| Ingredients | Amount Per Serving |
|---|---|
| 50 mg | |
| 400 mcg | |
| 0.8 mcg | |
| 133 mcg | |
| 433 mcg | |
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Proprietary Blend
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1.23 mL |
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(root)
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(whole)
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(root)
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(flower whole)
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Vegetable Glycerin, purified water Note: pH neutral
Below is general information about the effectiveness of the known ingredients contained in the product Zenapin-IR. 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 Zenapin-IR. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
POSSIBLY SAFE ...when used orally and appropriately, short-term. Ashwagandha has been used with apparent safety in doses of up to 1250 mg daily for up to 6 months (3710,11301,19271,90649,90652,90653,97292,101816,102682,102683) (102684,102685,102687,103476,105824,109586,109588,109589,109590). ...when used topically. Ashwagandha lotion has been used with apparent safety in concentrations up to 8% for up to 2 months (111538).
PREGNANCY: LIKELY UNSAFE
when used orally.
Ashwagandha has abortifacient effects (12).
LACTATION:
Insufficient reliable information available; avoid using.
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 in amounts commonly found in foods. German chamomile has Generally Recognized as Safe (GRAS) status in the US (4912,110318).
POSSIBLY SAFE ...when used orally, for medicinal purposes, short-term. German chamomile has been used with apparent safety at doses of up to 1500 mg daily for up to 26 weeks (6655,12724,12729,13089,19377,19716,104806,111380). ...when applied topically. A lotion containing 0.2% microencapsulated German chamomile extract has been applied to the skin with apparent safety for up to 35 days (108993). ...when used topically as an oral rinse (99853).
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
Preliminary clinical research suggests that several multi-ingredient products containing German chamomile are safe in infants when used for up to 4 weeks (16735,19705,19715,96278). ...when used topically and appropriately, short-term. Six drops of oil infused with German chamomile flower has been applied nightly with apparent safety for up to 6 weeks in children 6-18 years old (98621).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally, short-term. Kava extracts have been used safely in clinical trials under medical supervision for up to 6 months (2093,2094,2095,4032,7325,15046,15130,18314,18316,18318)(18320,29663,29671,98980,102086,112642). Historically, there has been some concern that kava preparations could induce hepatotoxicity and liver failure in patients taking relatively normal doses, short-term. At least 100 cases of liver toxicity following kava use have been reported. Although liver toxicity is more frequently associated with prolonged use of very high doses (6401,57346), in some cases the use of kava for as little as 1-3 months has been associated with the need for liver transplants, and even death (390,7024,7068,7086,7096,17086,57252)(57254,57297). However, some experts question the clinical validity of several of these cases (11369,11371).
PREGNANCY: POSSIBLY UNSAFE
when used orally.
There is some concern that pyrone constituents in kava can cause loss of uterine tone (19); avoid using.
LACTATION: POSSIBLY UNSAFE
when used orally.
There is concern that the toxic pyrone constituents of kava can pass into breast milk (19); avoid using.
LIKELY SAFE ...when used orally as a flavoring in foods. The US Food and Drug Administration (FDA) lists passion flower as a permitted food flavoring additive, to be used in the minimum quantity necessary (91203).
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Passion flower extract has been used with apparent safety at doses up to 800 mg daily for up to 8 weeks (88198,102866). A specific passion flower extract (Pasipay, Iran Darouk Pharmaceutical Company) has been safely used at a dose of 45 drops daily for up to one month (8007,95036). Also, a tea prepared by steeping 2 grams of the dried aerial parts of passion flower in 250 mL of boiling water for 10 minutes has been used nightly for 7 nights (17374). There is insufficient reliable information available about the safety of passion flower when used topically.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
A specific passion flower product (Pasipay, Iran Darouk Pharmaceutical Company) has been used safely in children aged 6-13 years at a dose of 0.04 mg/ kg daily for 8 weeks (88197).
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Some case reports suggest that passion flower use during the first and second trimesters of pregnancy may be associated with an increased risk for premature rupture of membranes and meconium aspiration syndrome; however, causality has not been confirmed (97279). The alkaloids harman and harmaline, which are sometimes found in passion flower, have been reported to have uterine stimulant activity (4,11020,95037). It is not known whether these constituents are present in sufficient quantities to have an effect.
LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately, short-term. L-theanine has been used safely in clinical research in doses of up to 900 mg daily for 8 weeks (12188,36439,96331,96332,96334,96341,97923,101986,104976). There is insufficient reliable information available about the safety of L-theanine when used long-term.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
A specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg twice daily has been used safely in males aged 8-12 years for up to 6 weeks (91744).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
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.
Below is general information about the interactions of the known ingredients contained in the product Zenapin-IR. 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, taking ashwagandha with antidiabetes drugs might increase the risk of hypoglycemia.
 Details
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Theoretically, taking ashwagandha with antihypertensive drugs might increase the risk of hypotension.
Details
Animal research suggests that ashwagandha might lower systolic and diastolic blood pressure (19279). Theoretically, ashwagandha might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.
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Theoretically, taking ashwagandha might increase the sedative effects of benzodiazepines.
Details
There is preliminary evidence that ashwagandha might have an additive effect with diazepam (Valium) and clonazepam (Klonopin) (3710). This may also occur with other benzodiazepines.
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Theoretically, taking ashwagandha might increase the sedative effects of CNS depressants.
Details
Ashwagandha seems to have sedative effects. Theoretically, this may potentiate the effects of barbiturates, other sedatives, and anxiolytics (3710).
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Theoretically, ashwagandha might decrease the levels and clinical effects of CYP1A2 substrates.
Details
In vitro research shows that ashwagandha extract induces CYP1A2 enzymes (111404).
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Theoretically, ashwagandha might decrease the levels and clinical effects of CYP3A4 substrates.
Details
In vitro research shows that ashwagandha extract induces CYP3A4 enzymes (111404).
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Theoretically, taking ashwagandha with hepatotoxic drugs might increase the risk of liver damage.
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Theoretically, taking ashwagandha might decrease the effects of immunosuppressants.
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Ashwagandha might increase the effects and adverse effects of thyroid hormone.
Details
Concomitant use of ashwagandha with thyroid hormones may cause additive therapeutic and adverse effects. Preliminary clinical research and animal studies suggest that ashwagandha boosts thyroid hormone synthesis and secretion (19281,19282,97292). In one clinical study, ashwagandha increased triiodothyronine (T3) and thyroxine (T4) levels by 41.5% and 19.6%, respectively, and reduced serum TSH levels by 17.4% from baseline in adults with subclinical hypothyroidism (97292).
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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, German chamomile might have additive effects when used with CNS depressants.
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Theoretically, large amounts of German chamomile might reduce the effectiveness of oral contraceptives.
Details
In vitro, German chamomile has demonstrated antiestrogenic activity (12728). Theoretically, concomitant use of large amounts of German chamomile might interfere with contraceptive drugs through competition for estrogen receptors.
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Theoretically, German chamomile might inhibit CYP1A2 and increase levels of drugs metabolized by these enzymes.
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Theoretically, German chamomile might inhibit CYP2C9 and increase levels of drugs metabolized by these enzymes.
Details
In vitro evidence shows that German chamomile might inhibit CYP2C9 (19720). So far, this interaction has not been reported in humans. However, there might be an increase in the levels of drugs metabolized by CYP2C9 in patients taking German chamomile.
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Theoretically, German chamomile might inhibit CYP2D6 and increase levels of drugs metabolized by these enzymes.
Details
In vitro evidence shows that German chamomile might inhibit CYP2D6 (19720). So far, this interaction has not been reported in humans. However, there might be an increase in the levels of drugs metabolized by CYP2D6 in patients taking German chamomile.
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Theoretically, German chamomile might inhibit CYP3A4 and increase levels of drugs metabolized by these enzymes.
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Theoretically, large amounts of German chamomile might reduce the effectiveness of estrogens.
Details
In vitro, German chamomile has demonstrated antiestrogenic activity (12728). Theoretically, large amounts of German chamomile might interfere with hormone replacement therapy through competition for estrogen receptors.
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Theoretically, large amounts of German chamomile might interfere with the activity of tamoxifen.
Details
In vitro, German chamomile has demonstrated antiestrogenic activity (12728).
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German chamomile might increase the effects of warfarin and increase the risk of bleeding.
Details
In one case, a 70-year-old female taking warfarin developed retroperitoneal hematoma and bilateral recti muscle bleeding along with an INR of 7.9 following ingestion of German chamomile tea 4-5 cups daily and use of a topical chamomile-based lotion applied 4-5 times daily (14309).
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Combining kava with alcohol may increase the risk of sedation and/or hepatotoxicity.
Details
Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Additionally, kava has been associated with over 100 cases of hepatotoxicity. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that alcohol not be used with kava (110318). |
Combining kava with CNS depressants can have additive sedative effects.
Details
Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that CNS depressants, including alcohol and benzodiazepines, not be used with kava (110318).
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It is unclear if kava inhibits CYP1A2; research is conflicting.
Details
Although in vitro research and a case report suggest that kava inhibits CYP1A2 (8743,12479,88593), more robust clinical evidence shows that kava has no effect on CYP1A2. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP1A2 activity (13536,98979).
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Theoretically, kava might increase levels of CYP2C19 substrates.
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Theoretically, kava might increase levels of CYP2C9 substrates.
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It is unclear if kava inhibits CYP1A2; research is conflicting.
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Kava might increase levels of CYP2E1 substrates.
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In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days inhibited the metabolism of CYP2E1 substrates (13536).
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It is unclear if kava inhibits CYP3AA; research is conflicting.
Details
Although in vitro research suggests that kava inhibits CYP3A4 (8743,12479), more robust clinical evidence shows that kava has no effect on CYP3A4. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP3A4 activity (13536,98979).
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Combining kava and haloperidol might increase the risk of cardiovascular adverse effects and hypoxia.
Details
Atrial flutter and hypoxia has been reported for a patient who received intramuscular injections of haloperidol and lorazepam after using kava orally. The side effects were attributed to kava-induced inhibition of CYP2D6, but might also have been related to additive adverse effects with the concomitant use of haloperidol, lorazepam, and kava (88593).
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Theoretically, using kava with hepatotoxic drugs might increase the risk of liver damage.
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It is unclear if kava inhibits P-glycoprotein (P-gp); research is conflicting.
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In vitro research shows that kava can inhibit P-gp efflux (15131). However, a clinical study in healthy volunteers shows that taking kava standardized to provide 225 mg kavalactones daily for 14 days does not affect the pharmacokinetics of digoxin, a P-gp substrate (15132,98979). It is possible that the use of other P-gp substrates or higher doses of kava might still inhibit P-gp.
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Taking kava with ropinirole might increase the risk for dopaminergic toxicity.
Details
A case of visual hallucinations and paranoid delusions has been reported for a patient who used kava in combination with ropinirole. The adverse effects were attributed to kava-induced inhibition of CYP1A2, which may have reduced the metabolism of ropinirole, resulting in excessive dopaminergic stimulation (88593).
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Concomitant use of passion flower with sedative drugs might cause additive effects and side effects.
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Theoretically, passion flower might decrease the effects of CYP3A4 substrates.
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In vitro research suggests that passion flower can induce CYP3A4 enzymes, albeit to a much lower degree than rifampin, a known CYP3A4 inducer (110704).
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Theoretically, passion flower might reduce the bioavailability of OATP2B1 and OATP1A2 substrates.
Details
In vitro research shows that the passion flower constituents apigenin and vitexin inhibit OATP2B1 and OATP1A2. This inhibition may be dose-dependent. One specific high-flavonoid passion flower extract (Valverde) seems to inhibit OATP2B1 and OATP1A2, while another extract with a lower flavonoid concentration (Arkocaps) shows less potent inhibition (105095). OATPs are responsible for the uptake of drugs and other compounds into the body; however, the specific activities of OATP2B1 and OATP1A2 are not well characterized.
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Theanine might lower blood pressure, potentiating the effects of antihypertensive drugs.
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Theoretically, theanine might have additive sedative effects when used in conjunction with CNS depressants. However, it is unclear if this concern is clinically relevant.
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Trimethoprim might increase blood levels of thiamine.
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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.
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Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.
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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.
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High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.
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Below is general information about the adverse effects of the known ingredients contained in the product Zenapin-IR. 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, ashwagandha seems to be well-tolerated.
Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, nausea, and vomiting. However, these adverse effects do not commonly occur with typical doses.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about acute hepatitis, acute liver failure, hepatic encephalopathy, the need for liver transplantation, and death due to liver failure with ashwagandha treatment.
Dermatologic ...Orally, dermatitis has been reported in three of 42 patients in a clinical trial (19276).
Endocrine ...A case report describes a 73-year-old female who had taken an ashwagandha root extract (unspecified dose) for 2 years to treat hypothyroidism which had been previously managed with levothyroxine. The patient was diagnosed with hyperthyroidism after presenting with supraventricular tachycardia, chest pain, tremor, dizziness, fatigue, irritability, hair thinning, and low thyroid stimulating hormone (TSH) levels. Hyperthyroidism resolved after discontinuing ashwagandha (108745). Additionally, an otherwise healthy adult who was taking ashwagandha extract orally for 2 months experienced clinical and laboratory-confirmed thyrotoxicosis. Thyrotoxicosis resolved 50 days after discontinuing ashwagandha, without other treatment (114111). Another case report describes a 37-year-old female who presented with moderate symptomatic hyponatremia secondary to adrenal insufficiency after chronic consumption of ashwagandha for 2 years. This subject was effectively managed with oral hydrocortisone (114790).
Gastrointestinal ...Orally, large doses may cause gastrointestinal upset, diarrhea, and vomiting secondary to irritation of the mucous and serous membranes (3710). When taken orally, nausea and abdominal pain (19276,110490,113609) and gastritis and flatulence (90651) have been reported.
Genitourinary ...In one case report, a 28-year-old male with a decrease in libido who was taking ashwagandha 5 grams daily over 10 days subsequently experienced burning, itching, and skin and mucous membrane discoloration of the penis, as well as an oval, dusky, eroded plaque (3 cm) with erythema on the glans penis and prepuce (32537).
Hepatic ...Orally, ashwagandha in doses of 154 mg to 20 grams daily has played a role in several case reports of cholestatic, hepatocellular, and mixed liver injuries. In most of these cases, other causes of liver injury were excluded, and liver failure did not occur. Symptoms included jaundice, pruritus, malaise, fatigue, lethargy, weight loss, nausea, diarrhea, abdominal pain and distension, stool discoloration, and dark urine. Symptom onset was typically 5-180 days from first intake, although in some cases onset occurred after more than 12 months of use (102686,107372,110490,110491,111533,111535,112111,113610,114113). Laboratory findings include elevated aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, serum bilirubin, and international normalized ratio (INR) (112111,113610,114113). In most cases, liver enzymes normalized within 1-5 months after discontinuation of ashwagandha (102686,107372,110491,111535,112111,114113). However, treatment with corticosteroids, lactulose, ornithine, ursodeoxycholic acid, and plasmapheresis, among other interventions, was required in one case (111533). Rarely, use of oral ashwagandha has been reported to cause hepatic encephalopathy, liver failure requiring liver transplantation, and acute-on-chronic liver failure resulting in death (110490,113610).
Neurologic/CNS ...Orally, ashwagandha has been reported to cause drowsiness (110492,113609). Headache, neck pain, and blurry vision have been reported in a 47-year-old female taking ashwagandha, cannabis, and venlafaxine. Imaging over the course of multiple years and hospital admissions indicated numerous instances of intracranial hemorrhage and multifocal stenosis of intracranial arteries, likely secondary to reversible cerebral vasoconstriction syndrome (RCVS) (112113). It is unclear whether the RCVS and subsequent intracranial hemorrhages were precipitated by ashwagandha, cannabis, or venlafaxine.
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 and topically, German chamomile is well tolerated.
Most Common Adverse Effects:
Orally and topically: Allergic reactions and irritation.
Dermatologic ...Topically, German chamomile may cause allergic dermatitis and eczema (9766,9768,10377,110318).
Gastrointestinal ...When used topically as an oral rinse, German chamomile has been reported to cause nausea and burning in the mouth in some patients (99853).
Immunologic ...Orally, German chamomile tea can cause allergic reactions including severe hypersensitivity reactions and anaphylaxis in some patients (567). In one case report, a 47-year-old female who tolerated drinking chamomile tea, reported sneezing, nasal and ocular itching, red and watery eyes, and severe rhinorrhea after 10 years of occupational exposure to German chamomile dust (90542).
Ocular/Otic ...If used near the eyes, German chamomile can cause irritation (10377).
General
...Orally, kava seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, dry mouth, dizziness, gastrointestinal upset, headache, memory problems, tremor.
Serious Adverse Effects (Rare):
Orally: There have been over 100 reported cases of hepatotoxicity and a few reported cases of rhabdomyolysis.
Cardiovascular ...Long-term use of very large amounts of kava, especially in high doses (400 mg kava pyrones daily), has been associated with overall poor health including symptoms of low body weight, reduced protein levels, puffy face, hematuria, increased red blood cell volume, decreased platelets and lymphocytes, and possibly pulmonary hypertension (4032,6402). Tachycardia and electrocardiogram (ECG) abnormalities (tall P waves) have been reported in heavy kava users (6402).
Dermatologic ...Orally, kava can cause allergic skin reactions, including sebotropic eruptions, delayed-type hypersensitivity, or urticarial eruption (4032,11370,28489,57277,57325,57343,114683). In one case of kava-associated urticarial eruption, biopsy revealed neutrophilic sebaceous glands with lymphocytic infiltrate (114683). Chronic use of high doses of kava has also been associated with kava dermopathy, which consists of reddened eyes; dry, scaly, flaky skin; and temporary yellow discoloration of the skin, hair, and nails (6240,6401,8414,8417,11370,28485,57342). This pellagra-like syndrome is unresponsive to niacinamide treatment (6240,7728,11370). The cause is unknown, but may relate to interference with cholesterol metabolism (6240). Kava's adverse effects on liver function might also contribute to kava dermopathy (6401,8417). Kava dermopathy usually occurs within three months to one year of regular kava use, and resolves when the kava dose is decreased or discontinued (6401,8414). Kava dose should be decreased or discontinued if kava dermopathy occurs (6401). In addition to kava cessation, oral or topical corticosteroids have been described as treatment options in some cases of kava associated dermatitis (114683).
Gastrointestinal ...Orally, kava may cause gastrointestinal upset, nausea, or dry mouth (2093,2094,4032,11370,18316,57228,57343).
Hematologic ...Orally, chronic use of very high doses of kava has been associated with increased red blood cell volume, reduced platelet volume, reduced lymphocyte counts, and reduced serum albumin (6402,57258). Hematuria has also been reported anecdotally (6402).
Hepatic
...Since the early 2000's, hepatotoxicity has been a particular concern with kava.
Worldwide, there have been at least 100 reported cases of hepatotoxicity following use of kava products (7024,7068,7086,7096,11795,17086)(57252,57254,57297). However, some experts question the clinical validity of several of these cases (11369,11371). Some cases were reported multiple times and in some cases it was unlikely that kava was the causative agent (7068,57253).
In susceptible patients, symptoms can show up after as little as 3-4 weeks of kava use. Symptoms include yellowed skin (jaundice), fatigue, and dark urine (7024,7068). Liver function tests can be elevated after 3-8 weeks of use, possibly followed by hepatomegaly and onset of encephalopathy (7024). Kava has also been reported to exacerbate hepatitis in patients with a history of recurrent hepatitis (390). However, in many cases, symptoms seem to resolve spontaneously, and liver function tests usually normalize within eight weeks (390,7068).
Liver toxicity is more frequently associated with prolonged use of very high doses (6401,57346). But there is some concern that even short-term use of kava in typical doses might cause acute hepatitis in some patients, including severe hepatocellular necrosis. The use of kava for as little as 1-3 months has resulted in need for liver transplant and death, although these events are rare (7024,7068,7086,7096,17086).
There is some speculation that the type of extraction method could be responsible for these rare cases of hepatotoxicity (17086). The "Pacific kava paradox" holds that while the alcohol and acetone extracts of kava used for commercial products cause liver toxicity, the traditional kava rhizome preparation mixed with water might not be toxic (11794,17086). However, a more recent analysis reports cases of hepatotoxicity from the aqueous kava extract and suggests that kava's hepatotoxic effects may be due to contaminants such as mold (29676). Other suggested causes of hepatotoxicity include quality of the kava plant, concomitant medications, large doses and prolonged use, and toxic constituents and metabolites of kava (57300,88532).
Some commercial kava extracts contain parts of the stems and other aerial parts in addition to the rhizome, and it has been suggested that a constituent called pipermethysine, which is only found in these aerial parts, might be partly responsible for hepatotoxicity (17086). Other constituents of kava which might contribute to hepatotoxicity are kavalactones, which are metabolized by cytochrome P450 (CYP450) enzymes in the liver. Reactive metabolites are produced which conjugate with glutathione, and might deplete glutathione in a similar manner to acetaminophen (17086). Increased levels of gamma-glutamyl transferase, involved in the production of glutathione, have been reported in chronic kava users (17086). One of the enzymes involved in production of reactive metabolites from kavalactones is cytochrome P450 2E1 (CYP2E1), which is induced by chronic alcohol intake. Alcohol may also compete for other enzymes which clear kavalactone metabolites from the body. This might explain the observation that alcohol ingestion seems to increase the risk of hepatotoxicity with kava (7068,17086).
There is also speculation that "poor metabolizers" or those patients with deficiency in the cytochrome P450 2D6 (CYP2D6) isoenzyme, which occurs in up to 10% of people of European descent, may be at increased risk for hepatotoxic effects from kava (7068). This deficiency has not been found in Pacific Islanders. However, this theory has not been confirmed.
Due to the concerns regarding the potential hepatotoxicity of kava, kava supplements were withdrawn from European and Canadian markets in 2002 (7086). However, many of the market withdrawals of kava have been lifted after re-evaluation of kava suggested that the risk of hepatotoxicity was minimal (91593,91594,91615). Still, clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend exercising caution when using kava in patients with preexisting liver issues (110318). Until more is known, tell patients to use kava cautiously and recommend liver function tests for routine users or those with underlying liver disease.
Immunologic ...Sjögren syndrome has been associated with an herbal supplement containing kava, echinacea, and St. John's wort. Echinacea may have been the primary cause, because Sjögren syndrome is an autoimmune disorder. The role of kava in this syndrome is unclear (10319).
Musculoskeletal
...Kava has been linked with reports of rhabdomyolysis.
A 34-year-old man who consumed kava tea several times a week developed rhabdomyolysis with a peak creatine kinase level of 32,500 units/liter (18212). However, there is speculation that this might have been due to product impurities rather than kava itself. Another case report describes rhabdomyolysis with myoglobinuria and a creatine kinase level of 100,500 units/liter in a 29-year-old man who had taken kava in combination with guarana and ginkgo biloba (18213).
Cases of ataxia and tremors have been reported in patients taking single doses of kava powder 205 grams (11373).
Neurologic/CNS
...Orally, kava may cause headache, dizziness, and drowsiness (4032,6402,11370,11372,11373,18316,112642).
It might also cause extrapyramidal side effects such as involuntary oral and lingual reflexes, twisting movements of the head and trunk, tremors, and other parkinsonian-like symptoms possibly due to dopamine antagonism (534,4055,7727,8415,102086). In one clinical trial, patients taking a kava supplement providing 120 mg of kavalactones twice daily for 16 weeks had a 3.2-fold greater risk of experiencing tremors when compared with patients taking placebo (102086). Theoretically, kava may worsen symptoms in patients with Parkinson disease or precipitate Parkinson-like symptoms in certain patients (4055,7727). Unlike benzodiazepines, kava is not thought to be associated with impaired cognitive function (2097,2098,11373,57332,57333). However, one clinical trial shows that taking a kava supplement providing 120 mg of kavalactones twice daily for 16 weeks increases the risk for memory impairment by 55% when compared with placebo (102086).
Orally, kava may reduce alertness and impair motor coordination in a dose-dependent manner. Some preliminary reports have noted a decline in accuracy of visual attention and slower reaction times after kava ingestion, particularly at higher doses and in combination with alcohol (11373,95926). Population research has also found that ingesting large amounts of kava tea (typically 50 times higher than what is used medicinally in the US) within a 12-hour period before driving increases the odds of being involved in a serious motor vehicle crash resulting in death or serious injury by almost 5-fold when compared to not drinking kava tea (95927). Use of normal doses of kava may also affect the ability to drive or operate machinery, and driving under the influence (DUI) citations have been issued to individuals observed driving erratically after drinking large amounts of kava tea (535). However, in computer-based driving simulator tests, there are no reported adverse effects of kava on performance (95926). Additionally, other research shows that consuming over 4400 mg of kavalactones over a 6-hour kava session does not seem to impair alertness or attention when compared with non-kava drinkers (103867). Similar research using a specific psychometric tool (Brain Gauge) shows that consuming approximately 3680 mg of kavalactones in a 6-hour kava session seems to impair temporal order judgment, which is associated with the brain's ability to track the order of events, when compared with non-kava drinkers. However, it does not seem to impact cognitive domains related to focus, accuracy, timing perception, plasticity, or fatigue when compared with non-kava drinkers (110435).
Ocular/Otic ...Orally, high doses of kava may cause eye irritation (7728). There is one case report of impaired accommodation and convergence, increased pupil diameter, and oculomotor disturbance following a single dose of kava (9920).
Psychiatric ...Apathy has been associated with traditional use of kava at high doses (57313).
Pulmonary/Respiratory ...Orally, kava may cause shortness of breath, possibly due to pulmonary hypertension (6402).
Renal ...Orally, kava may cause acute urinary retention (57349).
General
...Orally, passion flower is well tolerated.
Most Common Adverse Effects:
Orally: Confusion, dizziness, hypersensitivity, and sedation.
Cardiovascular ...There is a case report involving a 34-year-old female who was hospitalized with severe nausea, vomiting, drowsiness, prolonged QT interval, and episodes of nonsustained ventricular tachycardia following use of passion flower extract tablets (Sedacalm, Bioplus Healthcare), 1500 mg on day 1 and 2000 mg on day 2 to relieve stress. All symptoms resolved within one week after passion flower was discontinued (6251).
Genitourinary ...The alkaloids harman and harmaline, which are sometimes found in small amounts in passion flower, have been reported to have uterine stimulant activity (4,11020,95037).
Hematologic ...Orally, passion flower has been reported to cause epistaxis in one clinical trial (95038). Vasculitis has also been reported with use of a specific herbal product (Relaxir) produced mainly from the fruits of passion flower (6).
Hepatic ...There is debate about whether passion flower contains cyanogenic glycosides. Several related Passiflora species do contain these constituents (3), including Passiflora edulis, which is associated with liver and pancreatic toxicity (7).
Immunologic
...An idiosyncratic hypersensitivity reaction characterized by urticaria and cutaneous vasculitis has been reported in a 77-year-old male with rheumatoid arthritis after taking a specific combination product that included passion flower extract (Naturest) (68308).
It is unclear if these effects were caused by passion flower or other ingredients.
In clinical trials, passion flower has been reported to cause allergy symptoms including sinus irritation; however, the frequency of these events was statistically nonsignificant when compared to treatment with midazolam 15 mg (95038).
Musculoskeletal ...Orally, passion flower has been reported to cause muscle relaxation in a clinical trial (95038).
Neurologic/CNS ...Orally, sedation, dizziness, ataxia, and confusion have been reported in clinical trials. However, these events generally do not necessitate discontinuation (8007,15391,15392,95036,95038). Altered consciousness has been reported with use of a specific herbal product (Relaxir) produced mainly from the fruits of passion flower (6).
General
...Orally, L-theanine seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, headaches.
Neurologic/CNS
...Orally, L-theanine may cause headaches (36439).
Patients have also reported drowsiness, increased duration of sleep, and increased dream activity after oral L-theanine use (96331).
A case of subtle facial tic starting within 4 days of taking L-theanine 400 mg daily has been reported for a pediatric patient. Although the tics reportedly ceased once theanine was discontinued, the child had exhibited tics in the past. Therefore, the adverse effect was not thought to be related to L-theanine (91744).
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).
