Vitamin B9 or folate plays a vital role in cellular metabolism and energy production. It enables methylation and thus keeps homocysteine levels in check. Optimal folate intake is crucial for fetal development, liver and health, immunity, and more. Read on to learn the science behind folate health benefits, side effects, and recommended daily intake.
What is Vitamin B9/Folate?
Vitamin B9, also known as folate, is a water-soluble essential B vitamin [1].
The name folate comes from the Latin word folium meaning ‘leaf’ since it is found in many leafy plants. The best dietary sources of folate are green leafy vegetables, citrus fruit juices, and legumes [2, 3].
Different Forms
Folates occur in many chemical forms. They are naturally found in food and the body in the form of metabolically active tetrahydrofolate derivatives (e.g., 5-methyltetrahydrofolate) [4].
In contrast, folic acid, the synthetic form of Vitamin B9, has no physiological activity unless converted into folates. This primarily occurs in the liver, where folic acid is converted to tetrahydrofolate (THF) using the enzyme dihydrofolate reductase (DHFR) [4].
5-methyl-tetrahydrofolate (5-MTHF), the main circulating form of folate, has many essential roles in the body including nucleic acid and amino acid biosynthesis, amino acid conversions, DNA/RNA replication, and methylation, as well as functioning as a cofactor in certain biological reactions [5].
The production of active 5-MTHF depends on the MTHFR (methyl-tetrahydrofolate reductase) enzyme. People with certain MTHFR polymorphisms require more folate than others.
Antioxidant Effects
Folic acid exhibits efficient free radical scavenging activity (comparable to that of vitamin C and E) in a number of laboratory studies [6, 7].
In rats exposed to arsenic, folic acid supplementation was able to mitigate DNA and mitochondrial damage by suppressing oxidative biomarkers (i.e., malondialdehyde (MDA), nitric oxide (NO), and hydroxyl radical (OH(-)) and increasing antioxidant enzyme (e.g., SOD and catalase) activity [8].
Roles in Immunity
Increased susceptibility to infection is frequently observed in folate-deficient humans and animals [9].
Clinical folate deficiency commonly manifests as megaloblastic anemia, a condition that results in impaired immune responses (affecting mainly cell-mediated immunity). Fixing folate deficiencies with supplementation restores immune function in affected patients [10].
A folate-rich diet was able to reverse age-related changes in T-cell proliferation and cytokine production in rats [11].
Health Benefits
Effective:
1) Folate Deficiency
Both oral and injected folic acid can successfully treat and prevent folate deficiency of different origins [12].
Folate is required for red blood cell replication and division, and its deficiency can lead to megaloblastic anemia (a condition characterized by fewer and larger blood cells) [13, 14].
This condition is reversible and preventable with folic acid treatment (100 mcg-5 mg daily), including the risk groups such as pregnant women [15, 16].
Likely Effective:
2) Fetal Development
Folate plays a critical role in cell growth during the embryonic phase of fetal development [17].
Low folate levels in pregnant women are linked to fetal abnormalities, such as neural tube defects (i.e., spina bifida and anencephaly) [18].
Many clinical studies show that when women take folic acid before conception, the risk of neural tube defects (NTDs) is significantly reduced (up to 50-60%) [19, 20].
Other studies have found that when taken with a multivitamin supplement, folic acid may minimize the risk of congenital heart defects, cleft lips, and other abnormalities during the preconception period [19, 21].
3) Elevated Homocysteine
Elevated homocysteine concentrations in the blood (hyperhomocysteinemia) are linked to an increased risk of heart disease, cognitive impairment, and other health disorders [22, 23].
Supplementation with folic acid, alone or in combination with vitamin B12 and vitamin B6, can successfully reduce homocysteine levels. However, the impact of these supplements on heart disease risk is less convincing [24, 25, 26].
Note: 5-methyl-THF (active folate) is required to methylate homocysteine to methionine [27].
4) Kidney Disease
A large study of 15,000 patients with chronic kidney disease found that a combination of enalapril (blood pressure medication) and folic acid was more effective in improving kidney function than enalapril alone. The study suggested the use of folic acid for delaying chronic kidney disease progression in folate-deficient subjects [28].
In a large observational trial of 55,600 patients with end-stage renal disease (ESRD), folic acid supplementation increased survival rates by protecting the heart and preventing other complications [29].
High homocysteine is a major issue for ESRD patients and greatly contributes to their complications. Folic acid, alone or in combination with vitamins B6 and B12, successfully lowered homocysteine levels in multiple trials of people with ESRD [30, 31, 32].
5) Methotrexate Side Effects
Folic acid reduces the toxic side effects of methotrexate (a chemotherapeutic and immuno-suppressant drug) without impacting its efficacy [3, 33].
It can prevent liver damage and reduce digestive symptoms, such as nausea and vomiting, in the treatment of psoriasis, rheumatoid arthritis, and other conditions [34, 35].
Possibly Effective:
6) Depression
According to one meta-analysis, depressed patients have lower folate levels and lower dietary intake of this vitamin [36].
Folate is involved in the synthesis of serotonin and dopamine. An imbalance in these neurotransmitters can lead to the development of depression and anxiety disorders [37].
In four trials of over 590 depressed patients, folic acid had a stimulatory effect on serotonergic receptors in the brain and improved selective serotonin reuptake inhibitor (SSRI) responsivity [38, 39, 40].
Increasing folate levels in 22 people with eating disorders led to significant improvements in depressive symptoms [41].
7) Blood Pressure
According to a meta-analysis of 12 clinical trials, high-dose folic acid supplementation (min. 5mg/d for 6 weeks) may slightly lower systolic blood pressure (the higher value) and improve the function of blood vessels [42].
8) Vision Loss
Age-related macular degeneration (AMD) is one of the leading causes of blindness in older Americans. In a study of 5,442 older women, a combined intake of folic acid/vitamin B6/vitamin B12 over 7 years decreased the risk of AMD by 35-40% [43, 44].
9) Fertility
Folate’s role in DNA synthesis is vital for embryonic development and survival [45, 46].
Polymorphisms in folate pathway genes (i.e., MTHFR) may contribute to fertility complications in women, according to a preliminary trial of 71 participants [47].
Follicular fluid folate concentrations are associated with higher fertilization rates, oocyte quality, and live births in women undergoing infertility treatment [48, 49].
In a study of 211 participants, men with fertility issues experienced a 74% increase in sperm count after combined folic acid and zinc treatment [50].
Higher folate intakes are associated with lower frequencies of abnormal sperm (which may interfere with conception) in men [51].
In guinea pigs, a short-term deficiency of folate was found to dramatically decrease reproductive performance [52].
10) Vitiligo
In two trials of 115 patients with vitiligo (skin depigmentation), long-term supplementation with vitamins B9 and B12 significantly improved skin pigmentation. The authors emphasized the importance of sun exposure [53, 54].
Insufficient Evidence:
No valid clinical evidence supports the use of folic acid for any of the conditions in this section. Below is a summary of up-to-date animal studies, cell-based research, or low-quality clinical trials which should spark further investigation. However, you shouldn’t interpret them as supportive of any health benefit.
11) Brain Protection
Folate is critical for normal brain development and function [55].
Low blood folate levels may correlate with symptoms of cognitive decline in the elderly, epileptic, and psychiatric populations [56, 57].
They are also associated with degeneration of the cerebral cortex, the region of the brain that coordinates learning and memory [57].
This is likely due to increased homocysteine levels, which are toxic to neurons and linked to neurodegenerative conditions including Alzheimer’s disease, stroke, and epileptic seizures [58, 57].
In animal models of bacterial meningitis (swelling of the lining covering the brain and spinal cord), increasing folate levels preserved memory function and prevented oxidative damage to the frontal cortex [59].
Six-month folic supplementation significantly improved IQ scores, short-term memory, and motor skills in 180 older adults with mild cognitive impairment [60].
On the other hand, a study of 276 older people showed no benefits of homocysteine-lowering supplements (B6/B9/B12) on cognitive function [61].
In a large observational trial of 3718 older individuals, higher folate intake even correlated with faster cognitive decline [62].
12) Developmental Disorders
Since folate is required for fetal brain development, deficiencies are associated with neurodevelopmental defects including autism and schizophrenia [63, 64, 65].
Many child development studies (over 100K total participants) reveal an inverse correlation between prenatal folic acid supplements and the occurrence of autism, language delay, and social problems in children [66, 63, 67, 68]
Administration of folinic acid (another form of folate) in two trials of 65 autistic children with low brain folate levels resulted in an improvement in symptoms and a decrease in oxidative biomarkers (which are involved in the progression of autism) [69, 70].
13) Liver Damage
Evidence from animal and human studies support a causal relationship between low blood folate levels and oxidative stress, liver damage and cancer [71].
Excessive alcohol consumption is a known risk factor for liver disease and cancer. Oxidative stress due to folate depletion is a major underlying mechanism, and folate deficiency is known to correlate with alcoholic liver disease [72, 73, 74].
In animal studies, folic acid reversed the harmful effects of alcohol on the liver, likely by helping maintain methionine and glutathione levels, which are important for liver detox [75, 76].
14) Hearing Loss
An observational study of over 26,200 found that higher intakes of folate in people over 60 years old may reduce the risk of age-related hearing loss [77].
15) Arsenic Poisoning
Chronic arsenic exposure can increase the risk of cancer, heart disease, and stroke.
A study in 130 arsenic-exposed adults found that folic acid supplementation was able to lower blood arsenic levels by facilitating its urinary excretion [78].
Folate and Cancer
Folate coenzymes regulate DNA methylation, which is essential in controlling gene expression and cell differentiation. Abnormalities in this process have been linked to the development of mutations and cancer [79].
A folate-rich diet negatively correlated with a variety of cancers (i.e., breast, pancreatic, colon, lung, and esophageal cancers) in a number of observational studies [80, 81, 82, 83, 84, 85].
However, an excess of folic acid intake (above the normal dietary range) may actually accelerate tumor growth in cancer patients, indicating that the role of folate in cancer development control is more complex depends on the specific dosage [86].
Folate’s effects also appear to be dependent on the status of cell transformation. In animal colorectal cancer models, folic acid supplementation was found to prevent cancer development in normal tissues but promote tumor growth in pre-existing regions of abnormal tissue growth [1, 87, 88].
Thus, considerations of both the dose and timing of folate supplementation are critical. Despite the possible role of optimal folate intake in cancer prevention, the available evidence doesn’t support the use of folic acid supplements to treat or prevent cancer [89].
Folic Acid Safety and Side Effects Risks
Since folic acid is water-soluble, it is easily removed from the body through urinary excretion making the risk of toxicity relatively low. In adequate amounts, folic acid supplements are safe and well tolerated [90].
High doses of folate (15 mg/day) for 1 month were associated with sleep disturbances, mental confusion, and gastrointestinal effects in healthy individuals [3].
High doses of folic acid may have a masking effect on the diagnosis of anemia caused by vitamin B12 deficiency. For this reason, some experts suggest supplementing with both vitamins [91].
Folic acid is among the best-researched supplements for pregnant women with proven safety and efficacy. Taking it prior to a planned conception may be equally important for the beneficial effects on fetal development [92, 93].
Interactions
Supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. Always consult your doctor before supplementing and let them know about all drugs and supplements you are using or considering.
Alcohol impairs intestinal folate absorption [3].
Large doses (e.g., 3,900 mg/day) of NSAIDs (aspirin, ibuprofen, and acetaminophen) may inhibit folate binding and metabolism [3].
Chronic use of anticonvulsant drugs can interfere with folate absorption [3].
Vitamin C may improve folate bioavailability by limiting its degradation in the stomach [94].
A deficiency of vitamin B12 or iron may be masked by an excess of folic acid [95].
Folic Acid Intake, Dosage, and Supplements
The current Recommended Dietary Allowances for folate (developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies):
| Age | Male | Female | Pregnant | Lactating |
| 0- 6 months | 65 mcg DFE | 65 mcg DFE | ||
| 7–12 months | 80 mcg DFE | 80 mcg DFE | ||
| 1–3 years | 150 mcg DFE | 150 mcg DFE | ||
| 4–8 years | 200 mcg DFE | 200 mcg DFE | ||
| 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 and above years | 400 mcg DFE | 400 mcg DFE | 600 mcg DFE | 500 mcg DFE |
DFE refers to “Dietary Folate Equivalents”, which were established by the FNB to account for differences in folate bioavailability from foods and supplements. Since folate is more easily absorbed from supplements than from food sources, more food sources of folate are required to yield the same effect, which is why 1mcg from food is equivalent to 0.5mcg in supplements [96].
DFE is defined as follows [3]:
- 1 mcg DFE = 1 mcg folate found in food
- 1 mcg DFE = 0.6 mcg folic acid from fortified foods or supplements taken with a meal
- 1 mcg DFE = 0.5 mcg folic acid from supplements taken on an empty stomach
