Place · Level 3 · Supplement
Trimethylglycine / Betaine
甘氨酸戴 3 个甲基 · 同型半胱氨酸再甲基化双轨制副路 · MTHFR 突变者最受益 · 一碳代谢最后一块拼图
Story path
Chapter 1
Glycine with 3 methyls
Glycine with 3 methyls
TMG (trimethylglycine) = glycine + three methyl groups (-N(CH₃)₃⁺); its formal chemical name is betaine — named because it was first isolated from sugar beet (*Beta vulgaris*) in 1866.
Chemical structure:
The amine group (-NH₂) of glycine is replaced by three methyls → a quaternary ammonium compoundPositive and negative charges coexist (-N(CH₃)₃⁺ + -COO⁻) → a zwitterion, which is the root of its 'osmolyte' (osmoprotectant) propertyWater-soluble, mildly sweet (this is also where the '-ine' suffix in 'betaine' comes from)
Two independent roles:
1. Cellular osmoprotectant: protects cellular protein structure under hypertonic (high-salt) or dehydrated conditions (a member of the same osmolyte family as taurine / sorbitol / creatine)
2. Methyl donor: via the BHMT enzyme, it donates a methyl group to homocysteine → methionine (next scene)
Two ways the body obtains TMG:
Food: wheat germ / whole wheat / spinach / beetroot / quinoa / seafood (scallops, shrimp)Endogenous synthesis: choline → betaine — choline dehydrogenase + BADH in mitochondria oxidize choline in two steps into TMG
The second path links TMG directly to the choline story — choline is not just raw material for phospholipids / ACh / hepatic lipid transport, it is also the endogenous precursor of TMG and therefore supports the dual-track methylation system.
Chemical structure:
The amine group (-NH₂) of glycine is replaced by three methyls → a quaternary ammonium compoundPositive and negative charges coexist (-N(CH₃)₃⁺ + -COO⁻) → a zwitterion, which is the root of its 'osmolyte' (osmoprotectant) propertyWater-soluble, mildly sweet (this is also where the '-ine' suffix in 'betaine' comes from)
Two independent roles:
1. Cellular osmoprotectant: protects cellular protein structure under hypertonic (high-salt) or dehydrated conditions (a member of the same osmolyte family as taurine / sorbitol / creatine)
2. Methyl donor: via the BHMT enzyme, it donates a methyl group to homocysteine → methionine (next scene)
Two ways the body obtains TMG:
Food: wheat germ / whole wheat / spinach / beetroot / quinoa / seafood (scallops, shrimp)Endogenous synthesis: choline → betaine — choline dehydrogenase + BADH in mitochondria oxidize choline in two steps into TMG
The second path links TMG directly to the choline story — choline is not just raw material for phospholipids / ACh / hepatic lipid transport, it is also the endogenous precursor of TMG and therefore supports the dual-track methylation system.
Dietary TMG intake
Food TMG content (mg / 100 g):Wheat bran / wheat germ: 1300-1500 mg — far aheadSpinach: 600-650 mgBeetroot: 130-260 mg (raw vs cooked)Quinoa: ~400 mgShrimp / scallops: 200-300 mgWhole wheat bread: 200 mgWhite rice / refined pasta: ~10-20 mg (90% lost in milling)
Typical intake:
US NHANES: median ~200-300 mg/day (heavy whole-grain eaters 600-1000 mg/day; refined diets <100 mg/day)AI / RDA: no official RDA — TMG is not an essential nutrient (because endogenous choline can synthesize it), but when long-term low intake + low choline + low B12/folate coincide, both methylation tracks are impaired at once
Relationship to choline:
1 g choline → two-step mitochondrial oxidation → ~0.7 g TMGSo eating more eggs + offal + fish: supplements choline + directly raises the TMG poolVery low choline + very low TMG (vegan + refined grains) → both upstream substrates for the methylation backup (BHMT) drop together
Practical:
There is no deficiency syndrome — the body can synthesize from choline → so food not hitting 'ideal' doesn't immediately cause problemsIf you eat whole grains + spinach + eggs: almost certainly enoughIf you eat refined rice / white flour / no leafy greens or eggs: adding 5-15 g wheat germ to yogurt / salad is 10× more cost-effective than a supplement
Chapter 2
BHMT alternate route
BHMT alternate route
TMG's most important role in the atlas: the backup pathway for homocysteine remethylation.
Recap of the main pathway (covered in detail in the vitamin-b12/methylation L4 scene):
Homocysteine (Hcy) accumulation → cardiovascular + neurological riskMain route: MTR (methionine synthase) + methylcobalamin (B12) + 5-MTHF (folate) → Hcy + methyl → methionine (Met) → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups., the universal methyl donor → DNA / nerve myelin / neurotransmitter methylation across the boardB12 deficiency / folate deficiency / MTHFR mutation → main-route efficiency drops → Hcy rises
TMG's backup route:
BHMT enzyme (betaine-homocysteine methyltransferase)Reaction: Hcy + betaine (TMG) → methionine (Met) + dimethylglycine (DMG)Mainly expressed in liver and kidney (almost not at all in other tissues)Does not require B12 / folate — completely independent of the main route
Evolutionary meaning of the dual-track system:
The main route covers all tissues, but needs adequate B12 + folateThe backup is only in liver/kidney, but responds directly to substrate (TMG) and doesn't depend on B12/folateEvolution kept the dual-track design because the liver is the body's biggest methylation consumer (phosphatidylcholine synthesis + creatine synthesis + bile acids + detox) and needs redundancy
MTHFR C677T carriers:
About 10-30% of the population (high frequency in Asia and Mediterranean, low in Northern Europe) carry the MTHFR C677T polymorphismMTHFR enzyme activity ↓30-65% → insufficient 5-MTHF → main route (MTR) less efficient → high HcyThe backup route (BHMT + TMG) is relatively more important in these people — TMG supplementation gives larger Hcy improvement in MTHFR carriers (Olthof 2005 review)
Click 'Look more closely at this scene →' for the 4-step animation — the Hcy pool, full main vs backup contrast, and how the backup becomes the main player when MTHFR is mutated.
Core insight: TMG is not a 'magical new molecule', it is a backup power supply the body already has — supplementing it just adds substrate to a route that already exists.
Recap of the main pathway (covered in detail in the vitamin-b12/methylation L4 scene):
Homocysteine (Hcy) accumulation → cardiovascular + neurological riskMain route: MTR (methionine synthase) + methylcobalamin (B12) + 5-MTHF (folate) → Hcy + methyl → methionine (Met) → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups., the universal methyl donor → DNA / nerve myelin / neurotransmitter methylation across the boardB12 deficiency / folate deficiency / MTHFR mutation → main-route efficiency drops → Hcy rises
TMG's backup route:
BHMT enzyme (betaine-homocysteine methyltransferase)Reaction: Hcy + betaine (TMG) → methionine (Met) + dimethylglycine (DMG)Mainly expressed in liver and kidney (almost not at all in other tissues)Does not require B12 / folate — completely independent of the main route
Evolutionary meaning of the dual-track system:
The main route covers all tissues, but needs adequate B12 + folateThe backup is only in liver/kidney, but responds directly to substrate (TMG) and doesn't depend on B12/folateEvolution kept the dual-track design because the liver is the body's biggest methylation consumer (phosphatidylcholine synthesis + creatine synthesis + bile acids + detox) and needs redundancy
MTHFR C677T carriers:
About 10-30% of the population (high frequency in Asia and Mediterranean, low in Northern Europe) carry the MTHFR C677T polymorphismMTHFR enzyme activity ↓30-65% → insufficient 5-MTHF → main route (MTR) less efficient → high HcyThe backup route (BHMT + TMG) is relatively more important in these people — TMG supplementation gives larger Hcy improvement in MTHFR carriers (Olthof 2005 review)
Click 'Look more closely at this scene →' for the 4-step animation — the Hcy pool, full main vs backup contrast, and how the backup becomes the main player when MTHFR is mutated.
Core insight: TMG is not a 'magical new molecule', it is a backup power supply the body already has — supplementing it just adds substrate to a route that already exists.
Why BHMT is liver/kidney only
BHMT expression is restricted to liver and kidney — this is not random distribution, it aligns with the organs that consume the most methyl groups.Liver methylation consumption:
PEMT pathway: phosphatidylethanolamine → phosphatidylcholine (PC); each reaction consumes 3 S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. methyl groupsCreatine synthesis: GAA + SAM → creatine + SAH, accounts for 40-70% of the body's SAM usage, mostly in the liverBile acid conjugation / detoxification: large amount of small-molecule methylationDNA methylation: throughout the body, but denser in the liver as the metabolic hub
Kidney's special role:
High concentrations of osmolytes (including TMG) for medullary urine concentrationThe final step of creatine synthesis (GAA → creatine methylation) is partly in the kidneyIn chronic kidney disease, BHMT activity drops → indirectly raises Hcy → cardiovascular risk rises
Why other tissues don't express BHMT:
Brain / nerve / muscle / red cells rely on the MTR main routeNerve myelin maintenance + neurotransmitter methylation (covered in vitamin-b12/methylation) must have adequate B12 + folateThis is why vegan B12 deficiency causes neurological damage, but supplementing TMG cannot rescue nerve tissue — BHMT is not expressed there; in neural tissue TMG can only act as an osmolyte, not remethylate Hcy
So TMG's clinical positioning:
Can solve: systemic plasma Hcy reduction + liver methylation burden + some metabolic syndrome markersCannot solve: nerve-tissue B12 deficiency in vegans / strict vegetarians
This section is another concrete instance of the atlas's 'mechanism location determines clinical applicability' teaching — a molecule being effective is not enough, you also have to ask where it is effective.
Chapter 3
Hcy clinical RCT
Hcy clinical RCT
The clinical evidence that TMG lowers homocysteine (Hcy) is real — B grade.
**Olthof 2003 *J Nutr*** key RCT (n=24 healthy adults):
6 g/day TMG × 6 weeks vs placeboFasting Hcy ↓11-15%Post-meal Hcy peak ↓25-35% (the post-meal effect is bigger because protein intake produces a burst of Hcy)Fast absorption + onset: a single 6 g dose raises plasma TMG 5-10× within 1-2 hours, and Hcy drops immediately
**Olthof 2005 *Curr Drug Metab* review**:
Pooling multiple RCTs: 3-6 g/day TMG → Hcy down by 10-20% on averageMTHFR C677T carriers: down 15-30% (more significant)Effect comparable to or stronger than 5-MTHF (folate active form) 5 mg/day in some studies
**Cholewa 2018 *JISSN*** (n=23 college women, 8 weeks of resistance training):
2.5 g/day TMG: improved strength and protein-anabolic markers during resistance trainingPossible mechanisms: osmolyte cell-volume stability + indirect mechanistic target of rapamycin: The cell's master 'grow / build' switch — turned on by enough protein and resistance training. + partial Hcy reduction
Trepanowski 2011 + Lee 2010 + Hoffman 2009: small improvements in strength/power parameters with resistance training, but weak clinical significance (1-5% range).
Compared to 5-MTHF (active folate):
5-MTHF: A-grade evidence (main route), suitable for MTHFR mutation / high-Hcy general populationTMG: B-grade evidence (backup route), suitable for people already on 5-MTHF whose Hcy is still high / MTHFR carriers / high-protein diets that burn a lot of S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups.Combined 5-MTHF + B12 + TMG: multi-agent Hcy-lowering trials show additive effects on Hcy, but clinical endpoint trials (myocardial infarction / stroke / death) have all failed (HOPE-2, VISP, NORVIT, VITATOPS, SEARCH) — lowering Hcy ≠ reducing cardiovascular events
This is the second appearance in the atlas of the 'mechanism perfect + endpoint null' lesson (the first was vitamin E antioxidant RCTs). The 'Hcy hypothesis' was treated in the 1990s-2000s as a causal driver of CVD, but large intervention trials have not confirmed causality. Hcy remains a risk marker, but supplementing B vitamins to lower it does not reduce hard endpoints.
**Olthof 2003 *J Nutr*** key RCT (n=24 healthy adults):
6 g/day TMG × 6 weeks vs placeboFasting Hcy ↓11-15%Post-meal Hcy peak ↓25-35% (the post-meal effect is bigger because protein intake produces a burst of Hcy)Fast absorption + onset: a single 6 g dose raises plasma TMG 5-10× within 1-2 hours, and Hcy drops immediately
**Olthof 2005 *Curr Drug Metab* review**:
Pooling multiple RCTs: 3-6 g/day TMG → Hcy down by 10-20% on averageMTHFR C677T carriers: down 15-30% (more significant)Effect comparable to or stronger than 5-MTHF (folate active form) 5 mg/day in some studies
**Cholewa 2018 *JISSN*** (n=23 college women, 8 weeks of resistance training):
2.5 g/day TMG: improved strength and protein-anabolic markers during resistance trainingPossible mechanisms: osmolyte cell-volume stability + indirect mechanistic target of rapamycin: The cell's master 'grow / build' switch — turned on by enough protein and resistance training. + partial Hcy reduction
Trepanowski 2011 + Lee 2010 + Hoffman 2009: small improvements in strength/power parameters with resistance training, but weak clinical significance (1-5% range).
Compared to 5-MTHF (active folate):
5-MTHF: A-grade evidence (main route), suitable for MTHFR mutation / high-Hcy general populationTMG: B-grade evidence (backup route), suitable for people already on 5-MTHF whose Hcy is still high / MTHFR carriers / high-protein diets that burn a lot of S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups.Combined 5-MTHF + B12 + TMG: multi-agent Hcy-lowering trials show additive effects on Hcy, but clinical endpoint trials (myocardial infarction / stroke / death) have all failed (HOPE-2, VISP, NORVIT, VITATOPS, SEARCH) — lowering Hcy ≠ reducing cardiovascular events
This is the second appearance in the atlas of the 'mechanism perfect + endpoint null' lesson (the first was vitamin E antioxidant RCTs). The 'Hcy hypothesis' was treated in the 1990s-2000s as a causal driver of CVD, but large intervention trials have not confirmed causality. Hcy remains a risk marker, but supplementing B vitamins to lower it does not reduce hard endpoints.
Is MTHFR a real concern
MTHFR genotyping is one of the loudest 'genetic nutrition' marketing pitches in the supplement + integrative medicine market — but the clinical implications have been heavily exaggerated.The facts:
MTHFR C677T carrier frequency: ~25-50% in Asia, 30-50% in Mediterranean, 5-15% in Northern Europe, <5% in AfricaCT heterozygous: enzyme activity ↓~35%TT homozygous: enzyme activity ↓~65%A1298C is another common mutation with smaller effect
Real clinical impact:
Mild Hcy elevation (5-15% above wild-type)Slightly elevated folate requirement (but the standard 0.4 mg folic acid for pregnancy is usually enough)TT homozygous + very low folate intake: meaningful, but the impact is small once intake is corrected
The exaggerated parts (marketing):
'MTHFR mutation → serious health problems' — most SNP effects are subclinical'MTHFR carriers must take 5-MTHF (active folate); they can't take ordinary folate' — modern evidence (Greenberg 2011 *J Clin Lab Anal* review) shows that ordinary folic acid still works in MTHFR carriers (DHFR + alternate pathways convert it to active form); 5-MTHF's marginal advantage is small'MTHFR mutation → a full disease chain (miscarriage + autism + cardiovascular + depression)' — most associations are weak and causality is not established; the integrative medicine market oversells this
Practical:
If you've tested positive for MTHFR mutation or have a family history of high Hcy: the simple approach is to eat fortified-folate foods + eggs + leafy greens + whole wheat (TMG), or add 5-MTHF 0.4-1 mg/dayYou don't need to pay a premium for 5-MTHF or a custom TMG protocol 'because of MTHFR'TMG's real indication: already on 5-MTHF + B12 + folate but Hcy is still high; or strength training basics in place and you want to add 2.5-6 g/day as an experiment
Bottom line: MTHFR is a real genetic polymorphism, but it isn't a 'diagnosis' — it's a mild risk factor. Treat it as a risk factor, not a disease.
Chapter 4
Liver fat + strength
Liver fat + strength
Beyond lowering Hcy, TMG has two secondary but real clinical signals.
1. Liver fat / NAFLD improvement
Mechanism: TMG → provides methyls → supports the PEMT pathway (phosphatidylethanolamine → phosphatidylcholine) → builds VLDL particle shell → hepatic triglyceride exportThis overlaps completely with the choline-in-NAFLD mechanism — TMG sits upstream (choline's oxidation product, also the PEMT alternate substrate)**Abdelmalek 2009 *Hepatology***: 20 g/day TMG × 1 year (no placebo, single arm) → ALT/AST drop + hepatic lipid score improvedMukherjee 2014 RCT (NASH): 20 g/day × 12 months — signal present but not reaching clinical significanceOverall evidence: B-C grade (mechanism clear, clinical endpoint weak, high dose required)
2. Strength training + body composition
**Cholewa 2018 *JISSN*** (college women, n=23, 8 weeks): 2.5 g/day TMG + resistance training → improved strength, lean mass, and training-volume metabolic markersHoffman 2009 (college male athletes): 2.5 g/day × 14 days → improved resistance-training performance indicatorsTrepanowski 2011 (trained men, n=12): 2.5 g/day × 14 days → some metabolic markers improved; small strength parameter changesLee 2010: 2.5 g/day × 1 week → improved bench press + jump power parametersTrepanowski 2011 meta + Lee 2014 review: effect size small-to-moderate (1-5% improvement), mainly in submaximal strength work
Mechanism (training performance):
Cellular osmoregulation (osmolyte): protects cell volume during training + dehydrationMethyl supply for creatine synthesis: TMG → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → creatine (limited contribution)Hcy reduction indirectly improves endothelial functionCortisol / androgen ratio improvements: shown in some studies, mechanism unconfirmed
Practical positioning:
TMG is not a 'miracle muscle-builder' — effect size is far smaller than creatineOn top of an already-solid base (protein + training + sleep + creatine + caffeine), 2.5 g/day TMG may add a small extra improvementNAFLD patients: assess + possibly supplement (discuss with physician; cannot replace weight management + exercise + new drugs when needed)
1. Liver fat / NAFLD improvement
Mechanism: TMG → provides methyls → supports the PEMT pathway (phosphatidylethanolamine → phosphatidylcholine) → builds VLDL particle shell → hepatic triglyceride exportThis overlaps completely with the choline-in-NAFLD mechanism — TMG sits upstream (choline's oxidation product, also the PEMT alternate substrate)**Abdelmalek 2009 *Hepatology***: 20 g/day TMG × 1 year (no placebo, single arm) → ALT/AST drop + hepatic lipid score improvedMukherjee 2014 RCT (NASH): 20 g/day × 12 months — signal present but not reaching clinical significanceOverall evidence: B-C grade (mechanism clear, clinical endpoint weak, high dose required)
2. Strength training + body composition
**Cholewa 2018 *JISSN*** (college women, n=23, 8 weeks): 2.5 g/day TMG + resistance training → improved strength, lean mass, and training-volume metabolic markersHoffman 2009 (college male athletes): 2.5 g/day × 14 days → improved resistance-training performance indicatorsTrepanowski 2011 (trained men, n=12): 2.5 g/day × 14 days → some metabolic markers improved; small strength parameter changesLee 2010: 2.5 g/day × 1 week → improved bench press + jump power parametersTrepanowski 2011 meta + Lee 2014 review: effect size small-to-moderate (1-5% improvement), mainly in submaximal strength work
Mechanism (training performance):
Cellular osmoregulation (osmolyte): protects cell volume during training + dehydrationMethyl supply for creatine synthesis: TMG → S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → creatine (limited contribution)Hcy reduction indirectly improves endothelial functionCortisol / androgen ratio improvements: shown in some studies, mechanism unconfirmed
Practical positioning:
TMG is not a 'miracle muscle-builder' — effect size is far smaller than creatineOn top of an already-solid base (protein + training + sleep + creatine + caffeine), 2.5 g/day TMG may add a small extra improvementNAFLD patients: assess + possibly supplement (discuss with physician; cannot replace weight management + exercise + new drugs when needed)
PWO traces + LDL caveat
The TMG dose trap in pre-workout (PWO) blends (same logic as in the citrulline scene):A typical PWO scoop contains 0.5-1.5 g TMG, well below the research dose of 2.5 g/dayYou're paying for the 'advertised dose', not the 'effective dose'Buying single-ingredient TMG powder ($0.05-0.10/g) is 5-10× cheaper than PWO2.5 g TMG ≈ $0.15-0.25/day
Dose protocols:
Hcy reduction: 3-6 g/day divided (Olthof 2003 dose)Strength training: 2.5 g/day (Cholewa 2018 dose)NAFLD: 20 g/day divided (Abdelmalek 2009, high dose, needs medical supervision)
LDL side-effect warning (often overlooked):
Olthof 2005 + Schwab 2002: 6 g/day TMG may mildly raise low-density lipoprotein cholesterol: The so-called 'bad cholesterol' — the higher it is, the more plaque tends to build in artery walls. (10-15%)Mechanism is not fully clear; may be related to DMG (byproduct) → trimethylamine (TMA) → TMAO elevation (parallel to the gut TMAO pathway — see the choline story)Clinical meaning: short-term 6 g/day in healthy people is small, but people with existing cardiovascular disease / high LDL / on statins should be cautiousSolution: don't exceed 3 g/day + monitor lipids
Stacking with other methyl-related supplements:
+ 5-MTHF: synergistic Hcy reduction, but no additional liver-fat improvement (main + backup routes are independent)+ B12 (methylcobalamin): same, synergistic+ choline: upstream, dual support; but high doses of both together raise DMG / TMAO risk additively+ creatine: creatine synthesis consumes methyls → supplementing creatine spares S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. → TMG is freed for other pathways, indirectly synergistic
Safety + who shouldn't supplement:
Pregnancy / lactation: data lacking, skip (food TMG is safe)Chronic kidney disease (CKD): BHMT drops in the kidney + high TMG may add to renal metabolic burden, be cautiousDiagnosed high LDL: cap at 3 g/day + monitorMAO-A inhibitors: theoretical interaction (DMG and tyramine metabolism), be cautious
Overall: TMG is one of the most overlooked 'cheap + real + marketing-cold' molecules in the supplement aisle — in the same tier as glycine / NAC. Not revolutionary, but has real signal in the right population, and absurdly cheap.
Chapter 5
Decision tree
Decision tree
Do you need to supplement TMG?
Q1: What is your goal / situation?
MTHFR mutation + Hcy still high (even on 5-MTHF + B12): try 3-6 g/day TMG for 8-12 weeks, recheck HcyNAFLD / fatty liver + assessment shows low choline / TMG intake: discuss the 20 g/day high-dose protocol with hepatology + nutritionistResistance training + want a marginal improvement: 2.5 g/day (Cholewa protocol)High-protein diet (>2 g/kg) + heavy training volume: high methyl consumption, TMG may give marginal benefitHealthy general person + diet already has whole grains / spinach / eggs: food covers it, no supplement needed
Q2: Dose?
Hcy protocol: 3-6 g/day dividedTraining protocol: 2.5 g/day (single or divided; pre-training is reasonable)NAFLD protocol: 20 g/day (needs medical supervision)Maintenance low dose: 1-2 g/day + TMG-rich foods
Q3: Form?
TMG powder (anhydrous betaine): cheapest, mildly sweet, dissolves well in waterBetaine HCl: this is a different molecule — it's a stomach-acid aid, containing TMG + HCl to release gastric acid; only suitable for people with low stomach acid; does not overlap with TMG's nutritional functionMultivitamins + combo products: typically contain 50-500 mg TMG, far below research dosesPre-workout (PWO): trace dose, not enough
Q4: Who shouldn't supplement:
Pregnancy / lactation: data lacking (food TMG is safe)Chronic kidney disease: BHMT drops in kidney + TMG excretion changesDiagnosed high LDL / on statins: cap at 3 g/day + monitorOn MAO-A inhibitor medication (specific drugs for Parkinson's / depression): theoretical interactionLow Hcy + food TMG already adequate: not needed
Atlas overall verdict: TMG is one of the most overlooked cheap + real-signal + marketing-cold molecules in the supplement aisle. It's not a 'new molecule' (discovered in 1866), not 'revolutionary', but in the right population it has real Hcy + strength training + NAFLD signals. At $0.15-0.25/day its downside risk is very low, and it completes the atlas's 'one-carbon metabolism dual-track' teaching with the final piece of the puzzle.
Q1: What is your goal / situation?
MTHFR mutation + Hcy still high (even on 5-MTHF + B12): try 3-6 g/day TMG for 8-12 weeks, recheck HcyNAFLD / fatty liver + assessment shows low choline / TMG intake: discuss the 20 g/day high-dose protocol with hepatology + nutritionistResistance training + want a marginal improvement: 2.5 g/day (Cholewa protocol)High-protein diet (>2 g/kg) + heavy training volume: high methyl consumption, TMG may give marginal benefitHealthy general person + diet already has whole grains / spinach / eggs: food covers it, no supplement needed
Q2: Dose?
Hcy protocol: 3-6 g/day dividedTraining protocol: 2.5 g/day (single or divided; pre-training is reasonable)NAFLD protocol: 20 g/day (needs medical supervision)Maintenance low dose: 1-2 g/day + TMG-rich foods
Q3: Form?
TMG powder (anhydrous betaine): cheapest, mildly sweet, dissolves well in waterBetaine HCl: this is a different molecule — it's a stomach-acid aid, containing TMG + HCl to release gastric acid; only suitable for people with low stomach acid; does not overlap with TMG's nutritional functionMultivitamins + combo products: typically contain 50-500 mg TMG, far below research dosesPre-workout (PWO): trace dose, not enough
Q4: Who shouldn't supplement:
Pregnancy / lactation: data lacking (food TMG is safe)Chronic kidney disease: BHMT drops in kidney + TMG excretion changesDiagnosed high LDL / on statins: cap at 3 g/day + monitorOn MAO-A inhibitor medication (specific drugs for Parkinson's / depression): theoretical interactionLow Hcy + food TMG already adequate: not needed
Atlas overall verdict: TMG is one of the most overlooked cheap + real-signal + marketing-cold molecules in the supplement aisle. It's not a 'new molecule' (discovered in 1866), not 'revolutionary', but in the right population it has real Hcy + strength training + NAFLD signals. At $0.15-0.25/day its downside risk is very low, and it completes the atlas's 'one-carbon metabolism dual-track' teaching with the final piece of the puzzle.
Complete one-carbon teaching loop
TMG completes the last piece of the atlas's one-carbon metabolism + methylation puzzle.Related stories already in the atlas:
folate/one-carbon (L4): folate → DHFR → THF → 5,10-MTHF → MTHFR → 5-MTHF (main route upstream)vitamin-b12/methylation (L4): MTR + methylcobalamin + 5-MTHF → Hcy → Met → SAM (main route)vitamin-b12/nerve (L4): MUT + adenosylcobalamin → propionyl-CoA → succinyl-CoA (odd-chain fats + BCAA)choline/membrane: PEMT pathway transfers SAM methyls to phosphatidylethanolamine → phosphatidylcholine (the main consumer)glycine/metabolic-hub: Gly is the methyl pool that SHMT pathway derives from serineniacin-b3/nad: nicotinamide adenine dinucleotide: A coenzyme that ferries electrons to drive energy production — built from vitamin B3. is the energy partner on the SAM synthesis pathTMG/bhmt-pathway (new): backup route, BHMT, doesn't depend on B12/folatespirulina/pseudo-b12-trap: real B12 vs pseudo-B12, MTR reaction failure
Full chain:
```
Dietary folate → DHFR → THF
↓
SHMT (Gly enters)
↓
5,10-MTHF
↓
MTHFR (common mutation site)
↓
5-MTHF ←──── Main route: whole body, needs B12
↓ ↓
MTR + B12 ←────── Hcy ────→ BHMT + TMG (backup: liver + kidney)
↓ ↓
Met ←─────────────────────────┘
↓
S-adenosylmethionine: The body's main methyl-group donor — it tags DNA, neurotransmitters, and more with methyl groups. ── universal methyl donor ──→
│
├── PEMT → PC (phospholipid)
├── creatine synthesis (GAMT)
├── DNA / histone methylation
├── neurotransmitters
├── detox (COMT, etc.)
└── myelin (MBP methylation)
```
This diagram cannot be fully told in any single story — it is spread across 7-8 stories, letting the user walk the atlas themselves and assemble it piece by piece.
This is the most direct embodiment of the atlas's overall product philosophy: 'knowledge about the body should be organized as a system, not a dictionary.' One-carbon metabolism isn't a single concept; it is an interconnected metabolic map, and each nutrient is a node on that map. Understanding the relationships between nodes matters far more than memorizing the names of each one.