Betaine (Trimethylglycine)

Betaine, also known as trimethylglycine (TMG), is a naturally occurring zwitterionic amino‑acid derivative that functions primarily as a methyl‑group donor and an osmolyte. In humans it is derived from dietary choline and is widely present in plant and animal tissues where it helps maintain cellular hydration and supports methyl-group metabolism.

• Liver health: Clinical trials show betaine supplementation reduces hepatic steatosis and improves liver enzyme profiles (ALT, AST) in non‑alcoholic fatty liver disease (NAFLD) and alcoholic liver disease.
• Cardiovascular/metabolic: Betaine’s role as a methyl donor lowers homocysteine, a recognized cardiovascular risk factor, and modestly improves fasting glucose and lipid profiles in overweight adults.
• Exercise performance: Acute ingestion (2–3 g) improves power output and reduces fatigue during high‑intensity exercise, likely via enhanced muscle osmotic balance and creatine synthesis.
• Body composition: In resistance‑trained individuals, 2–6 g/day for 12 weeks modestly increases lean‑mass gains when combined with resistance training.
• Cognitive & mood: Limited but promising data indicate that betaine may support cognition and mood by supporting neurotransmitter synthesis (e.g., dopamine, serotonin) via methylation pathways.

• Methyl donor: Betaine acts as a methyl donor in the betaine‑homocysteine methyltransferase (BHMT) reaction, converting homocysteine to methionine, thus replenishing S‑adenosyl‑methionine (SAM) for downstream methylation reactions (DNA, neurotransmitters, phospholipids).
• Osmolyte: Betaine functions as an osmolyte: it accumulates in cells to counteract hyperosmolar stress, stabilizing protein structure and preserving cell volume, especially in renal medulla and skeletal muscle.
• Creatine synthesis: By supporting the methionine–SAM cycle, betaine indirectly boosts creatine synthesis (via SAM‑dependent methylation of guanidinoacetate), which enhances ATP regeneration during high‑intensity work.
• Gene expression: Its influence on the methylation of DNA and histones also modulates gene expression linked to lipid metabolism, inflammation, and oxidative stress, explaining the observed liver‑protective and metabolic effects.

• IUPAC name: (2‑Bromo‑2‑hydroxy‑N,N,N‑trimethyl‑ethanaminium) (but commonly referred to as N,N,N‑trimethylglycine).
• Molecular formula: C₅H₁₁NO₂.
• Molecular weight: 117.15 g/mol.
• Structure: A quaternary ammonium (–N⁺(CH₃)₃) attached to a glycine backbone where the carboxylate is deprotonated, giving a zwitterionic molecule (positive N, negative carboxylate). This neutral overall charge confers high water solubility (≈1 g/mL) and stability across pH 2–10.
• Physical properties: White crystalline powder, melting point 300 °C (decomposes), pKa of the carboxyl group ~2.3, pKa of the ammonium ~10.6.
• Stability: Stable under normal storage; sensitive to strong acids or bases that may convert it to betaine aldehyde; storage in a dry, cool environment preserves purity.

• Extraction: Betaine is extracted primarily from sugar beet (Beta vulgaris) molasses, where it occurs as the natural osmoprotectant betaine (≈1‑2 % w/w).
• Synthetic routes: Commercial production also utilizes synthetic routes: methylation of glycine with excess methyl iodide or dimethyl sulfate under controlled conditions, yielding high‑purity betaine suitable for pharmaceutical use.
• Natural food sources: Natural food sources include beets, spinach, quinoa, and shellfish; dietary intake averages 0.5–1 g/day in Western diets.
• Supplement quality: For supplements, USP‑grade or GMP‑certified betaine is preferred; analytical testing (HPLC, NMR) confirms ≥98 % purity and absence of heavy metals or residual solvents. Look for products that list “betaine anhydrous” or “betaine HCl” (the latter is a salt form with comparable bioavailability).