L-Methylfolate vs. Folic Acid Supplements for the MTHFR C677T Mutation
What is MTHFR?
The methylenetetrahydrofolate reductase (MTHFR) enzyme converts synthetic folic acid and dietary folate into its active form, L-methylfolate, which plays a critical role in neurotransmitter synthesis. Some individuals carry a mutation at the C677T SNP of the MTHFR gene, which results in a 35% reduction in activity for heterozygotes (C/T) and a 70% reduction in activity for homozygotes (T/T).1,2 Individuals who carry this mutation will have a reduced capacity to create L-methylfolate.
How can healthcare providers treat individuals with reduced MTHFR activity?
Both L-methylfolate and folic acid are possible treatment options for individuals with reduced MTHFR activity.
L-methylfolate: By bypassing the conversion step mediated by MTHFR, supplementation with L-methylfolate should improve serum and CNS folate levels, which may have an impact on depression response. Studies have found that taking L-methylfolate alone3–6 or in addition to an antidepressant6–8 improves depression. Only one study has evaluated the MTHFR C677T genotype in depressed patients taking L-methylfolate supplementation. This study found no significant improvement on the HDRS-28 scale for any MTHFR genotype.9 However, the study sample was small, and there was a trend for patients with MTHFR variation (CT/TT) benefiting more from L-methylfolate supplementation.
Folic acid: Supplementation with folic acid may compensate for the reduced MTHFR enzyme activity, leading to normal levels of the active L-methylfolate, which may have an impact on depression response. Studies investigating the effect of folic acid supplementation on depression response have produced mixed results.10–12 There have been more studies investigating the effect of taking folic acid as an adjunct to an antidepressant, but again the results are mixed, with some studies showing an improvement in depression13–15 and others, including a meta-analysis, showing no clinical benefit16–18. There are currently no studies evaluating the MTHFR C677T genotype in depressed patients taking folic acid supplementation.
What dose of folic acid or L-methylfolate should be used?
Assurex Health does not make dosing recommendations, as this is up to the discretion of the healthcare provider. There are currently no guidelines regarding dosage of folic acid or L-methylfolate. For folic acid, there is generally 400 mcg present in a multivitamin and 800 mcg present in a prenatal vitamin. L-methylfolate is available over-the-counter or as a prescription only product.
What are the risks of folic acid supplementation?
Although studies have produced mixed results19–25, some caution may be warranted in the administration of high doses of folic acid, as this may mask vitamin B12 deficiency. Additionally, some studies have shown that high intake of folic acid may exacerbate the neurologic effects of vitamin B12 deficiency.19,26,27 Healthcare providers should weigh the benefits of folic acid or L-methylfolate supplementation with possible risks associated with these treatment strategies.
- Frosst, P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10, 111–113 (1995).
- Chango, A. et al. 5,10-methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. Br. J. Nutr. 84, 891–6 (2000).
- Guaraldi, G. P., Fava, M., Mazzi, F. & La Greca, P. An Open Trial of Methyltetrahydrofolate in Elderly Depressed Patients. Ann. Clin. Psychiatry 5, 101–105 (1993).
- Passeri, M., Cucinotta, D., Abate, G. & Senin, U. Oral 5’methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging Clin. Exp. Res. 5, 63–71 (1993).
- Di Palma, C., Urani, R., Agricola, R., Giorgetti, V. & Dalla Verde, G. Is methylfolate effective in relieving major depression in ceronic alcoholics? A hypothesis of treatment. Curr. Ther. Res. – Clin. Exp. 55, 559–568 (1994).
- Shelton, R. C., Manning, J. S. & Barrentine, L. W. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord 15, 1–9 (2013).
- Godfrey, P., Toone, B., Carney, M., Flynn, T. & Bottiglieri, T. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392–395 (1990).
- Papakostas, G. I. et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallelsequential trials. Am. J. Psychiatry 169, 1267–74 (2012).
- Papakostas, G. I. et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J. Clin. Psychiatry 75, 855–63 (2014).
- Kohen, V. L. et al. A pilot study of folic acid supplementation for improving homocysteine levels , cognitive and depressive status in eating disorders A pilot study of folic acid supplementation for improving homocysteine levels , cognitive and depressive status in eating disorders. (2016). doi:10.3305/nh.2013.28.3.6335
- Adhikari, P. M. et al. Effect of vitamin B12 and folic acid supplementation on neuropsychiatric symptoms and immune response in HIV-positive patients. J. Neurosci. Rural Pract. 7, 362–367 (2016).
- de Koning, E. J. et al. Effects of Two-Year Vitamin B 12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations : Additional Results from the B-PROOF Study, an RCT. (2016). doi:10.3390/nu8110748
- Coppen, A. & Bailey, J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J. Affect. Disord. 60, 121–30 (2000).
- Resler, G. et al. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation 15, 145–152 (2008).
- Venkatasubramanian, R., Naveen, C. & Pandey, R. S. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J. Affect. Disord. 150, 644–648 (2013).
- Basoglu, C. et al. Adjuvant folate treatment to essitalopram and serum homocystein, folate, vitamin B-12 levels in patients with major depressive disorder. [Turkish]. Bull. Clin. Psychopharmacol. 19, 135–142 (2009).
- Bedson, E. et al. Folate augmentation of treatment – evaluation for depression (FolATED): randomised trial and economic evaluation. Health Technol. Assess. (Rockv). 18, (2014).
- Sarris, J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am. J. Psychiatry appiajp201615091228 (2016). doi:10.1176/appi.ajp.2016.15091228
- Morris, M. S., Jacques, P. F., Rosenberg, I. H. & Selhub, J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85, 193–200 (2007).
- Mills, J. L. et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am. J. Clin. Nutr. 77, 1474–1477 (2003).
- Ray, J. G., Vermeulen, M. J., Langman, L. J., Boss, S. C. & Cole, D. E. C. Persistence of vitamin B12 insufficiency among elderly women after folic acid food fortification. Clin. Biochem. 36, 387–391 (2003).
- Metz, J., McNeil, A. R. & Levin, M. The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate. Clin. Lab. Haem. 26, 323–325 (2004).
- Liu, S. et al. A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects. BMC Pregnancy Childbirth 4, (2004).
- Wyckoff, K. F. & Ganji, V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post-folic acid fortification period than in the pre-folic acid fortification period. Am. J. Clin. Nutr. 86, 1187–92 (2007).
- Qi, Y. P. et al. The prevalence of low serum vitamin B12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J Nutr 144, 170–176 (2014).
- Morris, M., Selhub, J. & Jacques, P. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham Heart Study. J Am Geriatr Soc 60, 1457–1464 (2012).
- Moore, E. M., Ames, D., Mander, A. G., Carne, R. P. & Brodaty, H. Among Vitamin B12 Deficient Older People, High Folate Levels are Associated with Worse Cognitive Function: Combined Data from Three Cohorts. J. Alzheimer’s Dis. 39, 661–668 (2014).