Effect of Folic Acid and Betaine Supplementation on Flow-Mediated Dilation: A Randomized, Controlled Study in Healthy Volunteers

Healthy adults aged 50 to 70 years with higher-normal homocysteine and no cardiovascular disease or hypertension were recruited from volunteers at Wageningen University in Wageningen, the Netherlands. This was a randomized, double-blind, placebo-controlled crossover trial; 39 participants completed and were analyzed in each active treatment arm.

Two oral supplementation regimens were tested in a randomized, double-blind, crossover design for 6 weeks each: folic acid 0.8 mg/d mixed with 6 g lactose, taken twice daily in water, and betaine 6 g/d, also taken twice daily in water. Placebo was 6 g lactose in the treatment sequence and is not an active intervention arm.

Neither folic acid nor betaine improved flow-mediated dilation compared with placebo, despite clear homocysteine lowering. FMD changed by -0.1 FMD% (95% CI, -0.9 to 0.7) after folic acid and by -0.4 FMD% (-1.2 to 0.4) after betaine versus placebo, while plasma homocysteine fell by 20% (-2.0 umol/L, 95% CI -2.3 to -1.6) with folic acid and by 12% (-1.2 umol/L, -1.6 to -0.8) with betaine. No serious adverse events occurred. The authors concluded that lowering homocysteine did not affect vascular function in these healthy older volunteers.

The trial was short, involved a relatively small sample of healthy older volunteers, and used a crossover design that limits broader generalizability. Findings apply to a population without cardiovascular disease or hypertension and do not rule out effects in other groups, longer treatment durations, or through mechanisms other than FMD.