Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh.

Randomized controlled trial in arsenic-exposed Bangladeshi adults from Araihazar, recruited from the HEALS cohort. Participants were generally healthy, nonpregnant adults using arsenic-removal water filters, with five active treatment groups and repeated urine biomarker measurements over 24 weeks.

Adults were assigned to oral daily supplements for 12 weeks: folic acid 400 μg/day, folic acid 800 μg/day, creatine 3 g/day, or creatine 3 g/day plus folic acid 400 μg/day, all given as pills. In the folic acid arms, a second phase from weeks 12 to 24 randomized participants to continue folic acid or switch to placebo to assess rebound after stopping supplementation.

Folic acid supplementation improved arsenic methylation, lowering urinary inorganic arsenic and monomethylarsonic acid and increasing dimethylarsinic acid, with the 800 μg/day dose generally producing a larger effect than 400 μg/day. At weeks 6 and 12, folic acid groups had significantly lower %InAs and %MMAs and higher %DMAs versus placebo; the 800 μg group showed a larger reduction in %MMAs than the 400 μg group at weeks 6 and 12 (P = 0.034). Creatine had a smaller effect, mainly lowering %MMAs without changing %InAs or %DMAs. After folic acid was stopped, metabolite proportions tended to move back toward baseline, consistent with a rebound effect.

The trial was relatively short and relied on biomarker outcomes rather than clinical endpoints. Some participants were excluded or lost to analysis, and adverse events, pregnancies, and missing samples reduced effective sample sizes within arms. Generalizability is limited to arsenic-exposed Bangladeshi adults with similar baseline folate status and exposure conditions.