What are the benefits, recommended dose, and contraindications of trimethylglycine (betaine) for lowering homocysteine in hyperhomocysteinemia and for treating non‑alcoholic fatty liver disease?

Benefits of Trimethylglycine (Betaine)

Trimethylglycine (betaine) effectively lowers homocysteine levels by 5-20% at doses of 4-6 g/day, but its use is limited by adverse effects on blood lipids, making folic acid and vitamin B12 the preferred first-line treatment for hyperhomocysteinemia. 1

Primary Benefit: Homocysteine Reduction

Betaine acts as a methyl donor that directly remethylates homocysteine to methionine, providing an alternative pathway to the folate-dependent remethylation route. 1, 2

Efficacy for Lowering Homocysteine

• Betaine supplementation at 6 g/day lowers fasting plasma homocysteine by up to 20% in healthy individuals with normal homocysteine levels. 2
• Lower doses (4 g/day minimum) for 6-24 weeks reduce plasma homocysteine by approximately 1.23 μmol/L (95% CI: -1.61 to -0.85), which is statistically significant. 3
• Betaine is particularly effective at reducing post-meal homocysteine spikes, lowering the increase after methionine loading by up to 50%, whereas folic acid has no effect on postprandial homocysteine. 2
• Dietary betaine intake (0.5-2 g/day from food sources) also demonstrates homocysteine-lowering effects, suggesting it may be an important dietary component for cardiovascular health. 2

Clinical Indications for Betaine Use

The European Society of Cardiology recommends betaine as an adjunct therapy when patients don't respond adequately to B vitamins alone, particularly in those with cystathionine β-synthase deficiency. 1

• For moderate hyperhomocysteinemia (15-30 μmol/L), betaine can be added when first-line folic acid therapy produces insufficient reduction. 1
• For intermediate hyperhomocysteinemia (30-100 μmol/L), betaine serves as adjunctive therapy to combination B-vitamin treatment. 1
• For severe hyperhomocysteinemia (>100 μmol/L), betaine is recommended as an important adjunct to high-dose vitamin therapy. 1
• Betaine in high doses (6 g/day and higher) is specifically used for homocystinuria due to inborn errors of homocysteine metabolism. 2

Recommended Dosing

The effective dose range for homocysteine lowering is 4-6 g/day, with higher doses producing greater reductions but also more pronounced lipid effects. 2, 3

• A minimum of 4 g/day for at least 6 weeks is required to achieve statistically significant homocysteine reduction. 3
• The dose-response relationship shows that 6 g/day produces maximal homocysteine lowering of approximately 20%. 2
• Dietary intake of betaine (0.5-2 g/day) from food sources also provides modest homocysteine-lowering benefits. 2

Major Contraindications and Adverse Effects

Betaine supplementation significantly raises LDL cholesterol and triglycerides, which may counteract any cardiovascular benefits from homocysteine lowering. 4

Lipid Effects (Critical Limitation)

• Betaine at 6 g/day increases LDL cholesterol by 0.36 mmol/L (95% CI: 0.25-0.46) and triglycerides by 0.14 mmol/L (95% CI: 0.04-0.23) relative to placebo after 6 weeks. 4
• The ratio of total cholesterol to HDL cholesterol increases by 0.23 (95% CI: 0.14-0.32), indicating an adverse shift in lipid profile. 4
• These lipid changes appear as early as 2 weeks after starting betaine supplementation. 4
• HDL cholesterol concentrations are not affected by betaine. 4
• Lower doses of betaine (<6 g/day) also raise LDL cholesterol, though these changes may not reach statistical significance. 4

Clinical Implications of Lipid Effects

The adverse effects on blood lipids may negate the potential cardiovascular benefits of betaine supplementation through homocysteine lowering, making the net clinical benefit uncertain. 4, 5

• Whether the homocysteine-lowering benefits outweigh the lipid-raising effects remains unclear and requires further study. 2, 5
• Folic acid supplementation (0.8 mg/day) has no effect on lipid concentrations and therefore remains the preferred treatment for lowering homocysteine. 4

Additional Potential Benefits (Preliminary Evidence)

Betaine demonstrates antithrombotic effects in animal models, delaying thrombotic occlusion and inhibiting platelet aggregation, though human data are lacking. 6

• In mice, betaine at doses of 10-40 mg/kg significantly delayed photochemically-induced thrombosis in both arterioles and venules. 6
• Betaine (0.01-1 mg/mL) significantly reversed ADP-induced platelet aggregation in vitro and prolonged PT and aPTT in a dose-dependent manner. 6
• Betaine reduced lipid peroxidation in plasma, suggesting potential antioxidant effects. 6

Clinical Algorithm for Betaine Use

Use betaine only as second-line or adjunctive therapy after optimizing B-vitamin supplementation (folic acid, B12, B6), and only in patients without dyslipidemia or established cardiovascular disease. 1, 4

Step-by-Step Approach:

1. First-line treatment: Initiate folic acid (0.4-5 mg/day) plus vitamin B12 (0.02-1 mg/day), which lowers homocysteine by 25-30% without adverse lipid effects. 1, 4

2. Assess response after 6-8 weeks by rechecking fasting homocysteine levels. 1

3. If homocysteine remains elevated despite adequate B-vitamin therapy, check baseline lipid panel before considering betaine. 4

4. Add betaine (4-6 g/day) only if:

   • LDL cholesterol is at goal
   • Triglycerides are normal
   • Patient has no established cardiovascular disease
   • Homocysteine remains significantly elevated (>30 μmol/L) despite B vitamins 1, 4

5. Monitor lipid panel at 2 weeks and 6 weeks after starting betaine, and discontinue if LDL cholesterol or triglycerides increase significantly. 4

Common Pitfalls to Avoid

• Never use betaine as first-line therapy for hyperhomocysteinemia—folic acid and B12 are more effective and safer. 4
• Do not assume homocysteine lowering with betaine translates to cardiovascular benefit, as the lipid effects may be counterproductive. 4, 5
• Avoid betaine in patients with dyslipidemia or established cardiovascular disease due to the LDL-raising effect. 4
• Do not overlook dietary sources of betaine (0.5-2 g/day from foods), which may provide modest benefits without the high-dose lipid effects. 2