Key Takeaways (expand)
- Folate is also known as vitamin B9, and includes both naturally occurring dietary folates as well as a synthetic form, called folic acid.
- Although folic acid is technically more bioavailable than natural forms of folate, it requires conversion into its active form (5-methyltetrahydrofolate) before being usable; this conversion is very inefficient for some people, particularly carriers of the C677T MTHFR polymorphism.
- Like other B vitamins, folate is used for producing healthy blood cells, forming important genetic material (like DNA), and promoting cellular growth and function.
- In the form of folate coenzymes, folate helps facilitate the transfer of one-carbon units—giving it wide-ranging roles in metabolizing DNA and RNA, assisting in methylation reactions, and breaking down amino acids.
- Through its role in DNA methylation, folate plays a role in regulating gene expression and cell differentiation.
- Folate works in conjunction with vitamins B6 and B12 to regulate the metabolism of homocysteine—an amino acid that affects inflammation and cardiovascular disease risk.
- Getting enough folate is particularly critical during pregnancy, due to the body’s rapid creation of new cells and DNA. Inadequate folate during this time can increase the risk of fetal growth and development problems, neural tube defects, cleft lip and cleft palate, and cardiovascular malformations.
- Folate is needed to support other components of reproductive health as well, including the development of sperm cells, and the multiple phases of cells within ovaries (oocytes) spanning from ovum maturation to fetal growth.
- Evidence suggests folate can protect against cardiovascular disease, including reducing the risk of heart attacks and stroke.
- Insufficient folate intake could increase the risk of certain cancers, likely due to its important role in synthesizing and methylating DNA and RNA.
- Folate may also help protect against cognitive and nervous system disorders, with low levels being linked to age-related cognitive dysfunction (including dementia and Alzheimer’s disease).
- Folate deficiency can occur not only from low dietary intake, but also malabsorption disorders, alcoholism, certain genetic variations (particularly in the MTHFR gene), or conditions involving rapid rates of cell division and metabolism (such as pregnancy and cancer).
- When folate deficiency occurs, it causes megaloblastic anemia (where red blood cells are large and underdeveloped), leading to impaired oxygen carrying capacity and causing symptoms like fatigue, pale palms and mucus membranes, shortness of breath, and weakness.
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Folate, also called folic acid or vitamin B9, is an oft-discussed but commonly misunderstood B vitamin. “Folate” is a generic term that refers to both naturally occurring dietary folates as well as a synthetic version called folic acid, which is used in fortified food and supplements due to its enhanced stability during processing and storage.
Folate was first discovered in 1931, when a researcher named Lucy Wills identified a substance present in liver and yeast that could prevent rats and pregnant humans from developing anemia. Over the next decade, this nutrient was given a number of different names (including vitamin M, Lactobacillus casei factor, factor ‘S,’ vitamin BC, and norit eluate factor!) before finally being termed folic acid—deriving from the Latin word for leaf, folium, and referring to its initial isolation from spinach.
Like other B vitamins, folate is needed for producing healthy blood cells; it’s also required for healthy cell growth and function, and for making important genetic material like DNA.
Natural food sources of folate include liver and other organ meats, green leafy vegetables (like spinach and lettuce), asparagus, avocados, Brussels sprouts, legumes (including peas and lentils), eggs, beets, citrus fruits, orange juice, strawberries, pomegranates, broccoli, nuts, and seeds. Many processed grain products like cornmeal and breakfast cereals are also fortified with folic acid.
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The Biological Roles of Vitamin B9 (Folate)
Unlike some of the B vitamins, which can have hundreds of functions in the body, the biochemical use of folate coenzymes is solely to mediate the transfer of “one-carbon units”—which means shuttling one carbon molecule between carriers. But, that’s far from a small job: it means that folate serves a major role in metabolizing nucleic acid precursors (including DNA and RNA), breaking down amino acids, and assisting in methylation reactions.
More specifically, folate coenzymes are involved in nucleic acid metabolism via two pathways: one, through synthesizing DNA from thymidine and purine precursors, and two, through synthesizing methionine from homocysteine (methionine, in turn, is used for synthesizing a methyl group donor called S-adenosylmethionine (SAM) that’s required for most methylation reactions, including for DNA, RNA, phospholipids, and proteins). Through its role in DNA methylation, folate is ultimately involved in regulating gene expression and cell differentiation. Meanwhile, folate coenzymes are also needed for metabolizing several important amino acids: cysteine, methionine, serine, glycine, and histidine.
Interactions with Other Nutrients
Folate has some important nutrient interrelationships, too. For example, folate works hand-in-hand with vitamins B6 (pyridoxine) and B12 (cobalamin) to regulate the metabolism of homocysteine, which is directly related to inflammation and cardiovascular disease risk. More specifically, homocysteine metabolism occurs through two different pathways, one of which requires both folate and vitamin B12 as cofactors (the methionine synthase pathway), and the other of which requires additional vitamin B6-dependent enzymes to convert homocysteine to cysteine. If the status of any of these nutrients is suboptimal, these pathways can be negatively impacted—potentially leading to elevated levels of homocysteine in the body.
Folate also functions with another B-complex vitamin, riboflavin (vitamin B2), in a less well-recognized fashion involving the MTHFR pathway. Vitamin B2 (riboflavin) is a precursor for a coenzyme called flavin adenine dinucleotide, which is required for MTHFR enzyme activity—including metabolizing folate into its active form, 5-methyltetrahydrofolate (which is needed for forming methionine from homocysteine). In people homozygous for the C677T polymorphism in the MTHFR gene (which causes lower MTHFR activity and higher homocysteine concentrations), the impact of riboflavin on folate metabolism and homocysteine reduction is particularly significant.
Interestingly, folate also interacts with vitamin C: vitamin C can limit the degradation of folic acid and folate coenzymes in the stomach, in turn improving folate bioavailability and absorption. In fact, one trial found that combining vitamin C with active folate (5-methyltetrahydrofolic acid) led to higher serum folate levels compared to folate supplementation alone. Certain folate-related genetic variations also appear to influence the degree to which vitamin C impacts folate metabolism.
Drug Interactions with Vitamin B9 (Folate)
In addition, vitamin B9 (folate) can interact with certain drugs, including some very common ones.
High doses of nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen and aspirin, can interfere with folate metabolism (although regular lower-dose use of NSAIDS doesn’t appear to harm folate status).
Cholesterol-lowering drugs (especially cholestyramine and colestipol) and long-term use of some anticonvulsants (especially phenytoin, phenobarbital, and primidone) have likewise been linked to impaired folate absorption.
And, a folate antagonist called methotrexate (which is commonly used to treat rheumatoid arthritis and psoriasis), as well as some anti-folate molecules used for cancer therapy (including pemetrexed, pralatrexate, aminopterin, and raltitrexed), can lead to symptoms of severe folate deficiency. When this happens, it can typically be treated with folic acid or folinic acid (a folic acid derivative) supplementation.
Vitamin B9 Forms: Folate vs. Folic Acid
Lastly, it’s important to understand the difference between the natural forms of folate and its synthetic form, folic acid. Food-derived folates mainly exist in the polyglutamyl form (bound to several glutamate amino acids), whereas folic acid is a monoglutamate (bound to just one glutamate moiety).
When it comes to bioavailability, this gives folic acid a major leg up: dietary folate must go through a two-step process to be absorbed in the gut, while folic acid is absorbed much more readily (it’s estimated that folic acid is absorbed at a rate of 85-100%, in contrast to 50-60% for folate from food!). However, folic acid is unusable by the body until being converted into its active form (5-methyltetrahydrofolate), and this conversion process can vary among different people. In particular, homozygous (two copy) carriers of the C677T MTHFR polymorphism have up to a 70% reduction in their ability to convert folic acid into 5-methyltetrahydrofolate.
Natural folates, by contrast, occur in many chemical forms, including the active form; so, while some food folate will need to go through the same series of chemical reactions as folic acid before it’s active in the body, some can be converted in fewer steps, and some does not require conversion at all. As a result, getting folate from foods, rather than vitamin supplements, is still a win!
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Vitamin B9 (Folate) in Health and Disease
Vitamin b9 (folate) is particularly important during pregnancy, when folate demands increase due to the rapid creation of new cells and DNA. Along with helping protect against fetal development problems, folate can support cardiovascular health, potentially protect against certain cancers, and reduce the risk of cognitive and neurological disorders later in life.
Vitamin B9 (Folate) and Pregnancy
Getting enough folate is especially critical during pregnancy and lactation. As with several other B vitamins, the need for folate goes up as demand to create new cells and DNA increases, and this is especially true during fetal growth and development. During pregnancy, adequate folate is necessary for preventing cardiovascular malformations, orofacial clefts like cleft lip and cleft palate, and neural tube defects—congenital abnormalities that occur from the failure of neural tube (which becomes the spinal cord, spine, brain and skull during development) closure during the first month of pregnancy (and which include encephalocele, anencephaly, and spina bifida). This is why folic acid supplements are highly recommended during early pregnancy, or even prior to conception, and why folate is always included in prenatal multivitamins.
Similarly, higher doses of folic acid or folate may help prevent low birth weight (and subsequent higher mortality risk) among infants. And, daily folate supplementation of 600 micrograms (mcg), both before and during pregnancy, has been associated with a reduced risk of autism spectrum disorders when both the mother and child carry the C677T MTHFR variant.
Folate is also important for other elements of reproductive health, including spermatogenesis (the origin and development of sperm cells) and the quality, maturation, implantation, placentation, and eventually fetal growth of oocytes (a cell within the ovaries that become an ovum, or egg).
Vitamin B9 (Folate) and Cardiovascular Disease
Folate may also play a role in protecting against cardiovascular disease. Diets rich in folate have been associated with a lower risk of heart disease, heart attacks, and stroke, and in observational studies, people consuming the most dietary folate have shown up to a 55% lower risk of experiencing an acute coronary event (like a heart attack) compared to people consuming the least dietary folate. This could be due in part to folate’s homocysteine-lowering abilities: numerous studies have linked elevated homocysteine levels to greater cardiovascular disease risk, possibly because of its effects on vasodilation, arterial wall thickening, and blood clotting. However, in clinical trials, folate supplementation has only demonstrated benefit for primary stroke prevention.
That being said, some research has also shown that folic acid supplementation can reduce the development of atherosclerosis, a component of cardiovascular disease; more specifically, it’s been shown to reduce the measurement of carotid intima-media thickness (a marker for early atherosclerosis and predictor for future cardiovascular events) among people at high risk of cardiovascular disease or who have chronic kidney disease.
Vitamin B9 (Folate) and Cancer
Across a number of studies, low folate status has been associated with an increased risk of cancer, possibly due to folate’s role in DNA and RNA synthesis and methylation. In the context of low folate intake, genome instability chromosome breakage become more likely—both of which often characterize cancer development.
Colorectal cancer, in particular, has been linked to folate intake, with studies showing a modest protective effect of dietary folate (some pooled estimates suggest a 2% lower risk of colorectal cancer for every 100 microgram increase of folate intake per day)—however, this protective effect seems more prominent in men than women. Interestingly, while folate appears to reduce the risk of developing colorectal cancer in the first place, some research has raised concern that high-dose folic acid supplementation could spur tumor growth in patients with already-established cancer—although not all studies have confirmed this, including several large randomized controlled trials that found no added risk of colorectal cancer recurrence in people taking as high as 1000 micrograms daily of folate for at least two years.
And, in women, alcohol intake may mediate a relationship between folate and breast cancer risk, with studies tending to show a protective effect of folate consumption in women who regularly consume alcohol (but not non-drinkers or minimal drinkers!).
Additional research, albeit limited, has shown a potential link between chronically low folate intake and elevated risk of ovarian, brain, cervical, and pancreatic cancers.
Vitamin B9 (Folate) and Neurodegenerative Disease
Due to folate’s role in brain development and the nervous system, low folate status has been linked to age-related cognitive dysfunction (ranging from mild impairments to severe dementia and Alzheimer’s). In elderly women, long-term low folate status (as indicated by red blood cell folate concentrations) tends to be lower in Alzheimer’s patients than in healthy individuals. But, the results of controlled trials have been mixed regarding whether folate supplementation itself (versus folate as part of a larger B-vitamin intervention) can help protect against cognitive dysfunction. More research here is needed!
Folate Metabolism Disorders
Some genetic disorders also affect the metabolism and transport of folate, and can be treated with high doses of the folic acid derivative folinic acid. These disorders include hereditary folate malabsorption (which affects gastrointestinal folate absorption, as well as folate transport into the brain), Cerebral Folate Deficiency syndrome (which involves low levels of folate coenzymes in the cerebrospinal fluid, even when blood levels are normal), and dihydrofolate reductase deficiency (which is a deficiency of an enzyme needed for reducing dihydrofolic acid to tetrahydrofolic acid).
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Health Effects of Vitamin B9 (Folate) Deficiency
Folate deficiency is usually caused by dietary insufficiency, but it can also result from:
- malabsorption disorders (like Crohn’s disease, ulcerative colitis, and celiac disease),
- heavy alcohol drinking (due to reduced folate absorption), and
- smoking (which has been linked with low folate status—according to some research, 15% lower levels on average among smokers compared to non-smokers!).
Conditions involving greater rates of cell division and metabolism—including pregnancy, inflammation, and cancer—likewise increase folate demand and can raise the risk of deficiency. And, certain genetic variations impact folate metabolism and influence a person’s folate status, particularly variations in the MTHFR gene. Individuals homozygous for the C667T variant of this gene typically have folate levels that are 16% lower than non-carriers, even when dietary folate intake is the same!
Both severe folate deficiency and vitamin B12 deficiency can lead to megaloblastic anemia—a form of anemia where the bone marrow produces big, underdeveloped red blood cells due to impaired DNA synthesis and reduced nuclear division. As the anemia progresses, it leads to impaired oxygen carrying capacity within the blood, causing symptoms such as fatigue, pale mucus membranes and palms, weakness, and shortness of breath. Because both folate and vitamin B12 deficiency can cause megaloblastic anemia, and the symptoms in both cases are identical, it’s important to correct the condition with the right nutrient: improperly treating B12-induced anemia with high doses of folate can perpetuate the vitamin B12 deficiency, potentially leading to irreversible brain damage.
When folate deficiency occurs during pregnancy, it can increase the risk of congenital anomalies (birth defects), including neural tube defects.
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How Much Vitamin B9 (Folate) Do We Need?
The recommended dietary allowance (RDA) for folate is actually represented as “dietary folate equivalents,” or DFE, which incorporate both folate and folic acid. The RDA for dietary folate equivalents for adults is set at 400 micrograms per day (600 micrograms while pregnant, 500 micrograms when breast feeding); alcoholics are advised to consume 600 micrograms daily due to their reduced ability to absorb this vitamin. Scientists are investigating whether people with genetically reduced MTHFR activity might need to consume more folate than the current RDA, but so far, the jury’s still out.
Nutrient Daily Values
Nutrition requirements and recommended nutrient intake for infants, children, adolescents, adults, mature adults, and pregnant and lactating individuals.
Best Food Sources of Vitamin B9 (Folate)
The following foods have high concentrations of vitamin B9 (folate), containing at least 50% of the recommended dietary allowance per serving, making them our best food sources of this valuable vitamin!
Good Food Sources of Vitamin B9 (Folate)
The following foods are also excellent or good sources of vitamin B9 (folate), containing at least 10% (and up to 50%) of the daily value per serving.
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