Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial.
Reviewed by: Alan Gaby, MD
Author: Obeid R, et al
Reference: Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial. Eur J Nutr 2016;55:1021-1028.
Design: Randomized single-blind trial.
Participants: Fifty-eight elderly individuals (mean age, 82 years).
Study Medication and Dosage: Folic acid alone (400 µg per day) or folic acid plus vitamin B6 (pyridoxine; 8 mg per day) and vitamin B12 (10 µg per day) for a median duration of 23 days.
Primary Outcome Measure: The serum concentration of unmetabolized folic acid.
Key Findings: After supplementation, the median concentration of unmetabolized folic acid was significantly lower by 72% in the group receiving all three B vitamins than in those receiving folic acid alone (0.17 vs. 0.61 nmol/L; p = 0.001). The proportion of individuals who had an unmetabolized folic acid concentration of 0.21 nmol/L or greater was lower in the group receiving all three B vitamins than in those receiving folic acid alone (33% vs. 76%; p value not stated).
Practice Implications: Unmetabolized folic acid is frequently present in the serum of people taking folic acid supplements and in elderly people receiving folic acid-fortified foods or supplements. Concerns have been raised that unmetabolized folic acid could have deleterious effects on health. Specifically, some have argued that unmetabolized folic acid could increase the risk of developing cancer. For this and other reasons, it has been suggested that folic acid should no longer be used as a supplement, and some manufacturers have replaced folic acid in multivitamin products with its biologically active form, 5-methyltetrahydrofolate (5-MTHF).
However, research on folic acid and cancer is conflicting, ranging from a protective effect, to no effect, to an adverse effect. Moreover, there is no clear evidence of any safety difference (cancer risk or otherwise) between unmetabolized folic acid and folic acid that has been metabolized to its biologically active form. The results of the present study suggest that efficient metabolism of folic acid depends on the presence of adequate amounts of other B vitamins. The clinical significance of this finding remains to be determined.
As I have argued elsewhere, routinely substituting folic acid with 5-MTHF, particularly in multiple-micronutrient products, is not supported by the available scientific evidence.
 Gaby AR. Which supplement should we use: folic acid or methylfolate? www.doctorgaby.com, in the section on Articles.