Folate or folic acid has been found to help depression in five double-blind studies.  It may also help in other nervous system disorders including schizophrenia, Alzheimer's disease, and Parkinson's disease. It is of help in preventing heart disease, stroke and several different cancers.  In pregnancy, it helps prevent birth defects including spina bifida and cleft lip.  Folate may even help arthritis.  The studies I list for the benefits of folate on depression and schizophrenia are so numerous that they have their own special page.  For these, see Folic Acid for Depression.  

Cereals in the U.S. have been fortified by 140 mcg of folate per 100 gm since 1998 to help avoid a birth defect of the neural tube.  While the depression research is quite old, much of the rest is newer with more studies in process.  Folate is found in fruits, leafy green vegetables, legumes, and whole grains, but many Americans get less than the recommended 400 mcg per day.

Folic acid is available in 800 mcg tablets for 1-2 cents per tab.  Usually, 400 mcg is put into multivitamin preparations, although I discourage multivitamins for non-pregnant adults due to many studies showing harmful effects from vitamin A supplements.  I recommend 800 mcg per day in addition to that obtained through an excellent diet.  With depression, 1,600 mcg might be better.  Older adults should always take vitamin B-12 along with folic acid, although I recommend B-12 for everyone.

I have seen one comment claiming that folic acid supplements have been associated with increased cancer.  However, the claim was without any reference.  I have found no such mentioned in hundreds of studies I have reviewed on folate and cancer.  In contrast, low folate has been linked to cancer of the cervix, colorectum, lung, esophagus, blood cells, and brain.

Alcohol: Heavy Drinking Plus Low Folate Causes Chronic Disease: In a 16-year follow-up of 83,929 women 34-59 years old, women drinking more than 2 drinks per day (30g) and who had a low folate intake had 36% more chronic diseases (RR = 1.36).  However, those with higher folates had much less chronic disease. Joint association of alcohol and folate intake with risk of major chronic disease in women.  Harvard. Jiang R, Hu FB, et al. Am J Epidemiol. 2003 Oct 15;158(8):760-71

Alzheimer's: Folic Acid Without B-12 Dangerous in Elderly: In a study of 1,300 adults over 59, 23% had low B-12 levels. Within this group, those with the highest folic acid levels were 2.6 times as likely to show cognitive impairment as those with less as well as 3.1 times as common to have anemia. However, for those with normal B-12 levels, folic acid appeared to protect against cognitive impairment and had no relationship to anemia. Morris MS, et al. Tufts University. Amer J Clin Nutr 1/07.

Alzheimer's: Folic Acid Helped Prevent: In a DB PC study of 818 Dutch adults ages 50-70, those taking folic acid 800 mcg daily for three years had significantly better memories and were faster at processing information, similar to adults almost five years younger. Taking folic acid also led to a significant reduction in levels of homocysteine. Jane Durga, fet al. University of Wageningen, Netherlands. Lancet 1/19/07.

Alzheimer's: Folate Helps Prevent: From the Baltimore Longitudinal Study of Aging, 579 over 59 without Alzheimer's disease were followed for nine years.  Foods rich in folate include oranges, bananas, leafy green vegetables, asparagus, broccoli, liver, and many types of beans and peas, as well as fortified bread. During follow-up, 57 developed Alzheimer's disease. Those with a higher dietary intake of folate had a 60% lower rate of the disease compared to the lowest quartile. Older adults whose total folate intake (diet and supplement) equaled or exceeded the 400 microgram RDA reduced their chances of developing Alzheimer's disease by 55 percent. No association was seen between intakes of vitamin C, carotenoids, or vitamin B-12. Vitamin E and B-6 had no effect when controlling for folate. Maria Corrada, et al. University of California, Irvine. WebMD 8/15/05

Alzheimer, Parkinson’s Affected by Folate: Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders. NIH. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Mattson MP, Shea TB. Trends Neurosci 2003 Mar;26(3):137-46 

Alzheimer's: Homocysteine Increased; B6-12 and Folate May Help: U Oxford found high blood homocysteine, which is associated with heart disease, was also more common in 76 Alzheimer’s patients. Robert Clarke Arch Neurol. 1/99. The upper tertile (upper third) in homocysteine had at least a 2-fold increase in Alzheimers (highest tertile to lowest RR 4.5). There were inverse correlations for serum folate (lowest tertile to highest = RR 3.3) and B12 (lowest tertile to highest RR 4.3) and Alzheimers (Clarke Arch Neurol 11/98 55:1449-55). Homocysteine increased with age, in male, with smoking, and with creatinine.  The decrease in these vitamins may be related to hyperhomocysteinemia because they are required for metabolizing it. Homocysteine has a direct neurotoxic effect. Polyvitamin treatment with B6, B12 and folate was effective in lowering homocysteine. Cereals in US have been fortified with folic acid since 1/1/98 to prevent neural tube defects but not enough to affect homocysteine. Arch Neurol 11/98 55:1407

Birth Defects, Cleft Palates: Meds Interfering with Folic Acid Increase: Babies have 2-3 times the rate of heart, palate, urinary tract defects if mothers take interfering meds. Those on antibiotic trimethoprim or the high blood pressure medicine triamterene might be able to compensate by taking extra folic acid, but that may not help patients on phenobarbital, primidone, phenytoin or carbamazepine for epilepsy. NEJM 11/30/00.

Brain Size and White Matter Densities Linked to Folate in Mentally Ill: In an archival study of MRIs and medical records of 34 non-schizophrenic inpatients in a geriatric psychiatry unit, homocysteine was related to white matter hyperdensities (WMH) grade, but not brain-volume measures. Folate was associated with hippocampus and amygdala volume, and negatively associated with WMH. B12 level was not statistically associated with any brain measure. Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Scott TM, Tucker KL, et al. Tufts University. Am J Geriatr Psychiatry. 2004 Nov-Dec;12(6):631-8.

Hearing (Low Frequency) Protected in Natherlands: In a 3-year DB PC study of 728 older Dutch adults with plasma total homocysteine concentrations 13 micromol/L or greater serum and vitamin B12 concentrations 200 pmol/L or greater at screening, and no hearing problems, daily folic acid (800 microg) held thresholds of the low frequencies increase to 1.0 dB vs. 1.7 dB in the placebo group (P = 0.020). Folic acid supplementation did not affect the decline in hearing high frequencies. Folic acid fortification of food is prohibited in the Netherlands during the study, so baseline folate levels in participants were about half of those found in the U.S. population. Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial. Durga J, et al. Wageningen University, The Netherlands. . Arch Intern Med 2007 Jan 2;146(1):1-9.

Hypertension: Folic Acid Supplements Lower Risk: In two 8-year prospective studies of 93,803 younger women ages 27-44 in the Nurses' Health Study II (1991-1999) and 62,260 older women ages 43-70 in the Nurses' Health Study I (1990-1998) without hypertension, 7373 younger women and 12,347 older women developed hypertension. After adjusting for multiple potential confounders, younger women who consumed at least 1000 microg/d of total folate (dietary plus supplemental) had a decreased risk of hypertension (relative risk [RR], 0.54; P <.001) compared with those who consumed less than 200 microg/d. The multivariable RR for the same comparison in older women was 0.82 (P = .05). Among women who did not take folic acid supplements, dietary folate intake of 400 microg/d or more was not significantly associated with risk of hypertension. Folate intake and the risk of incident hypertension among US women. Forman JP, Rimm EB, et al. Harvard. JAMA. 2005 Jan 19;293(3):320-9 

Heart Disease

Angioplasty Helped by Folate, B12, B6 in DB: 553 angioplasty Swiss DB PC with one group folate 1 g/d, B12 400 microg/d, B6 10 mg/d. Fewer deaths and infarctions in vitamin group. Homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) significantly decreases the incidence of major adverse events after percutaneous coronary intervention. Effect of homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002 Aug 28;288(8):973-9 Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM.

Cardiovascular: B-6, B-12, Folate Combination Not Good for Coronary Stenting: 636 patients who had undergone successful coronary stenting were randomly assigned to receive 1 mg of folic acid, 5 mg of vitamin B6, and 1 mg of vitamin B12 intravenously, followed by daily oral doses of 1.2 mg of folic acid, 48 mg of vitamin B6, and 60 microg of vitamin B12 for six months, or placebo. At follow-up, the mean minimal luminal diameter was significantly smaller in the supplement group than in the placebo group (1.59 mm vs. 1.74 mm, P=0.008), and the extent of late luminal loss was greater (0.90 mm vs. 0.76 mm, P=0.004). The restenosis rate was higher in the supplement  group than in the placebo group (34.5% vs. 26.5%, P=0.05), and a higher percentage of patients in the supplement  group required repeated target-vessel revascularization (15.8% vs. 10.6%, P=0.05). Folate therapy had adverse effects on the risk of restenosis in all subgroups except for women, patients with diabetes, and patients with markedly elevated homocysteine levels (15 micromol per liter or more) at baseline. Supplement therapy and in-stent restenosis after coronary stenting. Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, Pasalary MN, Scherer E, Dambrink JH. Bremen, Germany. N Engl J Med. 2004 Jun 24;350(26):2673-81. Ed: Since the folic acid and B-12 doses in this study were fairly small and toxicity from folic acid and B-12 are very rare, it appears to me that the B-6 might have been causing a harmful effect. B-6 toxicity is usually thought to occur at somewhat higher doses that in this study, but are much more commonly reported than the other two.

Heart Attacks and Homocysteine Less with Higher Folate Intake and Levels: In 32,826 women from the Nurses' Health Study who provided blood samples in 1989-1990, 237 CHD events were documented during 8 years of follow-up. The cases (1:2) were matched to controls on age, smoking, and month of blood draw. Plasma tHcy was inversely associated with blood levels of folate (partial r = -0.3, P < 0.0001) and B(2) (r = -0.2, P < 0.0001) and with dietary intake of folate (r = -0.1, P < 0.01) and B(2) vitamin (r = -0.1, P = 0.01). tHcy was positively associated with soluble tumor necrosis receptor (sTNF-R) 1 and 2 (partial r = 0.2, P < 0.0001). In a multivariate model adjusted for age, smoking, BMI, parental history, hypertension, diabetes, postmenopausal hormone use, physical activity and alcohol intake, the relative risk of CHD between the extreme quartiles of tHcy was 1.66 (P = 0.02). The association was not appreciably attenuated after further adjustments for sTNF-R1, sTNF-R2, CRP, or Total Cholesterol:/HDL-c ratio. Homocysteine as a risk factor for coronary heart diseases and its association with inflammatory biomarkers, lipids and dietary factors. Shai I, et al. Harvard. Atherosclerosis 2004 Dec;177(2):375-81

Cardiovascular: B-1, B-6, B-12, and Folate Prevent Heart Disease & Stroke: By lowering homocysteine. 12% humans genetically predisposed to high levels homocysteine and riboflavin (found in dairy) helps. U Ulster, 10/2/02

Cardiovascular: Folate Decreased Non-Fatal Heart Attacks: 1882 symptomatic coronary disease patients in PC DB of folate 5 mg/day for 1.7 years found a 14% decrease in homocysteine and non-fatal heart attacks were cut in half (12 vs. 23), but there was no significant effect on death. F Baker et al, Circulation 2002;106 suppl:II-741

Cardiovascular: Folate-B-12-Pyrodoxine Reduce Restenosis: At 1 mg folic acid, 400 microg B-12, and 10 mg/d B-6, this treatment reduced homocysteine 36% and cut restenosis in half (19.6% vs. 37.6%) in DB of 205 for 6 months after coronary angioplasty. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM. (Bern-Switz) N Engl J Med 2001 Nov 29;345(22):1593-600.; 

Chronic Fatigue Syndrome: B-12, Folate in Bovine Liver Extract No Benefit: 15 patients in a DB PC crossover study. Kaslow, UC Irvine, Arch Int Med ’98;149:2501

Diabetic Type 1 Children Endothelial Function Helped by Folic Acid: In a double-blind, crossover study of 36 diabetic children, 5 mg/day of folic acid was found to significantly improve the ability of blood vessels to dilate, etc. Folic acid improves endothelial function in children and adolescents with type 1 diabetes. Pena AS, Wiltshire E, Gent R, Hirte C, Couper J. University of Adelaide. J Pediatr. 2004 Apr;144(4):500-4

Homocysteine: Age, Male, Folate, B-12, B-6, Genes: While cigs, coffee assoc with high homocysteine, this disappeared when corrected for folate in Shanghai study of 486. Methylenetetrahydrofolate reductase genetic variations also associated with high levels when two abnormal genes. higher age and maleness strongly associated with higher homocysteine. Amer J Clin Nutr 2/01;236

Homocysteine: B-6, folate, B-12 injection Help Elderly with Normal Levels: 285 elderly at home or in hospital, all with normal blood levels, in a DB PC 3-week study, were given injections every 3 days. Treatment considerably lowered elevated homocysteine, methylmalonic acid, methylcitric acid, and cystathionine. Naurath, Germany, Lancet ’95;346:85

Homocysteine: Folate Makes Betaine Needless: Although trimethylglycine (betaine or Cystadane) is FDA-approved for homocystinuria and lowers plasma homocysteine (GR Steenge et al, J Nutr 2003;133:1291), in patients with end-stage renal disease, adding it to folate was of no value as folate alone lowered homocysteine concentrations (C van Guldener et al, J Intern Med 1999;245:175).

Homocysteine: Vegans Hyperhomocysteinemia: Frequency of hyperhomocysteinemia was 53% in the vegans group, 28% in vegetarians vs. 5% in omnivores. In conditions of lower methionine intake (reduced content in plant proteins), the remethylation pathway of homocysteine metabolism prevails and it is vitamin B12 and folate-dependent. The intake of vitamin B12 is equal to zero in vegans; vegetarians consume 124% of the RDA vs. 383% in omnivores. Serum vitamin levels are significantly lower in subjects consuming alternative nutrition with deficiency observed in 24% of vegetarians, 78% of vegans vs. 0% in omnivores. Serum folate levels are within the reference range in all groups. Scand J Clin Lab Invest 2000 Dec;60(8):657-64

Intimal Thickness and Homocysteine Both Decrease with Folate, B-6, and B-12: Carotid intima-media thickness (IMT) as an accepted marker of atherosclerotic changes. In a 1-year DB PC study of 50 patients (60+/-8 years) with IMT>/=1mm, daily 2.5mg folic acid, 25mg Vitamin B6, and 0.5mg Vitamin B12 decreased homocysteine from 10.50 to 6.56 mumol/l (P<0.0001) vs. no change with placebo. IMT decreased from 1.50 to 1.42 mm (P=0.034) vs. an increase from 1.47 to 1.54 mm for placebo (P=0.019). The IMT effect was independent of Hcy concentration. Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12. Till U, Rohl P, et al. Friedrich-Schiller-University, Jena, Germany. Atherosclerosis. 2005 Jul;181(1):131-5.

Osteoarthritis: B-12 and Folate Help: DB PC 27 pts with 6 yr osteo rx NSAID. Rx folate 6400 microg/d and B-12 20 microg/d for 3 wk or placebo. Grip better with vitamins and equal to NSAID while fewer tender joints with vitamins than with NSAID and far fewer S-E. Flynn, U Missouri, J Am Coll Nutr 8/94;13:351 

Stroke: B-6, B-12, Folate Not Help Stroke, Heart: In a 2 year DB PC study of 3,068 stroke victims given high dose (25 mg, 0.4 mg, 2.5 mg respectively) or low dose (0.2 mg, 0.006 mg, 0.02 mg), there was no difference what soever in strokes, heart attacks, or death during follow-up although there was a moderate decrease (2 micromol/L) in homocysteine. The study did find a more major decrease (3 micromol/L) in homocysteine was linked to decrease health risks. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. JAMA. 2004 Feb 4;291(5):565-75 

Cancer

Breast Cancer: Decreased Folate in Alcohol-Related: A 1999 JAMA study found breast cancer highest for drinkers who consumed low levels of folate. The risk decreased if they took a multivit, a major source of folate.

Breast Cancer: High Dose Folic Acid Linked to Possible Increase in Breast Cancer: In a study of 3187 pregnant women given either 0, 200, or 5000 micrograms/day of folic acid during pregnancy, 36 year follow-up found no difference in deaths due to cardiovascular disease but an increase in cancer deaths, especially breast cancer which was increased by 70% in the high dose group.  However, there were only 31 breast cancer deaths in all, suggesting that the findings may be chance findings. The differences did not quite reach statistical significance. A rat study found an increase in breast cancer in rats both deficient and on high dose folic acid vs. those on a healthy dose. Taking folate in pregnancy and risk of maternal breast cancer. Deborah Charles et al. Aberdeen Maternity Hospital, Scotland. BMJ  12/11/2004;329:1375-1376. Ed: The government recommended level for folate is 400 mcg/day.  A number of studies using somewhat higher doses provide benefit for depression and other conditions. My suggested treatment is 800-1000 mcg/day. Obviously, more research is need, especially for these very high dose treatments.  I can't imagine why anyone made the decision in 1966-7 to give pregnant women 5000 mcg of folate per day.  It seems awfully high, not only for the mother, but also for the child. A reasonable dose would be 1000 mcg or 1 mg/day, especially in a study of pregnant women.

Cervical Cancer: Dysplasia Helped: 47 women with class 1 or 2 dysplasia of the cervix (pre-cancerous changes) were treated for 3 months in a DB PC trial. Those on folate 10 mg/d had better biopsies afterward. Women on birth control pills had lower folate and those with dysplasia were even lower. All in study were on BCP. Butterworth, Am J Clin Nutr 1/82;35:73

Colon Cancer: Folate Decreases: 88,758 women who completed family history and detailed food frequency questionnaires. During 16 years of follow-up, colon cancer was diagnosed in 535. The inverse association of folic acid with colon cancer risk was greater in women with a family history of colon cancer. The risk for colon cancer with 400 microg folate was an RR of 0.81 and 0.48 if there was a positive family history. Fuchs, Harvard, Cancer Epidemiol Biomarkers Prev 2002 Mar;11(3):227-34

Colon Cancer: High Dose Folate Helps: Irish 11 people with recurrent pre-cancerous growths and abnormal cell activity in the colon. One group 2 mg/d folic acid x three months vs. placebo. The supplement produced a significant drop in abnormal cell activity. When the folic acid supplements were stopped completely, the abnormal cellular activity returned to its dangerous pre-study levels. Gut 7/02.

Colon Cancer: Folate Decreased a Little: 16 yr f/u of Cancer Prevention Study-II of 806,000 adults in US found a multivitamin with folate had a colon cancer risk RR 0.89. Cancer Causes Control 2001 Dec;12(10):927-34

DNA Chromosome Damage: B-12, Folate Didn't Help: B-12 & folate deficiencies are associated with increase chromosome damage and increased homocysteine. 64 men DB PC 4 mo 2mg folate. 23% were folate deficient, 5% B-12 deficient, 37% had increased homocysteine.  There was increased micronucleus index with deficiency but also with increased homocysteine without deficiencies. Supplement had no impact on decreasing the index. Fenech, Adelaide, Carcinogenesis ‘97’;18:1329 

DNA Damage Linked to Homocysteine and Decreased by B-12 and Folate: 63 healthy adults 18-32yo studied. Only one had a low B-12. Micronucleation was linked to low normal B-12 levels and high homocysteine. They were given 3 times the RDA for 3 months, then 10 times for 3 months. There was a decrease in micronucleation in the 50% initially higher in micronucleation and the decrease correlated with B-12 and homocysteine levels. DNA methlyation was not changed by supplements. Fenech, Adelaide, Carcinogenesis, 7/98;19:1163 

Leukemia in Childhood: Folate Prenatally Helps Avert: 83 kids with acute lymphoblastic leukemia compared to 166 controls. ALL most common child cancer and assoc parental exposure to toxins and infectious agents, genetic variations, etc. dozens of factors examined. Strong relationship with not taking folate supplements in pregnancy. Lancet 12/8/01. OR 0.37!. A very strong effect and only strong effect found in 67 factors investigated. Iran only weakly protective. Folate also associated with reduced colorectal adenoma and carcinoma.

Lung Cancer: B-12 and Folate Help Smokers: DB PC folate 10mg/d, B-12 500microg/d decreased atypia in sputum samples of 73 regular smokers with bronchial squamous metaplasia. Heimburger, U Alabama, JAMA ’88;259:1525.

Neuroblastoma in Kids Reduced by Folate Fortification: Folic acid food fortification in Canada in 1997 has resulted in a 60 per cent reduction in the incidence of neuroblastoma, the most deadly childhood cancer under age five which strikes 1 in 7000 and starts in utero. September 2003, Clinical Pharmacology & Therapeutics. Lymphoblastic leukemia and hepablastoma, two other embryonal cancers, rates not affected. 

Ovarian Cancer in Drinking Women May be Decreased by Folate: In a follow-up study of 60,000 Swedish women, women who drank two alcoholic drinks per week or more and were in the highest quarter in folate consumption (over 203 microg/day) had a 74% decreased risk of ovarian cancer compared to drinking women who had the lowest intake of folate.  There was no impact on non-drinkers.  Other research has already shown that dietary folate levels are inversely related to the risk of breast and colorectal cancer. Alicja Wolk, Karolinska Institute. J Natl Cancer Inst 2004;96:396-402.

Stroke

Folic Acid, B-12 Supplementation Prevents Strokes, Not B-6: In a study from Northwestern University, 43,732 men, aged 40 to 75 years, who were free of cardiovascular diseases and diabetes were followed for 14 years. There were 725 strokes, 455 ischemic, 125 hemorrhagic, and 145 unknown types. After adjustment for lifestyle and dietary factors, intake of folate was associated with a 30% lower risk of ischemic stroke. The multivariate relative risk of ischemic stroke was 0.71 (P=0.05) for men in the highest quintile of intake compared with the lowest quintile. Intake of vitamin B₁₂, but not B₆, was also inversely associated with risk of ischemic stroke. A major source of folate, B₆, and B₁₂ was vitamin supplements. Vitamin B₁₂ intake was also inversely associated with ischemic but not hemorrhagic stroke. Comparing men in the highest quintile of vitamin B₁₂ intake with those in the lowest, the multivariate RR was 0.73. Folate, Vitamin B₆, and B₁₂ Intakes in Relation to Risk of Stroke Among Men. Ka He, Anwar Merchant, et al. Stroke. 1/2004;35:169

Folate Helps: 9764 US men and women aged 25 to 74 years who participated in the National Health and Nutrition Examination Survey I Epidemiologic Follow-up. In 19 years of follow-up, 926 incident stroke events and 3758 incident CVD events were documented. The relative risk (RR) was 0.79 (95% confidence interval [CI], 0.63 to 0.99, P=0.03 for trend) for incident stroke events and 0.86 (P<0.001 for trend) for incident CVD events in the highest quartile of dietary folate intake (median, 405.0 microg/day) compared with those in the lowest quartile (median, 99.0 microg/day), after adjustment for established cardiovascular risk factors and dietary factors. Stroke 2002 May;33(5):1183-9

Dosage Studies

BP and Endothelium of Smokers Helped by Folate 5mg: 24 normal smokers DB PC 4 wk. Decreased BP 88 to 83. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. Decreased tHcy 30%. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. J Intern Med 2002 Dec;252(6):497-503

Coronary Artery Disease Endothelium Helped by Folate 5 mg: DB PC 33 pt 6 week study. Author says 400microg achieves maximum tHcy effect and that higher dose has added benefits. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ, Goodfellow J. Circulation 2002 Jan 1;105(1):22-6

Folate 2-5mg & Similar Amount B-12 Recommended: Alzheimers up 300%, Stroke 500%, Vascular Dementia 500% in upper quartile of normal range of homocysteine in case controlled study of 280 patients. McIlroy, U Belfast, J Amer Heart Assoc 10/02. However, two new meta-analyses confirm that a raised level of blood homocysteine is a risk factor for ischemic heart disease but find that the risk is lower than previously thought. Say routine screening for homocysteine levels and folate methylenetetrahydrofolate reductase (MTHFR) polymorphism not warranted. (JAMA 2002;288:2015-22, 2023-31).

Homocysteine Decreased by Folate 2 mg Better than 0.2 mg: DB PC 723 adults with 1.8 micromol decrease vs. 1.2 vs. 0 for placebo. Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Neal B, MacMahon S, Ohkubo T, Tonkin A, Wilcken D; PACIFIC Study Group. Eur Heart J 2002 Oct;23(19):1509-15

Folate 928 mcg Necessary in Elderly: 0, 50, 100, 200, 400 and 600 microg folic acid on plasma homocysteine DB PC 368 aged 65-75 years 6 weeks. Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo (p=0.038 and p<0.001, respectively). Using multiple linear regression and each individual's total folic acid intake (diet plus supplement), a total daily folic acid intake of 926 microg per day would be required to ensure that 95% of the elderly population would be without cardiovascular risk from folate deficiency. The effect of folic acid supplementation on plasma homocysteine in an elderly population. Rydlewicz A, Simpson JA, Taylor RJ, Bond CM, Golden MH. QJM 2002 Jan;95(1):27-35

Folate 1 mg/day = Folate 6 mg = Folate 21 mg for Homocysteine: DB PC 81 hemodialysis patients all rx B-12 1mg/d. Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia. Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, Scott-Douglas N. Kidney Int 2001 Mar;59(3):1103-9

Hemodialysis: Folate 15mg Better than Folate 30mg or 60mg: Hemodialysis patients (144) with high Homocysteinemia. All equally effective in decreasing in DB PC 4 weeks, but high rebound effect at higher dosages. Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study. Sunder-Plassmann G, Fodinger M, Buchmayer H, Papagiannopoulos M, Wojcik J, Kletzmayr J, Enzenberger B, Janata O, Winkelmayer WC, Paul G, Auinger M, Barnas U, Horl WH. J Am Soc Nephrol 2000 Jun;11(6):1106-16; Vienna

Folate .8mg Recommended for All Adults: Folic acid could reduce the risk of ischemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24%. The folic acid could be taken as tablets by high risk patients, and possibly supplied to the general public through food fortification or a combination of both. Result of meta-analysis of MTHFR gene polymorphism studies (lower folate metabolism) and prospective studies. BMJ 11/23/02

Folate .4mg>.2mg>.1mg for tHcy: 90 pre-menopausal women 10 weeks DB PC. Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age. Daly S, Mills JL, Molloy AM, Conley M, McPartlin J, Lee YJ, Young PB, Kirke PN, Weir DG, Scott JM. QJM 2002 Nov;95(11):733-40

Other Studies

SAMe: Folate Increases SAMe 43%: 3-month supplementation of patients having colon polyps with folic acid (5 mg/day) led to a 35% decrease in abnormally high ornithine decarboxylase activity in polyps that was accompanied by a 43% increase of S-adenosylmethionine content in polyps. Ann N Y Acad Sci 2001 Dec;952:175-6 The effect of high doses of folic acid on the overexpression of ornithine decarboxylase and S-adenosylmethionine content in human colon adenomatous polyps. Bukin YUV, Draudin-Krylenko VA, Levchuk AA, Poddubniy BK, Mazurov ST.

Betaine: Increased by Folic Acid: Remethylation of homocysteine to methionine can occur through either the folate-dependent methionine synthase pathway or the betaine-dependent betaine-homocysteine methyltransferase pathway. In a DB PC study of 6 different daily doses of folic acid (50-800 mug/d) or placebo in 308 Dutch adults ages 50-75, homocysteine (tHcy) levels were inversely related to the betaine concentration (P < 0.01), and the association was independent of age, sex, and serum concentrations of folate, creatinine, and cobalamin. Folic acid supplementation increased betaine concentration in a dose-dependent manner (P= 0.018); the maximum increase (15%) was obtained at daily doses of 400-800 mug/d. Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations. Melse-Boonstra A, Holm PI, et al. Wageningen University, Netherlands. Am J Clin Nutr. 2005 Jun;81(6):1378-82.

Marksmen: B-1, B-6, B-12 Used: Two studies, one open controlled and one DB(?). Accuracy improved on meds. Therefore, improved basal ganglia fine motor control of slow movement. Bonke, Germany, Int J Vitam Nutr Res Suppl ’89;30:198. Ed: This report is too sketchy to tell if it proved anything at all.

Yeast Extract Benefit Due to Folic Acid: In the British Medical Journal for Jan. 24, 2004, it noted that in 1931 that Lucy Wills described how yeast extract could be effective in preventing tropical macrocytic anaemia of late pregnancy. Folate was shown to be the crucial factor. BMJ  2004;328

Thymidylate Synthase Polymorphism Increases RBC Folate and Decreases Homocysteine: The thymidylate synthase (TYMS) 3'UTR ins/del polymorphism among non-smokers only was significantly associated with much higher red blood cell folate (RBC folate; P=0.002) and considerably lower homocysteine (P=0.03) concentrations. Researchers also found a possible additive effect for the impact of the TYMS 3'UTR del/del and MTHFR 677CC genotypes on RBC folate concentration. The TYMS 3'UTR del/del genotype confers protection against diseases caused by low folate/high homocysteine levels. A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations. Kealey C, Brown KS, et al. University of Pennsylvania. Hum Genet. 2005 Jan 29

Folate Protects DNA: Folate is essential for the synthesis, repair and methylation of DNA. Folate depletion causes nuclear genetic and epigenetic aberrations in cell culture, rodents and humans. This rat study found that folate depletion also damages mitochondrial DNA and induce large-scale deletions due to DNA breakage.  Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Crott JW, et al. Tufts University. Mutat Res. 2005 Feb 15;570(1):63-70

Heavy Women Have Lower Folate Levels: Higher pre-pregnancy body mass index (BMI) is associated with increased risk of neural tube defects (NTDs) and possibly other negative birth outcomes in the offspring. Examining the association of BMI with folate level in childbearing age women before and after the 1998 U.S. folate fortification program of cereal products, using data from two cross-sectional surveys of the U.S. population (NHANES III; 1988-1994 and NHANES 1999-2000), after controlling for intake of folate in food and nutritional supplements, increased BMI in childbearing age women was associated with a lower serum folate level in both surveys (p < 0.001). Women with a BMI of 30+ (obese) need to take an additional 350 microg/day of folate to achieve the same serum folate level as women in the BMI below 20 (thin) category. Body mass index and serum folate in childbearing age women. Mojtabai R. Beth Israel Medical Center, New York, NY. Eur J Epidemiol. 2004;19(11):1029-36

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com