Folacin

Folate/Drug Interactions:

  • AlcoholAlcohol: According to secondary sources, excessive use of alcohol may increase the requirement for folic acid.
  • Alzheimer's agentsAlzheimer's agents: Folic acid improved the efficacy of cholinesterase inhibitors in Alzheimer disease (328). Preliminary evidence indicates that low folate concentrations might be related to Alzheimer disease (329). In animal research, folic acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer disease transgenic model (330).
  • Aminosalicylic acidAminosalicylic acid: According to secondary sources, aminosalicylic acid may reduce dietary folate absorption, worsening the folate deficiency often seen with active tuberculosis, or preventing its reversal during treatment. Megaloblastic anemia occurs rarely and usually when there are other contributing factors, such as concurrent vitamin B12 malabsorption. Patients being treated for tuberculosis may be advised to take folic acid supplements if their dietary folate intake is low.
  • AntacidsAntacids: According to secondary sources, chronic use of large doses of antacids may reduce folic acid absorption, but this is likely only significant if dietary folate intake is very low. According to secondary sources, folic acid absorption from the small intestine is optimal at pH 5.5 to 6.0.
  • AntibioticsAntibiotics: According to secondary sources, antibiotic therapy may disrupt the normal gastrointestinal (GI) flora, interfering with the absorption of folic acid.
  • AnticonvulsantsAnticonvulsants: Folic acid reduced the rate of congenital abnormalities in children exposed to antiepileptic drugs in utero (331). In humans, oxcarbazepine did not decreased folic acid levels (332). However, very high doses may cause significant central nervous system (CNS) side effects. Supplemental folic acid might increase seizures in people with seizure disorders, particularly in very high doses.
  • AntidepressantsAntidepressants: Folic acid deficiency has been found in people with depression and has been linked to poor response to antidepressant treatment (333; 334). Higher blood levels of homocysteine are associated with increased depression in later life (335); however, a combination of folic acid, vitamin B12, and vitamin B6 had a lack of an effect on symptoms of depression in older men (336). Folate increased the antidepressive effects of antidepressants (132; 133).
  • AntidiabeticsAntidiabetics: In individuals with high blood sugar, folic acid in combination with enalapril resulted in a greater reduction in blood glucose levels compared to enalapril alone (116). According to secondary sources, metformin use might reduce folate levels.
  • AntihypertensivesAntihypertensives: Some studies suggest that folic acid supplementation might decrease blood pressure in humans (108; 109; 110; 111).
  • AntimalarialsAntimalarials: In humans, combined iron/folic acid supplements and malaria prophylaxis reduce neonatal mortality over iron/folate alone (337).
  • AntineoplasticsAntineoplastics: Preliminary evidence suggests that increased dietary folate intake or folate status is associated with decreased risk of colorectal or colon cancer (167; 168; 169; 176) and possibly cervical (170), pancreatic (171; 172), esophageal (171), and gastrointestinal cancer, but not breast cancer (173; 174; 175). The role of supplementation of folic acid in cancer prevention is unclear (338). Fluorouracil and leucovorin (folinic acid) are commonly used together in cancer therapy, sometimes in combination with other agents (177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 339; 340; 341; 342; 343; 344; 345; 346; 347). Leucovorin improved the response rate and survival over fluorouracil alone (216; 217). Folic acid is used along with oral uracil-tegafur (215). Preliminary evidence is unclear with respect to the use of folate in the reduction of toxicity associated with the cancer drug lometrexol (218; 219). However, folate has been reported to increase cancer incidence (9; 10; 11; 12; 13; 107; 14; 127) and may affect the action of some antineoplastic agents, including foilc acid antagonists (15).
  • AspirinAspirin: In humans, folic acid was reported to reverse the affect aspirin had on C-reactive protein (CRP) levels (112). According to secondary sources, aspirin may decrease serum folate levels, especially with chronic large doses. It has been suggested that folate is just being redistributed in the body rather than an actual folate deficiency.
  • Cardiovascular agentsCardiovascular agents: Homocysteine is considered a significant risk factor for cardiovascular disease and may be modified by B vitamins, including folate (348; 349; 350; 351; 352; 353; 354; 355; 356; 357). The effect of B vitamins on clinical outcomes, such as cardiovascular disease has also been investigated, and although homocysteine lowering is found with folate and other B vitamin supplementation, the evidence for cardiovascular disease outcomes is not as clear (358; 351; 359; 360; 361). Wald et al. determined thetheoretical cardiovascular efficacy and adverse effects of a polypill containing a statin, a blood pressure lowering drug, folic acid, and aspirin (362). Meta-analyses have found that folic acid supplementation reduced the progression of carotid intima-media thickness and stroke risk (123; 122; 153).
  • CholestyramineCholestyramine: According to secondary sources, cholestyramine may reduce folic acid absorption. It may lower serum and red blood cell folate levels in children taking large doses for several months.
  • ColestipolColestipol: According to secondary sources, colestipol (Colestid?) may interfere with absorption of folic acid, and reduced serum folate levels may occur.
  • Conjugated estrogensConjugated estrogens: According to secondary sources, reduced serum and red blood cell folate levels may occur in some women taking conjugated estrogens (Premarin?), but this is unlikely in women with adequate dietary folate intake.
  • CycloserineCycloserine: According to secondary sources, cycloserine may reduce serum folate levels, and rare cases of megaloblastic anemia have occurred.
  • DiureticsDiuretics: According to secondary sources, diuretics may increase excretion of folic acid. Reduced red blood cell folate levels, possibly contributing to increased homocysteine levels, were found in one group of people taking diuretics for six months or longer.
  • Folic acid antagonistsFolic acid antagonists: Folic acid antagonists include capecitabine, trimethoprim, triamterene, carbamazepine, chloramphenicol, phenytoin, phenobarbital, primidone, pyrimethamine, and fosphenytoin. These agents may reduce serum folate levels, but megaloblastic anemia has not been reported. Concerns due to low folate levels may occur in pregnant women.
  • Histamine2-receptor antagonist (H2 blocker)Histamine2-receptor antagonist (H2 blocker): According to secondary sources, chronic use of large doses of antacids may reduce folic acid absorption, but this is likely only significant if dietary folate intake is very low. According to secondary sources, folic acid absorption from the small intestine is optimal at pH 5.5 to 6.0. The increased pH associated with the use of H2 blockers [such as cimetidine (Tagamet?), famotidine (Pepcid?), nizatidine (Axid?), and ranitidine (Zantac?)] may therefore reduce folic acid absorption.
  • Homocysteine-lowering agentsHomocysteine-lowering agents: Homocysteine is considered a significant risk factor for cardiovascular disease and may be modified by B vitamins, including folate (348; 349; 350; 351; 352; 353; 354; 355; 356; 357). The effect of B vitamins on clinical outcomes, such as cardiovascular disease has also been investigated, and although homocysteine lowering is found with folate and other B vitamin supplementation, the evidence for cardiovascular disease outcomes is not as clear (358; 351; 359; 360; 361). In human research, homocysteine has also been lowered in diabetic patients supplemented with folic acid (134).
  • IronIron: An iron/folate supplement assisted maternal growth in pregnancy and reduced the risk of abdominal delivery (363). Iron and folate together are commonly studied for efficacy, including iron deficiency (364; 365; 366; 367; 311; 322; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377). The majority of these studies are investigating the effect of multiple micronutrients over iron/folate supplements or on iron levels in the blood. Folic acid fortification resulted in increased hemoglobin and hematocrit values and decreased prevalence of anemia, but the mechanism is unknown (378). Low folic acid status was associated with low iron stores and anemia in urban adolescent girls and women of childbearing age in Sri Lanka (379). In Indonesia, iron and folic acid supplements reduced early neonatal deaths (380). In vitro, folic acid increased cell turnover and lowered differentiation and iron content in human HT29 colon cancer cells (381).
  • MethotrexateMethotrexate: Folic acid has been suggested for patients that use methotrexate (2; 3; 4; 5; 6; 7), although the antipsoriatic effect of methotrexate may decrease if combined with folic acid (8). In humans, folic acid reduced side effects have been associated with methotrexate (382; 383; 384), and efficacy (385), and is commonly tested with methotrexate (386; 387). In humans, thymidine and leucovorin were used to reduce methotrexate toxicity (388). Folinic acid supplementation normalized urinary urinary 5-aminoimidazole-4-carboxamide levels during methotrexate therapy (389). Patients being treated with methotrexate for cancer should avoid folic acid supplements, unless suggested by their oncologist. Folic acid could interfere with the anticancer effects of methotrexate. In rheumatoid arthritis patients, catabolism of methotrexate to 7-hydroxymethotrexate is reduced by folic acid supplementation (390).
  • Methylprednisolone sodium succinate (Solu-Medrol?)Methylprednisolone sodium succinate (Solu-Medrol?): According to secondary sources, reduced serum folate levels have been noted in people with multiple sclerosis (MS) after treatment with methylprednisolone sodium succinate (Solu-Medrol?).
  • Neurologic agentsNeurologic agents: In patients with low or low-normal folate levels, levodopa administration is associated with a greater increase in homocysteine, and concomitant entacapone administration is associated with a greater reduction in homocysteine (391).
  • NitroglycerinNitroglycerin: In humans, folic acid might prevent nitroglycerin-induced nitrate tolerance and cross tolerance to endothelial nitric oxide (392).
  • Nonsteroidal anti-inflammatories (NSAIDs)Nonsteroidal anti-inflammatories (NSAIDs): According to secondary sources, folate-dependent enzymes have been inhibited in laboratory experiments by certain NSAIDs [ibuprofen (Advil?, Motrin?, Nuprin?), naproxen (Anaprox?, Aleve?), indomethacin (Indocin?), and sulindac (Clinoril?)].
  • Omega-3 fatty acidsOmega-3 fatty acids: According to a review, there is some preliminary evidence for a synergistic effect of B-vitamins and omega-3 fatty acids on cardiovascular diseases (393). In vitro, docosahexaenoic acid and folic acid supplementation had effects on placental apoptosis and proliferation (394).
  • Oral contraceptivesOral contraceptives: According to information from LACT-MED, severe clinical and hematological manifestations of folate deficiency occurred in a previously healthy, fully breastfed, 10 month-old infant whose mother took oral contraceptives (327). Early studies of oral contraceptives demonstrated a negative effect on folate levels; however, data are mixed (395). Further studies are needed to determine the true affect.
  • Pancreatic extractsPancreatic extracts: According to secondary sources, reduced folate levels may occur in some people taking pancreatic extracts (such as Pancrease?, Cotazym?, Viokase?, Creon?, Ultrase?) possibly due to reduced absorption. Folate levels should be checked in patients taking pancreatic enzymes for prolonged periods.
  • Pemetrexed disodiumPemetrexed disodium: Pemetrexed is an anti-folate agent (396). In humans, folic acid is suggested with pemetrexed disodium (397; 398).
  • PentamidinePentamidine: According to secondary sources, pentamidine may decrease serum folate levels and megaloblastic bone marrow changes may occur rarely with prolonged intravenous pentamidine.
  • PhenytoinPhenytoin: Early evidence shows that applying folic acid topically as well as oral folic acid may inhibit gingival hyperplasia secondary to phenytoin therapy (399; 400). In epileptic patients on phenytoin, folic acid supplementation increased serum folate and phenytoin steady state (401).
  • Proton pump inhibitorsProton pump inhibitors: According to secondary sources, chronic use of large doses of antacids may reduce folic acid absorption, but this is likely only significant if dietary folate intake is very low. According to secondary sources, folic acid absorption from the small intestine is optimal at pH 5.5 to 6.0. Proton pump inhibitors may affect folic acid.
  • SulfasalazineSulfasalazine: According to secondary sources, sulfasalazine may inhibit absorption and metabolism of folic acid. Patients on chronic sulfasalazine therapy may be advised to increase their dietary folate intake, and to take a supplement if they have any other condition, which could also contribute to deficiency.
  • SulfonamidesSulfonamides: According to a review, evidence suggests folic acid might ameliorate the potential risk of sulfonamides during pregnancy (402).
  • TobaccoTobacco: In humans, smoking resulted in decreased folic acid levels (403; 404; 405; 266).
  • TrimethoprimTrimethoprim: According to secondary sources, there is a general belief that folic/folinic acid supplements have a lack of an effect on the therapeutic effects of trimethoprim. However, this view has been challenged, and failure of trimethoprim therapy has occurred rarely when folinic acid is given concurrently.
  • Vitamin AVitamin A: In Chinese pregnant women, taking iron plus folate, retinol, and riboflavin supplementation decreased the prevalence of anemia (406). Vitamin A enhanced response to supplemental iron and folic acid in anemic teenagers in Bangladesh (407).
  • Vitamin B12Vitamin B12: According to a review, folate supplementation might mask vitamin B12 deficiency (113; 408). In older persons with low vitamin B12 status, high serum folate was associated with anemia and cognitive impairment (409). Some authors suggest adding 1mg cobalamin to folate supplements (141). In American seniors with a serum vitamin B12 concentration <148pmol/L, the presence of detectable circulating unmetabolized folic acid was related to lower cognitive test scores and lower mean cell volume (410). Vitamin B12 and folate may have increased effects on homocysteine levels over folate alone (411; 412; 413). A combination of B12 and folate had a lack of improvement on cognitive function in older adults (414) or vascular function (415). Post folic acid fortification, the proportion of individuals with low serum vitamin B12 concentrations without macrocytosis is higher in some (416) but not all (417) studies. Vitamin B12 may increase the preventive effects of folate on neural tube defects (NTDs) (418). A combination of B12 and folate in myocardial infarction survivors was studied (419). Further details are lacking.
  • WarfarinWarfarin: In adults, folic acid increased the formation clearance of (S)-7-hydroxywarfarin but had a lack of an effect on dosage requirements (420).
  • ZincZinc: Antenatal supplementation with folic acid, iron, and zinc improved linear growth and reduced peripheral adiposity in school-age children in rural Nepal (421). Iron and folic acid supplements were related to serum zinc levels among a cohort of pregnant women (422). Folic acid increased albumin-bound zinc in vitro (423). In young women, folic acid enrichment of bread had a lack of an effect on zinc absorption (424). According to secondary sources, although supplemental doses of folic acid are unlikely to have an adverse effect on zinc balance in people with adequate dietary zinc intake, the data on the effects of supplemental folic acid on dietary zinc absorption are conflicting.

    • Folate/Herb/Supplement Interactions:

  • Aged garlic extract (AGE)Aged garlic extract (AGE): In human research, AGE supplemented with B vitamins, folic acid, and L-arginine retards the progression of subclinical atherosclerosis (425).
  • AlcoholAlcohol: According to secondary sources, excessive use of alcohol may increase the requirement for folic acid.
  • Alzheimer's agentsAlzheimer's agents: Folic acid improved the efficacy of cholinesterase inhibitors in Alzheimer disease (328). Preliminary evidence indicates that low folate concentrations might be related to Alzheimer disease (329). In animal research, folic acid potentiates the effect of Alzheimer agents on spatial learning and neuronal protection in an Alzheimer disease transgenic model (330).
  • AntacidsAntacids: According to secondary sources, chronic use of large doses of antacids may reduce folic acid absorption, but this is likely only significant if dietary folate intake is very low. According to secondary sources, folic acid absorption from the small intestine is optimal at pH 5.5 to 6.0.
  • AntibacterialsAntibacterials: According to secondary sources, antibacterial therapy may disrupt the normal GI flora, interfering with the absorption of folic acid.
  • AnticonvulsantsAnticonvulsants: Folic acid reduced the rate of congenital abnormalities in children exposed to anticonvulsants in utero (331). In humans, anticonvulsants had a lack of an effect on folic acid levels (332). However, very high doses may cause significant CNS side effects. Supplemental folic acid might increase seizures in people with seizure disorders, particularly in very high doses.
  • AntidepressantsAntidepressants: Folic acid deficiency has been found among people with depression and has been linked to poor response to antidepressant treatment (333; 334). Higher blood levels of homocysteine are associated with increased depression in later life (335); however, a combination of folic acid, vitamin B12, and vitamin B6 lacked effects on symptoms of depression in older men (336). Folate increased the antidepressive effects of antidepressants (132; 133).
  • Anti-inflammatoriesAnti-inflammatories: According to secondary sources, folate-dependent enzymes have been inhibited in laboratory experiments by certain nonsteroidal anti-inflammatory agents.
  • AntimalarialsAntimalarials: In humans, combined iron/folic acid supplements and malaria prophylaxis reduce neonatal mortality over iron/folate alone (337).
  • AntineoplasticsAntineoplastics: Preliminary evidence suggests that increased dietary folate intake or folate status is associated with decreased risk of colorectal or colon cancer (167; 168; 169; 176) and possibly cervical (170), pancreatic (171; 172), esophageal (171), and gastrointestinal cancer, but not breast cancer (173; 174; 175). The role of supplementation of folic acid in cancer prevention is unclear (338). Fluorouracil and leucovorin (folinic acid) are commonly used together in cancer therapy, sometimes in combination with other agents (177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 339; 340; 341; 342; 343; 344; 345; 346). Leucovorin improved the response rate and survival over fluorouracil alone (216; 217). Folic acid is used along with oral uracil-tegafur (215). Preliminary evidence is unclear with respect to the use of folate in the reduction of toxicity associated with the cancer drug lometrexol (218; 219). However, folate has been reported to increase cancer incidence (9; 10; 11; 12; 13; 107; 14; 127) and may affect the action of some antineoplastic agents, including foilc acid antagonists(15).
  • AntioxidantsAntioxidants: In hemodialysis patients, folic acid increased antioxidant status (426). Antioxidant vitamins did not increase the effect of folic acid on folic acid or homocysteine levels or flow-mediated dilation (427).
  • B vitaminsB vitamins: Vitamins B12, B6, and folic acid are commonly studied together for homocysteine lowering or for other cardiovascular endpoints (428). A combination of B vitamins lacked significant effect on cancer risk (429) or cardiovascular risk (430) or type 2 diabetes risk (431) or cognitive function (432). This combination might reduce the risk of age-related macular degeneration (433). In Chinese pregnant women, taking iron plus folate, retinol, and riboflavin supplementation decreased the prevalence of anemia (406). The combination reduced adverse effects after coronary intervention (434). A meta-analysis found increased cancer risk in subjects with supplementation of 0.5-2.5mg of folic acid (either taken alone or in combination with aspirin, vitamin B6, or vitamin B12) daily for 3-8 years (107).
  • Cardiovascular agentsCardiovascular agents: Homocysteine is considered a significant risk factor for cardiovascular disease and may be modified by B vitamins, including folate (348; 349; 350; 351; 352; 353; 354; 355; 356; 357). The effect of B vitamins on clinical outcomes, such as cardiovascular disease has also been investigated, and although homocysteine lowering is found with folate and other B vitamin supplementation, the evidence for cardiovascular disease outcomes is unclear (358; 351; 359; 360; 361; 435). Wald et al. determined the theoretical cardiovascular efficacy and adverse effects of a polypill containing an antilipemic, folic acid, and aspirin (362). Meta-analyses have found that folic acid supplementation reduced the progression of carotid intima-media thickness and stroke risk (123; 122; 153).
  • DiureticsDiuretics: According to secondary sources, diuretics may increase the excretion of folic acid. Reduced red blood cell folate levels, possibly contributing to increased homocysteine levels, were found in one group of people taking diuretics for six months or longer.
  • Green teaGreen tea: In human research, researchers noted a potential interaction between tea and folic acid, with even low concentrations (0.3g extract/250mL) of green and black tea extracts yielding decreased bioavailabilities of folic acid (436). In vitro, folic acid uptake is inhibited by catechins and tea extracts in Caco-2 cells (437).
  • Homocysteine-lowering agentsHomocysteine-lowering agents: Homocysteine is considered a significant risk factor for cardiovascular disease and may be modified by B vitamins, including folate (348; 349; 350; 351; 352; 353; 354; 355; 356; 357; 438; 439; 440; 441). The effect of B vitamins on clinical outcomes, such as cardiovascular disease has also been investigated, and although homocysteine lowering is found with folate and other B vitamin supplementation, the evidence for cardiovascular disease outcomes is unclear (358; 351; 359; 360; 361). In human research, homocysteine has also been lowered in diabetic patients supplemented with folic acid (134).
  • HypoglycemicsHypoglycemics: In individuals with high blood sugar, folic acid in combination with hypoglycemics resulted in a greater reduction in blood glucose levels (116).
  • HypotensivesHypotensives: Some studies suggest that folic acid supplementation might decrease blood pressure in humans (108; 109; 110; 111).
  • IronIron An iron/folate supplement assisted maternal growth in pregnancy and reduced the risk of abdominal delivery (363). Iron and folate together are commonly studied for efficacy, including iron deficiency (364; 365; 366; 367; 311; 322; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377). The majority of these studies are investigating the effect of multiple micronutrients over iron/folate supplements or on iron levels in the blood. Folic acid fortification resulted in increased hemoglobin and hematocrit values and decreased prevalence of anemia, but the mechanism is unknown (378). Low folic acid status was associated with low iron stores and anemia in urban adolescent girls and women of childbearing age in Sri Lanka (379). In Indonesia, iron and folic acid supplements reduced early neonatal deaths (380). In vitro, folic acid increased cell turnover and lowered differentiation and iron content in human HT29 colon cancer cells (381).
  • Leaf concentrateLeaf concentrate: In India, leaf concentrate was found to be an effective, and more palatable, alternative to iron and folic acid supplements for treating anemia in adolescent girls (442).
  • Multiple micronutrientsMultiple micronutrients: Supplementation with multiple micronutrients might be more effective during pregnancy in developing-country settings (443; 444; 445) but are not always more effective (446; 447; 323; 448). Hemoglobin status was increased in multimicronutrient users over iron and folate alone in adolescent girls (449). Multiple micronutrients had limited impact over iron and folate alone in Bangladeshi infants (450).
  • Neurologic agentsNeurologic agents: In patients with low or low-normal folate levels, levodopa administration is associated with a greater increase in homocysteine, and concomitant entacapone administration is associated with a greater reduction in homocysteine (391).
  • Omega-3 fatty acidsOmega-3 fatty acids: According to a review, there is some preliminary evidence for a synergistic effect of B-vitamins and omega-3 fatty acids on cardiovascular diseases (393). In vitro, docosahexaenoic acid and folic acid supplementation had effects on placental apoptosis and proliferation (394).
  • Oral contraceptivesOral contraceptives: According to information from LactMed, severe clinical and hematological manifestations of folate deficiency occurred in a previously healthy, fully breastfed, 10 month-old infant whose mother took oral contraceptives (327). According to secondary sources, oral contraceptives may impair folate metabolism producing depletion, but the effect is unlikely to cause anemia or megaloblastic changes.
  • Pancreatic extractsPancreatic extracts: According to secondary sources, reduced folate levels may occur in some people taking pancreatic extracts (such as Pancrease?, Cotazym?, Viokase?, Creon?, Ultrase?) possibly due to reduced absorption. Folate levels should be checked in patients taking pancreatic enzymes for prolonged periods.
  • PhytoestrogensPhytoestrogens: According to secondary sources, reduced serum and red blood cell folate levels may occur in some women taking estrogens, but this is unlikely in women with adequate dietary folate intake.
  • ProbioticsProbiotics: In humans, ingestion of probiotics increased folic acid in feces (451).
  • SalicylatesSalicylates: In humans, folic acid was reported to reverse the affect aspirin had on CRP levels (112). According to secondary sources, aspirin may decrease serum folate levels, especially with chronic large doses. It is suggested that folate is just being redistributed in the body rather than an actual folate deficiency.
  • Vitamin AVitamin A: In Chinese pregnant women, taking iron plus folate, retinol, and riboflavin supplementation decreased the prevalence of anemia (406). Vitamin A enhanced response to supplemental iron and folic acid in anemic teenagers in Bangladesh (407).
  • Vitamin B12Vitamin B12: According to a review, folate supplementation might mask vitamin B12 deficiency (113; 408). In older persons with low vitamin B12 status, high serum folate was associated with anemia and cognitive impairment (409). Some authors suggest adding 1mg cobalamin to folate supplements (141). In American seniors with a serum vitamin B12 concentration <148pmol/L, the presence compared of detectable circulating unmetabolized folic acid was related to lower cognitive test scores and lower mean cell volume (410). Vitamin B12 and folate may have increased effects on homocysteine levels over folate alone (411; 412; 413). A combination of B12 and folate had a lack of improvement on cognitive function in older adults (414) or vascular function (415). Post folic acid fortification, the proportion of individuals with low serum vitamin B12 concentrations without macrocytosis is higher in some (416) but not all (417) studies. Vitamin B12 may increase the preventive effects of folate on NTDs (418). A combination of B12 and folate in myocardial infarction survivors was studied (419). Further details are lacking.
  • ZincZinc: Antenatal supplementation with folic acid, iron, and zinc improved linear growth and reduced peripheral adiposity in school-age children in rural Nepal (421). Iron and folic acid supplements were related to serum zinc levels among a cohort of pregnant women (422). Folic acid increased albumin-bound zinc in vitro (423). In young women, folic acid enrichment of bread had a lack of an effect on zinc absorption (424). According to secondary sources, although supplemental doses of folic acid are unlikely to have an adverse effect on zinc balance in people with adequate dietary zinc intake, the data on the effects of supplemental folic acid on dietary zinc absorption are conflicting.

    • Folate/Food Interactions:

  • B vitaminsB vitamins: Vitamins B12, B6, and folic acid are commonly studied together for homocysteine lowering or for other cardiovascular endpoints (428). A combination of B vitamins had significant lack of an effect on cancer risk (429), cardiovascular risk (430), type 2 diabetes risk (431), or cognitive function (432). This combination might reduce the risk of age-related macular degeneration (433). In Chinese pregnant women, taking iron plus folate, retinol, and riboflavin supplementation decreased the prevalence of anemia (406). The combination reduced adverse effects after coronary intervention (434). A meta-analysis found increased cancer risk in subjects with supplementation of 0.5-2.5mg of folic acid (either taken alone or in combination with aspirin, vitamin B6, or vitamin B12) daily for 3-8 years (107).
  • FiberFiber: The lack in reduction of colorectal cancer by fiber in epidemiological research was suggested to be due to confounding by folate and other factors (452).
  • Folate-containing foods (general)Folate-containing foods (general): In humans, folate-containing foods (fruit, vegetables, liver, etc.) increased folate intake and status (310; 453).
  • Folate-fortified foods (general)Folate-fortified foods (general): In various studies, folate fortified foods (e.g., cereals, bread, flour) increased folic acid intake and status (454; 455; 456; 310; 457; 96; 458; 459; 460; 461; 462; 278; 463; 464; 465).
  • Green teaGreen tea: In human research, researchers noted a potential interaction between tea and folic acid, with even low concentrations (0.3g extract/250mL) of green and black tea extracts, yielding decreased bioavailabilities of folic acid (436). In vitro, folic acid uptake is inhibited catechins and tea extracts in Caco-2 cells (437).
  • IronIron: An iron/folate supplement assisted maternal growth in pregnancy and reduced the risk of abdominal delivery (363). Iron and folate together are commonly studied for efficacy, including iron deficiency (364; 365; 366; 367; 311; 322; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377). The majority of these studies are investigating the effect of multiple micronutrients over iron/folate supplements or on iron levels in the blood. Folic acid fortification resulted in increased hemoglobin and hematocrit values and decreased prevalence of anemia, but the mechanism is unknown (378). Low folic acid status was associated with low iron stores and anemia in urban adolescent girls and women of childbearing age in Sri Lanka (379). In Indonesia, iron and folic acid supplements reduced early neonatal deaths (380). In vitro, folic acid increased cell turnover and lowered differentiation and iron content in human HT29 colon cancer cells (381).
  • MilkMilk: Milk enriched with omega-3 fatty acids, polyunsaturated fatty acids, oleic acid, folic acid, vitamin E, and/or vitamin B6 decreased various risk factors for cardiovascular disease, including homocystein (466; 467). The effects of folic acid are unclear.
  • Mineral waterMineral water: In humans, mineral water administration may increase kidney elimination of folic acid in a concentration-dependent fashion (468).
  • ProbioticsProbiotics: In humans, ingestion of probiotics increased folic acid in feces (451).
  • Vitamin AVitamin A: In Chinese pregnant women, taking iron plus folate, retinol, and riboflavin supplementation decreased the prevalence of anemia (406). Vitamin A enhanced response to supplemental iron and folic acid in anemic teenagers in Bangladesh (407).
  • Vitamin B12Vitamin B12: According to a review, folate supplementation might mask vitamin B12 deficiency (113; 408). In older persons with low vitamin B12 status, high serum folate was associated with anemia and cognitive impairment (409). Some authors suggest adding 1mg cobalamin to folate supplements (141). In American seniors with a serum vitamin B12 concentration <148pmol/L, the presence compared of detectable circulating unmetabolized folic acid was related to lower cognitive test scores and lower mean cell volume (410). Vitamin B12 and folate may have increased effects on homocysteine levels over folate alone (411; 412; 413). A combination of B12 and folate had a lack of improvement on cognitive function in older adults (414) or vascular function (415). Post folic acid fortification, the proportion of individuals with low serum vitamin B12 concentrations without macrocytosis is higher in some (416) but not all (417) studies. Vitamin B12 may increase the preventive effects of folate on NTDs (418). A combination of B12 and folate in myocardial infarction survivors was studied (419). Further details are lacking.
  • ZincZinc: Antenatal supplementation with folic acid, iron, and zinc improved linear growth and reduced peripheral adiposity in school-age children in rural Nepal (421). Iron and folic acid supplements were related to serum zinc levels among a cohort of pregnant women (422). Folic acid increased albumin-bound zinc in vitro (423). In young women, folic acid enrichment of bread had a lack of an effect on zinc absorption (424). According to secondary sources, although supplemental doses of folic acid are unlikely to have an adverse effect on zinc balance in people with adequate dietary zinc intake, the data on the effects of supplemental folic acid on dietary zinc absorption are conflicting.

    • Folate/Lab Interactions:

  • AlbuminAlbumin: In hemodialysis patients, folic acid, in combination with vitamin B complex, increased albumin (439).
  • Antioxidant statusAntioxidant status: In hemodialysis patients, folic acid increased antioxidant status (426). In human research, low-dose folic acid reduced vascular superoxide production (469).
  • ArsenicArsenic: Folic acid supplementation increased arsenic metabolism as shown by increased urinary metabolites (470) and decreased blood arsenic (471).
  • Asymmetric dimethylarginineAsymmetric dimethylarginine: In human research, folic acid treatment reduced elevated plasma levels of asymmetric dimethylarginine (472).
  • BetaineBetaine: In human research, folic acid increased betaine concentrations (473).
  • Blood pressureBlood pressure: Some studies suggest that folic acid supplementation might decrease blood pressure in humans (108; 109; 110; 111), and folic acid use was associated with a decreased risk of gestational hypertension (474).
  • Blood sugarBlood sugar: In individuals with high blood sugar, folic acid in combination with enalapril resulted in a greater reduction in blood glucose levels compared to enalapril alone (116). According to secondary sources, metformin use might reduce folate levels.
  • Blood viscosityBlood viscosity: In humans, folic acid supplementation in healthy elderly subjects without folic acid deficiency has not been reported to alter blood viscosity(475).
  • Body weightBody weight: In human research, significantly increased weights and lengths of newborns occurred during the first six months of life when receiving 1mg of supplementation, and in erythroblastotic infants, weight was significantly higher in the folic acid group (111). A meta-anylsis of dietary folate plus folic acid intake on pregnancy health outcomes also found an increase in birthweight following maternal supplementation (151).
  • Brachial pulse pressureBrachial pulse pressure: In humans, folic acid reduced brachial pulse pressure (476).
  • Carotid-intima-medial thicknessCarotid-intima-medial thickness: In humans, folate has been reported to decrease carotid-intima-medial thickness (477).
  • C-reactive protein (CRP)C-reactive protein (CRP): In humans, folic acid, in combination with vitamin B complex, decreased CRP in patients with hemodialysis (439). In humans, folic acid was reported to reverse the affect aspirin had on CRP levels (112).
  • Flow-mediated dilationFlow-mediated dilation: In human research, folic acid increased flow-mediated dilation following acute myocardial infarction (478), in amenorrheic runners (479) and in children and adolescents with type I diabetes (480). In obese children, folic acid had a lack of an improvement on flow-mediated dilation (481). In human research, low-dose folic acid increased nitric oxide-mediated endothelium-dependent vasomotor responses (469).
  • FolateFolate: In lactating women and women of childbearing age, 5-MTHF and folic acid increased mean red blood cell folate (324; 482). Bread fortified with folic acid increased serum (45%) and red blood cell folate (22%) (455). Other studies have shown that folic acid supplements increased serum and red blood cell folate (483; 484; 485; 481; 486; 110; 487; 243; 312; 232; 488; 489; 326; 490; 491; 461; 492) in a dose-dependent manner (493; 494; 460; 26).
  • HomocysteineHomocysteine: Homocysteine is considered a significant risk factor for cardiovascular disease and may be modified by B vitamins, including folate or derivatives (348; 349; 350; 351; 352; 353; 354; 355; 356; 357; 438; 439; 440; 441; 495; 496; 497; 412; 493; 426; 498; 499; 487; 500; 26; 501; 502; 503; 504; 505; 506). In renal and hemodialysis patients, homocysteine levels were more resistant to folic acid supplementation (507; 508; 509; 131). In human research, homocysteine has also been lowered in diabetic patients supplemented with folic acid (134).
  • MethionineMethionine: Folic acid supplementation had a lack of an effect on plasma methionine concentrations in young nonpregnant women (510).
  • Methylmalonic acidMethylmalonic acid: B vitamin supplementation reduced methylmalonic acid in older adults (486).
  • Red blood cell indicesRed blood cell indices: In human research, pediatric patients experienced a significant reduction in hemoglobin concentrations and mean corpuscular volume following folic acid supplementation (111).
  • Serum alpha-fetoproteinSerum alpha-fetoprotein: Folic acid fortification was associated with a decreased risk of high maternal serum alpha-fetoprotein values (233).
  • Systemic arterial complianceSystemic arterial compliance: In humans, folic acid increased systemic arterial compliance (476).