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Trimethylglycine / Betaine
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In one pass Betaine, also called TMG (trimethylglycine), was first extracted from sugar beet.
Educational content, not medical advice — consult a clinician.
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Chapter 1
What betaine is, where it's from
Betaine, also called (trimethylglycine), was first extracted from sugar beet. In the body it holds two unrelated jobs: it helps cells withstand dehydration and high salt (a kind of moisture shield), and it works as a methyl courier, converting a metabolic leftover called back into a useful amino acid, methionine.
The body gets betaine in two ways. One is eating it: it is in wheat germ, whole wheat, spinach, beetroot, quinoa, scallops and shrimp. The other is making it: mitochondria oxidize choline step by step, and what comes out at the end is betaine.
So choline is not only raw material for cell membranes and a neurotransmitter; it is also upstream of betaine (see Choline). Part of the choline you eat ends up doing its work as betaine. Healthy people who eat enough whole grains, spinach and eggs generally do not need to take extra.
The body gets betaine in two ways. One is eating it: it is in wheat germ, whole wheat, spinach, beetroot, quinoa, scallops and shrimp. The other is making it: mitochondria oxidize choline step by step, and what comes out at the end is betaine.
So choline is not only raw material for cell membranes and a neurotransmitter; it is also upstream of betaine (see Choline). Part of the choline you eat ends up doing its work as betaine. Healthy people who eat enough whole grains, spinach and eggs generally do not need to take extra.
Numbers · Where it is in food, how much we eat
Betaine in food (per 100 g):Wheat bran and wheat germ: 1300-1500 mg, far ahead of everything else.Spinach: 600-650 mg.Beetroot: 130-260 mg (raw and cooked differ).Quinoa: about 400 mg.Shrimp and scallops: 200-300 mg.Whole-wheat bread: 200 mg.White rice and refined pasta: about 10-20 mg (90% is lost in milling).
How much people eat — the estimates disagree:
Olthof 2003 and Olthof 2005 give a dietary estimate of 0.5-2 g a day.Estimates built on data such as the US national diet survey (NHANES) come out much lower. The estimates differ considerably, depending on which food-composition data and which population are used.Whichever way it is counted, heavy whole-grain eaters get clearly more, and people on refined diets much less.
Is there a recommended intake? There is no official recommended intake. Betaine is not counted as an essential nutrient, because the body can make it from choline; but if intake stays low for a long time while choline, B12 and folate are also short, both methylation routes are affected at once.
Its relationship to choline:
Choline is converted into betaine by two oxidation steps in the mitochondria. How much of the choline you eat takes this route has no reliable fixed conversion figure.So eating more egg yolks, organ meats and fish tops up choline and also adds raw material to the betaine pool.When both choline and betaine intake are very low (for example, a vegan diet heavy in refined grains), the raw materials for the backup methylation route (BHMT) run short together.
In practice:
There is no deficiency syndrome: the body can make it from choline, so falling short of the "ideal" in food does not cause immediate problems.If you eat whole grains, spinach and eggs: you almost certainly have enough.If you eat polished rice and white flour and skip leafy greens and eggs: adding 5-15 g of wheat germ to yogurt or salad is 10 times more cost-effective than a supplement.
Background · Where the name and structure come from
(trimethylglycine) is glycine carrying three methyl groups; its chemical name is betaine, after the sugar beet (*Beta vulgaris*) from which it was first isolated in 1866.Chemical structure:
The amino group of glycine (-NH₂) is replaced by -N(CH₃)₃⁺, which carries three methyl groups, making it a quaternary ammonium compound.One end of the molecule is positively charged (-N(CH₃)₃⁺) and the other negatively charged (-COO⁻), so it is a zwitterion; that is exactly why it can act as an osmolyte, a molecule that helps cells manage water balance.It dissolves easily in water and tastes slightly sweet. The name comes from the sugar beet's genus, *Beta*, plus the chemical suffix -ine often used for nitrogen-containing compounds.
Two unrelated roles:
1. A cellular osmolyte: in hypertonic (high-salt) or dehydrated conditions it keeps proteins inside the cell from losing their shape; it belongs to the same class of osmolytes as taurine, sorbitol and creatine.
2. A methyl donor: through the enzyme BHMT, it hands one methyl group to , turning it back into methionine; the chapter A backup route in liver and kidney covers this route.
The step the body does itself: in the mitochondria, choline dehydrogenase and betaine aldehyde dehydrogenase (BADH) oxidize choline into betaine in two steps. So choline is not only raw material for phospholipids, acetylcholine and fat export from the liver; it is also the body's own precursor of betaine, and through it supports both methylation routes.
Chapter 2
A backup route in liver and kidney
The body has two routes for turning the same metabolic leftover, , back into usable methionine.
The main route exists in every tissue, but it only turns when vitamin B12 and folate are both present — if either is missing, the leftover piles up in the blood. The backup route exists only in the liver and kidney, and it does not need B12: the betaine you eat hands over a methyl group on the spot, and the leftover becomes methionine again.
So when B12 is short, the backup can cover for a while in the liver and kidney, but it cannot reach the nerves — nerve tissue does not have this route's enzyme. Going by that distribution, extra betaine cannot help nerves that lack B12, and no trial has used it to treat that nerve damage. A long-term vegan who is short of B12 needs B12 itself.
Who leans on the backup most? By the mechanism, people with the C677T variant: the variant slows the supply of active folate () at the top of the main route, so the main route turns more slowly and the backup carries more of the load.
The main route exists in every tissue, but it only turns when vitamin B12 and folate are both present — if either is missing, the leftover piles up in the blood. The backup route exists only in the liver and kidney, and it does not need B12: the betaine you eat hands over a methyl group on the spot, and the leftover becomes methionine again.
So when B12 is short, the backup can cover for a while in the liver and kidney, but it cannot reach the nerves — nerve tissue does not have this route's enzyme. Going by that distribution, extra betaine cannot help nerves that lack B12, and no trial has used it to treat that nerve damage. A long-term vegan who is short of B12 needs B12 itself.
Who leans on the backup most? By the mechanism, people with the C677T variant: the variant slows the supply of active folate () at the top of the main route, so the main route turns more slowly and the backup carries more of the load.
Mechanism · Why the backup runs only in liver and kidney
The enzyme BHMT is found mainly in the liver and kidney. That is not a random distribution; it lines up with the organs that use the most methyl groups:Why the liver needs so many methyl groups:
The PEMT pathway: it converts phosphatidylethanolamine into phosphatidylcholine (PC), and every PC molecule made uses methyl groups from 3 molecules of (the body's universal methyl donor).Creatine synthesis: adding a methyl group to guanidinoacetate (GAA) to make creatine is often estimated to be one of the largest uses of the body's SAM, and this step happens mainly in the liver.Conjugation and detoxification: many small molecules have to carry a methyl group before they can be disposed of.DNA methylation: it happens throughout the body, but more densely in the liver, the metabolic hub.
The kidney's special role:
The inner kidney (the medulla) holds high concentrations of osmolytes, betaine among them, to concentrate urine.The first step of creatine synthesis happens in the kidney: GAA is made from arginine and glycine; the methylation step happens mainly in the liver.People with chronic kidney disease often have raised , partly because the kidney's capacity to metabolize it declines.
Why other tissues lack BHMT:
Brain, nerves, muscle and red blood cells rely mainly on the MTR main route (see Vitamin B12).Maintaining the myelin sheath of nerves and methylating neurotransmitters require enough B12 and folate.This is why B12 deficiency in vegans damages nerves, while extra betaine cannot rescue nerve tissue: there is no BHMT there, so betaine can only act as an osmolyte in nerve tissue and cannot methylate homocysteine. This is inferred from where the enzyme is, not tested directly in a trial.
So what betaine can and cannot do:
It can: lower homocysteine in the blood; by the mechanism, it can also cover part of the liver's methyl demand.It cannot: fix B12 deficiency in the nerve tissue of vegans or strict vegetarians.
A molecule being effective is not enough; you also have to ask where it is effective.
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Mechanism · The molecules on the main and backup routes
The main route (see Vitamin B12):Raised (Hcy) in the blood is associated with cardiovascular disease and nerve damage; but lowering it does not mean fewer cardiovascular events — covered in the chapter What lowering homocysteine achieves.The main route: methionine synthase (MTR), together with methylcobalamin (a form of B12) and (active folate), hands one methyl group to Hcy and turns it back into methionine (Met); methionine then becomes , the universal methyl donor responsible for the whole set of methylation reactions in DNA, nerve myelin and neurotransmitters.B12 deficiency, folate deficiency or an variant all make the main route less efficient and raise Hcy.
The backup route that betaine uses:
The enzyme BHMT (betaine-homocysteine methyltransferase).The reaction: Hcy plus betaine gives methionine and dimethylglycine (DMG).Found mainly in the liver and kidney (almost absent elsewhere).Needs no B12 or folate, and is completely independent of the main route.
Why there are two routes:
The main route covers every tissue, but needs enough B12 and folate.The backup exists only in the liver and kidney, but responds directly to its raw material (betaine) and does not depend on B12 or folate.A common explanation is that the liver is the body's biggest user of methyl groups (phosphatidylcholine synthesis, creatine synthesis, bile acids, detoxification) and needs a backup. That is a hypothesis, not a measured finding.
How common MTHFR C677T carriers are: the share with TT homozygosity varies sharply by ancestry (NIH ODS: about 25% of Hispanics, about 10% of Whites and of Asians, about 1% of African Americans).
So betaine is not a magical new molecule. It is a backup power supply the body already has: taking it simply adds a little more raw material to a route that already exists.
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Chapter 3
What lowering homocysteine achieves
Betaine can push down. That part is true. In Olthof 2003, four groups of 19 healthy adults took 1.5, 3 or 6 g of betaine a day, or placebo, for 6 weeks. After 6 weeks, fasting Hcy was 12%, 15% and 20% lower than on placebo; the rise after a large dose of methionine (a loading test) was 16%, 23% and 35% smaller than on placebo on day 1, and 23%, 30% and 40% smaller after 6 weeks. The trial did not genotype anyone.
But what happens once it is lower? The large trials that tracked hard outcomes such as heart attack and death used folic acid and B vitamins, not betaine; but what they tested was exactly pushing homocysteine down in itself. The result: homocysteine fell, and heart attacks and deaths did not.
A perfect mechanism with an outcome that never arrives is a lesson nutrition keeps relearning. Homocysteine remains a risk marker, not a switch you can press to prevent events.
But what happens once it is lower? The large trials that tracked hard outcomes such as heart attack and death used folic acid and B vitamins, not betaine; but what they tested was exactly pushing homocysteine down in itself. The result: homocysteine fell, and heart attacks and deaths did not.
A perfect mechanism with an outcome that never arrives is a lesson nutrition keeps relearning. Homocysteine remains a risk marker, not a switch you can press to prevent events.
In practice · Where it ranks among the options
Betaine's place is narrow. For people whose folate and B12 are already covered but whose is still high, it can be added as one more step under a doctor's guidance; it is not first-line, and it is not a substitute.Why that order? The Olthof 2005 review gives a few figures: folic acid lowers blood homocysteine by about 25% at most; in healthy people betaine lowers it in step with the dose, by up to about 20% at 6 g a day; and the spike in homocysteine after a high-protein meal can be cut by up to half (50%) with betaine, while folic acid has no effect on that spike. High-dose betaine, 6 g a day or more, is the established treatment when an inborn error of metabolism drives homocysteine extremely high (homocystinuria) — a disease on a different scale.
The same review also warns that betaine and choline may worsen blood lipids, which offsets part of the homocysteine benefit; the chapter Fatty liver and strength training covers this side effect.
Myth · Is an MTHFR variant a disease?
genotyping is one of the loudest "genetic nutrition" selling points in the supplement and integrative-medicine market, but its clinical meaning has been greatly exaggerated:The facts:
How common TT homozygosity (both copies carrying T) is: it varies sharply by ancestry; NIH ODS gives about 25% of Hispanics, about 10% of Whites and of Asians, and about 1% of African Americans.CT heterozygotes: moderately reduced enzyme activity.TT homozygotes: the largest reduction.A1298C is another common variant, with a smaller effect.
The real clinical impact:
Mildly raised (5-15% above the wild type).A slightly higher folate requirement (but the standard 0.4 mg of folic acid in pregnancy is usually enough).TT homozygous with very low folate intake: this matters; once folate intake is made up, the effect becomes small.
The exaggerated parts (marketing):
"An MTHFR variant causes serious health problems": most single-site genetic differences like this act below the level where symptoms appear."MTHFR carriers must take (active folate), not ordinary folic acid": ordinary folic acid still raises folate levels and brings homocysteine down in carriers. The reason is not that it bypasses MTHFR; it is that the TT enzyme has reduced activity, not none, so with more raw material the step still turns. The extra advantage of 5-MTHF is small."An MTHFR variant brings a whole chain of disease (miscarriage, autism, cardiovascular disease, depression)": most of these are weak associations, causation has not been established, and the integrative-medicine market oversells them.
In practice:
If you have tested positive for an MTHFR variant, or relatives have high homocysteine: the simple approach is to eat folate-fortified foods, egg yolks, leafy greens and whole grains (the last of which contain betaine), or to add 5-MTHF at 0.4-1 mg a day.There is no need, "because of MTHFR", to pay a premium for 5-MTHF or a custom betaine protocol.The real use for a betaine supplement: people already taking 5-MTHF and B12 whose homocysteine is still high. As for people who lift, have the basics in place and want to try 2.5-6 g a day, know that in the controlled trial it gave no advantage for strength or lean mass (the chapter Fatty liver and strength training).
MTHFR is a real genetic polymorphism, but it is not a diagnosis; it is a mild risk factor. Treat it as a risk factor, not as a disease.
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Evidence · The homocysteine-lowering trials
The clinical evidence that betaine lowers (Hcy), item by item:Olthof 2003 (*J Nutr*, four groups of 19 healthy adults):
1.5, 3 or 6 g of betaine a day, or placebo, for 6 weeks.After 6 weeks, fasting Hcy was 12%, 15% and 20% lower than on placebo.The rise after a methionine load: 16%, 23% and 35% smaller than on placebo on day 1; 23%, 30% and 40% smaller after 6 weeks.No genotyping was done.
Compared with (active folate):
Folic acid and 5-MTHF: they work through the main route, and many randomized trials consistently show they lower homocysteine (certainty of evidence: high); suitable for people with an variant or for the general population with raised homocysteine.Betaine: it works through the backup route, with evidence from a few small randomized trials (certainty of evidence: moderate); suitable for people already on folate whose Hcy is still high; by the mechanism, people with an MTHFR variant or on high-protein diets that use a lot of might also benefit.Folate, B12 and betaine together: by the mechanism, the effects of the two routes can add up; few trials have compared this directly.
And after it falls: from the 1990s to the 2000s, the homocysteine hypothesis was treated as a causal driver of cardiovascular disease; but the large intervention trials that tracked hard outcomes such as heart attack and death (using folic acid and B vitamins) saw no fall in events — lowering Hcy does not mean fewer cardiovascular events, and that causal link has not been confirmed.
Chapter 4
Fatty liver and strength training
Besides lowering , betaine has two lines that often come up.
Fatty liver: to ship out the fat it has stored, the liver first has to wrap it in a phospholipid shell; each turn of the shell-building step spends a methyl group, and betaine is exactly what hands those methyl groups over. The mechanism is clear, but in the only placebo-controlled trial, it did not improve liver fat compared with placebo.
Strength training: as an osmolyte, it helps cells hold their volume during training-related dehydration. But in an 8-week controlled trial, strength and lean mass did not grow more than with placebo; only body fat fell a little more than with placebo, and that result needs more trials to replicate it.
On top of that, pre-workout powders often contain too little, and high doses may worsen blood lipids.
Fatty liver: to ship out the fat it has stored, the liver first has to wrap it in a phospholipid shell; each turn of the shell-building step spends a methyl group, and betaine is exactly what hands those methyl groups over. The mechanism is clear, but in the only placebo-controlled trial, it did not improve liver fat compared with placebo.
Strength training: as an osmolyte, it helps cells hold their volume during training-related dehydration. But in an 8-week controlled trial, strength and lean mass did not grow more than with placebo; only body fat fell a little more than with placebo, and that result needs more trials to replicate it.
On top of that, pre-workout powders often contain too little, and high doses may worsen blood lipids.
Evidence · Fatty liver and strength: the two trials
Beyond lowering , betaine has two clinical lines that come up often.1. Fatty liver (metabolic dysfunction-associated steatotic liver disease, that is, (formerly NAFLD))
To move the fat it has stored, the liver first has to wrap it in a phospholipid shell and package it as very-low-density lipoprotein (VLDL) for release into the blood; the shell-building step (PEMT) spends methyl groups every time it turns, and betaine is what hands those methyl groups over. With enough methyl groups, the shell gets built and the can leave — the same road by which choline deficiency causes fatty liver (see Choline). The mechanism is clear, but the Abdelmalek 2009 placebo-controlled randomized trial, in patients with biopsy-confirmed steatohepatitis, was negative compared with placebo.
2. Strength training and body composition
Cholewa 2018 was a double-blind, randomized, placebo-controlled trial: 23 young women with no strength-training experience trained for 8 weeks on 2.5 g of betaine a day or placebo. Strength and lean mass increased over time, but did not differ between the groups, so this was not a betaine advantage. Body-fat percentage and fat mass did fall more than with placebo (body fat -3.3% vs -1.7%, fat mass -2.0 kg vs -0.8 kg) — a result from one small trial that needs to be replicated. Mechanistically, betaine is still an osmolyte that helps cells hold their volume during training-related dehydration.
Where it stands in practice:
Betaine is not a miracle muscle-builder; its effect size is far smaller than creatine's.Once protein, training, sleep, creatine and caffeine are in place, 2.5 g of betaine a day has no proven advantage for strength or lean mass.People with fatty liver: Abdelmalek 2009 was a placebo-controlled randomized trial, and it was negative; betaine cannot replace weight management, exercise and, where needed, medication.
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Safety · Dose traps and the LDL side effect
The dose trap in pre-workout powders (PWO):A typical scoop of pre-workout contains only 0.5-1.5 g of betaine, well below the research dose of 2.5 g a day.What you are buying is the advertised dose, not the dose used in trials.Buying single-ingredient betaine powder (0.05-0.10 US dollars per gram) is 5-10 times cheaper than a pre-workout.2.5 g of betaine costs about 0.15-0.25 US dollars a day.
Doses that trials have used:
Lowering : 3-6 g a day in divided doses (the Olthof 2003 doses).Strength training: 2.5 g a day is the Cholewa 2018 dose, and that trial found no betaine advantage for strength or lean mass.Fatty liver: Abdelmalek 2009 used 20 g a day, and the placebo-controlled trial was negative; this needs medical supervision and is not a proven protocol.
The blood-lipid side effect (often overlooked):
The Olthof 2005 review and studies such as Schwab 2002: 6 g of betaine a day may mildly raise low-density lipoprotein cholesterol (, the so-called bad cholesterol), by amounts that vary between studies. In Olthof 2005's words, betaine and choline may adversely affect blood lipids.Why this happens is not yet clear.Clinical meaning: 6 g a day in the short term has a small effect in healthy people; but people who already have cardiovascular disease, have high LDL or take a statin should be cautious.A conservative approach: no more than 3 g a day, with blood lipids monitored.
Taking it with other methyl-related supplements:
With or B12 (methylcobalamin): the two routes lower Hcy together, and by the mechanism the effects can add up.With choline: choline is upstream of betaine, so the two support each other; taken together at high doses, the lipid concern adds up in theory, with no data.With creatine: making creatine uses a lot of methyl groups, so when you take creatine the body makes less of its own, which by the mechanism saves some .
Safety, and who should not take it:
Pregnancy and breastfeeding: data are lacking, so do not take it (betaine in food is safe).Chronic kidney disease (): kidney metabolism has already changed, and there are no data on whether high-dose betaine adds to the kidney's load; be cautious.Diagnosed high LDL: no more than 3 g a day, with monitoring.People taking monoamine oxidase (MAO) inhibitors: a theoretical concern has been raised, with no human data; ask your doctor before adding any supplement.
Overall: betaine is cheap, has a good safety record, and its effect on homocysteine is real; but beyond that, no clinical use has yet held up in controlled trials.
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Evidence · Training and fatty-liver trials, one by one
The mechanisms proposed for training performance:Cellular osmotic regulation: protects cell volume during training and dehydration.Supplying methyl groups for creatine synthesis: betaine helps recycle , which then supplies methyl groups for making creatine (a limited contribution).Lowering : by the mechanism, it might indirectly improve the function of the blood-vessel lining; there is no direct evidence.An improved cortisol-to-androgen ratio: seen in some studies, with no confirmed mechanism.
Fatty liver: the trials one by one:
Abdelmalek 2009 (*Hepatology*): a placebo-controlled randomized trial in patients with biopsy-confirmed steatohepatitis, 20 g a day for 12 months; negative compared with placebo, with no improvement in fatty change in the liver.The remaining small studies are mixed, and none overturns that negative result.
Strength training: the trials one by one:
Cholewa 2018 (*JISSN*, 23 young women new to strength training, 8 weeks): 2.5 g a day plus strength training; the gains in strength and lean mass were an effect of time, not an advantage of betaine over placebo; body fat fell more than with placebo, which needs to be replicated.Hoffman 2009 (male college athletes): 2.5 g a day for 14 days; some strength-training performance measures improved.Lee 2010: 2.5 g a day for 1 week; bench-press and jump power measures improved.The strength and power improvements reported by Hoffman, Lee and Trepanowski were mostly between 1-5%, all in small samples, and of weak clinical importance.Trepanowski 2011 (trained men, n=12; a single crossover trial, not a ): 2.5 g a day for 14 days. In the main analysis, no performance measure differed significantly between the conditions; only in a paired person-by-person comparison were the total repetitions and total volume in 10 sets of bench press to failure about 6.5% higher. In other words, the signal on this line was already resting on borderline statistics — do not read it as a stable gain.
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Chapter 5
Do I need it?
Whether to take betaine depends on which route you are on. It is raw material for the backup methylation route: people whose main route (folate plus vitamin B12) is already covered but whose is still high can add it as one more step under a doctor's guidance; it is not first-line, and it is not a substitute.
Healthy people whose diet already includes whole grains, spinach and eggs do not need a supplement. If you lift, know that in the controlled trial it gave no advantage for strength or lean mass; the controlled trial in fatty liver was negative too.
When buying, keep one more thing apart: betaine hydrochloride is something else — a stomach-acid supplement with a different purpose from the betaine discussed here.
Healthy people whose diet already includes whole grains, spinach and eggs do not need a supplement. If you lift, know that in the controlled trial it gave no advantage for strength or lean mass; the controlled trial in fatty liver was negative too.
When buying, keep one more thing apart: betaine hydrochloride is something else — a stomach-acid supplement with a different purpose from the betaine discussed here.
In practice · Should you take it, and how much
Do you need to take betaine?Q1: What is your goal, and your situation?
You carry an variant and your is still high even on and B12: under a doctor's guidance, try 3-6 g of betaine a day for 8-12 weeks, then recheck Hcy.Fatty liver, where an assessment finds low choline and betaine intake: the Abdelmalek 2009 placebo-controlled trial was negative; discuss it with a liver specialist and a dietitian, and do not treat 20 g a day as a proven protocol.You lift and want a little more marginal improvement: 2.5 g a day is the Cholewa 2018 dose, and that trial found no betaine advantage for strength or lean mass.A high-protein diet (> 2 g per kilogram of body weight) with a heavy training load: methyl use is high, and by the mechanism betaine might add a small marginal benefit; no trial has tested it.A healthy person whose diet already includes whole grains, spinach and eggs: food covers it, and no supplement is needed.
Q2: What dose?
Lowering Hcy: 3-6 g a day, in divided doses.Strength training: 2.5 g a day (at once or split; before training is fine); know that it has no proven advantage.Fatty liver: the only controlled trial used 20 g a day and was negative, so it is not a protocol to follow; it only makes sense under a doctor's supervision.A low maintenance dose: 1-2 g a day, plus betaine-rich foods.
Q3: Which form?
Betaine powder (anhydrous betaine): the cheapest, slightly sweet, and dissolves easily in water.Betaine hydrochloride: this is a different thing! It releases hydrochloric acid in the stomach and is used as a stomach-acid supplement, suitable only for people with low stomach acid; it does not overlap with betaine's nutritional role.Multivitamins and combination products: usually contain 50-500 mg of betaine, far below research doses.Pre-workout powders: contain only a trace — not enough.
Q4: Who should not take it?
Pregnancy and breastfeeding: data are lacking (betaine in food is safe).Chronic kidney disease: kidney metabolism has already changed, and there are no data on high doses.Diagnosed high , or taking a statin: no more than 3 g a day, with monitoring.Taking monoamine oxidase (MAO) inhibitors (certain drugs for Parkinson's disease or depression): there is only a theoretical concern, with no human data; ask your doctor first.Homocysteine that is not high to begin with, and enough betaine from food: no point.
Overall: betaine is cheap and rarely marketed. It is not a new molecule (discovered in 1866), and it is not revolutionary. The evidence that it lowers Hcy is real; there is no betaine advantage for strength or lean mass; and the placebo-controlled trial in fatty liver was negative. At 0.15-0.25 US dollars a day its downside is small, but it is worth trying only in a narrow group of people.
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Mechanism · How the one-carbon map fits together
What betaine fills in is one piece of one-carbon metabolism — the chemistry the body uses to move single carbon atoms, that is, methyl groups. Put it back into the whole map:The nodes of one-carbon metabolism:
The folate stretch (see Folate): dietary folate is turned by dihydrofolate reductase (DHFR) into tetrahydrofolate (THF), then into 5,10-methylenetetrahydrofolate (5,10-MTHF), and finally by into . This is the top of the main route, and MTHFR is a common site of variants.The B12 stretch (see Vitamin B12): methionine synthase (MTR), using methylcobalamin, takes the methyl group from 5-MTHF to turn back into methionine (Met), and methionine then becomes . This is the main route.B12's other job: methylmalonyl-CoA mutase (MUT), using adenosylcobalamin, converts the downstream product (methylmalonyl-CoA) of propionyl-CoA — which comes from breaking down odd-chain fatty acids and several branched-chain amino acids — into succinyl-CoA.The choline stretch (see Choline): the PEMT pathway hands methyl groups from SAM to phosphatidylethanolamine to make phosphatidylcholine, one of the main consumers of methyl groups; oxidized choline can also become betaine.The glycine stretch: at the SHMT step, serine hands one carbon to tetrahydrofolate and becomes glycine itself.The niacin stretch: the DHFR and MTHFR steps both use (a coenzyme that supplies reducing power inside cells), which is made from niacin.The betaine stretch: the backup route, BHMT, which does not depend on B12 or folate and exists only in the liver and kidney.
The whole chain, walked through in order:
1. Dietary folate is turned into THF by DHFR.
2. At the SHMT step, serine hands one carbon to THF and becomes glycine, and THF becomes 5,10-MTHF.
3. MTHFR (a common variant site) turns 5,10-MTHF into 5-MTHF.
4. Main route (whole body, needs B12): MTR plus B12 uses the methyl group of 5-MTHF to turn Hcy back into Met.
5. Backup route (liver and kidney only): BHMT uses betaine's methyl group to turn Hcy back into Met.
6. Met becomes SAM, the universal methyl donor, which is then shared out: PEMT to make phosphatidylcholine, GAMT to make creatine, DNA and histone methylation, neurotransmitters, detoxification (for example COMT), and myelin (methylation of myelin basic protein).
This map cannot be told in a single story; it is spread across 7-8 of them. One-carbon metabolism is not a single concept but a connected metabolic map, and each nutrient is one node on it. Understanding how the nodes connect is far more useful than memorizing the name of each one.
References · 5
- Craig, S. A. S. (2004). Betaine in human nutrition. The American Journal of Clinical Nutrition, 80(3), 539-549. 10.1093/ajcn/80.3.539
- Olthof, M. R., & Verhoef, P. (2005). Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Current Drug Metabolism, 6(1), 15-22. Folic acid lowers plasma homocysteine by 25% maximally. In healthy volunteers, betaine lowers fasting homocysteine dose-dependently by up to 20% at 6 g/d and acutely reduces the rise after methionine loading by up to 50%, where folic acid has no effect. Dietary betaine is estimated at 0.5-2 g/d. Betaine and choline may adversely affect serum lipids, and whether the benefits outweigh this is unclear; the abstract gives no LDL percentage (abstract, PMID 15720203). 10.2174/1389200052997366
- Olthof, M. R., van Vliet, T., Boelsma, E., & Verhoef, P. (2003). Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. The Journal of Nutrition, 133(12), 4135-4138. 10.1093/jn/133.12.4135
- Cholewa, J. M., Hudson, A., Cicholski, T., et al. (2018). The effects of chronic betaine supplementation on body composition and performance in collegiate females: a double-blind, randomized, placebo controlled trial. Journal of the International Society of Sports Nutrition, 15, 37. 23 untrained young women, betaine 2.5 g/day (n = 11) or placebo (n = 12) with 8 weeks of resistance training. Lean mass, muscle thickness, vertical jump and 1RM rose over time with no betaine-by-time interaction. Body fat fell more with betaine: -3.3 ± 1.7% vs -1.7 ± 1.6% body fat and -2.0 ± 1.1 vs -0.8 ± 1.3 kg fat mass; weekly training volume only trended higher (p = .056) (abstract, PMID 30064450). 10.1186/s12970-018-0243-x
- Trepanowski, J. F., Farney, T. M., McCarthy, C. G., Schilling, B. K., Craig, S. A., & Bloomer, R. J. (2011). The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men. Journal of Strength and Conditioning Research, 25(12), 3461-3471. 10.1519/JSC.0b013e318217d48d