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Betaine (trimethylglycine, TMG)

Methyl donor; agent for the alternative homocysteine remethylation pathway

ATC code: A16AA06(Betaine (Cystadane))

Brand names: Betaine anhydrous (various), Trimethylglycine TMG, Cystadane

Updated · Methodology

Indications

A

Homocystinuria

First line

Betaine (Cystadane) is first-line treatment for classical homocystinuria and for methyltetrahydrofolate reductase deficiency or B12-dependent remethylation defects in children and adults. approved the drug in 1996; AEMPS confirms the indication. Dose: 100 mg/kg/day split into two intakes, titrated to plasma homocysteine below 15 µmol/L. Therapy is lifelong under a metabolic paediatrician and regular plasma amino-acid panels. There is no alternative regimen.

Sources

  1. FDA: Cystadane (betaine anhydrous) prescribing information (2017)
  2. J Inherit Metab Dis: Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. (2017)
  3. J Inherit Metab Dis: Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. (2017)
  4. AEMPS: Ficha técnica de Cystadane (betaína) (2022)

ICD-10: E72.1 · ICD-11: 5C50.B

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

D

Athletic endurance

Not recommended

Sports marketing positions betaine as a «legal anabolic equivalent»: doses of 2.5 g/day allegedly improve strength and endurance. A 2017 Cholewa meta-analysis showed statistically significant but clinically modest strength improvement (about 2%) in untrained men; in trained athletes the effect is not reproducible. International sports federations do not recognise the drug as ergogenic. AEMPS and AESAN consider performance-enhancement claims unsubstantiated.

Sources

  1. IOC: IOC consensus statement: dietary supplements and the high-performance athlete (2018)
D

Muscle mass gain (bodybuilding self-use)

Not recommended

TMG is sold in sports nutrition shops as a «muscle mass» supplement. Most studies show lean mass gain comparable to placebo. NIH ODS states explicitly: data are conflicting, insufficient for recommendation. AEMPS has not approved the drug for this use. Evidence-based muscle gain rests on progressive overload, 1.6–2.2 g/kg protein and adequate sleep, not a TMG sachet in water.

Sources

  1. IOC: IOC consensus statement: dietary supplements and the high-performance athlete (2018)
D

Non-alcoholic fatty liver disease

Not recommended

High-dose betaine (10–20 g/day) was studied in non-alcoholic fatty liver disease. Several small studies reported reduced ALT and improved histology, but larger randomised trials did not confirm the effect. 2024 and 2023 do not recommend it for MASLD/NAFLD. High doses raise plasma methionine, which may worsen the lipid profile and cause unpleasant body odour. Evidence-based treatment of fatty liver targets weight, diet, glucose and lipid control.

Sources

  1. EASL: EASL-EASD-EASO Clinical Practice Guidelines on metabolic dysfunction-associated steatotic liver disease (2024)
  2. FDA: Cystadane (betaine anhydrous) prescribing information (2017)

ICD-10: K76.0 · ICD-11: DB92

How to read tiers A–F
  • AStrong evidence – first or second line in international guidelines
  • BRecommended in selected cases
  • CStudy data contradict each other
  • DBenefit not proven, no documented harm
  • FDocumented harm, or risk without benefit

Mechanism of action

Betaine (trimethylglycine) donates a methyl group to homocysteine via betaine-homocysteine methyltransferase (BHMT), converting it to methionine. This is the alternative remethylation pathway; the main one uses methionine synthase with vitamin B12 and methylfolate. In classical homocystinuria and B12 deficiency betaine lowers homocysteine and prevents vascular, skeletal and lens damage. approved Cystadane in 1996 for this indication. As an iHerb supplement it is marketed as a «methylation booster», but in people without BHMT/CBS defects this use has no clinical meaning.

Safety

Contraindications

  • Hypersensitivity to betaine
  • Severe dyslipidaemia and ischaemic heart disease (with high doses)

Serious adverse effects

  • Hypermethioninaemia with cerebral oedema (single reports in homocystinuria – dose adjustment required)
  • Adverse lipid profile and ischaemic heart disease risk with long-term high-dose use

Common adverse effects

  • Nausea, vomiting
  • Abdominal pain, diarrhoea
  • Fishy body odour at high doses (trimethylaminuria)
  • Rise in LDL cholesterol and total methionine

Pregnancy: can you take Betaine (trimethylglycine, TMG)?

EMA summary of product characteristics for Cystadane (betaine anhydrous oral powder), section 4.6: data from a limited number of at-risk pregnancies show no adverse effects of betaine anhydrous on pregnancy or on the health of the fetus or newborn. No other relevant epidemiological data are available to date, and no animal reproduction studies have been done. In pregnancy, betaine anhydrous given together with pyridoxine, folate, an anticoagulant and diet, with close monitoring of plasma homocysteine, is compatible with good outcomes for both mother and fetus. Even so, Cystadane should not be used during pregnancy unless clearly necessary.

Breastfeeding: can you take Betaine (trimethylglycine, TMG)?

Use with caution. Hale L3. Limited data. In maternal homocystinuria Cystadane therapy continues; supplemental TMG doses during lactation are avoided.

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Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

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Frequently asked

What is Betaine (trimethylglycine, TMG) used for?

Betaine (trimethylglycine, TMG) is evaluated for the following indications with varying evidence strength: Homocystinuria (evidence tier A), Non-alcoholic fatty liver disease (evidence tier D), Athletic endurance (evidence tier D). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Betaine (trimethylglycine, TMG)?

Common side effects of Betaine (trimethylglycine, TMG) (≥ 1 in 100): Nausea, vomiting, Abdominal pain, diarrhoea, Fishy body odour at high doses (trimethylaminuria), Rise in LDL cholesterol and total methionine. See the Safety section for uncommon and serious reactions.

Is Betaine (trimethylglycine, TMG) safe during pregnancy?

EMA summary of product characteristics for Cystadane (betaine anhydrous oral powder), section 4.6: data from a limited number of at-risk pregnancies show no adverse effects of betaine anhydrous on pregnancy or on the health of the fetus or newborn. No other relevant epidemiological data are available to date, and no animal reproduction studies have been done. In pregnancy, betaine anhydrous given together with pyridoxine, folate, an anticoagulant and diet, with close monitoring of plasma homocysteine, is compatible with good outcomes for both mother and fetus. Even so, Cystadane should not be used during pregnancy unless clearly necessary.

Is Betaine (trimethylglycine, TMG) compatible with breastfeeding?

Use with caution. Hale L3. Limited data. In maternal homocystinuria Cystadane therapy continues; supplemental TMG doses during lactation are avoided.

Who should not take Betaine (trimethylglycine, TMG)?

Betaine (trimethylglycine, TMG) is contraindicated in: Hypersensitivity to betaine; Severe dyslipidaemia and ischaemic heart disease (with high doses). Full list in the Safety section.

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