Trimethylglycine (Betaine) for Homocysteine Reduction
For patients with homocystinuria or elevated homocysteine levels, betaine (trimethylglycine) should be used as adjunctive therapy at doses of 3-6 grams daily, particularly when response to B vitamins is insufficient or in patients with cystathionine β-synthase deficiency. 1
Primary Therapeutic Indications
Betaine acts as a methyl donor that directly remethylates homocysteine to methionine through the betaine-homocysteine methyltransferase pathway, making it particularly valuable in patients who don't respond adequately to B vitamin therapy alone. 1
Specific Clinical Scenarios for Betaine Use:
Homozygous homocystinuria: Betaine supplementation is recommended as part of the treatment regimen for patients with cystathionine β-synthase deficiency. 2
Moderate hyperhomocysteinemia (15-30 μmol/L): Betaine can be added as adjunct therapy when B vitamins alone provide insufficient homocysteine reduction. 1
Intermediate hyperhomocysteinemia (30-100 μmol/L): Betaine serves as important adjunctive treatment when response to folic acid (0.4-5 mg/day), vitamin B12 (0.02-1 mg/day), and vitamin B6 (10-50 mg/day) is inadequate. 1
Severe hyperhomocysteinemia (>100 μmol/L): Betaine is recommended as a critical adjunct to high-dose vitamin therapy. 1
Evidence-Based Dosing Recommendations
Standard Dosing Protocol:
3 grams daily: Reduces plasma homocysteine by 10% in healthy individuals with normal baseline levels. 3
6 grams daily: Achieves 14-20% reduction in fasting homocysteine concentrations. 3, 4
High-dose therapy (≥6 grams daily): Used specifically for homocystinuria due to inborn errors of homocysteine metabolism. 4
Pharmacokinetic Considerations:
Onset of action: Betaine lowers plasma homocysteine within 2 hours of oral administration, with effects sustained for 24 hours. 5
Dose-response relationship: Plasma betaine increases from baseline 31 μmol/L to 255 μmol/L in a dose-dependent manner (R² = 0.97). 3
Post-methionine loading: Betaine acutely reduces the homocysteine increase after methionine loading by up to 50%, whereas folic acid has no effect in this acute setting. 4
Combination Therapy Strategy
The most effective approach combines betaine with B vitamins rather than using betaine as monotherapy:
Betaine 6 grams + folic acid 1 mg daily: Produces an additional 5% reduction in homocysteine beyond betaine alone. 3
Standard combination for intermediate hyperhomocysteinemia: Folic acid 0.4-5 mg/day, vitamin B12 0.02-1 mg/day, vitamin B6 10-50 mg/day, with betaine added when insufficient response. 1
Severe cases: Pyridoxine 50-250 mg/day combined with folic acid 0.4-5 mg/day, vitamin B12 0.02-1 mg/day, and betaine supplementation. 1
Mechanism and Metabolic Pathway
Betaine provides an alternative remethylation pathway for homocysteine that is independent of folate-dependent mechanisms. 2, 1 This is particularly important because:
Betaine-homocysteine methyltransferase uses betaine as a methyl donor to convert homocysteine to methionine, producing N,N-dimethylglycine as a byproduct. 6
This pathway remains functional even when the folate-dependent methionine synthase pathway is impaired. 2
Betaine is especially effective in patients with MTHFR polymorphisms who may have reduced folate-dependent remethylation capacity. 1
Clinical Monitoring Parameters
Baseline Assessment:
Fasting plasma homocysteine: Obtain after at least 8 hours of fasting; single elevated value should be retested for confirmation. 1
Baseline plasma betaine: Normal ranges are 20-60 μmol/L in women and 25-75 μmol/L in men. 6
Follow-up Monitoring:
Recheck homocysteine at 3 months after initiating betaine supplementation to verify response. 7
Target homocysteine levels: Aim for 8-9 μmol/L with treatment. 1
Monitor serum lipids: Betaine may adversely affect total cholesterol and LDL-cholesterol concentrations, requiring periodic lipid monitoring. 8
Important Caveats and Pitfalls
Lipid Effects:
Serum total and LDL-cholesterol concentrations may increase with betaine supplementation (6 g daily for 12 weeks). 8 This creates a clinical dilemma where homocysteine-lowering benefits must be weighed against potential adverse lipid effects.
The long-term cardiovascular implications of betaine-induced lipid changes remain unclear. 4
Renal Considerations:
Urinary betaine excretion is minimal even following large doses, with normal excretion <35 mmol/mole creatinine. 6
Betaine is highly conserved by the kidneys, making it effective even in patients with renal impairment. 6
Dietary Context:
Dietary betaine intake is estimated at 0.5-2 grams daily from food sources. 4
Betaine can also be synthesized endogenously from its precursor choline. 4
Even doses in the range of dietary intake (1-2 grams) can lower homocysteine, suggesting that betaine-rich diets may provide cardiovascular benefits. 4
Evidence Limitations
The clinical evidence for betaine in homocystinuria is stronger than for general cardiovascular prevention. 2 While betaine effectively lowers homocysteine in healthy individuals and those with moderate elevations, the American Heart Association notes that "except in individuals with homozygous homocystinuria, there is little evidence that these methods are clinically useful" for preventing cardiovascular events. 2
However, more recent evidence suggests that homocysteine-lowering with B vitamins (and by extension, betaine) may reduce stroke risk by 18-25% when treatment duration exceeds 3 years and homocysteine reduction exceeds 20%. 2, 1
Practical Implementation
Start with 3 grams daily and titrate to 6 grams daily based on homocysteine response at 3 months. 3, 5 Combine with appropriate B vitamin supplementation (folic acid 0.4-5 mg, vitamin B12 0.02-1 mg, vitamin B6 10-50 mg) based on severity of hyperhomocysteinemia. 1 Monitor lipid profile at baseline and 3 months after initiation. 8