Bacteria make B12. Bacteria even make some B12 in the large intestine, but we won't get any of that B12 absorbed in the small intestine, without eating poop, as some dogs seem to like to do. Maybe plants grown in soil fertilized or contaminated with poop might have enough B12. But it seems super-risky to me to go vegan or vegetarian today without taking a B12 supplement.

Unfortunately, Dorothy Crowfoot Hodgkin's 1964 Nobel Chemistry Prize winning research on vitamin B12's structure mistakenly concluded that a cyanide group (—CN) was an intrinsic part of vitamin B12 (Hodgkin 1958). Since then, almost all research on vitamin B12 has been done on cyanocobalamin, a synthetic form of cobalamin different from the two coenzyme forms of cobalamin the body uses.

Yikes! The synthetic form cyanocobalamin is now commonly sold and added to multivitamins and even to fortified flour and breakfast cereal simply as "vitamin B12." The synthetic form has high stability and low cost. The synthetic cyano form can avoid extreme B12 deficiency for some or many people. But the synthetic cyano B12 also has adverse effects on some or many people, including me. Regular "vitamin B12," cyanocobalamin, made me feel more anxious when I took a high-dose 500 mcg tablet for years, and then better when I stopped.

B12 active-form metabolism is still in early stages of research. (Obersby 2015.)

It may take several steps to convert cyanocobalamin into the forms of vitamin B12 that the body uses. The steps may include decyanation and then reduction, followed by methylation to make methyl B12 or a second reduction to make adenosyl B12. Decyanation and reduction may require availability of several other nutrients, including active form B2 riboflavin, active form B3 niacin, GSH glutathione, SAM-e, active form B9 L-methyl-folate, and/or vitamin E alpha-tocopherol. (Kelly 1997; Pezacka 1990).

The chaperone protein that actively transports B12 within a cell, called MMACHC, may be able to decyanate cyanocobalamin and strip away the cyanide functional group to allow B12 in the base-off form to be converted into active forms as needed. (Kim 2008). However, the capacity of MMACHC chaperone protein is limited. Therefore, some people don't seem to have enough MMACHC to detoxify cyanocobalamin. They may go active-B12 deficient at the cellular level even with high vitamin B12 blood levels.

B12 supplements can be taken in the active forms the body needs — methyl B12 and adenosyl B12. Methyl B12 dissolved in the mouth was shown in a double-blind, placebo-controlled study to normalize the homocysteine levels of B12-deficient vegetarians and vegans. (Obersby 2015.) Sublingual supplements can achieve blood concentrations that allow the active B12 to enter the cell by diffusion, even if the MMACHC carrier protein is not bringing B12 in at sufficient capacity. (Freddd 2013).

Active B12 sublinguals protect against limitations in the complex B12 absorption process as well as in the B12 transport process.

Aside from the previously discussed active forms of methyl-B12 and adenosyl-B12 and the synthetic form of cyano-B12, it's worth thinking about the hydroxocobalamin (hydroxo-B12) form. Unlike cyano-B12, hydroxo-B12 is commonly occurring in the body and in animal foods. Hydroxo-B12 is sometimes used for B12 shots. Watson et al proposed that although hydroxo-B12 is not used as a coenzyme, it complexes with glutathione to form glutathionylcobalamin, which stores B12 and protects the methyl and adenosyl coenzyme forms from rapid degradation (Watson 2004). Carmen Wheatley has proposed that glutathionylcobalamin is involved along with the coenzyme forms, methyl and adenosyl B12, in regulating anti-inflammatory processes (Wheatley 2009).

Freddd is a Phoenix Rising forum user who has written about his experiences curing himself of hundreds of debilitating chronic fatigue symptoms using a protocol centered around active B12s. Freddd has reported that many people sensitive to supplements of the active forms of B12 will have methylation dangerously impaired by supplements of cyanocobalamin, hydroxocobalamin, glutathione, or glutathione precursors such as N-acetyl-cysteine. The mechanism may involve glutathione binding and critically depleting methyl B12, which some people have difficulty remaking. (Freddd and Van Konynenburg 2011).

Perhaps hydroxo-B12 is helpful to people with normal B12 metabolism, and might provide a storage form on which some people seem to be able to thrive for months or years without eating any B12. However, once a person is deficient in methyl-B12 and unable to make enough, the hydroxo-B12 may be harmful by virtue of its complex with glutathione blocking methyl-B12 formation.

Luckily, the two natural coenzyme forms of vitamin B12 are now both readily available as supplements. The two natural forms are called methylcobalamin (also methyl B12 or MeCbl) and adenosylcobalamin (also adenosyl B12 or AdoCbl or dibencozide).

Those extremely sensitive to the effects of B12 notice huge differences in the potency of various brands. The brand may matter more than the nominal dosage amount on the label. For example, I personally have found Enzymatic Therapy methyl B12 three times as effective as the Solgar brand, despite both being labeled as 1000 mcg methylcobalamin tablets. The recommended brands from Freddd and others on the Phoenix Rising forums who have tested many brands include:

  • Enzymatic Therapy B12 Infusion (Methyl B12 1,000 mcg) (Place a tablet or part of one under upper lip to dissolve slowly for maximum absorption, start with ¼ tablet or less)
  • Anabol Naturals Dibencozide (Adenosyl B12 10,000 mcg) (Same intraoral method, start with 1/10 tablet or less).
  • B12 Oils Adenosyl Methyl Oil (Adenosyl B12 and Methyl B12) (spray, absorbed through skin).

The intraoral methyl and adenosyl B12 have been super effective for me. They improve energy and mood. The methyl B12 made my lifelong, mostly-seasonal, low-energy depression go away years ago, and never return. I look forward to try the B12 oil too.

Especially for vegans and vegetarians, who will get little or no dietary B12, methyl B12 may be the most crucial supplement to avoid failures in methylation processes all over the body.

Related Article: Vitamin B12: Types, Brands, Dosage Levels, and Methods.

B2 (Riboflavin).

Vitamin B2 (aka riboflavin) often seems overlooked in its importance to methylation. Also overlooked is the likelihood for vegans to be deficient in B2.

B2 is necessary to recycle both B12 and folate (B9) into their methylated active forms in the methylation cycle, so that they in turn can recycle more homocysteine back into methionine and then SAM-e. MTRR is the B12 recycling enzyme; MTHFR is the folate (B9) recycling enzyme. Both MTRR and MTHFR are B2 dependent. (Kennedy 2016).

The best sources of B2 include dairy and eggs, so vegans may be lower in B2 than omnivores and vegetarians.

The relative abundance of the other B vitamins in a rich plant-based diet can actually deplete vitamin B2. And, similarly, so can multivitamins and B complex vitamins which are usually over-abundant in the other B vitamins relative to B2. Our friend B2 is necessary for metabolism to make the active forms of B3, B6, B9, and B12. (Linus Pauling Institute 2013; Greg from B12Oils 2014 ). So when too much of the other B vitamins are around, B2 can become depleted through the metabolism of the other B vitamins.

B2 deficiency has been suggested as a reason why some people cannot metabolize hydroxocobalamin into the active forms of B12. Perhaps B2 deficiency might also block metabolism of synthetic cyanocobalamin into the active forms of B12. The cofactors for making the active B12 are the active forms of B2 (FMN and FAD). In turn, iodine, selenium and molybdenum are cofactors to making these active forms of B2, so deficiency of these minerals can lead to functional B2 deficiency, and in turn, functional B12 deficiency. (Greg from 2014).

B2 is available as a sublingual supplement in its active FMN form, Source Naturals Co-Enzymated B2. My first experience with this supplement was that it gave me an intense feeling of happiness, spontaneous laughter, and connection with the universe which lasted around an hour before gently fading. One of the most intensely happy moments! I think I had been very deficient in B2.

The Methyl Life Methylated Multi and Methyl Life Non-Methylated Multi have helped me and other people I know. These are hard-to-find multivitamins which have a high proportion of B2 relative to the other B vitamins. They also include the cofactors iodine, molybdenum, and selenium, from which the body can make additional active B2. I currently rely on the Methyl Life Non-Methylated Multi as my B2 supplement.

Either of the Methyl Life multis, or another B2 supplement, may be super for methylation support, especially for vegans!

L-Methyl Folate.

L-Methyl Folate (aka (6S)-5-methyltetrahydrofolate aka 5-MTHF) is the active form of vitamin B9 which recycles homocysteine back into methionine and then SAM-e.

Folate, vitamin B9, is abundant in green vegetables, legumes, and some fruits. However, people have varying abilities to convert the vegetable folates into the active methyl folate form, and the vegetable folates may even block the folate cycle for some. Folates in veggies and legumes may make it hard for vegans who are sensitive to plant folates to get enough protein and other nutrients without overdoing the vegetable folates.

Yikes! The synthetic form of vitamin B9, folic acid, is now commonly sold and added to multivitamins and even to fortified flour and breakfast cereal simply as "folate" or "vitamin B9." Some people can metabolize folic acid, but many others can only activate a limited amount, and a substantial amount of people cannot metabolize folic acid at all.

In fact, unmetabolized folic acid may accumulate in the body and block folate metabolism. The synthetic folic acid form may be the culprit for many of the adverse effects commonly attributed to "folate supplements." The bad rap for folate likely comes because nearly all of the research on folate has been done on the synthetic folic acid form.

Instead of folic acid, the active form of folate, methyl folate, is available as a supplement in various calcium and glucosamine salts (Methyl Life 2015). The methyl folate dosages people take vary widely, from 100 mcg to 45 mg or more daily.

Methyl folate is somewhat of a risky supplement because it can produce wonderful results and horrible results (Lynch 2012). I have tried dosages from 100 mcg up to 7.5 mg 6 times daily = 45 mg daily — and in the end I come out currently taking none at all.

Methyl folate seems to help methylation symptoms a lot, but sometimes makes a hard crash later with symptoms worse or much worse than before. The folate crashes can be relieved, sometimes successfully, by quadrupling the dosage or more (Freddd 2013), or by taking other supplements (Lynch 2012).

L-methylfolate regulates the methylation cycle by binding GNMT, the enzyme that methylates glycine to sarcosine. More about the GNMT reaction appears in a separate section below. 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).

Methyl folate supplements work better with methyl B12 alongside them. Otherwise, folate deficiency symptoms can be caused by methyl B12 deficiency. Too much L-methylfolate can deplete methyl B12 because they work together in the methionine synthase pathway. If a cell runs out of methyl B12, it will leak or expel the methyl folate. This condition is called a partial or complete methyl trap, and will require methyl B12 to correct itself. (Duncan 2013; Van Konynenburg 2011; Reed 2006; Shane 1985; Wagner 1985; Scott 1981).

Methyl folate supplementation might help some vegetarians and vegans. Avoiding folic acid might help too.

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.

The Fruits of Methylation: Creatine, Phosphatidylcholine, L-Carnitine, Sarcosine, and Many Others

Just a few compounds constitute around 90% or more of the methylation products. They are creatine, phosphatidylcholine, L-carnitine, and sarcosine.

Many people often discuss increasing the supply of methyl groups. We have another excellent option available which may turn out equally important or even more important. That option is to reduce demand for methyl groups by providing our bodies with pre-formed methylation products. Then the body won't need to do quite so much methylation.

Vegans and vegetarians start at a disadvantage on methyl demand. Their food contains much less of the primary methylation end-products. Therefore, they need to do much more methylation to make more of the methylation products. But the disadvantage easily can be turned to an advantage with a few simple foods and supplements.


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:

70 kg male, 20-39, in mmol/day 70 kg female, 20-39, in mmol/day
Methylation Flux, Total 16.7-23.41 (a) 16.7-23.41 (a)
Methylation Flux, Middle of Range 20.1 20.1
Creatine Loss 14.6 (b) 0.8 * 14.6 = 11.7 (b)
Dietary creatine, omnivore 7.9 (b) 5.0 (b)
Uptake from dietary creatine, omnivore 6.3 (b) 4.0 (b)
Dietary creatine, vegan or vegetarian ~= 0 (b) ~= 0 (b)
Creatine production in body, omnivore 14.6 – 6.3 = 8.3 11.7 – 4.0 = 7.7
Creatine production in body, vegan or vegetarian 14.6 – 0 = 14.6 11.7 – 0 = 11.7
Portion of methylation flux used to make creatine, omnivore 8.3 / ~20.1 = ~41% 7.7 / ~20.1 = ~38%
Additional methylation demand for vegans and vegetarians relative to omnivores, from creatine production alone (14.6 – 8.3) / ~20.1 = ~31% (11.7 – 7.7) / ~20.1 = ~20%
Sources: (a) Mudd 2007; (b) Brosnan 2011

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 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:

Carnitine, mg per 100g avocado dry matter Avocado, % dry matter Carnitine, mg per 100g of avocado Calculated Carnitine, mg per 136g medium avocado, without skin and seed
Seline 2007 1.72 25% 0.43 0.58
Panter 1969 4.8 1.2 (calculated) 1.6
Demarquoy 2004 8.1 11

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:

70 kg person, 20-39, in mmol/day
Methylation Flux, Total 16.7-23.41 (a)
Methylation Flux, Middle of Range 20.1
Dietary L-carnitine, omnivore 0.14-0.84 (b)
Dietary L-carnitine, vegan 0.007 (b)
L-carnitine production in body, omnivore 0.084 (b)
Total L-carnitine requirement 0.084 / 0.25 = 0.336 (b)
Dietary L-carnitine used by body, omnivore 0.336 * 0.75 = 0.252 (b)
L-carnitine production in body, vegan 0.336 – 0.007 = 0.329
Methyl groups required (if triple methylation of L-lysine is the first step) to produce L-carnitine in body, omnivore 0.084 * 3 = 0.252
Methyl groups required (if triple methylation of L-lysine is the first step) to produce L-carnitine in body, vegan 0.329 * 3 = 0.987
Portion of methylation flux used to make L-carnitine, omnivore 0.252 / ~20.1 = ~1.3%
Portion of methylation flux used to make L-carnitine, vegan 0.987 / ~20.1 = ~4.9%
Additional methylation demand for vegans relative to omnivores, from L-carnitine production alone ~4.9% – ~1.3% = ~3.6%
Sources: (a) Mudd 2007; (b) Vaz 2002

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).

The Transsulfuration Pathway: An Escape Route for Methionine, With Important Products

The transsulfuration pathway allows homocysteine to be irreversibly converted to cystathionine, and then to several important sulfur-containing products including cysteine and glutathione. When more methionine and SAM-e is present, more activity occurs on the transsulfuration pathway. Whereas excess methyl groups may escape via the sarcosine pathway, excess of the central methionine molecule may escape additional methylation cycles via the transsulfuration pathway. (Finkelstein 1990; Martinov 2000).

Too much methylation over an extended period might lead to too much transsulfuration, which could produce excessive sulfur-containing toxic products. However, intermittent periods of the high-methionine steady state in the liver might allow greater production of cysteine and other sulfur compounds when needed. (Finkelstein 1990; Martinov 2000).

Excessive dosages of B12 and folate supplements could overdrive the methionine synthase pathway (recycling pathway #1 in Figure 1), leaving insufficient homocysteine to fuel the transsulfuration pathway. In addition to cysteine and other sulfur compounds, the amino acid serine would become depleted. Also, sarcosine would be produced in overabundance, which could contribute to development of cancers. (Van Konynenburg 2010).

Vegans and vegetarians probably get enough vitamin B6 to support the transsulfuration pathway — especially if they eat some bananas and sweet potatoes.

The cystathionine synthase enzyme at the start of the transsulfuration pathway contains heme iron. (Finkelstein 1998). Iron may be a nutrient of interest for some vegans and vegetarians. (Norris 2013).

Related Article Section: For my subsequent reflections on the material in this article, please see Researching Methylation.

Related Article: For more about methylation, please see Folate for Thought: 12 Ideas about Methylation, mostly based on Mathematical Models.