Each capsule contains: Ubidcarenone (co enzyme Q10) 50 mg • Ginkgo biloba leaf extract (equivalent to dry) 500 mg • Thiamine Hydrochloride (vitamin B1) 20 mg • Riboflavin (B2) 20 mg • Nicotinamide 20 mg • Calcium Pantothenate 22.2 mg • Vitamin B6 (pyridoxine hydrochloride) 20 mg • Vitamin B12 (cyanocobalamin) 50 mcg • Folic Acid 50 mcg • Vitamin E (d alpha tocopherol 6.7 mg) 10 IU.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
This product has been discontinued by the manufacturer.
This product has been discontinued by the manufacturer. This product is now manufactured by Sanofi-aventis (Australia)
Below is general information about the effectiveness of the known ingredients contained in the product MICROgenics Co Enzyme Q10 Plus Ginkgo and B Vitamins. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product MICROgenics Co Enzyme Q10 Plus Ginkgo and B Vitamins. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally or parenterally and appropriately. Folic acid has been safely used in amounts below the tolerable upper intake level (UL). The UL for folic acid is based only on supplemental folic acid and is expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for folic acid in adults is 1000 mcg (6241). In cases of megaloblastic anemia resulting from folate deficiency or malabsorption disorders such as sprue, oral doses of 1-5 mg per day can also be used safely until hematologic recovery is documented, as long as vitamin B12 levels are routinely measured (6241,7725,8739).
POSSIBLY SAFE ...when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks (104913,104914) and a dose of 113 mcg daily for 24 weeks (104920). A specific L-5-MTHF product (Metafolin, Eprova) has been used with apparent safety at a dose of 1.3 mg daily for 12 weeks (104912).
POSSIBLY UNSAFE ...when used orally in large doses, long-term. Clinical research shows that taking folic acid daily in doses of 800 mcg to 1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo (12150,13482,16822,17041). Doses above 1 mg per day should also be avoided if possible to prevent precipitation or exacerbation of neuropathy related to vitamin B12 deficiency (6241,6242,6245). However, there is contradictory evidence suggesting that higher doses may not be harmful. There is some evidence that doses of 5 mg per day orally for up to 4 months can be used safely if vitamin B12 levels are routinely measured (7725). Also, other clinical research suggests that folic acid supplementation at doses up to 5 mg, usually in combination with vitamin B12, does not increase the risk of cancer when taken for 2-7 years (91312). Very high doses of 15 mg per day can cause significant central nervous system (CNS) and gastrointestinal side effects (505).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Folic acid has been safely used in children in amounts below the tolerable upper intake level (UL). The ULs for folic acid are based only on supplemental folic acid and are expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for children is: 1-3 years of age, 300 mcg; 4-8 years of age, 400 mcg; 9-13 years of age, 600 mcg; 14-18 years of age, 800 mcg (6241).
CHILDREN: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately.
One clinical study in infants aged 27 days and younger shows that consuming a formula containing L-5-MTHF (Metafolin, Merck & Cie) 10.4 mcg/100 mL daily has been used with apparent safety for up to 12 weeks (104918).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately.
Folic acid 300-400 mcg is commonly used during pregnancy for prevention of neural tube defects (8739). Miscarriage rates and negative impacts on fetal growth have not been shown to increase with peri-conception supplemental folic acid intakes of 4 mg per day (91320,91322). However, other research shows that taking more than 5 mg per day during pregnancy may reduce development of cognitive, emotional, and motor skills in infants (91318). Also, the tolerable upper intake level (UL) of folic acid for pregnant or lactating women is 800 mcg daily for those 14-18 years of age and 1000 mcg daily for those 19 years and older (6241).
PREGNANCY AND LACTATION: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term.
L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks during lactation. Compared to folic acid, this form seems to further increase the folate concentration of red blood cells, but not breast milk (104913,104914).
LIKELY SAFE ...when used orally and appropriately. Standardized ginkgo leaf extracts have been used safely in trials lasting for several weeks up to 6 years (1514,1515,3461,5717,5718,6211,6212,6213,6214,6215)(6216,6222,6223,6224,6225,6490,14383,14499,16634,16635)(16636,16637,17402,17716,17718,87794,87819,87826,87848,87864)(87888,87897,87901,87904,89701,89707,107359,107360). There have been some reports of arrhythmias associated with ginkgo leaf extract. However, it is not yet clear if ginkgo might cause arrhythmia (105253,105254). There is some concern about toxic and carcinogenic effects seen in animals exposed to a ginkgo leaf extract containing 31.2% flavonoids, 15.4% terpenoids, and 10.45 ppm ginkgolic acid, in doses of 100 to 2000 mg/kg five times per week for 2 years (18272). However, the clinical relevance of this data for humans, using typical doses, is unclear. The content of the extract used is not identical to that commonly used in supplement products, and the doses studied are much higher than those typically used by humans. A single dose of 50 mg/kg in rats is estimated to be equivalent to a single dose of about 240 mg in humans (18272).
POSSIBLY SAFE ...when used intravenously, short-term. A standardized ginkgo leaf extract called EGb 761 ONC has been safely administered intravenously for up to 14 days (9871,9872,107360,107452). A Chinese preparation containing ginkgo leaf extract and dipyridamole has been safely administered intravenously for up to 30 days (102881,102882). ...when applied topically, short-term. There was no dermal irritation during a 24-hour patch test using the leaf extract, and no sensitization with repeat applications (112946). When used topically in cosmetics, extracts of ginkgo leaves are reported to be safe, but there is insufficient data to determine the safety of nut and root extracts, and isolated biflavones and terpenoids (112946).
POSSIBLY UNSAFE ...when the roasted seed or crude ginkgo plant is used orally. Consuming more than 10 roasted seeds per day can cause difficulty breathing, weak pulse, seizures, loss of consciousness, and shock (8231,8232). Crude ginkgo plant parts can exceed concentrations of 5 ppm of the toxic ginkgolic acid constituents and can cause severe allergic reactions (5714).
LIKELY UNSAFE ...when the fresh ginkgo seed is used orally. Fresh seeds are toxic and potentially deadly (11296).
PREGNANCY: POSSIBLY UNSAFE
when used orally.
There is concern that ginkgo might have labor-inducing and hormonal effects. There is also concern that the antiplatelet effects of ginkgo could prolong bleeding time if taken around the time of labor and delivery (15052). Theoretically, ginkgo might adversely affect pregnancy outcome; avoid using during pregnancy.
LACTATION:
Insufficient reliable information available; avoid using.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term (87790,89708).
A specific ginkgo dried extract (Ginko T.D., Tolidaru Pharmaceuticals), has been safely used in doses of 80-120 mg daily for 6 weeks in children aged 6-14 years (17112,95669). Another specific combination product containing ginkgo leaf extract and American ginseng extract (AD-FX, CV Technologies, Canada) has also been safely used in children aged 3-17 years for up to 4 weeks (8235).
CHILDREN: LIKELY UNSAFE
when ginkgo seed is used orally.
The fresh seeds have caused seizures and death in children (8231,11296).
LIKELY SAFE ...when prescription products are used orally and appropriately (12033). ...when niacinamide supplements are taken orally in doses below the tolerable upper intake level (UL) set by the Institute of Medicine (IOM). The UL of niacinamide is 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243).
POSSIBLY SAFE ...when used orally in doses greater than 30 mg but less than 900 mg daily. The European Food Safety Authority has set the tolerable upper intake level (UL) of niacinamide at 900 mg daily (104937). However, oral niacinamide has been safely used in doses up to 1500 mg daily for 12 weeks in some clinical trials (25561,94188,98940,107709,110502) and up to 1000 mg daily for 12 months in other trials (93362,113559,113560). ...when used topically and appropriately for up to 16 weeks (5940,93360,110497,110498,110501,113681,113683,113684).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Niacinamide has been safely used in children for up to 7 years in doses below the tolerable upper intake level (UL) (4874,9957). The UL of niacinamide for children by age is: 1-3 years, 10 mg daily; 4-8 years, 15 mg daily; 9-13 years, 20 mg daily; 14-18 years, 30 mg daily (6243).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL) for niacinamide.
The UL of niacinamide during pregnancy and lactation is 30 mg daily for those 14-18 years of age and 35 mg daily for those 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacinamide or topical niacinamide; avoid using.
LIKELY SAFE ...when used orally and appropriately. The pantothenic acid derivative calcium pantothenate has a generally recognized as safe (GRAS) status for use in food products (111258). While a tolerable upper intake level (UL) has not been established, pantothenic has been used in doses of 10-20 grams daily with apparent safety (15,6243,111258) ...when applied topically and appropriately, short-term. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and its derivatives are safe for use in cosmetic products in concentrations up to 5.3% (111258). Gels or ointments containing a derivative of pantothenic acid, dexpanthenol, at concentrations of up to 5%, have been used safely for up to 30 days (67802,67806,67817).
POSSIBLY SAFE ...when applied intranasally and appropriately, short-term. A dexpanthenol nasal spray has been used with apparent safety up to four times daily for 4 weeks (67826). ...when applied in the eyes appropriately, short-term. Dexpanthenol 5% eyedrops have been used with apparent safety for up to 28 days (67783). ...when injected intramuscularly and appropriately, short-term. Intramuscular injections of dexpanthenol 500 mg daily for up to 5 days or 250 mg weekly for up to 6 weeks have been used with apparent safety (67822,111366).
CHILDREN: LIKELY SAFE
when used orally and appropriately (15,6243).
Calcium pantothenate is generally recognized as safe (GRAS) when used as a food additive and in infant formula (111258). However, a tolerable upper intake level (UL) has not been established (15,6243). ...when applied topically and appropriately (67795,105190,111262). Infant products containing pantothenic acid and its derivatives have been used safely in concentrations of up to 5% for infant shampoos and 2.5% for infant lotions and oils. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and derivatives are safe for use in topical infant products. (111258).
PREGNANCY: LIKELY SAFE
when used orally and appropriately.
The daily adequate intake (AI) during pregnancy is 6 mg (3094).
LACTATION: LIKELY SAFE
when used orally and appropriately.
The daily adequate intake (AI) during lactation is 7 mg (3094).
LIKELY SAFE ...when used orally and appropriately. Riboflavin 400 mg daily has been taken for up to 3 months, and 10 mg daily has been taken safely for up to 6 months (4912,91752,105480). A tolerable upper intake level (UL) has not been established (3094,91752,94089).
CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts.
A tolerable upper intake level (UL) has not been established (3094,94089). ...when used orally in higher doses for up to 1 year. Doses of 100-200 mg daily have been used safely for 4-12 months in children ages 9-13 years (71483,105484).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in dietary amounts.
A tolerable upper intake level (UL) has not been established (3094,94089).
LIKELY SAFE ...when used orally and appropriately. A tolerable upper intake level (UL) has not been established for thiamine, and doses up to 50 mg daily have been used without adverse effects (15,6243). ...when used intravenously or intramuscularly and appropriately. Injectable thiamine is an FDA-approved prescription product (15,105445).
CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts.
A tolerable upper intake level (UL) has not been established for healthy individuals (6243).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 1.
4 mg daily. A tolerable upper intake level (UL) has not been established for healthy individuals (3094,6243).
LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111334,111551).
PREGNANCY: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA).
The RDA for vitamin B12 during pregnancy is 2.6 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 during pregnancy.
LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA).
The RDA of vitamin B12 during lactation is 2.8 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 while breastfeeding.
LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily in the form of pyridoxine for adults (15,6243). ...when used parenterally and appropriately. Injectable vitamin B6 (pyridoxine) is an FDA-approved prescription product (15).
POSSIBLY SAFE ...when used orally and appropriately in doses of 101-200 mg daily (6243,8558).
POSSIBLY UNSAFE ...when used orally in doses at or above 500 mg daily. High doses, especially those exceeding 1000 mg daily or total doses of 1000 grams or more, pose the most risk. However, neuropathy can occur with lower daily or total doses (6243,8195). ...when used intramuscularly in high doses and frequency due to potential for rhabdomyolysis (90795).
CHILDREN: LIKELY SAFE
when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 30 mg daily for children aged 1-3 years, 40 mg daily for 4-8 years, 60 mg daily for 9-13 years, and 80 mg daily for 14-18 years (6243).
CHILDREN: POSSIBLY SAFE
when used orally and appropriately in amounts exceeding the recommended dietary allowance (5049,8579,107124,107125,107135).
CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses, long-term (6243).
PREGNANCY: LIKELY SAFE
when used orally and appropriately.
A special sustained-release product providing vitamin B6 (pyridoxine) 75 mg daily is FDA-approved for use in pregnancy. Vitamin B6 (pyridoxine) is also considered a first-line treatment for nausea and vomiting in pregnancy by the American College of Obstetrics and Gynecology (111601). However, it should not be used long-term or without medical supervision and close monitoring. The tolerable upper intake level (UL) refers to vitamin B6 in the form of pyridoxine and is 80 mg daily for those aged 14-18 years and 100 mg daily for 19 years and older (6243).
PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses.
There is some concern that high-dose maternal vitamin B6 (pyridoxine) can cause neonatal seizures (4609,6397,8197).
LACTATION: LIKELY SAFE
when used orally in doses not exceeding the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 80 mg daily for those aged 14-18 years and 100 mg daily for those 19 years and older.
The recommended dietary allowance (RDA) in lactating women is 2 mg daily (6243). There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.
LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.
POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388).
...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately.
The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.
LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL).
The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).
LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).
Below is general information about the interactions of the known ingredients contained in the product MICROgenics Co Enzyme Q10 Plus Ginkgo and B Vitamins. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, high doses of folic acid might increase the toxicity of 5-fluorouracil.
 Details
Increases in gastrointestinal side effects of 5-fluorouracil, such as stomatitis and diarrhea, have been described in two clinical studies when leucovorin, a form of folic acid, was administered with 5-fluorouracil (16845).
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Use of high-dose folic acid might contribute to capecitabine toxicity.
Details
Clinical research suggests that higher serum folate levels are associated with an increased risk for moderate or severe toxicity during capecitabine-based treatment for colorectal cancer (105402). Additionally, in one case report, taking folic acid 15 mg daily might have contributed to increased toxicity, including severe diarrhea, vomiting, edema, hand-foot syndrome, and eventually death, in a patient prescribed capecitabine (16837).
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Folic acid might reduce the efficacy of methotrexate as a cancer treatment when given concurrently.
Details
Methotrexate exerts its cytotoxic effects by preventing conversion of folic acid to the active form needed by cells. There is some evidence that folic acid supplements reduce the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia, and theoretically they could reduce its efficacy in the treatment of other cancers (9420). Advise cancer patients to consult their oncologist before using folic acid supplements. In patients treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis, folic acid supplements can reduce the incidence of side effects, without reducing efficacy (768,2162,4492,4493,4494,4546,9369).
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Folic acid might have antagonistic effects on phenobarbital and increase the risk for seizures.
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Folic acid might reduce serum levels of phenytoin in some patients.
Details
Folic acid may be a cofactor in phenytoin metabolism (4471). Folic acid, in doses of 1 mg daily or more, can reduce serum levels of phenytoin in some patients (4471,4477,4531,4536). Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, monitor serum phenytoin levels closely. If phenytoin and folic acid are started at the same time and continued together, adverse changes in phenytoin pharmacokinetics are avoided (4471,4472,4473,4531). Note that phenytoin also reduces serum folate levels.
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Folic acid might have antagonistic effects on primidone and increase the risk for seizures.
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Folic acid might antagonize the effects of pyrimethamine.
Details
Folic acid can antagonize the antiparasitic effects of pyrimethamine against toxoplasmosis and Pneumocystis carinii pneumonia. Folic acid doesn't antagonize the effects of pyrimethamine in the treatment of malaria, because malarial parasites cannot use exogenous folic acid. Use folinic acid as an alternative to folic acid when indicated (9380).
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Theoretically, ginkgo might decrease the levels and clinical effects of alprazolam.
Details
In clinical research, ginkgo extract (Ginkgold) 120 mg twice daily seems to decrease alprazolam levels by about 17%. However, ginkgo does not appear to decrease the elimination half-life of alprazolam. This suggests that ginkgo is more likely to decrease absorption of alprazolam rather than induce hepatic metabolism of alprazolam (11029).
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Ginkgo has been shown to increase the risk of bleeding in some people when taken with warfarin. Theoretically, ginkgo might increase the risk of bleeding if used with other anticoagulant or antiplatelet drugs.
Details
Several pharmacodynamic studies suggest that ginkgo inhibits platelet aggregation. It is thought that the ginkgo constituent, ginkgolide B, displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation (6048,9760). Several case reports have documented serious bleeding events in patients taking ginkgo (244,578,579,8581,13002,13135,13179,13194,14456,87868). However, population and clinical studies have produced mixed results. Some evidence shows that short-term use of ginkgo leaf does not significantly reduce platelet aggregation and blood clotting (87732). A study in healthy males who took a specific ginkgo leaf extract (EGb 761) 160 mg twice daily for 7 days found no change in prothrombin time (12114). An analysis of a large medical record database suggests that ginkgo increases the risk of a bleeding adverse event by 38% when taken concurrently with warfarin (91326). It has been suggested that ginkgo has to be taken for at least 2-3 weeks to have a significant effect on platelet aggregation (14811). However, a meta-analysis of 18 studies using standardized ginkgo extracts, 80-480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT (17179). In addition, a single dose of ginkgo plus clopidogrel (14811) or ticlopidine does not seem to significantly increase bleeding time or platelet aggregation (17111,87846). Also, taking ginkgo leaf extract daily for 8 days in conjunction with rivaroxaban does not affect anti-factor Xa activity; however, this study did not evaluate bleeding time (109526).
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Theoretically, ginkgo might reduce the effectiveness of anticonvulsants.
Details
Ginkgo seeds contain ginkgotoxin. Large amounts of ginkgotoxin can cause neurotoxicity and seizure. Ginkgotoxin is present in much larger amounts in ginkgo seeds than leaves (8232). Ginkgo leaf extract contains trace amounts of ginkgotoxin. The amount of ginkgotoxin in ginkgo leaf and leaf extract seems unlikely to cause toxicity (11296). However, there are anecdotal reports of seizure occurring after use of ginkgo leaf both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090).
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Theoretically, taking ginkgo with antidiabetes drugs might alter the response to antidiabetes drugs.
Details
Ginkgo leaf extract seems to alter insulin secretion and metabolism, and might affect blood glucose levels in people with type 2 diabetes (5719,14448,103574). The effect of ginkgo seems to differ depending on the insulin and treatment status of the patient. In diet-controlled diabetes patients with hyperinsulinemia, taking ginkgo does not seem to significantly affect insulin or blood glucose levels. In patients with hyperinsulinemia who are treated with oral hypoglycemic agents, taking ginkgo seems to decrease insulin levels and increase blood glucose following an oral glucose tolerance test. Researchers speculate that this could be due to ginkgo-enhanced hepatic metabolism of insulin. In patients with pancreatic exhaustion, taking ginkgo seems to stimulate pancreatic beta-cells, resulting in increased insulin and C-peptide levels, but with no significant change in blood glucose levels in response to an oral glucose tolerance test (14448).
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Theoretically, ginkgo might decrease the levels and clinical effects of atorvastatin.
Details
In humans, intake of ginkgo extract appears to increase atorvastatin clearance, reducing the area under the curve of atorvastatin by 10% to 14% and the maximum concentration by 29%. However, this interaction does not appear to affect cholesterol synthesis and absorption (89706). Further, a model in rats with hyperlipidemia suggests that administering ginkgo extract does not impact blood levels of atorvastatin and leads to lower total cholesterol, low-density lipoprotein cholesterol, and triglycerides when compared with rats given atorvastatin alone (111331).
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Theoretically, ginkgo might increase levels of drugs metabolized by CYP1A2.
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Theoretically, ginkgo might decrease levels of drugs metabolized by CYP2C19.
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Some clinical research shows that a specific ginkgo leaf extract (Remembrance, Herbs Product LTD) 140 mg twice daily can induce CYP2C19 enzymes and potentially decrease levels of drugs metabolized by these enzymes (13108). However, other clinical research shows that taking ginkgo 120 mg twice daily for 12 days has no effect on levels of drugs metabolized by CYP2C19 (87824).
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Theoretically, ginkgo might increase levels of drugs metabolized by CYP2C9.
Details
In vitro, a specific standardized extract of ginkgo leaf (EGb 761) inhibits CYP2C9 activity (11026,12061,14337). The terpenoid (ginkgolides) and flavonoid (quercetin, kaempferol, etc.) constituents seem to be responsible for this effect. Most ginkgo extracts contain some amount of these constituents. Therefore, other ginkgo leaf extracts might also inhibit the CYP2C9 enzyme. However, clinical research suggests that ginkgo might not have a significant effect on CYP2C9 in humans. Ginkgo does not seem to significantly affect the pharmacokinetics of CYP2C9 substrates diclofenac or tolbutamide.
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Theoretically, ginkgo might decrease levels of drugs metabolized by CYP3A4.
Details
There is conflicting evidence about whether ginkgo induces or inhibits CYP3A4 (1303,6423,6450,11026,87800,87805,111330). Ginkgo does not appear to affect hepatic CYP3A4 (11029). However, it is not known if ginkgo affects intestinal CYP3A4. Preliminary clinical research suggests that taking ginkgo does not significantly affect levels of donepezil, lopinavir, or ritonavir, which are all CYP3A4 substrates (11027,87800,93578). Other clinical research also suggests ginkgo does not significantly affect CYP3A4 activity (10847). However, there are two case reports of decreased efavirenz concentrations and increased viral load in patients taking ginkgo. It is suspected that terpenoids from the ginkgo extract reduced drug levels by inducing cytochrome P450 3A4 (CYP3A4) (16821,25464).
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Theoretically, ginkgo might decrease the levels and clinical effects of efavirenz.
Details
There are two case reports of decreased efavirenz concentrations and increased viral load in patients taking ginkgo. In one case, an HIV-positive male experienced over a 50% decrease in efavirenz levels over the course of 14 months while taking ginkgo extract. HIV-1 RNA copies also increased substantially, from less than 50 to more than 1500. It is suspected that terpenoids from the ginkgo extract reduced drug levels by inducing cytochrome P450 3A4 (CYP3A4) (16821). In another case report, a patient stable on antiviral therapy including efavirenz for 10 years, had an increase in viral load from <50 copies/mL to 1350 copies/mL after 2 months of taking a combination of supplements including ginkgo. After stopping ginkgo, the viral load was again controlled with the same antiviral therapy regimen (25464).
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Theoretically, ginkgo might increase the risk of bleeding when used with ibuprofen.
Details
Ginkgo might have antiplatelet effects and has been associated with several case reports of spontaneous bleeding. In one case, a 71-year-old male had taken a specific ginkgo extract (Gingium, Biocur) 40 mg twice daily for 2.5 years. About 4 weeks after starting ibuprofen 600 mg daily he experienced a fatal intracerebral hemorrhage (13179). However, the antiplatelet effects of ginkgo have been questioned. A meta-analysis and other studies have not found a significant antiplatelet effect with standardized ginkgo extracts, 80 mg to 480 mg taken daily for up to 32 weeks (17179).
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Theoretically, taking ginkgo with oral, but not intravenous, nifedipine might increase levels and adverse effects of nifedipine.
Details
Animal research and some clinical evidence suggests that taking ginkgo leaf extract orally in combination with oral nifedipine might increase nifedipine levels and cause increased side effects, such as headaches, dizziness, and hot flushes (87764,87765). However, taking ginkgo orally does not seem to affect the pharmacokinetics of intravenous nifedipine (87765).
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Theoretically, taking ginkgo with omeprazole might decrease the levels and clinical effects of omeprazole.
Details
Clinical research shows that a specific ginkgo leaf extract (Remembrance, Herbs Product LTD) 140 mg twice daily can induce cytochrome P450 (CYP) 2C19 enzymes and decrease levels of omeprazole by about 27% to 42% (13108).
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Theoretically, taking ginkgo with P-glycoprotein substrates might increase the levels and adverse effects of these substrates.
Details
A small clinical study in healthy volunteers shows that using ginkgo leaf extract 120 mg orally three times daily for 14 days can increase levels of the P-glycoprotein substrate, talinolol, by 36% in healthy male individuals. However, single doses of ginkgo do not have the same effect (87830).
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Theoretically, taking ginkgo with risperidone might increase the levels and adverse effects of risperidone.
Details
A single case of priapism has been reported for a 26-year-old male with schizophrenia who used risperidone 3 mg daily along with ginkgo extract 160 mg daily (87796). Risperidone is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4. CYP3A4 activity might be affected by ginkgo. Theoretically, ginkgo may inhibit the metabolism of risperidone and increase the risk of adverse effects.
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Theoretically, ginkgo might decrease the levels and clinical effects of rosiglitazone.
Details
Animal research shows that ginkgo leaf extract orally 100 or 200 mg/kg daily for 10 days alters the pharmacodynamics of rosiglitazone in a dose-dependent manner. The 100 mg/kg and 200 mg/kg doses reduce the area under the concentration time curve (AUC) of rosiglitazone by 39% and 52%, respectively, and the half-life by 28% and 39%, respectively. It is hypothesized that these changes may be due to induction of cytochrome P450 2C8 by ginkgo (109525).
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Theoretically, taking ginkgo with drugs that lower the seizure threshold might increase the risk for convulsions.
Details
Ginkgo seeds contain ginkgotoxin. Large amounts of ginkgotoxin can cause neurotoxicity and seizure. Ginkgotoxin is present in much larger amounts in ginkgo seeds than leaves (8232). Ginkgo leaf extract contains trace amounts of ginkgotoxin. The amount of ginkgotoxin in ginkgo leaf and leaf extract seems unlikely to cause toxicity (11296). However, there are anecdotal reports of seizure occurring after use of ginkgo leaf both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090,14281).
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Theoretically, ginkgo might decrease the levels and clinical effects of simvastatin.
Details
Clinical research shows that taking ginkgo extract can reduce the area under the curve and maximum concentration of simvastatin by 32% to 39%. However, ginkgo extract does not seem to affect the cholesterol-lowering ability of simvastatin (89704).
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Theoretically, ginkgo might increase the levels and clinical effects of sofosbuvir.
Details
Animal research in rats shows that giving a ginkgo extract 25 mg/kg orally daily for 14 days increases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 11%, increases the half-life by 60%, and increases the plasma concentration at 4 hours by 38%. This interaction appears to be related to the inhibition of intestinal P-glycoprotein by ginkgo (109524).
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Theoretically, ginkgo might increase the blood levels of tacrolimus.
Details
In vitro evidence suggests that certain biflavonoids in ginkgo leaves (i.e. amentoflavone, ginkgetin, bilobetin) may inhibit the metabolism of tacrolimus by up to 50%. This interaction appears to be time-dependent and due to inhibition of cytochrome P450 (CYP) 3A4 by these bioflavonoids. In rats given tacrolimus 1 mg/kg orally, amentoflavone was shown to increase the area under the concentration time curve (AUC) of tacrolimus by 3.8-fold (111330).
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Taking ginkgo with talinolol seems to increase blood levels of talinolol.
Details
There is some evidence that using ginkgo leaf extract 120 mg orally three times daily for 14 days can increase levels of talinolol by 36% in healthy male individuals. However, single doses of ginkgo do not seem to affect talinolol pharmacokinetics (87830).
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Theoretically, ginkgo might increase the levels and clinical effects of trazodone.
Details
In a case report, an Alzheimer patient taking trazodone 20 mg twice daily and ginkgo leaf extract 80 mg twice daily for four doses became comatose. The coma was reversed by administration of flumazenil (Romazicon). Coma might have been induced by excessive GABA-ergic activity. Ginkgo flavonoids are thought to have GABA-ergic activity and act directly on benzodiazepine receptors. Ginkgo might also increase metabolism of trazodone to active GABA-ergic metabolites, possibly by inducing cytochrome P450 3A4 (CYP3A4) metabolism (6423).
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Ginkgo has been shown to increase the risk of bleeding in some people when taken with warfarin.
Details
Several pharmacodynamic studies suggest that ginkgo inhibits platelet aggregation. It is thought that the ginkgo constituent, ginkgolide B, displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation (6048,9760). Several case reports have documented serious bleeding events in patients taking ginkgo (244,576,578,579,8581,13002,13135,13179,13194,14456,87868). Information from a medical database suggests that when taken concurrently with warfarin, ginkgo increases the risk of a bleeding adverse event by 38% (91326). There is also some evidence that ginkgo leaf extract can inhibit cytochrome P450 2C9, an enzyme that metabolizes warfarin. This could result in increased warfarin levels (12061). However, population and clinical research has produced mixed results. Clinical research in healthy people suggests that ginkgo has no effect on INR, or the pharmacokinetics or pharmacodynamics of warfarin (12881,15176,87727,87889). A meta-analysis of 18 studies using standardized ginkgo extracts, 80 mg to 480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT (17179). There is also some preliminary clinical research that suggests ginkgo might not significantly increase the effects of warfarin in patients that have a stable INR (11905).
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Theoretically, niacinamide may have additive effects when used with anticoagulant or antiplatelet drugs, especially in patients on hemodialysis.
Details
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Niacinamide might increase the levels and adverse effects of carbamazepine.
Details
Plasma levels of carbamazepine were increased in two children given high-dose niacinamide, 60-80 mg/kg/day. This might be due to inhibition of the cytochrome P450 enzymes involved in carbamazepine metabolism (14506). There is not enough data to determine the clinical significance of this interaction.
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Niacinamide might increase the levels and adverse effects of primidone.
Details
Case reports in children suggest niacinamide 60-100 mg/kg/day reduces hepatic metabolism of primidone to phenobarbital, and reduces the overall clearance rate of primidone (14506); however, there is not enough data to determine the clinical significance of this potential interaction.
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Theoretically, taking riboflavin with tetracycline antibiotics may decrease the potency of these antibiotics.
Details
In vitro research suggests that riboflavin may inhibit the potency of tetracycline antibiotics (23372). It is not clear if this effect is clinically significant, as this interaction has not been reported in humans.
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Trimethoprim might increase blood levels of thiamine.
Details
In vitro, animal, and clinical research suggest that trimethoprim inhibits intestinal thiamine transporter ThTR-2, hepatic transporter OCT1, and renal transporters OCT2, MATE1, and MATE2, resulting in paradoxically increased thiamine plasma concentrations (111678).
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Theoretically, vitamin B6 might increase the photosensitivity caused by amiodarone.
Details
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Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.
Details
Research in hypertensive rats shows that vitamin B6 can decrease systolic blood pressure (30859,82959,83093). Similarly, clinical research in patients with hypertension shows that taking high doses of vitamin B6 may reduce systolic and diastolic blood pressure, possibly by reducing plasma levels of epinephrine and norepinephrine (83091).
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Vitamin B6 may increase the metabolism of levodopa when taken alone, but not when taken in conjunction with carbidopa.
Details
Vitamin B6 (pyridoxine) enhances the metabolism of levodopa, reducing its clinical effects. However, this interaction does not occur when carbidopa is used concurrently with levodopa (Sinemet). Therefore, it is not likely to be a problem in most people (3046).
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High doses of vitamin B6 may reduce the levels and clinical effects of phenobarbital.
Details
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High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.
Details
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.
Details
There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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Concomitant use of vitamin E and anticoagulant or antiplatelet agents might increase the risk of bleeding.
Details
Vitamin E seems to inhibit of platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors (4733,4844,11580,11582,11583,11584,11586,112162). These effects appear to be dose-dependent, and are probably only likely to be clinically significant with doses of at least 800 units daily (11582,11585). Mixed tocopherols, such as those found in food, might have a greater antiplatelet effect than alpha-tocopherol (10364). RRR alpha-tocopherol (natural vitamin E) 1000 IU daily antagonizes vitamin K-dependent clotting factors (11999). Advise patients to avoid high doses of vitamin E, especially in people with low vitamin K intake or other risk factors for bleeding.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of antitumor antibiotics.
Details
There's concern that antioxidants could reduce the activity of antitumor antibiotic drugs such as doxorubicin, which generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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A specific form of vitamin E might increase absorption and levels of cyclosporine.
Details
There is some evidence that one specific formulation of vitamin E (D-alpha-tocopheryl-polyethylene glycol-1000 succinate, TPGS, tocophersolan, Liqui-E) might increase absorption of cyclosporine. This vitamin E formulation forms micelles which seems to increase absorption of cyclosporine by 40% to 72% in some patients (624,625,10368). However, this interaction is unlikely to occur with the usual forms of vitamin E.
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Theoretically, vitamin E might induce metabolism of CYP3A4, possibly reducing the levels CYP3A4 substrates.
Details
Vitamin E appears to bind with the nuclear receptor, pregnane X receptor (PXR), which results in increased expression of CYP3A4 (13499,13500). Although the clinical significance of this is not known, use caution when considering concomitant use of vitamin E and other drugs affected by these enzymes.
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Vitamin E might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.
Details
A combination of niacin and simvastatin (Zocor) effectively raises high-density lipoprotein (HDL) cholesterol levels in people with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% (7388,11537). Vitamin E alone combined with a statin does not seem to decrease HDL levels (11286,11287). It is not known whether the adverse effect on HDL is due to one of the other antioxidants or to the combination. It also is not known whether it will occur in other patient populations.
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Taking selumetinib with vitamin E can result in a total daily dose of vitamin E that exceeds safe limits and therefore might increase the risk of bleeding.
Details
Selumetinib contains 48-54 IU vitamin E per capsule (102971). The increased risk of bleeding with vitamin E appears to be dose-dependent (11582,11585,34577). Be cautious when using selumetinib in combination with supplemental vitamin E, especially in patients at higher risk of bleed, such as those with chronic conditions and those taking antiplatelet drugs (102971).
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Using vitamin E with warfarin might increase the risk of bleeding.
Details
Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).
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Below is general information about the adverse effects of the known ingredients contained in the product MICROgenics Co Enzyme Q10 Plus Ginkgo and B Vitamins. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, folic acid is generally well-tolerated in amounts found in fortified foods, as well as in supplemental doses of less than 1 mg daily.
Most Common Adverse Effects:
Orally: At doses of 5 mg daily - abdominal cramps, diarrhea, and rash. At doses of 15 mg daily - bitter taste, confusion, hyperactivity, impaired judgment, irritability, nausea, sleep disturbances.
Serious Adverse Effects (Rare):
Orally: Cancer (long-term use), cardiovascular complications, liver injury, seizures.
All ROAs: Allergic reactions such as bronchospasm and anaphylactic shock.
Cardiovascular ...There is some concern that high oral doses of folic acid might increase the risk of adverse cardiovascular outcomes. Clinical research shows that taking doses of 800 mcg to 1.2 mg/day might increase the risk of adverse cardiovascular events in patients with cardiovascular disease (12150,13482). High doses of folic acid might promote cell growth by providing large amounts of the biochemical precursors needed for cell replication. Overgrowth of cells in the vascular wall might increase the risk of occlusion (12150). Although some research suggests that use of folic acid might increase the need for coronary revascularization, analysis of multiple studies suggests that taking folic acid up to 5 mg/day for up to 24 months does not appear to affect coronary revascularization risk (90798).
Dermatologic ...Orally, folic acid 1-5 mg daily can cause rash (7225,90375,91319). Folic acid 15 mg daily can sometimes cause allergic skin reactions (15).
Gastrointestinal ...Orally, folic acid 5 mg daily can cause abdominal cramps and diarrhea (7225). Folic acid 15 mg daily can sometimes cause nausea, abdominal distention, flatulence, and bitter taste in the mouth (15). In children aged 6-30 months at risk of malnourishment, taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg daily, with or without vitamin B 12 0.9-1.8 mcg daily, for 6 months increases the likelihood of having persistent diarrhea (90391).
Hepatic ...Liver dysfunction, with jaundice and very high liver enzymes, occurred in a 30-year-old pregnant patient with severe nausea and vomiting taking a folic acid supplement (Folic acid, Nature Made) 400 mcg daily. Based on the timing of ingestion, the lack of other etiological factors, a positive drug-induced lymphocyte stimulation test, and liver function normalization once the folic acid had been stopped, the authors suggest the folic acid supplement was the cause. However, the authors did not determine which substance in the folic acid supplement was responsible and therefore it cannot be determined that folic acid itself was the cause (91309).
Neurologic/CNS ...Orally, folic acid 15 mg daily can sometimes cause altered sleep patterns, vivid dreaming, irritability, excitability, hyperactivity, confusion, and impaired judgment (15). Large doses of folic acid can also precipitate or exacerbate neuropathy in people deficient in vitamin B12 (6243). Use of folic acid for undiagnosed anemia has masked the symptoms of pernicious anemia, resulting in lack of treatment and eventual neurological damage (15). Patients should be warned not to self-treat suspected anemia. There is also some concern that consuming high amounts of folic acid from the diet and/or supplements might worsen cognitive decline in older people. A large-scale study suggests that people over 65 years of age, who consume large amounts of folic acid (median of 742 mcg/day), have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg/day). It's not known if this is directly attributable to folic acid. It is theorized that it could be due to folic acid masking a vitamin B12 deficiency. Vitamin B12 deficiency is associated with cognitive decline (13068). More evidence is needed to determine the significance of this finding. For now, suggest that most patients aim for the recommended folic acid intake of 400 mcg/day.
Oncologic
...There is some concern that high dose folic acid might increase the risk of cancer, although research is unclear and conflicting.
A large-scale population study suggests that taking a multivitamin more than 7 times per week with a separate folic acid supplement significantly increased the risk of prostate cancer (15607). Clinical research also shows that taking folic acid 1 mg daily increase the absolute risk of prostate cancer by 6.4% over a 10-year period when compared with placebo. However, those with a higher baseline dietary intake of folic acid had a lower rate of prostate cancer, but this was not statistically significant. Also, folate and folic acid intake in patients with prostate cancer is not associated with the risk of prostate cancer recurrence after radical prostatectomy (91317). However, it is possible that discrepancies are due to dietary folate versus folic acid intake. Large analyses of population studies suggest that while dietary folate/folic acid is not associated with prostate cancer, high blood folate/folic acid increases the risk of prostate cancer (50411,91316).
Additional clinical research shows that taking folic acid 800 mcg daily, in combination with vitamin B12 400 mcg, significantly increases the risk of developing cancer, especially lung cancer, and all-cause mortality in patients with cardiovascular disease (17041). However, this may be due to vitamin B12, as other observational research found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). Meta-analyses of large supplementation trials of folic acid at levels between 0.5-2.5 mg daily also suggest an increased risk of cancer (50497,110318). Also, in elderly individuals, taking folic acid 400 mcg daily with vitamin B12 500 mcg daily increased the risk of cancer. The risk was highest in individuals over 80 years of age and in females and mainly involved gastrointestinal and colorectal cancers (90393).
Not all researchers suspect that high intake of folic acid supplements might be harmful. Some research suggests that increased dietary intake of folic acid, along with other nutrients, might be protective against cancer (16822). A meta-analysis of multiple clinical trials suggests that folic acid supplementation studies with folic acid levels between 500 mcg to 50 mg/day does not increase the risk of general or site-specific cancer for up to 7 years (91312,91321). Also, a post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378).
Psychiatric ...Orally, folic acid 15 mg daily can sometimes cause exacerbation of seizure frequency and psychotic behavior (15).
Pulmonary/Respiratory ...Folic acid use in late pregnancy has been associated with an increased risk of persistent and childhood asthma at 3. 5 years in population research (50380). When taken pre-pregnancy or early in pregnancy, population research has not found an association with increased risk of asthma or allergies in childhood (90799,103979). Folic acid use in pregnancy has been associated with a slightly increased risk of wheeze and lower respiratory tract infections up to 18 months of age in population research (50328).
General
...Orally, ginkgo leaf extract is generally well tolerated when used for up to 6 years.
However, the seed and crude plant contain toxic constituents and should be avoided.
Intravenously, ginkgo leaf extract seems to be well tolerated when used for up to 30 days.
Topically, no adverse effects have been reported with ginkgo as a single ingredient. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Dizziness, gastrointestinal symptoms, headache.
Serious Adverse Effects (Rare):
Orally: Arrhythmia, bleeding, Stevens-Johnson syndrome.
Cardiovascular
...Cardiac arrhythmias suspected to be related to ginkgo have been reported.
Internationally, there are at least 162 reports from 18 countries, with 34% of cases considered serious, involving five deaths and four life-threatening events. Additionally, a report from Canada found that 10 out of 15 cases of arrhythmia were considered serious. Ginkgo was the only suspect ingredient in 57% of all international reports, with symptoms generally presenting within days of initiation. The most common symptoms included palpitations, tachycardia, bradycardia, syncope, and loss of consciousness. Most cases were reported to be related to oral use of ginkgo leaf products; however, some cases were associated with oral use of the seed, and others with intravenous or intramuscular use of the leaf. Documented discontinuation of ginkgo led to recovery in approximately 84% of cases where ginkgo was the sole suspect. Despite these findings, ginkgo cannot be confirmed as the causal agent. It is possible that these reports are confounded by underlying co-morbidities. Of the reported cases, the main reason for ginkgo use was tinnitus, a symptom commonly associated with pre-existing arrhythmias (105253,105254). Despite this large number of reports, only three cases of cardiac arrhythmia have been published in the literature (105253,105254). In one case, frequent nocturnal episodes of paroxysmal atrial fibrillation were reported for a 35-year-old female taking ginkgo extract 240 mg daily orally for 2 months. Arrythmias ceased following discontinuation of ginkgo (87884).
Increases in blood pressure were commonly reported with ginkgo in a safety database analysis; however, information on the magnitude of the increase was limited, and reports included both oral and intravenous administration (115628).
In one clinical trial, the rate of ischemic stroke and transient ischemic attacks was significantly higher in patients taking ginkgo extract orally when compared with placebo (16635). It is unclear if these events were due to ginkgo, other factors, or a combination.
Dermatologic ...Topically, ginkgo fruit pulp can cause contact dermatitis, with intense itching, edema, papules, and pustules which take 7-10 days to resolve after stopping contact (112946).
Gastrointestinal
...Orally, ginkgo extract may cause mild gastrointestinal discomfort or pain (3965,8543,17112,87818,87858), nausea and vomiting (8543,17112,87728,87844,87858), diarrhea (87844), dry mouth (17112), and constipation (5719,87787).
However, post-market surveillance suggests that the incidence of these events is relatively low, occurring in less than 2% of patients (88007).
Fresh ginkgo seeds can cause stomach ache, nausea, vomiting, or diarrhea. Ingesting roasted seeds in amounts larger than the normal food amounts of 8-10 seeds per day, or long-term, can also cause these same adverse reactions (8231,8232).
Genitourinary ...Orally, ginkgo extract has been reported to cause blood in the urine (87858,115628).
Hematologic
...Spontaneous bleeding is one of the most concerning potential side effects associated with ginkgo.
There are several published case reports linking ginkgo to episodes of minor to severe bleeding; however, not all case reports clearly establish ginkgo as the cause of bleeding. In most cases, other bleeding risk factors were also present including taking other medications or natural medicines, old age, liver cirrhosis, recent surgery, and other conditions. In most cases, bleeding occurred after several weeks or months of taking ginkgo (13135). Large-scale clinical trials and a meta-analysis evaluating standardized ginkgo leaf extracts show that the incidence of bleeding in patients taking ginkgo is not significantly higher than in those taking placebo (16634,16635,17179,17402).
There are several case reports of intracerebral bleeding. Some of these cases resulted in permanent neurological damage and one case resulted in death (244,578,8581,13135,13179,14456,87868,87977).
There are at least 4 cases of ocular bleeding including spontaneous hyphema (bleeding from the iris into the anterior part of the eye) and retrobulbar hemorrhage associated with ginkgo use (579,10450,13135).
There are also cases of surgical and post-surgical complications in patients using ginkgo. Retrobulbar hemorrhage (bleeding behind the eye) during cataract surgery has been associated with ginkgo use (10450). Excessive postoperative bleeding requiring transfusion has also occurred following laparoscopic surgery in a patient who had been taking ginkgo leaf extract (887). There have also been two cases of excessive bleeding during surgery and post-surgical hematoma in patients undergoing rhytidoplasty and blepharoplasty (13002). In another case, an elderly patient taking ginkgo experienced excessive postoperative bleeding following total hip arthroplasty (13194). In another case, use of ginkgo following liver transplantation surgery was associated with subphrenic hematoma requiring evacuation by laparotomy. The patient also subsequently experienced vitreous hemorrhage (14315). In another case, an elderly patient who had taken ginkgo chronically experienced excessive post-operative bleeding following an ambulatory surgical procedure (14453).
In another case, an elderly man experienced nose bleeds and ecchymosis following use of ginkgo. One case of diffuse alveolar hemorrhage in a female taking ginkgo and ginseng for over one year has been reported (95670). These instances of bleeding stopped when ginkgo was discontinued, and recurred when the patient started taking ginkgo again (13135).
Persistent bleeding has also occurred following dental surgery (87862) and laparoscopic cholecystectomy (88000). Nosebleed has also been reported as an adverse effect in a clinical trial (87813).
Immunologic ...Orally, ginkgo leaf extract can cause allergic skin reactions in some patients (14449,15578,112946). In one case, a patient developed acute generalized exanthematous pustulosis 48 hours after taking a single-ingredient ginkgo product. The rash resolved within 10 days after discontinuing ginkgo (14449). In another case, progressive erythema of the face, neck, trunk, and extremities occurred after two 60 mg oral doses of ginkgo extract (112946). There is also a case of Stevens-Johnson syndrome following a second administration of a preparation containing ginkgo leaf extract, choline, vitamin B6, and vitamin B12 (208). In another case, systemic edema and severe arthralgia was reported after contact with a ginkgo tree nut and manifested as multifocal lymphadenopathy associated with an allergic reaction on PET/CT scan imaging (95672).
Musculoskeletal ...Edema has been reported for three patients treated with ginkgo extract 40 mg orally three times daily (87818).
Neurologic/CNS ...Orally, ginkgo extract may cause headache (6220,8543,87818), dizziness (5719,87818), increased desire to sleep (87839,115628), and sedation (10893) in some patients. In addition, although ginkgo leaf and ginkgo leaf extract contain only small amounts of ginkgotoxin, there are anecdotal reports of seizure occurring after use of ginkgo leaf preparations both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090,11296,14281).
Ocular/Otic
...Orally, ginkgo may cause tinnitus is some patients (8543,115628).
Topically, eye drops containing ginkgo extract and hyaluronic acid may cause stinging sensations in some people (87829).
Psychiatric ...Orally, ginkgo has been associated with a single case of mood dysregulation. A 50-year-old female with schizophrenia developed irritability, difficulty controlling anger, and agitation after one week of taking ginkgo 80 mg twice daily. The mood changes resolved within 2-3 days of discontinuation. When ginkgo was re-trialed at a later date, the same symptoms reappeared, and again dissipated after discontinuation of the ginkgo product. The relationship between ginkgo and mood dysregulation was considered to be "probable" based on the Naranjo adverse drug reaction probability scale (96763); however, the exact mechanism by which ginkgo may have affected mood regulation is unknown.
General
...Orally, niacinamide is well tolerated in amounts typically found in food.
When used topically and orally in higher doses, niacinamide seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, itching, gastrointestinal disturbances, headache, and rash.
Topically: Burning sensation, itching, and mild dermatitis.
Dermatologic ...Orally, large doses of niacinamide are associated with occasional reports of rashes, itching, and acanthosis nigricans (4880,11695,11697,14504,107709), though a meta-analysis of 19 clinical studies suggests that dermatological adverse event rates are similar between niacinamide and control (110497). Topically, application of niacinamide in a cream has been reported to cause a burning sensation, itching and pruritus, crusting, and mild dermatitis (93357,93360,110501,110498).
Endocrine ...Orally, niacinamide in high doses, 50 mg/kg daily, has been associated with modestly higher insulin requirements in patients with type 1 diabetes, when compared with taking niacinamide 25 mg/kg daily. Theoretically, high-dose niacinamide might increase insulin resistance, although to a lesser extent than niacin (4881,14512).
Gastrointestinal ...Orally, large doses of niacinamide can cause gastrointestinal disturbances including nausea, vomiting, heartburn, anorexia, epigastric pain, flatulence, and diarrhea (6243,11694,11695,11696,11697,107709,110497,113682).
Hematologic ...Orally, niacinamide supplementation might increase the risk for thrombocytopenia in patients undergoing hemodialysis (98940,107709). A meta-analysis of small clinical studies shows that taking niacinamide during hemodialysis to reduce phosphate levels is associated with a 2.8-fold increased risk for thrombocytopenia when compared with placebo. In one of the included studies, platelet levels returned to normal within 20 days after niacinamide discontinuation (98940).
Hepatic ...Orally, older reports of elevated liver function tests with high doses of niacinamide (3 grams or more daily) have raised concerns about liver toxicity. However, newer studies have not reported this concern; it is possible that some of these cases were due to contamination with niacin (4880,11694,11695,14503).
Neurologic/CNS ...Orally, large doses of niacinamide can cause dizziness, drowsiness, and headaches (11694,11695,11696,11697,107709).
General
...Orally, pantothenic acid is generally well tolerated.
Topically and intramuscularly, dexpanthenol, a synthetic form of pantothenic acid, seems to be well tolerated.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, eczema, irritation, and itching related to dexpanthenol.
Cardiovascular ...There is one case of eosinophilic pleuropericardial effusion in a patient taking pantothenic acid 300 mg per day in combination with biotin 10 mg per day for 2 months (3914).
Dermatologic ...Topically, dexpanthenol has been associated with itching, burning, skin irritation, contact dermatitis, and eczema (67779,67781,67788,111258,111262). Three cases of allergic contact dermatitis have been reported (111260,111261).
Gastrointestinal ...Orally, pantothenic acid has been associated with diarrhea (67822,111258).
General
...Orally, riboflavin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dose-related nausea and urine discoloration.
Gastrointestinal ...Orally, riboflavin has been associated with rare diarrhea and dose-related nausea (1398,71483). In one clinical study, one subject out of 28 reported having diarrhea two weeks after starting riboflavin 400 mg daily (1398).
Genitourinary ...Orally, high doses of riboflavin can cause bright yellow urine. Furthermore, in one clinical study, one subject out of 28 reported polyuria two weeks after starting riboflavin 400 mg daily (1398,3094).
General
...Orally and parenterally, thiamine is generally well tolerated.
Serious Adverse Effects (Rare):
Parenterally: Hypersensitivity reactions including angioedema and anaphylaxis.
Immunologic
...Orally, thiamine might rarely cause dermatitis and other allergic reactions.
Parenterally, thiamine can cause anaphylactoid and hypersensitivity reactions, but this is also rare (<0.1%). Reported symptoms and events include feelings of warmth, tingling, pruritus, urticaria, tightness of the throat, cyanosis, respiratory distress, gastrointestinal bleeding, pulmonary edema, angioedema, hypotension, and death (15,35585,105445).
In one case report, a 46-year-old female presented with systemic allergic dermatitis after applying a specific product (Inzitan, containing lidocaine, dexamethasone, cyanocobalamin and thiamine) topically by iontophoresis; the allergic reaction was attributed to thiamine (91170).
General
...Orally, intramuscularly, and topically, vitamin B12 is generally well-tolerated.
Most Common Adverse Effects:
Intramuscular: Injection site reactions.
Serious Adverse Effects (Rare):
Intramuscularly: Severe hypokalemia has been rarely linked with correction of megaloblastic anemia with vitamin B12.
Cardiovascular ...In human clinical research, an intravenous loading dose of folic acid, vitamin B6, and vitamin B12, followed by daily oral administration after coronary stenting, increased restenosis rates (12150). Hypertension following intravenous administration of hydroxocobalamin has been reported in human research (82870,82864).
Dermatologic
...Orally or intramuscularly, vitamin B12 can cause allergic reactions such as rash, pruritus, erythema, and urticaria.
Theoretically, allergic reactions might be caused by the cobalt within the vitamin B12 molecule (82864,90373,90381,103974). In one case report, oral methylcobalamin resulted in contact dermatitis in a 59-year-old Japanese female with a cobalt allergy (103974). In another case report, a 69-year-old female developed a symmetrical erythematous-squamous rash for 5 years after oral vitamin B12 supplementation for 10 years. A patch test confirmed that the systemic allergic dermatitis was due to vitamin B12 supplementation, which resolved 3 months after discontinuation (114578).
Vitamin B12 (intramuscular or oral) has also been associated with at least 19 cases of acneiform eruptions which resolved upon discontinuation of vitamin B12 (90365,90369,90388). High-dose vitamin B12 (20 mcg daily) and vitamin B6 (80 mg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may last up to four months after the supplement is stopped and can be treated with systemic corticosteroids and topical therapy (10998,82870,82871).
Gastrointestinal ...Intravenously, vitamin B12 (hydroxocobalamin) 2. 5-10 grams can cause nausea and dysphagia (82864).
Genitourinary ...Intravenously, vitamin B12 (hydroxocobalamin) 5-15 grams has been associated with chromaturia in clinical research (82870,82871,112282,112264).
Hematologic ...According to case report data, the correction of megaloblastic anemia with vitamin B12 may result in fatal hypokalemia (82914).
Musculoskeletal ...According to case report data, correction of megaloblastic anemia with vitamin B12 has precipitated gout in susceptible individuals (82879).
Neurologic/CNS ...Treatment with vitamin B12 has been rarely associated with involuntary movements in infants with vitamin B12 deficiency (90370,90385,90397). In some cases these adverse reactions were misdiagnosed as seizures or infantile tremor syndrome (90370,90385). These adverse reactions presented 2-5 days after treatment with vitamin B12 and resolved once vitamin B12 was discontinued (90370,90385,90397).
Oncologic ...Although some epidemiological research disagrees (9454), most research has found that elevated plasma levels of vitamin B12 are associated with an increased risk of various types of cancer, including lung and prostate cancers and solid tumors (50411,102383,107743). One study found, when compared with blood levels of vitamin B12 less than 1000 ng/mL, plasma vitamin B12 levels of at least 1000 ng/mL was strongly associated with the occurrence of solid cancer (107743). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of cancer. It is possible that having cancer increases the risk of vitamin B12 elevation. However, one observational study has found that the highest quintile of dietary intake of vitamin B12 is associated with a 75% increased incidence of developing esophageal cancer when compared with the lowest quintile in never drinkers, but not drinkers (107147).
Renal ...There is a case report of oxalate nephropathy in a 54-year-old male which was determined to be related to the use of intravenous hydroxocobalamin as treatment for cyanide poisoning. Intermittent hemodialysis was started 5 days after admission, along with a low-oxalate diet, oral calcium acetate, and pyridoxine 5 mg/kg daily (107148). A review of the use of intravenous hydroxocobalamin for suspected cyanide poisoning in 21 intensive care units in France between 2011 and 2017 resulted in a 60% increased odds of acute kidney injury and a 77% increased odds of severe acute kidney injury in the first week. However, biopsies were not conducted and a direct link with use of hydroxocobalamin could not be made (107139).
Other ...Several studies have found that higher vitamin B12 levels may be associated with increased mortality or decreased survival rates in hospitalized elderly patients (82889,82812,82857,82895). Human research has also found a positive correlation between vitamin B12 status and all-cause mortality in Pima Indians with diabetes (82863).
General
...Orally or by injection, vitamin B6 is well tolerated in doses less than 100 mg daily.
Most Common Adverse Effects:
Orally or by injection: Abdominal pain, allergic reactions, headache, heartburn, loss of appetite, nausea, somnolence, vomiting.
Serious Adverse Effects (Rare):
Orally or by injection: Sensory neuropathy (high doses).
Dermatologic ...Orally, vitamin B6 (pyridoxine) has been linked to reports of skin and other allergic reactions and photosensitivity (8195,9479,90375). High-dose vitamin B6 (80 mg daily as pyridoxine) and vitamin B12 (20 mcg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy (10998).
Gastrointestinal ...Orally or by injection, vitamin B6 (pyridoxine) can cause nausea, vomiting, heartburn, abdominal pain, mild diarrhea, and loss of appetite (8195,9479,16306,83064,83103,107124,107127,107135). In a clinical trial, one patient experienced infectious gastroenteritis that was deemed possibly related to taking vitamin B6 (pyridoxine) orally up to 20 mg/kg daily (90796). One small case-control study has raised concern that long-term dietary vitamin B6 intake in amounts ranging from 3.56-6.59 mg daily can increase the risk of ulcerative colitis (3350).
Hematologic ...Orally or by injection, vitamin B6 (pyridoxine) can cause decreased serum folic acid concentrations (8195,9479). One case of persistent bleeding of unknown origin has been reported in a clinical trial for a patient who used vitamin B6 (pyridoxine) 100 mg twice daily on days 16 to 35 of the menstrual cycle (83103). It is unclear if this effect was due to vitamin B6 intake.
Musculoskeletal ...Orally or by injection, vitamin B6 (pyridoxine) can cause breast soreness or enlargement (8195).
Neurologic/CNS ...Orally or by injection, vitamin B6 (pyridoxine) can cause headache, paresthesia, and somnolence (8195,9479,16306). Vitamin B6 (pyridoxine) can also cause sensory neuropathy, which is related to daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 grams or more pose the most risk, although neuropathy can occur with lower daily or total doses as well (8195). The mechanism of the neurotoxicity is unknown, but is thought to occur when the liver's capacity to phosphorylate pyridoxine via the active coenzyme pyridoxal phosphate is exceeded (8204). Some researchers recommend taking vitamin B6 as pyridoxal phosphate to avoid pyridoxine neuropathy, but its safety is unknown (8204). Vitamin B6 (pyridoxine) neuropathy is characterized by numbness and impairment of the sense of position and vibration of the distal limbs, and a gradual progressive sensory ataxia (8196,10439). The syndrome is usually reversible with discontinuation of pyridoxine at the first appearance of neurologic symptoms. Residual symptoms have been reported in patients taking more than 2 grams daily for extended periods (8195,8196). Daily doses of 100 mg or less are unlikely to cause these problems (3094).
Oncologic ...In females, population research has found that a median intake of vitamin B6 1. 63 mg daily is associated with a 3.6-fold increased risk of rectal cancer when compared with a median intake of 1.05 mg daily (83024). A post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378). Also, in patients with nasopharyngeal carcinoma, population research has found that consuming at least 8.6 mg daily of supplemental vitamin B6 during treatment was associated with a lower overall survival rate over 5 years, as well as a reduced progression-free survival, when compared with non-users and those with intakes of up to 8.6 mg daily (107134).
General
...Orally and topically, vitamin E is generally well-tolerated.
Serious Adverse Effects (Rare):
Orally: Bleeding, hemorrhagic stroke, cardiovascular complications.
Inhaled: Vitamin E acetate is thought to be responsible for e-cigarette, or vaping, product-use associated lung injury (EVALI).
Cardiovascular
...Some evidence suggests that taking vitamin E supplements, especially greater than or equal to 400 IU taken by mouth daily for over one year, might also increase the risk of mortality in non-healthy patients (12212,13036,15305,16709,83339).
A population study shows that vitamin E use is associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease such as stroke or myocardial infarction (16709). In an analysis of clinical trials, patients who took either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) in doses of 400 IU/day or higher had an increased risk of mortality from all causes. The risk of mortality seems to increase when higher doses are used (12212). A large-scale study also suggests that patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily have an increased risk of heart failure and heart failure-related hospitalization (13036). However, in another large scale study, taking 600 IU vitamin E every other day for 10 years did not increase the risk of heart failure in healthy females over 45 years of age (90068). There is speculation that high-dose vitamin E might disrupt the normal antioxidant balance and result in pro-oxidant rather than antioxidant effects.
There is some evidence that vitamin E in combination with simvastatin (Zocor), niacin, selenium, vitamin C, and beta-carotene might lower high density lipoprotein-2 (HDL-2) by 15%. HDL-2 is considered to be the most cardioprotective component of HDL (7388). However, vitamin E and a statin alone don't seem to negatively affect HDL (11286,11287). In addition, vitamin E has been associated with increased triglycerides (85215). Although only certain isomers of vitamin E are included for determination of dietary requirements, all isomers are considered for determining safe intake levels. All the isomers are thought to potentially contribute to toxicity.
Dermatologic
...Topically, vitamin E has been associated with contact dermatitis, inflammatory reactions, and eczematous lesions (11998,85066,85285).
Dermatitis, often associated with moisturizers containing vitamin E, has a scattered generalized distribution, is more common on the face than the hands, and is more common in females with a history of atopic dermatitis. In a retrospective analysis of results of patch tests for DL-alpha-tocopherol sensitivity, 0.9% of patients had a definite positive reaction, while over 50% had a weakly positive, non-vesicular erythematous reaction (107869).
Orally, vitamin E has been associated with pruritus in one clinical trial (34596).
Subcutaneously, vitamin E has been associated with reports of lipogranuloma (85188,112331). In one case, subcutaneous injection of a specific supplement (1Super Extenze), containing mineral oil and tocopherol acetate, into the penile tissue resulted in penile disfigurement due to sclerosing lipogranuloma (85188). In another case, a 50-year-old Iranian female presented with lipogranuloma of the face, characterized by severe facial erythema, edema, and tenderness, 3 months after receiving subcutaneous injections of vitamin E to the cheeks for "facial rejuvenation." The patient had noticed initial symptoms within 3 days, and her symptoms progressively worsened over time (112331).
Gastrointestinal ...Orally, vitamin E supplementation has been associated with abdominal pain, nausea, diarrhea, or flu-like symptoms (85040,85323). Intravenously, large doses of vitamin E in premature infants are associated with an increased risk of necrotizing enterocolitis and sepsis (85083,85231).
Genitourinary ...There is contradictory evidence about the effect of vitamin E on prostate cancer risk. One large-scale population study shows that males who take a multivitamin more than 7 times per week and who also take a separate vitamin E supplement have a significantly increased risk of developing prostate cancer (15607). In a large-scale clinical trial (The SELECT trial) in males over the age of 50 years, taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily increased the risk of developing prostate cancer by 17% when compared with placebo. However, the difference in prostate cancer risk between vitamin E and placebo became significant only 3 years after patients stopped taking supplementation and were followed in an unblinded fashion. Interestingly, patients taking vitamin E plus selenium did not have a significantly increased risk of prostate cancer (17688).
Hematologic ...High doses of vitamin E might increase the risk of bleeding due to antagonism of vitamin K-dependent clotting factors and platelet aggregation. Patients with vitamin K deficiencies or taking anticoagulant or antiplatelet drugs are at a greater risk for bleeding (4098,4844,11999,34596,34538,34626,34594,112162).
Neurologic/CNS ...There is concern that vitamin E might increase the risk of hemorrhagic stroke (16708,34594,34596,108641). In one clinical study, there was a higher incidence of hemorrhagic stroke in male smokers taking all-rac-alpha-tocopherol (synthetic vitamin E) for 5-8 years compared to those not taking vitamin E (3949). Other studies lasting from 1.4-4.5 years and using either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) showed no significantly increased risk for stroke (2307,3896,3936). A meta-analysis of studies shows that vitamin E in doses of 300-800 IU daily, including both natural and synthetic forms, does not significantly affect total stroke risk. However, it significantly increases the risk of hemorrhagic stroke by 22%. This means that there will be one additional hemorrhagic stroke for every 1250 patients taking vitamin E. In contrast to this finding, the analysis also found that vitamin E significantly reduces the risk of ischemic stroke by 10%. This means that one ischemic stroke will be prevented for every 476 patients taking vitamin E (14621). In patients with moderately severe Alzheimer disease, taking vitamin E 2000 IU for 2 years has been associated with a modest, but significant, increase in falls and episodes of syncope when compared to placebo (4635).
Pulmonary/Respiratory ...When inhaled, vitamin E acetate is thought to play a role in the development of e-cigarette, or vaping, product-use associated lung injury (EVALI). Although a causal link has not yet been determined, in two case series, vitamin E acetate has been found in most bronchoalveolar lavage samples taken from the primary site of lung injury in patients with EVALI, whereas no vitamin E was found in healthy control samples. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. EVALI has resulted in death in some patients (101062,102970).
Other ...In an analysis of 3 trials, taking vitamin E 400 IU with vitamin C 1000 mg daily for 14-22 weeks during gestation appears to increase the risk of gestational hypertension by 30% compared to placebo in patients at risk of pre-eclampsia. However, the risk of pre-eclampsia itself was not increased (83450).
