B9, an essential nutrient?

Methylfolate (Vitamin B9), the natural form of folate, has many advantages over synthetic folic acid. ¹

For example, methylfolate is well absorbed and its bioavailability is not affected by metabolic defects.

What is this essential nutrient used for?

Vitamin B9 (folate) is an essential water-soluble vitamin that is used during periods of rapid cell growth and division, in the maintenance of new cells, and in the manufacture of DNA and RNA. ¹ Although primarily known for its support of pregnancy and fertility, there is growing recognition that folate also has benefits for cardiovascular health, mood, and cognition. ^2,3,4

Folic acid, in the form of medication or supplemented food, is the main synthetic source of vitamin B9 prescribed, especially for women planning or experiencing pregnancy, to ensure proper development of the neural tube in the fetus. However, several studies have shown that 5-methyltetrahydrofolate <5-MTHF or methylfolate> represents a better alternative to folic acid. In fact, folic acid must first be converted to methylfolate by the liver before it can be effectively used by the body. Methylfolate can also enter the brain across the blood-brain barrier. Methylfolate regulates the synthesis of three important neurotransmitters (serotonin, dopamine, and norepinephrine) that are involved in mood control and can therefore be used as an adjunct to therapy for depression. ³

1. Scaglione, Francesco & Panzavolta, Giscardo. (2014). Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica; the fate of foreign compounds in biological systems. 44. 10.3109/00498254.2013.845705.

2. Carboni L. Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integra Med (Encinitas). 2022 Jul;21(3):36-41. PMID: 35999905; PMCID: PMC9380836.

3. Stahl SM. Novel therapeutics for depression: l-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr. 2007;12(10):739–744.

4. Smith AD, Kim YI, Refsum H. Effects of vitamins and polyunsaturated fatty acids on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials. Eur J Nutr. 2024 Feb 1. doi: 10.1007/s00394-024-03324-y.

• High folic acid intake may be harmful for some people because they have a lower genetic ability to convert folic acid into methylfolate, the form used by the body. ¹
• High blood levels of folic acid may be linked to a decrease in the ability of certain cells in the immune system to kill pathogens. ¹
• In older adults, a combination of high folate levels and low vitamin B-12 status may be associated with an increased risk of cognitive impairment and anemia, and in pregnant women, an increased risk of insulin resistance and obesity in their children. ¹

^{1. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr. 2008 Mar;87(3):517-33. doi:10.1093/ajcn/87.3.517. PMID: 18326588.}

What can a deficiency cause?

• Vitamin B9 deficiency could not only cause anemia, fatigue, pallor, irritability, shortness of breath and dizziness, but also pose a risk of birth defects to the fetus in pregnant women. ^1,2

1. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):862-77. doi: 10.1093/oxfordjournals.aje.a010290. PMID: 10791559. 2. https://www.livi.fr/sante/malnutrition/carence-alimentaire/ (I also suggest https://www.merckmanuals.com/fr-ca/professional/troubles-nutritionnels/carence-dependance-et-toxicité-des-vitamines/déficit-en-folates)

2. Ami N, Bernstein M, Boucher F, Rieder M, Parker L; Canadian Paediatric Society, Drug Therapy and Hazardous Substances Committee. Folate and neural tube defects: the role of supplements and fortified foods. Paediatr Child Health. 2016 Apr;21(3):150–4. French. PMCID: PMC4933078.

Vitamin B9 & Anxiety

Methylfolate may be a game changer for people with anxiety caused by a deficiency of this nutrient, not by the environment.

^{1. Scaglione, Francesco & Panzavolta, Giscardo. (2014). Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica; the fate of foreign compounds in biological systems. 44. 10.3109/00498254.2013.845705.}

^{2. Carboni L. Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integra Med (Encinitas). 2022 Jul;21(3):36-41. PMID: 35999905; PMCID: PMC9380836.}

Vitamin B9 & Depression

L-methylfolate is a medical food intended for people with folate deficiency. L-methylfolate is also used in people with major depressive disorder who are folate deficient, or in people with schizophrenia who have hyperhomocysteinemia related to folate deficiency.

L-methylfolate is not an antidepressant or antipsychotic. However, L-methylfolate may enhance the effects of antidepressant medications. ¹

1. https://www.drugs.com/search.php?searchterm=l-methylfolate&a=1

Vitamin B9 - Stress & Cortisol

It is suggested that dietary intake of vitamins, particularly B vitamins, including B6, B9 and B12, may have a number of positive effects on mood and stress.
This is according to a study that provided preliminary evidence suggesting that 16-week supplementation with a multivitamin containing high-dose B vitamins did not differentially affect perceived stress compared to placebo. Nevertheless, supplementation was associated with changes in the cortisol wakefulness response at 16 weeks. Given that serum levels of red blood cell folate(B9) and B6 were found to be associated with the cortisol wakefulness response at 16 weeks, this provides evidence suggesting that the elevation in the cortisol wakefulness response was mediated by the effects of folate(B9) and B6. To further explore these relationships, further research is needed. ¹

1. Camfield DA, Wetherell MA, Scholey AB, Cox KH, Fogg E, White DJ, Sarris J, Kras M, Stough C, Sali A, Pipingas A. The effects of multivitamin supplementation on diurnal cortisol secretion and perceived stress. Nutrients. 2013 Nov 11;5(11):4429-50. doi:10.3390/nu5114429. PMID: 24284609; PMCID: PMC3847740. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847740/pdf/nutrients-05-04429.pdf