Everything You Need to Know About Folate & Folic Acid

Folate is the natural form of vitamin B9, water-soluble and naturally found in many foods, like leafy greens, beans and nuts. And if you have or are expecting a child, you probably have heard that folic acid — a form of folate — is essential for fetal development. But there’s a lot more to unpack about folate. In this article, we explain what folate is, how much folate you should consume, how to best supplement folate, and what happens when you’re deficient in folate.

What is folate?

Folate is a water-soluble B vitamin, also known as vitamin B9 and folic acid. The forms of folate used in fortified foods and supplements are folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). Technically speaking, folate and folic acid are not the same. Folate is the reduced form of the vitamin naturally found in foods and in organic tissues. Folic acid refers to the oxidized form of the vitamin — not found naturally in foods, it is the synthetic form commonly used in supplements and fortified foods. [1]

Folate plays a critical role in cell division and the synthesis of DNA and red blood cells — it's critical for pregnant women to get enough folate to support fetal growth, but everyone benefits from the nutrient. 

What is MTHFR? And why is methylation important?

For many processes involving folate, your body needs to methylate folic acid and folate. But approximately 40% of people have a gene mutation — MTHFR polymorphism — that interferes in the methylation of folic acid [2]. Therefore, First & Foremost provides methylated folate (measured to your full RDA) in our formulation to make the nutrient more bioavailable for all. Methylation can also positively influence mood stability, sleep and melatonin levels and detoxification.

Using the naturally occurring 5-MTHF has several advantages over the synthetic folic acid: 

• It is well absorbed and increases blood folate concentrations more than folic acid. [3]
• It’s less likely to mask hematological symptoms of vitamin B12 deficiency. [4]
• It overcomes metabolic defects caused by methylenetetrahydrofolate reductase (MTHFR) polymorphism. [5]
• It prevents the potential negative effects of unconverted folic acid in blood circulation. [3]

The MTHFR polymorphism gene can have mutations that can specifically interfere with your ability to absorb certain vitamins and detox the body efficiently. Research has shown an association between the MTHFR mutations and the following health issues: 

• ADHA [6]
• Autism [7]
• Autoimmune diseases [8]
• Bipolar disorder [9]
• Cardiovascular disease [10]
• Colitis [11]
• Depression [9]
• Schizophrenia [9]

Out of the estimated 40% of people with the MTHFR gene mutation, most do not know they have this genetic change. If you are concerned, consider asking your functional medicine doctor about completing a lab test to verify. 

What is the recommended daily allowance for folate?

Experts at the Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine developed the intake recommendations for folate as mcg of dietary folate equivalents (DFEs). The FNB created DFEs to reflect the higher bioavailability of supplemental folate than that of food folate, because supplemental folate is much more bioavailable than the folate naturally present in foods. 

• 1 mcg DFE = 1 mcg food folate
• 1 mcg DFE = 0.6 mcg folic acid from fortified foods/ supplements consumed with foods
• 1 mcg DFE = 0.5 mcg folic acid from supplements taken on an empty stomach

Even though research supports the effectiveness in the bioavailability of the 5-MTHF form over folic acid, factors for converting mcg DFE to mcg for supplemental folate in the form of 5-MTHF have not been formally established at this time. Therefore, we use the same conversion that is in place for folic acid on product labels. 

Recommended Dietary Allowance for Folate [12].

Age	Male	Female	Pregnant	Lactating
9-13 years	300 mcg DFE	300 mcg DFE
14-18 years	400 mcg DFE	400 mcg DFE	600 mcg DFE	500 mcg DFE
19+ years	400 mcg DFE	400 mcg DFE	600 mcg DFE	500 mcg DFE

What is the best way to get folate?

Folate is naturally present in foods, including dark green leafy vegetables, fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, and grains. These foods contain the highest folate levels [12]:

• Spinach
• Liver
• Asparagus
• Brussels Sprouts

To reduce the risk of neural tube defects in 1998, the U.S. Food and Drug Administration (FDA) initiated requirements of manufacturers to add 140 mcg folic acid per 100 g to enrich breads, cereals, flours, pastas, rice, and other grain products.  

Folate is an essential micronutrient, which means it cannot be synthesized in the body, so people are dependent on supplementation from food or supplements to maintain normal levels. Most countries have met recommended intakes through supplementation and fortified foods using folic acid as the primary source. 

However, synthetic folic acid poses risks in at least 40% of the population. Dietary supplements containing 5-methyl-THF are thought to be more beneficial than folic acid, especially for those with the MTHFR polymorphism. The bioavailability of 5-methyl-THF in supplements is the same as or greater than that of folic acid [3, 13].

How does folate work with other nutrients?

Within the body, folate works with vitamin C to help the body break down and synthesize new proteins, and it activates vitamin B12. The synergistic relationship between folate and vitamin B12 is referred to as the methyl-folate trap, meaning that vitamin B12 deficiency can lead to lowered levels of methionine synthetase, which results in a functional folate deficiency by trapping an increased proportion of folate as the 5-methyl derivative and preventing the conversion of other folate forms needed for DNA synthesis. [1,14] These dynamic relationships underscore why it’s so important to ensure you’re meeting your RDA every day through a combination of food and supplementation.

Does folate interact with medicine?

Consult your primary care provider if you are taking any of these medications or any other medications not listed:

• Methotrexate (Rheumatrex®, Trexall®)
• Antiepileptic medications, such as phenytoin (Dilantin®), carbamazepine (Carbatrol®, Tegretol®, Equetro®, Epitol®), and valproate (Depacon®)
• Sulfasalazine (Azulfidine®)

What happens when you’re deficient in folate?

Folate deficiency has been linked with an increased risk of neural tube defects in utero, cardiovascular disease, cancer and cognitive dysfunction. It typically coincides with other nutrient deficiencies because of its strong link with poor diet, alcoholism, and malabsorptive disorders. Megaloblastic anemia (characterized as large, abnormally shaped red blood cells) is a typical clinical sign of folate or vitamin B12 deficiency. Symptoms include weakness, fatigue, difficulty concentrating, irritability, headache, heart palpitations, and shortness of breath. [12]

Those at risk of folate inadequacy include: 

• People with alcohol use disorder, because alcohol interferes with folate absorption and uptake, speeds up breakdown, and increases renal excretion
• Women of childbearing age
• Pregnant women
• People with malabsorptive disorders
• People with the MTHFR polymorphism

Can you take too much folate?

Concerns have been identified for high folic acid intakes that might speed up the progression of preneoplastic lesions, increasing the risk of colorectal and possibly other cancers in certain individuals. High intakes (1,000 mcg or more per day) of folic acid from supplements during periconception have been associated with lower test scores of cognitive development in children at ages 4-5 years. As well as the high intakes of folic acid from foods and/or supplements that exceed the body’s ability to reduce it to THF lead to unmetabolized folic acid in the blood, which has been linked to reduced number and activity of natural killer cells, suggesting it could affect the immune system. [12, 15]

Treating megaloblastic anemia with large amounts of folate supplementation can “mask” a vitamin B12 deficiency, and neurological damage can result. 

The FNB established Tolerable Upper Intake Levels (ULs) for the synthetic forms of folate; however, the FNB did not establish ULs for folate from food sources because high intakes are not associated with adverse effects. 

ULs for Synthetic Folate from Supplements or Fortified Foods [12]

Age	Male	Female	Pregnant	Lactating
9-13 years	600 mcg/ day	600 mcg/ day
14-18 years	800 mcg/ day	800 mcg/ day	800 mcg/ day	800 mcg/ day
19+ years	1,000 mcg/ day	1,000 mcg/ day	1,000 mcg/ day	1,000 mcg/ day

How can I get the right amount of folate?

• Include a variety of vegetables, fruits and grains in your diet each day — legumes, asparagus, leafy greens and beets are good sources of folate. 
• Include a variety of protein foods in your diet. Beef liver contains high amounts of folate, as do peas, beans, nuts, and eggs. 
• Limit your consumption of alcohol and added sugars. 

References

1. Advanced Nutrition and Human Metabolism; 7th edition; S. Gropper, J. Smith, T. Carr. Page 341-352.
2. https://www.psychologytoday.com/us/blog/the-integrationist/201409/genetic-mutation-can-affect-mental-physical-health
3. Henderson AM, Aleliunas RE, Loh SP, et al. l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women. J Nutr. 2018;148(6):885-890. doi:10.1093/jn/nxy057
4. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488. doi:10.3109/00498254.2013.845705
5. Kedar, R., Chandel, D. MTHFR gene polymorphism and associated nutritional deficiency in the etiology and pathogenesis of Down syndrome. Egypt J Med Hum Genet 20, 12 (2019). https://doi.org/10.1186/s43042-019-0010-9
6. Krull KR, Brouwers P, Jain N, et al. Folate pathway genetic polymorphisms are related to attention disorders in childhood leukemia survivors. J Pediatr. 2008;152(1):101-105. doi:10.1016/j.jpeds.2007.05.047. https://pubmed.ncbi.nlm.nih.gov/18154909/
7. Pu, D., Shen, Y., & Wu, J. (2013). Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism research : official journal of the International Society for Autism Research, 6(5), 384–392. https://doi.org/10.1002/aur.1300
8. Richardson B. (2003). DNA methylation and autoimmune disease. Clinical immunology (Orlando, Fla.), 109(1), 72–79. https://doi.org/10.1016/s1521-6616(03)00206-7
9. Simon Gilbody, Sarah Lewis, Tracy Lightfoot, Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review, American Journal of Epidemiology, Volume 165, Issue 1, 1 January 2007, Pages 1–13, https://doi.org/10.1093/aje/kwj347
10. Wierzbicki A. S. (2007). Homocysteine and cardiovascular disease: a review of the evidence. Diabetes & vascular disease research, 4(2), 143–150. https://doi.org/10.3132/dvdr.2007.033
11. Chen M, Xia B, Rodriguez-Gueant RM, Bigard M, Gueant JL. Genotypes 677TT and 677CT+1298AC of methylenetetrahydrofolate reductase are associated with the severity of ulcerative colitis in central China. Gut. 2005;54(5):733-734. doi:10.1136/gut.2004.062539
12. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#en11
13. Lamers Y, Prinz-Langenohl R, Bramswig S, et al. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 2006;84:156-61. https://pubmed.ncbi.nlm.nih.gov/16825690/
14. Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu Rev Nutr. 1985;5:115-141. doi:10.1146/annurev.nu.05.070185.000555
15. Paniz C, Bertinato JF, Lucena MR, et al. A daily dose of 5 mg folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults. J Nutr 2017;147:1677-85. [PubMed abstract]