Vitamin B9; nutrient essential for DNA synthesis
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.
Folate in the form of folic acid is used to treat anemia caused by folate deficiency. Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby. NTDs include anencephaly and spina bifida, among other defects. Low levels in early pregnancy are believed to be the cause of more than half of babies born with NTDs. More than 80 countries use either mandatory or voluntary fortification of certain foods with folic acid as a measure to decrease the rate of NTDs. Long-term supplementation with relatively large amounts of folic acid is associated with a small reduction in the risk of stroke and an increased risk of prostate cancer.
Not consuming enough folate can lead to folate deficiency. This may result in a type of anemia in which red blood cells become abnormally large. Symptoms may include feeling tired, heart palpitations, shortness of breath, open sores on the tongue, and changes in the color of the skin or hair. Folate deficiency in children may develop within a month of poor dietary intake. In adults, normal total body folate is between 10 and 30mg with about half of this amount stored in the liver and the remainder in blood and body tissues. In plasma, the natural folate range is 150 to 450nM.
Folate was discovered between 1931 and 1943. It is on the World Health Organization's List of Essential Medicines. In 2023, it was the 94th most commonly prescribed medication in the United States, with more than 7million prescriptions. The term "folic" is from the Latin word folium (which means leaf) because it was found in dark-green leafy vegetables.
Safety at a Glance
- Toxicity: Folate has a very favorable acute toxicity profile. No toxic dose has been established for 5-MTHF or food-form folate...
- Start with a low dose and wait for onset before redosing
- Test your substance with reagent kits when possible
- Never use alone — have a sober person present
If someone is in crisis, call 911 or Poison Control: 1-800-222-1222
Dosage
Oral
Duration
Oral
Total: 12 hrs – 24 hrsHow It Feels
Folate (B9) supplementation produces no perceptible acute effects. Its benefits are structural and preventive, supporting DNA synthesis, methylation processes, and neural development. In individuals with folate deficiency or MTHFR polymorphisms, supplementation may gradually improve mood, reduce homocysteine-related inflammation, and support overall cognitive function, but these improvements develop over weeks and are subtle.
Pharmacology
Folate/folic acid exists in multiple interconvertible forms. Dietary folates are polyglutamate derivatives absorbed after intestinal deconjugation. Folic acid (synthetic, in supplements and fortified foods) is reduced to dihydrofolate (DHF), then tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). The key active form in circulation is 5-methyltetrahydrofolate (5-MTHF).
The methyl cycle: 5-MTHF donates its methyl group to homocysteine via methionine synthase (requiring methylcobalamin/B12 as cofactor) to regenerate methionine. Methionine is then adenylated to S-adenosylmethionine (SAMe) — the body's universal methyl donor. SAMe methylates DNA (epigenetic regulation), RNA, proteins, phospholipids, and neurotransmitters. After methyl donation, SAMe becomes S-adenosylhomocysteine → homocysteine, completing the cycle.
Neurotransmitter relevance: SAMe methylation is required for: catecholamine degradation (COMT methylates catechols), creatine synthesis, myelin production (phosphatidylcholine methylation), and serotonin synthesis (methylation of aromatic amine intermediates). SAMe is itself used as an antidepressant supplement, directly demonstrating the link between methylation and mood.
MTHFR polymorphisms: The enzyme methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methyleneTHF to 5-MTHF (the methylation-active form). The C677T polymorphism (homozygous in ~10% of most populations; heterozygous in ~40%) reduces enzyme activity by 35–70%, increasing homocysteine and potentially impairing folate-dependent methylation. Supplementing with the already-active 5-MTHF (methylfolate) bypasses this genetic bottleneck, as does high-dose folic acid.
Neural tube development: Folate is critical during neural tube closure (days 21–28 of embryonic development, before many women know they are pregnant). Deficiency causes neural tube defects (NTDs) including spina bifida and anencephaly. The required dose for NTD prevention (400–800 mcg/day) must begin before conception.
Interactions
No documented interactions.
History
Folate's discovery emerged from research on nutritional anemias in the 1930s. Lucy Wills, a British physician working in Bombay (Mumbai) in 1930–1931, discovered that a factor in yeast extract (Marmite) prevented and cured a dangerous anemia in pregnant women in India. She called this the "Wills factor." Subsequent research in the late 1930s and 1940s identified the same factor in spinach and other vegetables — hence the name "folate" (from Latin folium, leaf).
Folic acid was chemically characterized and synthesized in 1945 by Bob Stokstad and colleagues at American Cyanamid. Its structure as a pteridine-glutamic acid conjugate was established, and it was recognized as a vitamin essential for nucleotide synthesis and cell division.
The link to neural tube defects was established through decades of epidemiological work. British physician Richard Smithells in the 1970s observed that periconceptional multivitamin use reduced NTD recurrence. The landmark Medical Research Council (MRC) trial published in 1991 definitively demonstrated that 4,000 mcg/day folic acid reduced NTD recurrence by 72%. Subsequent studies confirmed 400 mcg/day was protective for primary prevention.
The US FDA mandated folic acid fortification of enriched grain products in 1998 — one of the most successful public health nutrition interventions, reducing NTD rates in the US by approximately 27% within a few years. Many countries adopted similar fortification programs, though uptake has been uneven globally.
MTHFR polymorphism research came to prominence in the 1990s–2000s, leading to substantial consumer interest in "methylfolate" supplementation, often promoted with clinical importance that exceeds what the evidence supports for individuals with adequate dietary folate. The distinction between folic acid and active folate forms has become central to functional medicine and nutrigenomic approaches to supplementation.
Harm Reduction
Prefer methylfolate (5-MTHF) over folic acid. The active form 5-methyltetrahydrofolate bypasses MTHFR polymorphisms, avoids unmetabolized folic acid accumulation, and is the form naturally present in foods. It is more expensive but more universally effective across genotypes. Brands like Methylpro, Thorne, and Solgar offer methylfolate supplements.
Always test B12 before high-dose folate. If you are over 50, vegetarian, or have risk factors for B12 deficiency, check serum B12 (and ideally methylmalonic acid for functional B12 status) before starting doses above 400 mcg folic acid/day. B12 masking by folate is a real clinical hazard.
Pregnancy planning. Neural tube defect prevention requires folate supplementation before conception — ideally starting 3 months before becoming pregnant, as neural tube closure occurs before most women know they're pregnant. The recommended dose is 400 mcg/day for women at average risk; 4,000–5,000 mcg/day for women with a previous NTD-affected pregnancy (this must be under medical supervision).
MTHFR variants. If you have confirmed MTHFR C677T or A1298C variants, methylfolate supplementation is preferable to folic acid. However, the clinical significance of MTHFR variants in the context of adequate folate intake is often overstated — many homozygous C677T individuals have normal folate status and no increased disease risk with adequate dietary folate.
Food sources. Leafy greens (spinach, romaine, kale), legumes, citrus, and avocado are rich in folate. The RDA is 400 mcg DFE (dietary folate equivalents) for non-pregnant adults and 600 mcg for pregnant women.
Toxicity & Safety
Folate has a very favorable acute toxicity profile. No toxic dose has been established for 5-MTHF or food-form folate. The toxicity concerns relate to folic acid (synthetic form) specifically and to interactions with B12 deficiency.
The B12 masking problem is the most clinically significant safety concern: high-dose folic acid supplementation can correct the megaloblastic anemia of B12 deficiency (because folate and B12 share pathways in red blood cell formation) while failing to correct the neurological damage of B12 deficiency (subacute combined degeneration of the spinal cord). This allows B12 deficiency to progress to irreversible neurological harm without the anemia that would otherwise prompt investigation. This concern is greatest in elderly populations (more likely to be B12 deficient) taking high-dose folic acid supplements.
Potential promotion of existing cancers: Folate has a dual role in cancer biology — adequate folate reduces cancer initiation risk, but supplemental folic acid may promote progression of established cancers (particularly colorectal, prostate) by providing synthetic methyl groups that facilitate tumor proliferation. This is a theoretical concern based on biological mechanisms and some epidemiological data; it primarily applies to high-dose folic acid supplementation rather than dietary folate.
MTHFR context: For individuals with MTHFR C677T variants, high doses of unmetabolized folic acid can accumulate in blood (called unmetabolized folic acid, UMFA), as their DHFR enzyme is overwhelmed. The health implications of UMFA accumulation are debated but may include immune suppression. 5-MTHF supplementation does not cause UMFA accumulation.
Standard supplemental doses (400–800 mcg/day) are extremely safe. The UL of 1,000 mcg/day applies to folic acid (synthetic), not to food folate or 5-MTHF.
Addiction Potential
No addiction potential.
Tolerance
| Full | Not applicable — nutritional supplement |
| Half | N/A |
| Zero | N/A |
Cross-tolerances
Legal Status
This substance is not a controlled or scheduled substance in any major jurisdiction. It is widely available as a dietary supplement, food additive, or over-the-counter product in the United States, United Kingdom, European Union, Canada, and Australia. In the US, it falls under the Dietary Supplement Health and Education Act (DSHEA) of 1994 and is regulated by the FDA as a dietary supplement rather than a drug. Manufacturers are responsible for ensuring safety and accurate labeling, but pre-market approval is not required.
In the European Union, it is regulated under the Food Supplements Directive (2002/46/EC) and may be subject to maximum permitted levels set by individual member states. In the United Kingdom, it falls under the Food Supplements (England) Regulations 2003 and similar devolved legislation. In Australia, it is typically listed on the Australian Register of Therapeutic Goods (ARTG) as a complementary medicine or is available as a food product. In Canada, it may be classified as a Natural Health Product (NHP) requiring a product license from Health Canada.
No prescription is required in any of these jurisdictions, and there are no criminal penalties associated with possession, purchase, or use.
Tips (2)
Quality varies enormously between Vitamin B9 supplement brands. Look for products with third-party testing (USP, NSF, ConsumerLab). Cheaper brands may contain fillers, incorrect doses, or contaminants.
Consider whether Vitamin B9 is better absorbed with food or on an empty stomach. Fat-soluble nutrients need dietary fat for absorption. Taking supplements correctly improves bioavailability significantly.
See Also
References (3)
- PubChem: Vitamin B9
PubChem compound page for Vitamin B9 (CID: 135398658)
pubchem - Vitamin B9 - TripSit Factsheet
TripSit factsheet for Vitamin B9
tripsit - Vitamin B9 - Wikipedia
Wikipedia article on Vitamin B9
wikipedia