Vitamin B9 - Folate
Image credit: Unsplash
Folate. This is a big one. Of all the B vitamins, folate (aka vitamin B9) and B12 seem to get the most attention. Folate gets an extra amount of focus because of its role in MTHFR function. MTHFR is a gene (it stands for methylene tetrahydrofolate reductase…which is a mouthful, and is why we just call it MTHFR) that comes up a lot in integrative and functional medicine because there are common variants that can reduce how well it works (and how well your body uses folate). And it’s true that folate is a linchpin in methylation (also known as one carbon metabolism), which is regulated, in part, by MTHFR. Because of its role in methylation, folate is essential is essential for making DNA, for repairing DNA, for detoxification, for making red blood cells, for mental health, for histamine metabolism, for muscle growth, and for prevention of neural tube defects.
What happens if you don’t get enough folate? If you have trouble with thoughts that get stuck in loops, recurrent allergies, unexplained cardiovascular disease, or unexplained depression or anxiety, folate deficiency might be part of the picture. Because of its role in methylation, folate deficiency can lead to elevations of another compound, called homocysteine (which is a byproduct of methylation). Elevated homocysteine is associated with several chronic and degenerative conditions, including cardiovascular disease and dementia (largely because it indicates that methylation is not functioning properly). Because folate, in a roundabout way, plays a role in breaking down histamine, folate deficiency can be linked to conditions involved in high histamine levels (think allergies). The classic symptom of folate deficiency is anemia. The usual pattern is fewer red blood cells than you want; the ones that you do have are larger than normal (this is called a “macrocytic anemia”). Other, general symptoms include fatigue, brain fog, numbness and tingling in the hands and feet, restless leg syndrome, problems with digestion, and even dementia. When it comes to pregnancy, folate is well known for its role in preventing neural tube defects (which are birth defects in which the spinal cord doesn’t form correctly—these can be fatal)—as a result, every prenatal vitamin always contains folate. And when it comes to mental health, folate is very underappreciated. In fact, some studies have suggested that the rate of folate deficiency may be nearly 40% (!) in patients with depression, and patients with folate deficiency are less likely to respond well to antidepressants. Folate also plays an important role in muscle growth because it is required for making creatinine (the supplement body builders use, and a compound all of us need).
How much folate do you need? The recommended daily amount (RDA) for folate is measured in something called dietary folate equivalents, or DFE, because different types of folate are absorbed better than others. 1 mcg of folate from food counts for 1 DFE. 1 mcg of folate in a supplement form counts for 1.7 mcg DFE. The idea is that folate in supplement form is more bioavailable that folate in natural food—the folate in foods might be locked in and difficult to absorb (as is often the case in seeds, nuts, and grains). Several long-term studies have validated the 1.7x multiplier. For most adults, the RDA is 400 mcg DFE; this increases during pregnancy.
Where do you get folate? The best sources are liver (a great source for many vitamins and nutrients—3 oz of liver contains over half the RDA), legumes (chickpeas and other beans), and leafy greens (as well as other green vegetables, like broccoli). Sprouting increases the amount of folate (and many other nutrients) in legumes. Per usual with the B vitamins, unfortified nutritional yeast is a good source (though unlike some of the other B’s, the amount isn’t huge). Eggs can also be a good source, and pasture-raised eggs have more folate (and are generally superior from a nutrition standpoint to conventional eggs). Many processed foods are also fortified with folate. For example, the FDA requires that cereal-grain products be fortified with folate (because processed grains have many of their nutrients removed during the refining process). It’s also worth noting that cooking plant foods decreases the amount of folate – it can be either destroyed by heat or leached out in cooking water. Freezing can also down folate—so that bag of frozen veggies in your freezer may not bea great folate source, even if it’s a bag of frozen leafy greens (some studies have shown that freezing veggies can decrease folate by as much as 95%)!
Folate can also be supplemented and comes in a variety of forms. The most common form is folic acid. Folic acid is synthetic – it doesn’t occur naturally in food – and is often demonized as being less effective than other forms. It can be effective; it is cheap, it’s stable, and it can definitely cure folate deficiency. In some individuals, though—specifically people with a variant of the gene DHFR (dihydrofolate reductase) it is harder to metabolize (unfortunately, there’s not an easy test to check DHFR status). This becomes especially relevant for people who are taking anti-folate drugs, like methotrexate, because these drugs BLOCK DHFR. When supporting folate status in these patients and otherwise counteracting the effect of the drugs, we don’t use folic acid—we typically use folinic acid (also known as leucovorin). Folinic acid can also be used as a supplement and is commonly used in multivitamins and B complexes that are designated as “methyl free” (more about that in a second). In supplements, folinic acid may appear on the list as calcium folinate. Folinic acid bypasses DHFR but not MTHFR. Another type of folate commonly found in supplements is 5-MTHF (5-methyltetrahydrofolate, often just referred to as methyl folate, or pre-methylated folate, or “active” folate). This type of folate is found in food, and it is often favored in patients with less active forms of MTHFR because it DOES bypass MTHFR. It is typically listed on a supplement as L-5-MTHF or (6S)-5-methyltetrahydrofolate. It is generally well tolerated—but some people develop unpleasant symptoms when they take methylated forms of vitamins. These aren’t well described in the literature, but I and many other have seen it happen, and they probably result from a rapid switch from not having enough methylation (undermethylation) to having too much (overmethylation). Symptoms can include tachycardia, palpitations, anxiety, headaches, irritability, etc. In those cases, I would recommend folinic acid (or maybe folic acid), or starting with extremely low doses of methyl folate.
It’s worth noting that, while folate is critical for effective methylation, it is not the only part of the puzzle. Other vitamins and micronutrients are also key. These include B1, B2, B3, B5, B6, B12, iron, phosphorus, sulfur, magnesium, potassium, and zinc. Other compounds, like choline and creatinine, can help take some of the burden off methylation as well. Methylation is a complex.
Is it possible to get too much folate? Yes. The most important instance in which this happens is when someone has B12 deficiency AND folate deficiency. Folate deficiency can mask B12 deficiency—so if folate is replenished, but B12 isn’t, high doses of folate can actually worsen the symptoms of B12 deficiency (symptoms like cognitive impairment and neuropathy). There is also evidence that high doses of folic acid can also lead to something called “pseudo-MTHFR” deficiency, which can lead to problems with lipid metabolism, liver injury, fatty liver disease. This happens because high levels of folic acid can inhibit MTHFR activity and reduce MTHFR protein levels. The current consensus is to limit synthetic folic acid intake to 1000 mcg DFE per day in adults (a consensus that is supported by both the American Academy of Pediatrics and the Institute of Medicine). Even in cases of very low MTHFR function, it’s not clear to me that mega doses of folate make a lot of sense.
Measuring folate can be a bit nuanced. One approach is to complete comprehensive micronutrient testing, like the Nutreval or similar. Another approach is to measure both serum and red blood cell (RBC) folate levels, as well as homocysteine levels. Serum folate gives a sense of the total availability of folate; RBC folate tells how well it is being used (and would point to problems in MTHFR or any of the other vitamins involved in methylation). Similarly, homocysteine gives a general sense of how well methylation is flowing.
In summary, folate (vitamin B9) is essential for making DNA, for repairing DNA, for detoxification, for making red blood cells, for mental health, for histamine metabolism, for muscle growth, and for prevention of neural tube defects. Not getting enough can lead to depression and obsessive thinking (deficiency is quite common in depression), recurrent allergies, or unexplained cardiovascular disease. Good sources of folate are liver, legumes (preferably sprouted), and leafy greens. The RDA for folate is 400 mcg DFE per day; there is some concern that doses over 1000 mcg DFE per day can cause problems. You need just the right amount!
How much folate are you getting?
References
1. Office of Dietary Supplements - Folate. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
2. Suitor CW, Bailey LB. Dietary folate equivalents: interpretation and application. J Am Diet Assoc. 2000;100(1):88-94. doi:10.1016/S0002-8223(00)00027-4
3. Masterjohn, C. Vitamin B9: Folate. Harnessing the Power of Nutrients. Published June 27, 2022. . https://chrismasterjohnphd.substack.com/p/vitamin-b9-folate
4. Saini RK, Nile SH, Keum YS. Folates: Chemistry, analysis, occurrence, biofortification and bioavailability. Food Res Int Ott Ont. 2016;89(Pt 1):1-13. doi:10.1016/j.foodres.2016.07.013
5. Botez MI. Folate deficiency and neurological disorders in adults. Med Hypotheses. 1976;2(4):135-140. doi:10.1016/0306-9877(76)90068-2
6. Brosnan ME, Brosnan JT. Histidine Metabolism and Function. J Nutr. 2020;150:2570S-2575S. doi:10.1093/jn/nxaa079
7. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145-149. doi:10.1111/j.1753-4887.1997.tb06468.x
8. Shea TB, Lyons-Weiler J, Rogers E. Homocysteine, folate deprivation and Alzheimer neuropathology. J Alzheimers Dis JAD. 2002;4(4):261-267. doi:10.3233/jad-2002-4401
9. Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol. 2014;120:927-943. doi:10.1016/B978-0-7020-4087-0.00061-9
10. Weir DG, Scott JM. Homocysteine as a risk factor for cardiovascular and related disease: nutritional implications. Nutr Res Rev. 1998;11(2):311-338. doi:10.1079/NRR19980020
11. FoodData Central. https://fdc.nal.usda.gov/fdc-app.html#/food-details/719244/nutrients
12. Czarnowska M, Gujska E. Effect of freezing technology and storage conditions on folate content in selected vegetables. Plant Foods Hum Nutr Dordr Neth. 2012;67(4):401-406. doi:10.1007/s11130-012-0312-2
13. Czarnowska-Kujawska M, Draszanowska A, Gujska E, Klepacka J, Kasińska M. Folate Content and Yolk Color of Hen Eggs from Different Farming Systems. Molecules. 2021;26(4):1034. doi:10.3390/molecules26041034
14. Scientific opinion on the tolerable upper intake level for folate | EFSA. https://www.efsa.europa.eu/en/efsajournal/pub/8353
15. Nutrients | Free Full-Text | Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. https://www.mdpi.com/2072-6643/15/21/4699
16. Excessive folic acid intake and relation to adverse health outcome - PubMed. https://pubmed.ncbi.nlm.nih.gov/27131640/
17. Christensen KE, Mikael LG, Leung KY, et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015;101(3):646-658. doi:10.3945/ajcn.114.086603