Betaine (TMG / Trimethylglycine)

Mechanism of Action

Betaine (trimethylglycine) serves as a methyl donor in the betaine-homocysteine methyltransferase (BHMT) reaction, converting homocysteine to methionine — this is the alternative methyl cycle pathway (parallel to the folate-dependent methionine synthase pathway). It functions as an osmolyte, protecting cells from osmotic stress by maintaining intracellular water balance (critical for kidney medulla and muscle cells). Athletic performance benefits likely derive from enhanced creatine synthesis (methyl donation), improved power output via osmotic cell protection, and reduced homocysteine-mediated vascular impairment.

Dosing Protocol

Notes

Dual role: (1) essential methyl donor when supplementing NMN/NR (NAD+ metabolism consumes methyl groups, potentially depleting SAMe — TMG replenishes the methyl pool); (2) ergogenic aid for strength and power performance. The NMN/NR + TMG pairing is considered mandatory by most longevity practitioners. Do NOT confuse TMG (trimethylglycine/betaine anhydrous) with Betaine HCl (hydrochloric acid form for digestive support). The fishy odor side effect is the main compliance issue — not all individuals are affected.

Stacking

• NMN or NR (essential methyl replenishment)
• Creatine
• B-Complex
• L-Citrulline

Interactions

• Methotrexate [LOW] — Betaine supports methylation which methotrexate disrupts — may be supportive but discuss with oncologist

Contraindications

• Trimethylaminuria (fish odor syndrome — impaired TMA metabolism)
• Homocystinuria (under medical management — betaine is actually used therapeutically here, but dosing requires physician oversight)

Side Effects

• Fishy body odor (TMA production)
• GI upset/diarrhea
• Nausea
• Methionine elevation (theoretical concern with chronic high-dose use in cancer context)

Key Papers

• 10.1186/1550-2783-10-39
• 10.1016/j.jfca.2016.01.003
• 10.1007/s00726-012-1354-9

Source Quality

Betaine anhydrous (TMG) powder or capsule. Betaine HCl is a different product used for stomach acid support — not the same as TMG. Brands: NOW TMG, Thorne Methyl-Guard (combination product), BulkSupplements TMG Powder.

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