Large amounts of folic acid—10 mg per day—have been shown to improve the abnormal Pap smears of women who are taking birth control pills.¹ Folic acid does not improve the Pap smears of women who are not taking oral contraceptives.^{2 , 3} High blood levels of folate (the food form of folic acid) have been linked to protection against the development of cervical dysplasia but these higher levels may only be a marker for eating more fruit and vegetables.^{4 , 5}

Several studies and clinical trials have shown that 50% or more of NTDs can be prevented if women consume a folic acid-containing supplement before and during the early weeks of pregnancy.^{6 , 7} The United States Department of Public Health, the Centers for Disease Control and Prevention (CDC), and the March of Dimes recommend that all women who are capable of becoming pregnant supplement with 400 mcg folic acid daily. Daily supplementation prior to pregnancy is necessary because most pregnancies in the United States are unplanned⁸ and the protective effect of folic acid occurs in the first four weeks of fetal development,⁹ before most women know they are pregnant.

For women who have had a previous NTD-affected pregnancy, the CDC recommends daily supplementation with 4,000 mcg per day of folic acid. In a preliminary study, this amount of supplemental folic acid before and during early pregnancy resulted in a 71% reduction in the recurrence rate of NTDs.¹⁰

A deficiency of the B vitamin folic acid can also disturb mood. A large percentage of depressed people have low folic acid levels.¹¹ Folic acid supplements appear to improve the effects of lithium in treating manic-depressives.¹² Depressed alcoholics report feeling better with large amounts of a modified form of folic acid.¹³ Anyone suffering from chronic depression should be evaluated for possible folic acid deficiency by a doctor. Those with abnormally low levels of folic acid are sometimes given short-term, high amounts of folic acid (10 mg per day).

Vitamin B6, folic acid, and vitamin B12 all play a role in converting homocysteine to other substances within the body. By so doing, they consistently lower homocysteine levels in research trials,^{14, 15, 16} a finding that is now well accepted. Several studies have used (and some doctors recommend) 400–1,000 mcg of folic acid per day, 10–50 mg of vitamin B6 per day, and 50–300 mcg of vitamin B12 per day.

Of these three vitamins, folic acid supplementation lowers homocysteine levels the most for the average person.^{17 , 18} It also effectively lowers homocysteine in people on kidney dialysis.¹⁹ In 1996, the FDA required that all enriched flour, rice, pasta, cornmeal, and other grain products contain 140 mcg of folic acid per 3½ ounces.²⁰ This level of fortification has led to a measurable decrease in homocysteine levels.²¹ However, even higher levels of food fortification with folic acid have been reported to be more effective in lowering homocysteine,²² suggesting that the FDA-mandated supplementation is inadequate to optimally protect people against high homocysteine levels. Therefore, people wishing to lower their homocysteine levels should continue to take folic acid supplements despite the FDA-mandated fortification program.

Most doctors, many other healthcare professionals, and the March of Dimes recommend that all women of childbearing age supplement with 400 mcg per day of folic acid. Such supplementation could protect against the formation of neural tube defects (such as spina bifida) during the time between conception and when pregnancy is discovered.

The requirement for the B vitamin folic acid doubles during pregnancy, to 800 mcg per day from all sources.²³ Deficiencies of folic acid during pregnancy have been linked to low birth weight²⁴ and to an increased incidence of neural tube defects (e.g., spina bifida) in infants. In one study, women who were at high risk of giving birth to babies with neural tube defects were able to lower their risk by 72% by taking folic acid supplements prior to and during pregnancy.²⁵ Several preliminary studies have shown that a deficiency of folate in the blood may increase the risk of stunted growth of the fetus.^{26 , 27 , 28 , 29 , 30 , 31 , 32 , 33} This does not prove, however, that folic acid supplementation results in higher birth weights. Although some trials have found that folic acid and iron, when taken together, have improved birth weights,^{34 , 35 , 36 , 37} other trials have found supplementation with these nutrients to be ineffective.^{38 , 39 , 40}

The relationship between folate status and the risk of miscarriage is also somewhat unclear. In some studies, women who have had habitual miscarriages were found to have elevated levels of homocysteine (a marker of folate deficiency).^{41 , 42 , 43 , 44} In a preliminary study, 22 women with recurrent miscarriages who had elevated levels of homocysteine were treated with 15 mg per day of folic acid and 750 mg per day of vitamin B6, prior to and throughout their next pregnancy. This treatment reduced homocysteine levels to normal and was associated with 20 successful pregnancies.⁴⁵ It is not known whether supplementing with these vitamins would help prevent miscarriages in women with normal homocysteine levels. As the amounts of folic acid and vitamin B6 used in this study were extremely large and potentially toxic, this treatment should be used only with the supervision of a doctor.

In other studies, however, folate levels did not correlate with the incidence of habitual miscarriages.^{46 , 47 , 48}

Preliminary⁴⁹ and double-blind⁵⁰ evidence has shown that women who use a multivitamin-mineral formula containing folic acid beginning three months before becoming pregnant and continuing through the first three months of pregnancy have a significantly lower risk of having babies with neural tube defects (e.g., spina bifida) and other congenital defects.

In addition to achieving significant protection against birth defects, women who take folic acid supplements during pregnancy have been reported to have fewer infections, and to give birth to babies with higher birth weights and better Apgar scores. ⁵¹ (An Apgar score is an evaluation of the well-being of a newborn, based on his or her color, crying, muscle tone, and other signs.) However, if a woman waits until after discovering her pregnancy to begin taking folic acid supplements, it will probably be too late to prevent a neural tube defect.

People with schizophrenia may have a greater tendency to be deficient in folic acid, than the general population⁵² and they may show improvement when given supplements. A preliminary trial found that, among schizophrenic patients with folic acid deficiency, those given folic acid supplements had more improvement, and shorter hospital stays than those not given supplements.⁵³ In a double-blind trial, a very high amount of folic acid (15 mg daily) was given to schizophrenic patients being treated with psychiatric medications who had low or borderline folic acid levels. The patients receiving the folic acid supplements had significant improvement, which became more significant over the six-month course of the trial.⁵⁴ The symptoms of folic acid deficiency can be similar to those of schizophrenia, and two cases of wrong “schizophrenia” diagnoses have been reported.^{55 , 56} In one of these cases, an initial supplement of 20 mg daily of folic acid and a maintenance supplemental intake of 10 mg daily, led to resolution of symptoms.⁵⁷

In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.⁵⁸ All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.

In a double-blind trial, elderly people with high homocysteine levels received 800 mcg of folic acid per day or a placebo for three years. Compared with placebo, folic acid supplementation significantly slowed the rate of decline of memory and of other measures of cognitive function.⁵⁹ Whether folic acid would slow cognitive decline in people with normal homocysteine levels is not known.

Blood levels of an amino acid called homocysteine have been linked to atherosclerosis and heart disease in most research,^{60 , 61} though uncertainty remains about whether elevated homocysteine actually causes heart disease.^{62 , 63} Although some reports have found associations between homocysteine levels and dietary factors, such as coffee and protein intakes,⁶⁴ evidence linking specific foods to homocysteine remains preliminary. Higher blood levels of vitamin B6, vitamin B12, and folic acid are associated with low levels of homocysteine⁶⁵ and supplementing with these vitamins lowers homocysteine levels.^{66 , 67}

While several trials have consistently shown that B6, B12, and folic acid lower homocysteine, the amounts used vary from study to study. Many doctors recommend 50 mg of vitamin B6, 100–300 mcg of vitamin B12, and 500–800 mcg of folic acid. Even researchers finding only inconsistent links between homocysteine and heart disease have acknowledged that a B vitamin might offer protection against heart disease independent of the homocysteine-lowering effect.⁶⁸ In one trial, people with normal homocysteine levels had demonstrable reversal of atherosclerosis when supplementing B vitamins (2.5 mg folic acid, 25 mg vitamin B6, and 250 mcg of vitamin B12 per day).⁶⁹ Similar results were seen in another study.⁷⁰

For the few cases in which vitamin B6, vitamin B12, and folic acid fail to normalize homocysteine, adding 6 grams per day of betaine (trimethylglycine) may be effective.⁷¹ Of these four supplements, folic acid appears to be the most important.⁷² Attempts to lower homocysteine by simply changing the diet rather than by using vitamin supplements have not been successful.⁷³

Among women who drink alcohol, those who consume relatively high amounts of folate from their diet have been reported to be at reduced risk of breast cancer, compared with women who drink alcohol but consumed less folate, according to a preliminary study.⁷⁴ In a similar report, consumption of folic acid-containing supplements was associated with a lower risk of breast cancer in women who drank alcohol, compared with women who drank alcohol but did not take such supplements.⁷⁵

The damaging effect alcohol has on DNA—the material responsible for normal replication of cells—is partially reversed by folic acid. Therefore, a potential association between both dietary folate and folic acid supplements and protection against breast cancer in women who drink alcohol is consistent with our understanding of the biochemical effects of these substances. A combined intake from food and supplements of at least 600 mcg per day was associated with a 43% reduced risk of breast cancer in women who consumed 1.5 drinks per day or more, compared with women who drank the same amount but did not take folic acid-containing supplements.⁷⁶

No research has yet explored the effect of folic acid supplementation in people who have already been diagnosed with cancer. Cancer patients taking the chemotherapy drug methotrexate must not take folic acid supplements without the direction of their oncologist.

The malabsorption that occurs in celiac disease can lead to multiple nutritional deficiencies. The most common nutritional problems in people with celiac disease include deficiencies of essential fatty acids, iron, vitamin D, vitamin K, calcium, magnesium, and folic acid.⁷⁹ Zinc malabsorption also occurs frequently in celiac disease⁸⁰ and may result in zinc deficiency, even in people who are otherwise in remission.⁸¹ People with newly diagnosed celiac disease should be assessed for nutritional deficiencies by a doctor. Celiac patients who have not yet completely recovered should supplement with a high-potency multivitamin-mineral. Some patients may require even higher amounts of some of these vitamins and minerals—an issue that should be discussed with their healthcare practitioner. Evidence of a nutrient deficiency in a celiac patient is a clear indication for supplementation with that nutrient.

After commencement of a gluten-free diet, overall nutritional status gradually improves. However, deficiencies of some nutrients may persist, even in people who are strictly avoiding gluten. For example, magnesium deficiency was found in 8 of 23 adults with celiac disease who had been following a gluten-free diet and were symptom-free. When these adults were supplemented with magnesium for two years, their bone mineral density increased significantly.⁸²

People with ulcerative colitis (UC) are at increased risk for colon cancer. Many patients with this disease take the drug sulfasalazine, which depletes folic acid.⁸³ In a preliminary report, patients with long-standing UC who took folic acid supplements (at least 400 mcg per day) had a 62% lower incidence of colon cancer or precancerous changes in the colon, compared with those who did not supplement with folic acid.⁸⁴ Although this difference was not statistically significant, the researchers recommended that people who take sulfasalazine should supplement with folic acid to potentially reduce the risk of colon cancer.⁸⁵

As dietary folate increases, the risks of precancerous polyps in the colon⁸⁶ and colon cancer itself decrease, according to some,⁸⁷ but not all, reports.⁸⁸ In one study, women who had taken folic acid supplements had a statistically significant 75% reduction in the risk of colon cancer, compared with women not taking folic acid supplements, but only when they had been supplementing with folic acid for more than 15 years.⁸⁹ In another report, the association between dietary folate and protection from precancerous polyps grew much stronger when use of folic acid supplements was considered (as opposed to studying only folate intake from food).⁹⁰ However, one double-blind study found that supplementing with 1 mg of folic acid per day for three to eight years did not prevent recurrences of precancerous polyps in people who had already had at least one polyp.⁹¹

The protection from colon cancer associated with high intake of folate has been reported to occur more in consumers of alcohol than in nondrinkers.⁹² This finding fits well with evidence that folate reverses damage to DNA caused by alcohol consumption.⁹³ Damaged DNA can lead to abnormal cellular replication—a step toward cancer.

Some nutritionally oriented doctors recommend folic acid supplementation for prevention of recurrences in patients who formerly had colon cancer but are now in complete remission. However, no research has yet explored the effect of folic acid supplementation in people who have already been diagnosed with cancer. Cancer patients taking the chemotherapy drug methotrexate must not take folic acid supplements without the direction of their oncologist.

Nutritional supplements recommended by some doctors for prevention and treatment of periodontitis include vitamin C (people with periodontitis are often found to be deficient),⁹⁴ vitamin E, selenium, zinc, coenzyme Q10, and folic acid.⁹⁵ Folic acid has also been shown to reduce the severity of gingivitis when taken as a mouthwash.⁹⁶

High blood levels of the amino acid homocysteine have been linked to an increased risk of heart attack in most,^{97 , 98 , 99 , 100} though not all,^{101 , 102} studies. A blood test screening for levels of homocysteine, followed by supplementation with 400 mcg of folic acid and 500 mcg of vitamin B12 per day could prevent a significant number of heart attacks, according to one analysis.¹⁰³ Folic acid^{104 , 105} and vitamins B6 and B12 are known to lower homocysteine.¹⁰⁶

There is a clear association between low blood levels of folate and increased risk of heart attacks in men.¹⁰⁷ Based on the available research, some doctors recommend 50 mg of vitamin B6, 100–300 mcg of vitamin B12, and 500–800 mcg of folic acid per day for people at high risk of heart attack.

Men with intermittent claudication consumed a fortified milk product or regular milk daily for one year. The fortified product provided daily 130 mg of eicosapentaenoic acid and 200 mg of docosahexaenoic acid (EPA and DHA, two fatty acids in fish oil), small amounts of supplemental vitamin E, folic acid, and vitamin B6, and additional amounts of oleic acid and alpha-linolenic acid. Compared with regular milk, the fortified milk product significantly increased the distance the participants could walk before the onset of pain.¹⁰⁸

In a double-blind study of female health professionals who had cardiovascular disease or cardiovascular disease risk factors, daily supplementation with folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) for 7.3 years significantly decreased the incidence of age-related macular degeneration.¹⁰⁹ 

Women with preeclampsia have been shown to have elevated blood levels of homocysteine.^{114 , 115 , 116 , 117} Research indicates elevated homocysteine occurs prior to the onset of preeclampsia.¹¹⁸ Elevated homocysteine damages the lining of blood vessels,^{119 , 120 , 121 , 122 , 123 , 124 , 125} which can lead to the preeclamptic signs of elevated blood pressure, swelling, and protein in the urine.¹²⁶

In one preliminary trial, women with a previous pregnancy complicated by preeclampsia and high homocysteine supplemented with 5 mg of folic acid and 250 mg of vitamin B6 per day, successfully lowering homocysteine levels.¹²⁷ In another trial studying the effect of vitamin B6 on preeclampsia incidence, supplementation with 5 mg of vitamin B6 twice per day significantly reduced the incidence of preeclampsia. Women in that study were not, however, evaluated for homocysteine levels.¹²⁸ In fact, no studies have yet determined whether lowering elevated homocysteine reduces the incidence or severity of preeclampsia. Nevertheless, despite a lack of proof that elevated homocysteine levels cause preeclampsia, many doctors believe that pregnant women with elevated homocysteine should attempt to reduce those levels to normal.

People with schizophrenia may have a greater tendency to be deficient in folic acid, than the general population¹²⁹ and they may show improvement when given supplements. A preliminary trial found that, among schizophrenic patients with folic acid deficiency, those given folic acid supplements had more improvement, and shorter hospital stays than those not given supplements.¹³⁰ In a double-blind trial, a very high amount of folic acid (15 mg daily) was given to schizophrenic patients being treated with psychiatric medications who had low or borderline folic acid levels. The patients receiving the folic acid supplements had significant improvement, which became more significant over the six-month course of the trial.¹³¹ The symptoms of folic acid deficiency can be similar to those of schizophrenia, and two cases of wrong “schizophrenia” diagnoses have been reported.^{132 , 133} In one of these cases, an initial supplement of 20 mg daily of folic acid and a maintenance supplemental intake of 10 mg daily, led to resolution of symptoms.¹³⁴

In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.¹³⁵ All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.

In a preliminary trial, 20 patients with sickle cell anemia were given either 1 mg of folic acid per day or folic acid plus 6 grams of aged garlic extract, 6 grams of vitamin C, and 1,200 mg of vitamin E per day for six months.¹³⁶ Patients taking the combination had a significant improvement in their hematocrit (an index of anemia) and less painful crises than those taking just folic acid.

Preliminary research has found that patients with sickle cell anemia are more likely to have elevated blood levels of homocysteine compared to healthy people.^{137 , 138} Elevated homocysteine is recognized as a risk factor for cardiovascular disease.¹³⁹ In particular, high levels of homocysteine in sickle cell anemia patients have been associated with a higher incidence of stroke.¹⁴⁰ Deficiencies of vitamin B6, vitamin B12, and folic acid occur more frequently in people with sickle cell anemia than in others^{141 , 142 , 143} and are a cause of high homocysteine levels.¹⁴⁴ A controlled trial found homocysteine levels were reduced 53% in children with sickle cell anemia receiving a 2–4 mg supplement of folic acid per day, depending on age, but vitamin B6 or B12 had no effect on homocysteine levels.¹⁴⁵ A double-blind trial of children with sickle cell anemia found that children given 5 mg of folic acid per day had less painful swelling of the hands and feet compared with those receiving placebo, but blood abnormalities and impaired growth rate associated with sickle cell anemia were not improved.¹⁴⁶ In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily.¹⁴⁷ Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional.

An older preliminary report suggested that large amounts of folic acid given both orally and by injection could promote healing of chronic skin ulcers due to poor circulation.¹⁴⁸ No controlled research has further investigated this claim.

Test tube studies have shown that propionyl-L-carnitine (a form of L-carnitine) protects red blood cells of people with thalassemia against free radical damage.¹⁴⁹ In a preliminary study, children with beta thalassemia major who took 100 mg of L-carnitine per 2.2 pounds of body weight per day for three months had a significantly decreased need for blood transfusions.¹⁵⁰ Some studies have found people with thalassemia to be frequently deficient in folic acid, vitamin B12,¹⁵¹ and zinc.^{152 , 153} Researchers have reported improved growth rates in zinc-deficient thalassemic children who were given zinc supplements of 22.5 to 90 mg per day, depending on age.^{154 , 155} Magnesium has been reported to be low in thalassemia patients in some,^{156 , 157} but not all,¹⁵⁸ studies. A small, preliminary study reported that oral supplements of magnesium, 7.2 mg per 2.2 pounds of body weight per day, improved some red blood cell abnormalities in thalassemia patients.¹⁵⁹

UC is linked to an increased risk of colon cancer. Studies have found that people with UC who take folic acid supplements or who have high blood levels of folic acid have a reduced risk of colon cancer compared with people who have UC and do not take folic acid supplements.^{160 , 161 , 162} Although these associations do not prove that folic acid was responsible for the reduction in risk, this vitamin has been shown to prevent experimentally induced colon cancer in animals.¹⁶³ Moreover, low blood folic acid levels have been found in more than half of all people with UC.¹⁶⁴ People with UC who are taking the drug sulfasalazine, which inhibits the absorption of folic acid,¹⁶⁵ are at a particularly high risk of developing folic acid deficiency. Folic acid supplementation may therefore be important for many people with UC. Since taking folic acid may mask a vitamin B12 deficiency, however, people with UC who wish to take folic acid over the long term should have their vitamin B12 status assessed by a physician.

Alcohol consumption is known to promote folic acid deficiency and has also been linked to an increased risk of colon cancer.¹⁶⁶ People with UC should, therefore, keep alcohol intake to a minimum.

A clinical report describes the use of vitamin supplements in the treatment of vitiligo.¹⁶⁷ Folic acid and/or vitamin B12 and vitamin C levels were abnormally low in most of the 15 people studied. Supplementation with large amounts of folic acid (1–10 mg per day), along with vitamin C (1 gram per day) and intramuscular vitamin B12 injections (1,000 mcg every two weeks), produced marked repigmentation in eight people. These improvements became apparent after three months, but complete repigmentation required one to two years of continuous supplementation. In another study of people with vitiligo, oral supplementation with folic acid (10 mg per day) and vitamin B12 (2,000 mcg per day), combined with sun exposure, resulted in some repigmentation after three to six months in about half of the participants.¹⁶⁸ This combined regimen was more effective than either vitamin supplementation or sun exposure alone.

In a study of female health professionals who had cardiovascular disease or cardiovascular disease risk factors, daily supplementation with folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) for 5.4 years had no effect on cognitive function. However, supplementation appeared to prevent age-related cognitive decline in the 30% of women who had low dietary intake of B vitamins.¹⁶⁹

Some researchers have found an association between Alzheimer’s disease and deficiencies of vitamin B12 and folic acid;^{170 , 171} however, other researchers consider such deficiencies to be of only minor importance.¹⁷² In a study of elderly Canadians, those with low blood levels of folate were more likely to have dementia of all types, including Alzheimer’s disease, than those with higher levels of folate.¹⁷³ Little is known about whether supplementation with either vitamin would significantly help people with this disease. Nonetheless, it makes sense for people with Alzheimer’s disease to be medically tested for vitamin B12 and folate deficiencies and to be treated if they are deficient.

Both folic acid and vitamin B12 are used in the body to manufacture serotonin and other neurotransmitters. It is well known that deficiency of either nutrient is associated with depression.^{174 , 175} There is some evidence that patients diagnosed with mania are also more likely to have folate deficiencies than healthy controls.¹⁷⁶ Other studies, however, have found that folic acid deficiency was not more common in bipolar patients taking lithium than in healthy people.^{177 , 178 , 179} Some studies have found that people who take lithium long term, and who also have high blood levels of folic acid, respond better to lithium.^{180 , 181} Not all studies have confirmed these findings, however.¹⁸² A double-blind study of patients receiving lithium therapy showed that the addition of 200 mcg of folic acid per day resulted in clinical improvement, whereas placebo did not.¹⁸³

Crohn’s disease often leads to malabsorption. As a result, deficiencies of many nutrients are common. For this reason, it makes sense for people with Crohn’s disease to take a high potency multivitamin-mineral supplement. In particular, deficiencies in zinc, folic acid, vitamin B12, vitamin D, and iron have been reported.^{184 , 185 , 186} Zinc, folic acid, and vitamin B12 are all needed to repair intestinal cells damaged by Crohn’s disease. Some doctors recommend 25 to 50 mg of zinc (balanced with 2 to 4 mg of copper), 800 mcg of folic acid, and 800 mcg of vitamin B12. Iron status should be evaluated by a doctor before considering supplementation.

People with DH frequently have mild malabsorption (difficulty absorbing certain nutrients) associated with low stomach acid (hypochlorhydria) and inflammation of the stomach lining (atrophic gastritis).¹⁸⁷ Mild malabsorption may result in anemia¹⁸⁸ and nutritional deficiencies of iron, folic acid,^{189 , 190} vitamin B12,^{191 , 192} and zinc.^{193 , 194 , 195} More severe malabsorption may result in loss of bone mass.¹⁹⁶ Additional subtle deficiencies of vitamins and minerals are possible, but have not been investigated. Therefore, some doctors recommend people with DH have their nutritional status checked regularly with laboratory studies. These doctors may also recommend multivitamin-mineral supplements and, to correct the low stomach acid, supplemental betaine HCl (a source of hydrochloric acid).

Acute diarrhea can damage the lining of the intestine. Folic acid can help repair this damage. In one preliminary trial, supplementing with very large amounts of folic acid (5 mg three times per day for several days) shortened the duration of acute infectious diarrhea by 42%.¹⁹⁷ However, a double-blind trial failed to show any positive effect with the same level of folic acid.¹⁹⁸ Therefore, evidence that high levels of folic acid supplementation will help people with infectious diarrhea remains weak.

The red blood cells of people with Down’s syndrome are unusual in ways that suggest either vitamin B12 or folic acid deficiency.^{199 , 200 , 201} However, folic acid levels have been found to be normal in each of these studies, and only one study has found lower levels of vitamin B12 in Down’s syndrome as compared with healthy individuals.²⁰² Intervention trials using either vitamin B12 or folic acid have not been done.

Folic acid supplementation (5 mg per day) was reported to reduce epileptic seizure frequency, though the effect was not significantly better than with placebo.²⁰³ Folic acid supplementation of as little as 800 mcg per day has also been reported to interfere with the action of anticonvulsant medications, resulting in an increase in the frequency and/or severity of seizures;^{204, 205, 206, 207} this effect occurs only in a small number of cases.^{208, 209} People taking anticonvulsant medications should consult with the prescribing physician before deciding whether to use folic acid.

In HIV-positive people with B-vitamin deficiency, the use of B-complex vitamin supplements appears to delay progression to and death from AIDS.²¹⁰ Thiamine (vitamin B1) deficiency has been identified in nearly one-quarter of people with AIDS.²¹¹ It has been suggested that a thiamine deficiency may contribute to some of the neurological abnormalities that are associated with AIDS. Vitamin B6 deficiency was found in more than one-third of HIV-positive men; vitamin B6 deficiency was associated with decreased immune function in this group.²¹² In a population study of HIV-positive people, intake of vitamin B6 at more than twice the recommended dietary allowance (RDA is 2 mg per day for men and 1.6 mg per day for women) was associated with improved survival.²¹³ Low blood levels of folic acid and vitamin B12 are also common in HIV-positive people.²¹⁴

Folic acid and vitamin B12 work together in the body to help cells replicate normally. In a double-blind trial, smokers with precancerous changes in the lungs were given a placebo or the combination of 10,000 mcg of folic acid and 500 mcg of vitamin B12 per day for four months.²¹⁵ A significant reversal of precancerous changes occurred in those given vitamin supplements compared with those given the placebo.²¹⁶ No trials have investigated whether either vitamin given alone or the combination of both vitamins would help to treat people who already have lung cancer.

As with other vascular diseases, people with TAO are more likely to have high levels of homocysteine and low levels of folic acid.²¹⁷ However, no research has tested folic acid as prevention or treatment for this disease.

Folic acid antagonist drugs have been used to treat psoriasis. In one preliminary report, extremely high amounts of folic acid (20 mg taken four times per day), combined with an unspecified amount of vitamin C, led to significant improvement within three to six months in people with psoriasis who had not been taking folic acid antagonists;those who had previously taken these drugs saw a worsening of their condition.²¹⁸

In some people with RLS, the condition may be genetic. People with familial RLS appear to have inherited an unusually high requirement for folic acid. Although not all people with RLS suffer from uncomfortable sensations, folate-deficient people with this condition always do.²¹⁹ In one report, 45 people were identified to be from families with folic acid-responsive RLS. The amount of folic acid required to relieve their symptoms was extremely large, ranging from 5,000 to 30,000 mcg per day.²²⁰ Such amounts should only be taken under the supervision of a healthcare professional.

One physician reported that injections of B-complex vitamins were useful in the treatment of seborrheic dermatitis in infants.²²¹ A preliminary trial found that 10 mg per day of folic acid was helpful in 17 of 20 cases of adult seborrheic dermatitis.²²² However, this study also found that oral folic acid did not benefit infants with cradle cap. A preliminary study found that topical application of vitamin B6 ointment (containing 10 mg B6 per gram of ointment) to affected areas improved adult seborrheic dermatitis.²²³ However, oral vitamin B6 (up to 300 mg per day) was ineffective. Injections of vitamin B12 were reported to improve in 86% of adults with seborrheic dermatitis in a preliminary trial.²²⁴ Oral administration of vitamin B12 for seborrheic dermatitis has not been studied.

Elevated blood levels of homocysteine, a toxic amino acid byproduct, have been linked to risk of stroke in most studies.^{225 , 226 , 227} Supplementation with folic acid, vitamin B6, and vitamin B12 generally lowers homocysteine levels in humans.^{228 , 229 , 230} In a pooled analysis (meta-analysis) of eight randomized trials, folic acid supplementation in varying amounts (usually 0.5 mg to 5 mg per day) reduced stroke risk by 18%.²³¹