Betaine
Betaine, also known as Trimethylglycine (TMG), is a naturally occurring, stable, and non-toxic compound that serves as an essential nutrient and a key metabolite in the human body. It was first identified in the 19th century in sugar beets (Beta vulgaris), from which it derives its name [1]. Betaine is an active metabolite of choline and is found in various food sources, including wheat bran, wheat germ, spinach, and seafood [1, 2].
Chemical/Botanical Basics
Chemically, betaine is a zwitterionic quaternary ammonium compound with the formula (CH₃)₃N⁺CH₂COO⁻. It is an amino acid derivative, specifically the N-trimethylated form of the amino acid glycine. It is often referred to as Betaine Anhydrous when used as a supplement.
Mechanism of Action
Betaine primarily functions through two major mechanisms:
- Methyl-Group Donor: Betaine is a crucial donor of three methyl groups (-CH₃). Its most vital role is in the remethylation of homocysteine to form the amino acid methionine. This reaction is catalyzed by the enzyme betaine-homocysteine methyltransferase (BHMT), primarily in the liver and kidneys. By lowering levels of the potentially toxic metabolite homocysteine, betaine helps maintain proper methionine homeostasis and supports the production of S-adenosylmethionine (SAMe), a universal methyl donor essential for numerous cellular processes, including DNA and protein methylation [1, 3].
- Osmolyte: Betaine acts as an osmolyte, a molecule that helps cells maintain their volume and hydration status under osmotic stress. By accumulating within cells, betaine helps balance the intracellular osmotic pressure, protecting cellular proteins and enzymes from denaturation and preserving cell function, particularly in organs like the kidney and liver [1].
2. Chemical Composition/Key Bioactive Roles
The primary bioactive molecule is Betaine Anhydrous (Trimethylglycine). Its key roles are summarized below:
| Compound | Chemical Class | Key Bioactive Role | Primary Metabolite |
|---|---|---|---|
| Betaine Anhydrous (TMG) | Quaternary Ammonium Compound/Amino Acid Derivative | Methyl-group donor, Osmolyte | S-adenosylmethionine (SAMe), Dimethylglycine (DMG) |
| Homocysteine | Non-proteinogenic Amino Acid | Substrate for remethylation | Methionine |
| Methionine | Essential Amino Acid | Precursor to SAMe | – |
| S-adenosylmethionine (SAMe) | Methyl Donor | Universal methyl donor for cellular methylation reactions | – |
3. Health Benefits
Betaine supplementation has been linked to a variety of health benefits, primarily through its roles in homocysteine metabolism and cellular osmoregulation, supported by scientific evidence:
- Cardiovascular Health and Homocysteine Reduction: Betaine is clinically approved for the treatment of homocystinuria, a genetic disorder characterized by dangerously high levels of homocysteine [3]. Elevated homocysteine is an independent risk factor for cardiovascular disease. By facilitating the conversion of homocysteine to methionine, betaine effectively reduces circulating homocysteine levels, which is beneficial for overall cardiovascular health [1, 4].
- Liver Protection and Detoxification: Betaine has shown protective effects against both alcohol-induced and metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD) [1]. Its mechanism involves restoring methylation potential and promoting fat oxidation, thereby preventing the accumulation of fat (steatosis) in the liver [1].
- Enhanced Athletic Performance: Betaine has been studied for its ergogenic properties, particularly in strength and power sports. Research suggests that TMG supplementation can improve body composition, increase muscle endurance, and enhance power output, potentially by acting as an osmolyte to increase cell volume and protect muscle proteins from stress [4, 5].
- Neuroprotective Effects: As a methyl donor, betaine supports the synthesis of SAMe, which is crucial for the production of neurotransmitters. Studies suggest a neuroprotective role and potential benefits in managing symptoms of depression, although more research is needed [1, 4].
4. Dosage and Usage
Recommended Dosages
Dosages for betaine vary depending on the intended use and individual health status.
| Indication | Recommended Daily Dosage | Notes |
|---|---|---|
| Homocystinuria (Medical) | 3 to 6 grams per day, divided into two doses | Under medical supervision; can be increased to 20 grams/day [3]. |
| Cardiovascular/Heart Health | 4 grams per day | Primarily for homocysteine reduction [4]. |
| Athletic Performance | 1.25 to 2.5 grams per day, typically split into two doses | Often taken pre- and post-workout [4, 5]. |
| General Supplementation | 1.5 to 3 grams per day | Effective for general maintenance and health in healthy individuals [4]. |
Food Sources
Betaine is readily available in the diet, with the highest concentrations found in:
- Wheat Bran: High concentration (up to 1,339 mg per 100g)
- Wheat Germ: High concentration
- Spinach: Significant source
- Beets (Beta vulgaris): The original source of the compound
- Seafood: Various types of fish and shellfish
5. Safety and Precautions
Betaine is generally well-tolerated, especially at typical supplemental doses. However, certain side effects and precautions should be noted.
Side Effects
The most common side effects are related to the gastrointestinal system:
- Gastrointestinal Discomfort: Nausea, stomach upset, diarrhea, and stomach cramps [6].
- Body Odor: A distinctive, fishy body odor has been reported, particularly at higher doses, due to the metabolic breakdown of betaine into trimethylamine [3, 6].
Contraindications and Warnings
- Kidney Disease: Betaine is metabolized in the kidney. Individuals with pre-existing kidney conditions should use betaine with caution and under medical advice.
- High Homocysteine with Folate/B12 Deficiency: Betaine lowers homocysteine by converting it to methionine. If the body is deficient in Vitamin B12 or Folate, this conversion may be impaired, and methionine levels can become excessively high. It is crucial to rule out or treat B12/Folate deficiencies before starting betaine supplementation, especially for homocystinuria [3].
Drug Interactions
Betaine may interact with certain medications, including:
- Methotrexate: Betaine may increase the effectiveness of methotrexate, a drug used to treat cancer and autoimmune diseases, by affecting the folate pathway.
- Folic Acid and B Vitamins: While not a direct interaction, betaine works synergistically with folic acid, Vitamin B6, and Vitamin B12 in the methionine cycle. Taking them together is generally safe and beneficial, but high doses of one without the others may unbalance the metabolic pathway.
- Celiprolol: Betaine may increase the bradycardic (heart rate lowering) activities of Celiprolol, a beta-blocker [7].
Serious Warning: If betaine is being used to treat homocystinuria, it must be used under the strict supervision of a healthcare provider. Do not use betaine if you have an untreated deficiency of Vitamin B12 or Folate, as this can lead to a dangerous buildup of methionine.
6. References
[1] Arumugam, M. K., et al. (2021). Beneficial Effects of Betaine: A Comprehensive Review. Biology (Basel), 10(6), 456.URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224793/ [2] Examine.com. (2025). Betaine benefits, dosage, and side effects.
URL: https://examine.com/supplements/betaine/ [3] DrugBank. (n.d.). Betaine: Uses, Interactions, Mechanism of Action.
URL: https://go.drugbank.com/drugs/DB06756 [4] Vitality-Pro. (2024). Guide To Trimethylglycine Use, Dosage & Risks.
URL: https://vitality-pro.com/tmg/benefits-dosage-side-effects-tmg/ [5] Healthline. (2021). TMG Supplements: Benefits, Side Effects, Dosage, and More.
URL: https://www.healthline.com/nutrition/tmg-supplement [6] Mayo Clinic. (2025). Betaine (oral route) – Side effects & dosage.
URL: https://www.mayoclinic.org/drugs-supplements/betaine-oral-route/description/drg-20062216 [7] Drugs.com. (2024). Betaine Uses, Side Effects & Warnings.
URL: https://www.drugs.com/mtm/betaine.html
Category: Methyl donor
