From the Guidelines
Folic acid is generally safe at recommended doses and does not cause significant toxicity, with the most recent and highest quality evidence suggesting that supplementation at usual doses is not associated with serious harms 1. When considering the potential for folic acid to cause toxicity, it's essential to differentiate between the recommended supplementation levels and excessive intake. Normal supplementation at recommended levels (400-800 mcg daily for most adults) is generally safe and effective in preventing neural tube defects, as supported by the USPSTF recommendation statement 1.
Key Considerations
- The USPSTF concludes that, for women who are planning or capable of pregnancy, there is high certainty that the net benefit of folic acid supplementation is substantial, with inadequate evidence for any potential harm to the mother or baby 1.
- High-dose folic acid can mask vitamin B12 deficiency by correcting the anemia while allowing neurological damage to progress undetected, which is particularly concerning for older adults who are at higher risk for B12 deficiency 1.
- Excessive folic acid may potentially increase cancer risk in some individuals with pre-existing neoplastic lesions, though research is ongoing, and findings from studies like the NORVIT trial suggest that high-dose folic acid may not have a significant effect on cardiovascular risk 1.
Recommendations
- For safety, most people should not exceed the upper limit of 1,000 mcg daily unless specifically prescribed by a healthcare provider for conditions like severe folate deficiency or certain pregnancy complications.
- Women who are planning or capable of pregnancy should take folic acid supplements at the recommended dose of 400-800 μg (0.4-0.8 mg) daily, as reaffirmed by the USPSTF in 2017 1.
- Higher doses of folate supplementation (>400 μg or >0.4 mg) with or without additional vitamins and minerals do not have any effect on the prevalence or recurrence of neural tube defects, according to a Cochrane meta-analysis 1.
From the FDA Drug Label
Folic acid is relatively nontoxic in man. Rare instances of allergic responses to folic acid preparations have been reported and have included erythema, skin rash, itching, general malaise, and respiratory difficulty due to bronchospasm One patient experienced symptoms suggesting anaphylaxis following injection of the drug. Gastrointestinal side effects, including anorexia, nausea, abdominal distention, flatulence, and a bitter or bad taste, have been reported in patients receiving 15 mg folic acid daily for 1 month Other side effects reported in patients receiving 15 mg daily include altered sleep patterns, difficulty in concentrating, irritability, overactivity, excitement, mental depression, confusion, and impaired judgment.
Folic acid toxicity is relatively rare, but it can cause allergic responses and gastrointestinal side effects. The most common side effects include:
- Allergic reactions (e.g., erythema, skin rash, itching)
- Gastrointestinal issues (e.g., anorexia, nausea, abdominal distention)
- Neurological effects (e.g., altered sleep patterns, difficulty in concentrating, irritability) According to the study 2, folic acid is relatively nontoxic, but high doses may cause adverse reactions.
From the Research
Folic Acid Toxicity
- Folic acid is generally regarded as non-toxic for normal humans, but it may cause neurological injury when given to patients with undiagnosed pernicious anemia 3.
- High doses of folic acid may exacerbate vitamin B12 deficiency, particularly in the elderly, leading to adverse clinical outcomes such as anemia and cognitive impairment 4.
- Excessive folic acid intake has been linked to various adverse health outcomes, including:
- However, the evidence for these adverse effects is not conclusive, and more research is needed to fully understand the potential risks of excessive folic acid intake 6.
- The weight of current evidence suggests that daily supplements of 5-15 mg folic acid do not have significant adverse effects on zinc nutriture in healthy non-pregnant subjects 3.
- Further investigation is needed to clarify the safety of folic acid supplements in patients with various disorders, including malignant and non-malignant conditions 3.