Researchers are continuing to investigate whether enhanced folate intake from foods or
folic acid supplements may reduce the risk of cancer.
ADVERSE EFFECTS OF FOLIC ACID SUPPLEMENTS
Although folate is safe and almost free of toxicity [73], concerns that folic acid
fortification could mask symptoms of vitamin B12 deficiency and precipitate neurological
complications have been raised [74]. Other examples of potential safety issues are the
interactions with drugs, hypersensitivity reactions, increase of twinning rate and genetic
Folic Acid and Masking of B12 Deficiency
Folic acid is generally considered to be safe [73]. Although the risk of toxicity is low,
there are some concerns about its interaction with vitamin B12 [76]. Vitamin B12 deficiency
could affect up to 10–15% of the population over 60 years of age and it is often undiagnosed.
Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated.
Folic acid supplements can correct the anemia associated with vitamin B12 deficiency.
Unfortunately, folic acid will not correct changes in the nervous system that result from
vitamin B12 deficiency. The US Institute of Medicine [77] determined that there is suggestive,
but not conclusive, evidence that folic acid, in addition to masking vitamin B12 deficiency,
precipitates or exacerbates the neurological damage caused by vitamin B12 deficiency.
This concern is related to public health fears of introducing additional folic acid to the
whole population (through food fortification), and uncertainty about unforeseen risks,
especially in vulnerable groups such as children and also the elderly in whom vitamin B12
deficiency is a particular risk.
Recent evidence suggests, however, that small doses of folic acid (200 to 400μg daily)
are unlikely to cause this problem [78] The risk of "masking" the condition increases at folic
acid intakes exceeding 1,000μg a day [78]. The Institute of Medicine [77] has in fact
established a tolerable upper intake level (UL) for folate of 1,000 µg for adult men and
women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18
years of age. Therefore, supplements should not exceed the UL to prevent folic acid from
masking symptoms of vitamin B12 deficiency. In fact, evidence that such masking actually
occurs is scarce, and there is no evidence that folic acid fortification in Canada or the US has
increased the prevalence of vitamin B12 deficiency or its consequences [74].
However, it could be important to be aware of the B12 status before taking a supplement
Folic Acid and Health: An Overview 49
Folic Acid and Anticonvulsivant Drugs
Long-term antiepileptic phenytoin therapy can result in folate deficiency, whereas
supplementation with folic acid might lower serum phenytoin. No appreciable changes in
values of phenytoin drug concentrations were found in relation to food fortification in a large
trial in Canada [79]. Furthermore, evidence does not lend support to a substantial increase in
seizure frequency in patients who are treated with oral folic acid [75].
The use of multivitamin supplements containing folic acid has been associated with an
increase in twinning rates [80-82]. Twin pregnancies are at greater risk for infant morbidity
and mortality [83]. This positive association may in part be explained by residual
confounding of in-vitro fertilization and ovarian stimulation, or by the effect of other
vitamins on the multivitamins consumed [84-86]. Post fortification twinning rates were not
higher in the USA [87, 89] and similarly, in the extensive intervention study in China, folic
acid supplements showed no effect [90]. This debate is not yet closed [91].
Folic Acid and Genetic Selection
It has been hypothesized that increased amounts of folic acid during the periconceptional
period could lead to a genetic selection by improving the survival of embryos carrying the
MTHFR 677C→T mutation. This could raise homocysteine concentrations if folate intake is
subsequently restricted in the child [92, 93].
Folic Acid and Hypersensitivity Reactions
A few case reports have described hypersensitivity reactions to oral and parenteral folic
acid, but most reactions were probably due to other components of the folic acid drug [94].
Folic Acid and Methotrexate for Cancer
Methotrexate is a drug used to treat cancer which interferes with folate metabolism;
infact, it inhibits the production of tetrahydrofolate, which is the active form of folic acid.
Unfortunately it can be toxic [95-97] and Folinic acid is a form of folate that can help
"rescue" or reverse the toxic effects of methotrexate [98]. Folic acid supplements have little
established role in cancer chemotherapy [99,100]. It is important for anyone receiving
methotrexate to follow medical advice on the use of folic or folinic acid supplements.
Folic Acid and Methotrexate for Non-Cancerous Diseases
Low dose methotrexate is also used to treat a wide variety of non-cancerous diseases
such as rheumatoid arthritis, lupus, psoriasis, asthma, sarcoidoisis, primary biliary cirrhosis,
and inflammatory bowel disease [101]. Low doses of methotrexate can deplete folate stores
and cause side effects that are similar to folate deficiency. Both high folate diets and
supplemental folic acid may help reduce the toxic side effects of low dose methotrexate
without decreasing its effectiveness [102,103]. Anyone taking low dose methotrexate for the
health problems listed above should consult with a physician about the need for a folic acid
It is only recently that folate deficiency has been associated with the risk of neural tube
defects (NTDs), cardiovascular disease, mental disorders and some forms of cancer; there is
not sufficient data available concerning the relationship with osteoporosis.
The evidence for a reduction in risk with increased folic acid intake is powerful for
NTDs and is increasing for cardiovascular disease. There may also be benefit in terms of
prevention of colorectal cancer and Alzheimer's disease, but more clinical trials are needed.
Findings suggest that folate supplementation might decrease or increase the risk of diseases
depending on dosage and timing, but there is also an emerging picture which takes in
consideration a more complex interaction of multiple nutritional and genetic factors.
Supplements are already recommended for women during the peri-conceptional period
but, given that not all women are happy to take it and that pregnancies may also be
unplanned, there is a need to ensure adequate folate intake by some other means. Food
fortification is one method, but strategies for increasing consumption of natural food folates
could also be explored and, in particular, whether sufficient amounts can be absorbed from
these foods to protect against disease. Finally, research in relation to safety issues of folic
acid fortification is required.
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