Two caplets contain: Para-gone Blend 600 mg: Garlic bulb, Pau d'Arco , Plantago Ovata , Papaya leaf, Pumpkin seed • Mushroom Blend 500 mg: Coriolus versicolor , Grifola frondosa , Lentinula Edodes , Schizophyllum Commune • Intestinal Blend 325 mg: Caprylic Acid Caprylic Acid (Form: from Magnesium Caprylate, and Calcium Caprylate) , Ginger , Slippery Elm , Rosemary • Systemic Botanical Blend 190 mg: Grapefruit whole powder, Lemon peel powder, Black Walnut , Oregon Grape , Wormwood . Other Ingredients: Microcrystalline Cellulose, Pirosil PS 200, Magnesium Stearate.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
Below is general information about the effectiveness of the known ingredients contained in the product CapraSite. 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
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
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 CapraSite. 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 the fruit (nut) is consumed in amounts normally found in food.
POSSIBLY UNSAFE ...when the bark is used orally or topically, due to its juglone content (2). When applied topically, juglone-containing bark can cause skin irritation. When used orally on a daily basis, the juglone-containing bark of a related species (English walnut) is associated with increased risk of tongue cancer and lip leukoplakia (2,12). There is insufficient reliable information available about the safety of the leaf or hull when used orally as a medicine or when applied topically.
PREGNANCY AND LACTATION: LIKELY SAFE
when the fruit (nut) is consumed in amounts normally found in foods.
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when the bark is used orally or topically (12); avoid using.
There is insufficient reliable information available about the safety of black walnut leaf or hull when used orally in medicinal amounts during pregnancy or lactation; avoid using.
LIKELY SAFE ...when used orally with appropriate fluid intake (93216). Blond psyllium preparations have been safely used in doses up to 20 grams per day for up to 6 months (1376,2324,2327,6261,6262,8060,8061,8066,8423,9422) (10095,13102,22961,22962,22963,22964,22966,54260,22968,22969) (22970,22972,22973,22976,22977,22978,22979,22980,22981,22986) (22987,22988,22989,22990,22992,22993,22994,22995,22996,22998) (23402,23403,23404,23405,92198,106859). The U.S. Food and Drug Administration (FDA) requires over-the-counter medicines that contain dry or incompletely hydrated psyllium to carry a warning that they should be taken with at a least a full glass of liquid to reduce the risk of choking. This labeling also applies to foods containing psyllium that are marketed with a health claim regarding coronary heart disease (93217,93218).
POSSIBLY SAFE ...when used in eye drops. Blond psyllium mucilage has been used with apparent safety in eye drops four times daily for 6 weeks (105274). There is insufficient reliable information available about the safety of blond psyllium when used topically.
LIKELY UNSAFE ...when used orally without adequate fluid intake due to the risk for choking and gastrointestinal obstruction (93218). ...when granular dosage forms containing blond psyllium are used as over the counter (OTC) laxatives. The U.S. Food and Drug Administration (FDA) states that these granular dosage forms are not generally recognized as safe and effective as OTC laxatives due to an increased risk of choking and gastrointestinal obstruction (93219).
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
Blond psyllium husk has been used with apparent safety in doses up to 12 grams daily for 4 weeks (110763).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (272).
LIKELY SAFE ...when used orally in amounts commonly found in foods. Caprylic acid has Generally Recognized as Safe (GRAS) status in the US (19507).
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Caprylic acid has been safely used in clinical research at a daily dose of 16 mg/kg for 20 days (97662,100176).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those found in foods.
LIKELY SAFE ...when the fruit is consumed orally in food amounts (13527). There is insufficient reliable information available about the safety of European barberry when used orally in medicinal amounts or when used topically.
CHILDREN: LIKELY UNSAFE
when used orally in newborns.
The berberine constituent of European barberry can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589). There is insufficient reliable information available about the safety of European barberry when used orally in older children.
PREGNANCY: LIKELY UNSAFE
when used orally.
Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).
LACTATION: LIKELY UNSAFE
when used orally.
Berberine and other harmful constituents can be transferred to the infant through breast milk (2589).
LIKELY SAFE ...when used orally and appropriately. Garlic has been used safely in clinical studies lasting up to 7 years without reports of significant toxicity (1873,4782,4783,4784,4785,4786,4787,4789,4790,4797)(4798,6457,6897,14447,96008,96009,96014,102016,102670,103479)(107238,107239,107352,108607,110722,111763).
POSSIBLY SAFE ...when used topically. Garlic-containing gels, lipid-soluble garlic extracts, garlic pastes, and garlic mouthwashes have been safely used in clinical research for up to 3 months (4766,4767,8019,15030,51330,51386). ...when used intravaginally. A vaginal cream containing garlic and thyme has been safely used nightly for 7 nights (88387).
POSSIBLY UNSAFE ...when raw garlic is used topically (585). Raw garlic might cause severe skin irritation when applied topically.
PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).
PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts.
Garlic is reported to have abortifacient activity (11020). One study also suggests that garlic constituents are distributed to the amniotic fluid after a single dose of garlic (4828). However, there are no published reports of garlic adversely affecting pregnancy. In clinical research, garlic 800 mg daily was used during the third trimester of pregnancy with no reported adverse outcomes (9201,51626). There is insufficient reliable information available about the safety of topical garlic during pregnancy.
LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).
LACTATION: POSSIBLY UNSAFE
when used orally in amounts greater than those found in foods.
Several small studies suggest that garlic constituents are secreted in breast milk, and that nursing infants of mothers consuming garlic are prone to extended nursing (3319,4829,4830). There is insufficient reliable information available about the safety of topical garlic during lactation.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately for up to 8 weeks.
Garlic extract 300 mg three times daily has been used with apparent safety for up 8 weeks in children ages 8-18 years (4796). There is insufficient reliable information available about the safety of garlic when used over longer durations or in higher doses.
CHILDREN: POSSIBLY UNSAFE
when raw garlic is used topically.
Raw garlic might cause severe skin irritation when applied topically (585,51210).
LIKELY SAFE ...when used orally and appropriately. Ginger has been safely used in multiple clinical trials (721,722,723,5343,7048,7084,7085,7400,7623,11346)(12472,13080,13237,13244,17369,17928,17929,89889,89890,89894)(89895,89898,89899,90102,96252,96253,96259,96260,96669) (101760,101761,101762,103359,107903).
POSSIBLY SAFE ...when used topically and appropriately, short-term (89893,89897).
CHILDREN: LIKELY SAFE
when consumed in the amounts typically found in foods.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term.
Ginger powder has been used with apparent safety at a dose of up to 750 mg daily for 4 days in girls aged 14-18 years (96255).
PREGNANCY: LIKELY SAFE
when consumed in the amounts typically found in foods.
Ginger is considered a first-line nonpharmacological treatment option for nausea in pregnancy by the American College of Obstetrics and Gynecology (ACOG) (111601). However, it should not be used long-term or without medical supervision and close monitoring.
PREGNANCY: POSSIBLY SAFE
when used for medicinal purposes.
Despite some early reports of adverse effects (721,7083) and one observational study suggesting that taking dried ginger and other herbal supplements during the first 20 weeks of pregnancy marginally increased the chance of stillbirth (96254), most research shows that ginger is unlikely to cause harm to the baby. The risk for major malformations in infants of parents who took ginger when pregnant does not appear to be higher than the baseline rate of 1% to 3% (721,1922,5343,11346,13071,13080,96254). Also, other research suggests that ginger intake during various trimesters does not significantly affect the risk of spontaneous abortion, congenital malformations, stillbirth, perinatal death, preterm birth, low birth weight, or low Apgar scores (18211,90103). Ginger use has been associated with an increase in non-severe vaginal bleeding, including spotting, after week 17 of pregnancy (18211).
LACTATION: LIKELY SAFE
when consumed in the amounts typically found in foods.
There is insufficient reliable information available about the safety of ginger when used for medicinal purposes; avoid amounts greater than those found in foods.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapefruit has Generally Recognized as Safe status (GRAS) in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. A grapefruit seed extract has been safely used in clinical research (5866). In addition, capsules containing grapefruit pectin 15 grams daily have been used in clinical research for up to 16 weeks (2216).
POSSIBLY UNSAFE ...when used orally in excessive amounts. Preliminary population research shows that consuming a quarter or more of a whole grapefruit daily is associated with a 25% to 30% increased risk of postmenopausal breast cancer (14858). Grapefruit juice is thought to reduce estrogen metabolism resulting in increased endogenous estrogen levels. More evidence is needed to validate this finding.
PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of using medicinal amounts of grapefruit during pregnancy and lactation; avoid using.
LIKELY SAFE ...when used in amounts commonly found in foods. Lemon has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY SAFE ...when inhaled in amounts used for aromatherapy, short-term. Lemon essential oil has been used with apparent safety as aromatherapy for up to 2 weeks in clinical research (93475,98128,98129). There is insufficient reliable information available about the safety of lemon when used topically, or when used orally or intranasally in medicinal amounts.
PREGNANCY AND LACTATION:
Insufficient reliable information available.
Avoid using in amounts greater than those typically found in foods.
POSSIBLY SAFE ...when used orally and appropriately, short-term. Lentinan has been used with apparent safety in doses of 15 mg daily for 12 weeks (34779). ...when used intravenously under the supervision of a healthcare professional. Lentinan has been used with apparent safety in conjunction with chemotherapy at doses of 1-2 mg twice daily or twice monthly (96863). ...when used intrapleurally under the supervision of a healthcare professional. Lentinan has been used with apparent safety in conjunction with cisplatin at doses of 1-10 mg, up to 3 times weekly, for a total of up to 8 doses (103368,103369).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately as extracts. A maitake mushroom extract 3 mg/kg twice daily has been used safely for up to 12 weeks (92843). Doses up to 5 mg/kg twice daily of another maitake mushroom extract have been used safely for up to 3 weeks (61239). Maitake mushroom polysaccharides (MMP) 1-1.5 grams daily have also been used safely for up to 2 years (8188).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately (11726,11727,11728,11729,11730,93729). ...when used parenterally and appropriately (2275,2276,2278,11726,11727,11728,11729). There is insufficient reliable information available about the safety of MCTs when used topically.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally in amounts commonly found in food.
POSSIBLY SAFE ...when used topically and appropriately (854,856,857,14000,14333). A specific 10% Oregon grape cream (Relieva, Apollo Pharmaceutical) has been used with apparent safety in studies lasting up to 12 weeks (14000,14333). There is insufficient reliable information available about the safety of Oregon grape when used orally in medicinal amounts.
CHILDREN: LIKELY UNSAFE
when used orally in newborns.
The berberine constituent of Oregon grape can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).
PREGNANCY: LIKELY UNSAFE
when used orally.
Berberine, a constituent of Oregon grape, is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).
LACTATION: LIKELY UNSAFE
when used orally.
Berberine and other harmful constituents can be transferred to the infant through breast milk (2589).
LIKELY SAFE ...when the ripe fruit is used orally in amounts commonly found in foods. Papaya has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY SAFE ...when the leaf extract is used orally and appropriately in medicinal amounts, short term. The leaf extract has been used with apparent safety in doses of up to 3300 mg daily for up to 5 days (102799,102800). ...when the ripe fruit is used topically and appropriately, short term. The fruit has been applied with apparent safety to the gingiva or skin for up to 10 days (93090,93091).
POSSIBLY UNSAFE ...when the unripe fruit containing papaya latex and raw papain is used orally. Raw papain has been reported to cause esophageal perforation (6,93083). ...when papaya latex is used topically. Papaya latex, which contains raw papain, is a severe irritant and vesicant (6).
PREGNANCY: LIKELY SAFE
when the ripe fruit is consumed in amounts commonly found in foods.
PREGNANCY: POSSIBLY UNSAFE
when the unripe fruit containing papaya latex is used orally; avoid using.
There is some concern that crude papain, a constituent of papaya latex, is teratogenic and embryotoxic (6); however, this might be due to extraneous substances rather than papain (11). Some evidence also suggests that high doses of papaya seed extract have abortifacient activity and can adversely affect fetal development (67870). Theoretically, eating large amounts of papaya seeds may have similar effects.
LACTATION: LIKELY SAFE
when the ripe fruit is consumed in amounts commonly found in foods.
There is insufficient reliable information available about the safety of using papaya medicinally; avoid using.
POSSIBLY UNSAFE ...when used orally. The safety of pau d'arco in typical doses is unclear. Serious toxicities have been found with high doses of the lapachol constituent (91939). In patients with cancer, doses of lapachol above 1.5 grams daily were associated with significant gastrointestinal toxicities and an increased risk of bleeding (91939). However, in patients with dysmenorrhea, doses of pau d'arco 1050 mg plus rutin 75 mg daily for up to 8 weeks did not lead to serious adverse effects (114012). There is insufficient reliable information available about the safety of pau d'arco when used topically.
PREGNANCY: POSSIBLY UNSAFE
when used orally in typical doses.
Animal studies have found that lapachol, a constituent of pau d'arco, has teratogenic and abortifacient effects (68314,68315); avoid using. There is insufficient reliable information available about the safety of pau d'arco when used topically in pregnancy; avoid using.
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods.
POSSIBLY SAFE ...when the seed or seed oil is used orally and appropriately in medicinal amounts, short-term. Pumpkin seed has been used with apparent safety in a dose of up to 10 grams daily for up to 12 months (92383). Pumpkin seed oil has been used with apparent safety in a dose of up to 400 mg daily for up to 6 months (92378). There is insufficient reliable information available about the safety of pumpkin seed oil when used topically.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using amounts greater than those found in food.
LIKELY SAFE ...when used orally in amounts typically found in foods. Rosemary has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY SAFE ...when the leaf is used orally and appropriately in medicinal amounts (18). Powdered rosemary leaf has been used with apparent safety as a single dose of up to 1.5 grams (18246,91731) or at a dose of 1-4 grams daily for up to 8 weeks (91727,98536,105327,109561). ...when the essential oil is used topically and appropriately for up to 7 months (5177,91729,109560). ...when the essential oil is used by inhalation as aromatherapy, short-term (7107,18323,105324,109559).
LIKELY UNSAFE ...when the essential oil or very large quantities of rosemary leaf are used orally. Ingestion of undiluted rosemary oil or very large quantities of rosemary leaf can cause serious adverse effects (18,515).
PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts.
Rosemary might have uterine and menstrual flow stimulant effects (4,12,18), and might increase metabolism of estradiol and estrone (18331); avoid using. There is insufficient reliable information available about the safety of rosemary when used topically during pregnancy.
LACTATION:
There is insufficient reliable information available about the safety of using rosemary in medicinal amounts during lactation; avoid using.
LIKELY SAFE ...when consumed in typical food amounts (6).
POSSIBLY SAFE .... ..when the shiitake mushroom extract AHCC is used orally and appropriately. AHCC 4.5-6 grams daily has been used with apparent safety in clinical trials lasting up to 6 months (22926,30419). Population research identified no safety concerns with the use of AHCC 3 grams daily for up to 9 years (30353,94830).
POSSIBLY UNSAFE ...when shiitake mushroom powder is used orally in medicinal amounts. Ingestion of shiitake mushroom powder 4 grams daily for 10 weeks can cause eosinophilia (1149). ...when uncooked shiitake mushroom is ingested. The lentinan component, which is broken down by heat, can cause toxic reactions, including shiitake dermatitis (94354).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid consuming greater than food amounts.
POSSIBLY SAFE ...when used orally and appropriately (4,12,272,512,1740).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
Slippery elm bark has historically been inserted into the cervix to induce abortion. As a result, slippery elm has been reported in some sources to have abortifacient activity. However, there is no reliable information available about whether slippery elm has abortifacient activity when taken orally.
LIKELY SAFE ...when turkey tail mushroom is used orally and appropriately (5477). ...when polysaccharide krestin (PSK) and polysaccharide peptide (PSP) isolates of turkey tail mushroom are used orally and appropriately (1635,1636,1640,1641,1648,1649,1650,1651,1652,1653,1654) (1655,1656,1657,1658,1659,1660,1661,1662,70167,70168,70171,70188,70200,94076). There is insufficient reliable information available about the safety of turkey tail mushroom when used topically or intravaginally.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally in the amounts commonly found in foods. Wormwood extracts are included in bitters, vermouth, absinthe, and other food or drink products (12814,15007). Wormwood products that are thujone-free have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912); however, products containing thujone might not be safe. Wormwood is described in the pharmacopoeia of various European countries. After being banned for a period of time, it is now allowed in European Union countries; however, beverages must not contain thujone in concentrations greater than 35 mg/kg (12814,15007,86551).
POSSIBLY SAFE ...when wormwood products not containing thujone are used orally in medicinal amounts, short-term (93468,93469). A specific product
POSSIBLY UNSAFE ...when wormwood products containing thujone are used orally. Thujone is a neurotoxin that is present in wormwood oil (12617). Seizures, rhabdomyolysis, and acute kidney failure can occur when as little as 10 mL of wormwood oil is ingested (662,12817).
PREGNANCY:
LIKELY UNSAFE .
.when used orally in amounts greater than those found in foods (662,12817). Some wormwood products contain thujone, a neurotoxin. Theoretically, thujone also has potential uterine and menstrual stimulant effects (12617). There is insufficient reliable information available about the safety of wormwood when used topically during pregnancy.
LACTATION:
Insufficient reliable information available; avoid using.
Below is general information about the interactions of the known ingredients contained in the product CapraSite. 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, blond psyllium might reduce the effects of carbamazepine and increase the risk for convulsions.
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Theoretically, taking blond psyllium at the same time as digoxin might reduce digoxin absorption.
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Theoretically, taking blond psyllium at the same time as ethinyl estradiol might alter levels of estradiol.
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Concurrent use of blond psyllium with ethinyl estradiol results in a slight increase in the extent of ethinyl estradiol absorption and a slower rate of absorption. However, this is unlikely to be clinically significant (12421).
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Theoretically, taking blond psyllium at the same time as lithium might reduce lithium absorption.
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Theoretically, blond psyllium might increase the therapeutic and adverse effects of metformin.
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Concurrent use of blond psyllium with metformin slows and increases metformin absorption (99433). To avoid changes in absorption, take psyllium 30-60 minutes after metformin.
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Theoretically, taking blond psyllium at the same time as olanzapine might reduce olanzapine absorption.
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The fiber in blond psyllium might decrease the absorption of olanzapine. A single case report describes a reduction in the effectiveness of olanzapine when it was taken concomitantly with an unspecified type of psyllium 3 grams orally twice daily. This effect was reversed when psyllium was stopped (106858).
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Theoretically, psyllium might increase, decrease, or have no effect on the absorption of oral drugs.
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Psyllium seems to have variable effects on drug absorption. To avoid changes in absorption, take psyllium 30-60 minutes after oral medications. Animal research shows that blond psyllium delays and increases the absorption of metformin and ethinyl estradiol (12421,99433). Conversely, case reports and animal research suggest that blond psyllium might reduce absorption of lithium, digoxin, olanzapine, and carbamazepine (12,18,272,93214,106858). Finally, some pharmacokinetic studies show that psyllium does not affect the absorption of levothyroxine or warfarin (12420,103940).
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Theoretically, caprylic acid might increase the risk of hypotension when used with antihypertensive drugs.
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Animal research suggests that caprylic acid might have positive inotropic effects, resulting in reduced arterial pressure and vascular resistance and increased cardiac output (25805).
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Theoretically, caprylic acid might increase plasma concentrations of NSAIDs.
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Theoretically, caprylic acid might increase plasma concentrations of warfarin.
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In vitro research suggests that high doses of caprylic acid might displace warfarin from albumin binding sites (25807). This effect has not been reported in humans.
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Theoretically, taking European barberry with anticholinergic drugs might cause additive effects.
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In vitro evidence suggests that European barberry might have anticholinergic properties (13527).
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Theoretically, European barberry may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, taking European barberry with antidiabetes drugs might increase the risk of hypoglycemia.
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Preliminary clinical evidence suggests that European barberry juice reduces fasting glucose levels in patients with type 2 diabetes who are also taking antidiabetes drugs (98575). Additionally, some animal studies show that berberine, a constituent of European barberry, has antiglycemic potential (33622,33667). Monitor blood glucose levels closely.
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Theoretically, taking European barberry with antihypertensive drugs might increase the risk of hypotension.
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Theoretically, taking European barberry with cholinergic drugs might decrease the effects of cholinergic drugs.
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In vitro evidence suggests that European barberry might have anticholinergic properties (13527).
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Theoretically, concomitant use with drugs that have sedative properties may cause additive effects.
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Theoretically, concomitant use with cyclosporine may cause additive effects.
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Berberine, a constituent of European barberry, can reduce the metabolism and increase serum levels of cyclosporine. This effect is attributed to the ability of berberine to inhibit cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524). Theoretically, European barberry might have a similar effect.
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Theoretically, European barberry might increase the levels and clinical effects of CYP3A4 substrates.
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There is very preliminary evidence suggesting that berberine, a constituent of European barberry, might inhibit the CYP3A4 enzyme (13524). Theoretically, European barberry might have a similar effect.
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Garlic may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, taking garlic with antidiabetes drugs might increase the risk of hypoglycemia.
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Theoretically, taking garlic with antihypertensive drugs might increase the risk of hypotension.
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Theoretically, garlic might decrease levels and effects of atazanavir.
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In a case report, a patient consuming six stir-fried garlic cloves three times weekly developed suboptimal atazanavir levels and increases in HIV viral load. While the exact cause of this interaction is unclear, there is speculation that garlic might decrease the intestinal absorption of atazanavir or increase its metabolism by inducing cytochrome P450 3A4 (CYP3A4) (88388). Until more is known, advise patients not to consume large amounts of garlic while taking atazanavir.
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Garlic might increase levels of drugs metabolized by CYP2E1.
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Clinical research suggests garlic oil can inhibit the activity of CYP2E1 by 39% (10847). Use garlic oil cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, garlic products containing allicin might induce intestinal CYP3A4 and inhibit hepatic CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.
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Some human research suggests that garlic may induce INTESTINAL CYP3A4, reducing levels of drugs metabolized by this enzyme. This is primarily based on a study showing that taking a specific allicin-containing garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induced CYP3A4 in the gut mucosa (7027,93578). Another study shows that giving docetaxel intravenously, bypassing the CYP3A4 enzymes in the gut mucosa, along with the same specific garlic product for 12 consecutive days, does not affect docetaxel levels (17221). Conversely, there is concern that garlic may inhibit HEPATIC CYP3A4. In a single case report, increased tacrolimus levels and liver injury occurred in a liver transplant patient after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days (96010). Several other studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).
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Theoretically, garlic might decrease levels of isoniazid.
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Animal research suggests that an aqueous extract of garlic reduces isoniazid levels by about 65%. Garlic reduced the maximum concentration (Cmax) and area under the curve (AUC), but not the half-life, of isoniazid. This suggests that garlic extract might inhibit isoniazid absorption across the intestinal mucosa (15031); however, the exact mechanism of this potential interaction is not known.
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Theoretically, garlic products containing allicin might decrease levels of PIs.
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Protease inhibitors are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4, reducing plasma levels of protease inhibitors. This is primarily based on a study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces levels of saquinavir, a PI, by approximately 50%. It is speculated that the allicin constituent induce CYP3A4 in the gut mucosa (7027,93578). Several studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).
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Theoretically, garlic containing allicin might decrease levels of saquinavir.
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Saquinavir is a substrate of cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4 and cause subtherapeutic levels of saquinavir. This is primarily based on a pharmacokinetic study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induces CYP3A4 in the gut mucosa (7027,93578). Several pharmacokinetic studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506). Until more is known about this potential interaction, use garlic containing allicin cautiously in patients taking saquinavir.
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Theoretically, taking garlic with sofosbuvir might decrease its effectiveness.
Details
Animal research in rats shows that giving aged garlic extract 120 mg/kg orally daily for 14 days decreases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 36%, increases the clearance by 63%, and decreases the plasma concentrations at 1 and 8 hours by 35% and 58%, respectively. This interaction is hypothesized to be due to induction of intestinal P-glycoprotein expression by garlic (109524).
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Theoretically, garlic might increase levels of tacrolimus.
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In one case report, a liver transplant patient taking tacrolimus experienced increased tacrolimus levels and liver injury after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days. It is speculated that garlic inhibited hepatic cytochrome P450 3A4 (CYP3A4), which increased plasma levels of tacrolimus (96010).
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Theoretically, garlic might increase the risk of bleeding with warfarin.
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Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397). In addition, there is a report of two patients who experienced an increase in a previously stabilized international normalized ratio (INR) with concomitant garlic and warfarin use (51228,51631). However, this report has been subsequently debated due to limited clinical information. Other clinical studies have not identified an effect of garlic on INR, warfarin pharmacokinetics, or bleeding risk (15032,16416). More evidence is needed to determine the safety of using garlic with warfarin.
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Ginger may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs. However, research is conflicting.
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Laboratory research suggests that ginger inhibits thromboxane synthetase and decreases platelet aggregation (7622,12634,20321,20322,20323,96257). However, this has not been demonstrated unequivocally in humans, with mixed results from clinical trials (96257). Theoretically, excessive amounts of ginger might increase the risk of bleeding when used with anticoagulant/antiplatelet drugs.
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Theoretically, taking ginger with antidiabetes drugs might increase the risk of hypoglycemia.
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Theoretically, taking ginger with calcium channel blockers might increase the risk of hypotension.
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Some animal and in vitro research suggests that ginger has hypotensive and calcium channel-blocking effects (12633). Another animal study shows that concomitant administration of ginger and the calcium channel blocker amlodipine leads to greater reductions in blood pressure when compared with amlodipine alone (107901).
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Theoretically, when taken prior to cyclosporine, ginger might decrease cyclosporine levels.
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In an animal model, ginger juice taken 2 hours prior to cyclosporine administration reduced the maximum concentration and area under the curve of cyclosporine by 51% and 40%, respectively. This effect was not observed when ginger juice and cyclosporine were administered at the same time (20401).
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Theoretically, ginger might increase the levels of CYP1A2 substrates.
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In vitro research shows that ginger inhibits CYP1A2 activity (111544). However, this interaction has not been reported in humans.
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Theoretically, ginger might increase the levels of CYP2B6 substrates.
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In vitro research shows that ginger inhibits CYP2B6 activity (111544). However, this interaction has not been reported in humans.
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Theoretically, ginger might increase the levels of CYP2C9 substrates.
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In vitro research shows that ginger inhibits CYP2C9 activity (111544). However, this interaction has not been reported in humans.
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Ginger might increase or decrease the levels of CYP3A4 substrates.
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In vitro research and some case reports suggest that ginger inhibits CYP3A4 activity (111544,111644). Three case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking ginger and cancer medications that are CYP3A4 substrates (imatinib, dabrafenib, and crizotinib). However, the causality of this interaction is unclear due to the presence of multiple interacting drugs and routes of administration (111644).
Conversely, other in vitro research suggests that ginger induces CYP3A4 activity, leading to reduced levels of CYP3A4 substrates (111404). However, this interaction has not been reported in humans. |
Theoretically, ginger might increase levels of losartan and the risk of hypotension.
Details
In animal research, ginger increased the levels and hypotensive effects of a single dose of losartan (102459). It is not clear if ginger alters the concentration or effects of losartan when taken continuously. Additionally, this interaction has not been shown in humans.
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Theoretically, ginger might increase levels of metronidazole.
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In an animal model, ginger increased the absorption and plasma half-life of metronidazole. In addition, the elimination rate and clearance of metronidazole was significantly reduced (20350).
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Ginger may have antiplatelet effects and increase the risk of bleeding if used with nifedipine.
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Clinical research shows that combined treatment with ginger 1 gram plus nifedipine 10 mg significantly inhibits platelet aggregation when compared to nifedipine or ginger alone (20324).
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Ginger might increase the absorption and blood levels of P-glycoprotein (P-gp) substrates.
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In vitro research and case reports suggest that ginger inhibits drug efflux by P-gp, potentially increasing absorption and serum levels of P-gp substrates (111544,111644). Two case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking ginger and cancer medications that are P-gp substrates (trametinib, crizotinib). However, the causality of this interaction is unclear due to the presence of multiple interacting drugs and routes of administration (111644).
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Ginger might increase the risk of bleeding with phenprocoumon.
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Phenprocoumon, a warfarin-related anticoagulant, might increase the international normalized ratio (INR) when taken with ginger. There is one case report of a 76-year-old woman with a stable INR on phenprocoumon that increased to greater than 10 when she began consuming dried ginger and ginger tea (12880).
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Ginger might increase the risk of bleeding with warfarin.
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Laboratory research suggests that ginger might inhibit thromboxane synthetase and decrease platelet aggregation (7622,12634,20321,20322,20323). In one case report, ginger increased the INR when taken with phenprocoumon, which has similar pharmacological effects as warfarin (12880). In another case report, ginger increased the INR when taken with a combination of warfarin, hydrochlorothiazide, and acetaminophen (20349). A longitudinal analysis suggests that taking ginger increases the risk of bleeding in patients taking warfarin for at least 4 months (20348). However, research in healthy people suggests that ginger has no effect on INR, or the pharmacokinetics or pharmacodynamics of warfarin (12881,15176). Until more is known, monitor INRs closely in patients taking large amounts of ginger.
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Grapefruit juice can decrease blood levels of acebutolol, potentially decreasing the clinical effects of acebutolol.
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Clinical research shows that grapefruit juice can modestly decrease acebutolol levels by 7% and reduce peak plasma concentration by 19% by inhibiting organic anion transporting polypeptide (OATP) (17603,18101). The acebutolol half-life is also extended by 1.1 hours when grapefruit juice is consumed concomitantly (18101). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of aliskiren, potentially decreasing the clinical effects of aliskiren.
Details
Clinical research shows that grapefruit juice can decrease aliskiren levels by approximately 60% by inhibiting organic anion transporting polypeptide (OATP) (91428). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.
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Grapefruit juice might decrease blood levels of amprenavir, although this is not likely to be clinically significant.
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Some clinical research shows that grapefruit juice can slightly decrease amprenavir levels (17673); however, this is probably not clinically significant.
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Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.
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Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.
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Clinical research shows that grapefruit juice can increase plasma triazolam concentrations. Repeated consumption of grapefruit juice greatly increases triazolam concentrations and prolongs the half-life, probably due to inhibition of cytochrome P450 3A4 (CYP3A4) (7776,22118,22131,22133). Some studies show that grapefruit juice, particularly when taken in large quantities, reduces the clearance and increases the maximum blood levels, area under the plasma concentration curve (AUC), and duration of effect of midazolam. However, there is no effect on intravenous midazolam (4300,10159,11275,17601,22117,22119,16711,91427,95978). Grapefruit juice has also been shown to increase the maximum blood levels and duration of effect of diazepam, but the clinical significance of this is not known (3228). This interaction does not appear to occur with alprazolam (17674).
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Grapefruit juice can increase blood levels of blonanserin, potentially increasing the effects and adverse effects of blonanserin.
Details
Blonanserin is metabolized primarily by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral blonanserin increases exposure to blonanserin almost 6-fold due to inhibition of intestinal CYP3A4 by grapefruit juice and prolongs the elimination half-life of blonanserin by 2.2-fold due to inhibition of hepatic CYP3A4 by grapefruit juice (96943).
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Grapefruit juice can increase blood levels of budesonide, potentially increasing the effects and adverse effects of budesonide.
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Budesonide is metabolized by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral budesonide increases the plasma concentration of budesonide. This effect is attributed to grapefruit-induced inhibition of CYP3A4 in both the colon and small intestine (91425).
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Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.
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Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone (3771).
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Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.
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Clinical research shows that grapefruit juice decreases caffeine clearance (4300).
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Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.
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Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine (523), nifedipine (528,22114), nisoldipine (529), verapamil (7779,8285), felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine (524,528,1388,4300,7780,11276,22136,53338,22138,22139) (22140,22141,22142,22143,22147,22148,22149,53367,22158),
This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4 (7779,7780), although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying (22167). Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50% (8285). However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil (3230,4300,22159). Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously (22144,22146). There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results (7777,7779,8285). In healthy older adults, the hemodynamic response to felodipine plus grapefruit juice might be influenced by altered autonomic regulation. In older healthy adults, a single dose of grapefruit juice and felodipine enhanced the blood pressure-lowering effects of felodipine. However, after a week of grapefruit juice and felodipine (steady state), the hypotensive activity was reduced, possibly due to compensatory tachycardia (1392). Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine (5068,5069,6453,22145).
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Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.
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Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine (524).
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Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.
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Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16% (5071).
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Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.
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In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85% (91421). This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP) (17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.
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Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.
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Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen (5064).
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Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.
Details
Clopidogrel is an antiplatelet prodrug that is metabolized primarily by cytochrome P450 2C19 (CYP2C19) to form the active metabolite. A small clinical study shows that taking grapefruit juice with clopidogrel decreases plasma levels of the active metabolite by more than 80% and impairs the antiplatelet effect of clopidogrel. This effect is possibly due to grapefruit-induced inhibition of CYP2C19 (91419).
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Theoretically, grapefruit juice might increase blood levels of colchicine, potentially increasing the effects and adverse effects of colchicine.
Details
Colchicine is an alkaloid that undergoes P-glycoprotein (P-gp) mediated drug efflux in the intestines, followed by metabolism by cytochrome P450 3A4 (CYP3A4). There is concern that grapefruit juice will increase the effects and adverse effects of colchicine due to grapefruit-induced inhibition of P-gp and/or CYP3A4. In vitro evidence shows that grapefruit juice increases absorption of colchicine by inhibiting P-gp (94158). A case of acute colchicine toxicity has been reported for an 8-year-old female who drank grapefruit juice while taking high-dose colchicine, long-term (94157). However, one small clinical study in healthy adults shows that drinking grapefruit juice 240 mL twice daily for 4 days does not affect the bioavailability or adverse effects of a single dose of colchicine 0.6 mg taken on the fourth day (35762).
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Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.
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In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes (12479). So far, this interaction has not been reported in humans.
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.
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In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes (12479). Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19 (91419).
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.
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In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes (12479). So far, this interaction has not been reported in humans.
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Grapefruit juice can increase levels of drugs metabolized by CYP3A4.
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Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (3227,3774,8283,8285,8286,22129,91427,104190). When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours (91427). Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient (112287).
Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice (95970,95972). |
Grapefruit juice can increase blood levels of dapoxetine, potentially increasing the effects and adverse effects of dapoxetine.
Details
Pharmacokinetic research shows that drinking grapefruit juice 250 mL prior to taking dapoxetine 60 mg can increase the maximum plasma concentration of dapoxetine by 80% and prolong the elimination half-life by 43%. This effect is attributed to the inhibition of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) by grapefruit (95975).
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Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.
Details
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels (11362).
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Grapefruit juice can increase blood levels of erythromycin, potentially increasing the effects and adverse effects of erythromycin.
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Clinical research shows that concomitant use of erythromycin with grapefruit can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of erythromycin, increasing plasma concentrations of erythromycin by 35% (8286).
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Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.
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Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes (525,526,14858). Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females (525,526,22160).
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Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.
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Clinical research shows that grapefruit juice decreases the absorption and plasma concentrations of etoposide. There is some evidence that grapefruit juice co-administered with oral etoposide can reduce levels of etoposide by about 26% (8744). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of fexofenadine, thereby decreasing the clinical effects of fexofenadine.
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Clinical research shows that grapefruit juice can significantly decrease oral absorption and blood levels of fexofenadine. In one study, consuming a drink containing grapefruit juice 25% decreased bioavailability of fexofenadine by about 24%. Consuming a full-strength grapefruit juice drink reduced bioavailability by 67% (7046). In another study, consuming grapefruit juice 300 mL decreased fexofenadine levels by 42%. Consuming 1200 mL of grapefruit juice reduced levels by 64% (17602). Similarly, drinking grapefruit juice 240 mL decreased the oral bioavailability of fexofenadine by 25% in another pharmacokinetic study (112288). Fexofenadine manufacturer data indicates that concomitant administration of grapefruit juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that grapefruit also reduces the clinical response to fexofenadine (17603).
Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604). |
Grapefruit juice can increase blood levels of fluvoxamine, potentially increasing the effects and adverse effects of fluvoxamine.
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Clinical research shows that grapefruit juice inhibits metabolism and increases fluvoxamine levels and peak concentration (17675).
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Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.
Details
Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism, which increases halofantrine levels and peak concentration, as well as a marker of ventricular tachyarrhythmia potential (22129).
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Grapefruit juice can increase blood levels of statins that are metabolized by cytochrome P450 3A4 (CYP3A4), potentially increasing the effects and adverse effects of these statins. Additionally, grapefruit juice might interfere with the bioavailability of statins that are substrates of organic anion transporting polypeptides (OATP).
Details
Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin (527,11274), simvastatin (3774,7782,22127), and atorvastatin (3227,12179,22126). Keep in mind that there is considerable variability in the effect of grapefruit juice on drug metabolism, so individual patient response is difficult to predict (7777,7781).
Some statins, including pravastatin, fluvastatin, pitavastatin, and rosuvastatin, are not metabolized by CYP3A4. However, grapefruit juice might still affect the bioavailability of these statins. These statins are substrates of OATP. Grapefruit juice can inhibit OATP. Therefore, grapefruit juice may reduce the bioavailability or increase drug levels of these statins depending on the type of OATP. However, grapefruit juice affects OATP for only a short time. Therefore, separating drug administration by at least 4 hours is likely to avoid this interaction (3227,12179,17601,22126,91420). |
Grapefruit juice can interfere with itraconazole absorption, although the clinical significance of this interaction is unclear.
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Grapefruit juice can decrease blood levels of levothyroxine, potentially decreasing the effectiveness of levothyroxine.
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Clinical research shows that grapefruit juice modestly decreases levothyroxine levels by 11% by inhibiting organic anion transporting polypeptide (OATP) (17604,22163). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of the active metabolite of losartan, potentially decreasing the clinical effects of losartan.
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Losartan is an inactive prodrug which must be metabolized to its active form, E-3174, to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174 (1391).
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Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.
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Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations (17676). In one case, a 51-year-old male taking methadone 90 mg daily and no other medications was found unresponsive. The patient reported drinking grapefruit juice 500 mL daily for 3 days prior to the event. Methadone is a substrate of cytochrome P450 3A4 (CYP3A4), and grapefruit juice-induced inhibition of CYP3A4 is the likely cause of this interaction (102056).
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Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.
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Clinical research shows that grapefruit juice can increase the plasma concentration of orally administered methylprednisolone. Grapefruit juice 200 mL three times daily given with methylprednisolone 16 mg increased methylprednisolone half-life by 35%, peak plasma concentration by 27%, and total area under the curve by 75% (3123).
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Grapefruit juice might decrease blood levels of nadolol, potentially decreasing the clinical effects of nadolol.
Details
Nadolol is a substrate of organic anion transporting polypeptide 1A2 (OATP1A2) (17603,17604,22161). Some research shows that grapefruit juice and its constituent naringin can inhibit organic anion transporting polypeptides (OATP), which can reduce the bioavailability of OATP substrates (17603,17604,22161,91427). However, preliminary clinical research shows that grapefruit juice containing a low amount of naringin does not significantly affect levels of nadolol (91422). It is not known if grapefruit juice containing higher amounts of naringin reduces the bioavailability of nadolol.
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Grapefruit juice can increase blood levels of nilotinib, potentially increasing the effects and adverse effects of nilotinib.
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Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of nilotinib. Grapefruit juice increases nilotinib levels by 29% and peak concentration by 60% (17677).
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Grapefruit juice can decrease levels of drugs that are substrates of OATP.
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In vitro and clinical research show that consuming grapefruit juice inhibits OATP, which reduces the bioavailability of oral drugs that are substrates of OATP. Various clinical studies have shown reduced absorption of OATP substrates when taken with grapefruit, including fexofenadine, acebutolol, aliskiren, celiprolol, levothyroxine, nadolol, and pitavastatin (17603,17604,18101,22126,22134,22161,22163,91420,91427,91428,112288). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of oxycodone, potentially increasing the effects and adverse effects of oxycodone.
Details
Oxycodone is metabolized by both cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). A small clinical study shows that grapefruit juice can increase plasma levels of oral oxycodone about 1.7-fold by inhibiting CYP3A4. While the analgesic effects of oxycodone do not seem to be affected, taking grapefruit juice along with oxycodone may theoretically increase the adverse effects of oxycodone (91423).
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Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.
Details
While most in vitro research shows that grapefruit products inhibit P-gp, (1390,11270,11278,11362,95976), research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys (11277,11282). It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe (105568). Grapefruit juice has been shown to reduce levels of fexofenadine (7046,17602,112288), and increase levels of quinidine (5067,22121). However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.
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Grapefruit juice can increase blood levels of pitavastatin, potentially increasing the effects and adverse effects of pitavastatin.
Details
Pharmacokinetic research shows that taking grapefruit juice with pitavastatin 2-4 mg can increase blood levels of pitavastatin by 13% to 14%. Unlike simvastatin and atorvastatin, pitavastatin is not significantly metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice appears to increase levels of pitavastatin by inhibiting its uptake by organic anion transporting polypeptide 1B1 (OATP1B1) into hepatocytes for metabolism and clearance from the body (22126,91420). Grapefruit juice seems to increase levels of pitavastatin to a greater degree in patients homozygous for a specific polymorphism (388A>G) in the OATP1B1 gene compared to those heterozygous for this polymorphism (91420).
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Grapefruit juice can decrease blood levels of the active metabolite of prasugrel, thereby decreasing the antiplatelet effect of prasugrel.
Details
Prasugrel is a prodrug that is metabolized by cytochrome P450 3A4 (CYP3A4) into its active metabolite. A small pharmacokinetic study in healthy volunteers shows that drinking grapefruit juice 200 mL three times daily for 4 days and taking a single dose of prasugrel 10 mg with an additional 200 mL of grapefruit juice on day 3, results in a 49% lower peak plasma level and a 26% lower overall plasma exposure to the active metabolite when compared with drinking water. However, despite the reduced exposure, platelet aggregation seems to be reduced by an average of only 5% (105567). The clinical significance of this interaction is unclear.
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Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.
Details
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of praziquantel. Plasma concentrations of praziquantel can increase by as much as 160% when administered with 250 mL of commercially available grapefruit juice (8282).
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Grapefruit juice may increase blood levels of primaquine, potentially increasing the effects and adverse effects of primaquine.
Details
Clinical research shows that grapefruit juice increases the bioavailability of primaquine by approximately 20% (22130). The clinical significance of this interaction is not clear.
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Grapefruit or grapefruit juice, especially if consumed in large amounts, can cause additive QT interval prolongation when taken with QT interval-prolonging drugs, potentially increasing the risk of ventricular arrhythmias.
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Clinical research in healthy volunteers shows that drinking 6 liters of grapefruit juice over 6 hours prolonged the QTc by a peak amount of 14 milliseconds (ms). This prolongation was similar to the QT prolongation caused by the drug moxifloxacin. In individuals with long QT syndrome, a smaller dose of grapefruit juice, 1.5 liters, resulted in a greater peak QTc prolongation of about 30 ms (100249). The effect of smaller quantities of grapefruit juice on the QT interval is unclear.
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Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.
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Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4 (3227,3774,8283,8285,8286,22129,91427,104190). In one case report, a healthy 28-year-old female with bipolar disorder stabilized on quetiapine 800 mg daily presented with quetiapine toxicity considered to be related to consuming a gallon of grapefruit juice over the past 24 hours (108848).
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Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.
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Grapefruit juice can increase blood levels of saquinavir, potentially increasing the effects and adverse effects of saquinavir.
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Grapefruit juice can increase blood levels of scopolamine, potentially increasing the effects and adverse effects of scopolamine.
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Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of scopolamine, increasing its absorption and plasma concentrations. Oral bioavailability of scopolamine can increase by 30% when administered with 150 mL of grapefruit juice (8284).
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Grapefruit juice can increase blood levels of sertraline, potentially increasing the effects and adverse effects of sertraline.
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Clinical research shows that grapefruit juice inhibits the cytochrome P450 3A4 (CYP3A4) metabolism of sertraline, increasing blood levels of sertraline (22122).
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Grapefruit juice can increase blood levels of sildenafil, potentially increasing the effects and adverse effects of sildenafil.
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Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of sildenafil, increasing its absorption and plasma concentrations. Oral bioavailability of sildenafil can increase by 23% when administered with 500 mL of commercially available grapefruit juice (8283).
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Grapefruit juice may slightly increase blood levels of sunitinib, potentially increasing the effects and adverse effects of sunitinib.
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Sunitinib is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit and grapefruit juice can inhibit CYP3A4 and increase levels of some drugs metabolized by this enzyme. One small clinical study shows that drinking 200 mL of grapefruit juice three times daily can increase the bioavailability of sunitinib by 11% (91429). While this effect is unlikely to be clinically significant, patients should use caution when using grapefruit along with sunitinib. Dose adjustments may be necessary.
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Grapefruit juice can increase blood levels of tacrolimus, potentially increasing the effects and adverse effects of tacrolimus.
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Clinical research shows that drinking grapefruit juice 200 mL daily while taking tacrolimus 3 mg daily increases the trough blood concentration of tacrolimus by approximately 3-fold in patients with connective tissue diseases (95974). A single case has also reported a 10-fold increase in tacrolimus trough levels after the ingestion of grapefruit juice over 3 days (22122). This effect is attributed to the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit (95974).
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Theoretically, grapefruit juice might increase blood levels of tadalafil, potentially increasing the effects and adverse effects of tadalafil.
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Animal research shows that grapefruit juice increases tadalafil serum concentrations and overall exposure, likely through inhibition of cytochrome P450 3A4 enzymes (104189).
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Grapefruit juice might decrease blood levels of talinolol, potentially decreasing the clinical effects of talinolol.
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Clinical research suggests that grapefruit juice reduces talinolol bioavailability, likely by inhibiting intestinal uptake (22135). The clinical significance of this effect is unclear.
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Grapefruit juice can increase blood levels of terfenadine, potentially increasing the effects and adverse effects of terfenadine.
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Grapefruit juice can decrease blood levels of theophylline, potentially decreasing the effectiveness of theophylline.
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Clinical research shows that grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (11013). The mechanism of this interaction is unknown.
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Grapefruit juice can increase blood levels of ticagrelor, thereby increasing the effects and adverse effects of ticagrelor.
Details
Ticagrelor is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that taking grapefruit juice with ticagrelor increases blood levels of ticagrelor more than two-fold and increases the antiplatelet activity of ticagrelor (91418).
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Grapefruit juice can increase blood levels of tolvaptan, potentially increasing the effects and adverse effects of tolvaptan.
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Tolvaptan is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that grapefruit juice can increase the bioavailability and blood levels of tolvaptan by approximately 1.6-fold for up to 16 hours (91426).
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Theoretically, drinking large amounts of grapefruit juice might increase the effects and adverse effects of warfarin.
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In one case report, a patient experienced significantly increased international normalized ratio (INR) associated with consumption of 50 ounces of grapefruit juice daily (12061). However, smaller amounts of grapefruit juice might not be a problem. In a small clinical trial, consumption of 24 ounces of grapefruit juice daily for one week had no effect on INR in males treated with warfarin (12063).
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Theoretically, taking itraconazole capsules or tablets with a beverage containing lemon might increase the levels and clinical effects of itraconazole.
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In one case report, dissolving itraconazole tablets in a small amount of specific beverages containing lemon prior to administration increased the level of itraconazole in a lung transplant patient. In this case, the increased bioavailability was desirable and was likely due to improved tablet dissolution in the acidic beverage (110781).
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Laboratory evidence suggests that lentinan might increase the activity of cytochrome P450 1A2 (CYP1A2) (103366). So far, this interaction has not been reported in humans. However, watch for a decrease in the levels of drugs metabolized by CYP1A2 in patients taking lentinan.
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Some drugs metabolized by CYP1A2 include amitriptyline (Elavil), haloperidol (Haldol), ondansetron (Zofran), propranolol (Inderal), theophylline (Theo-Dur, others), verapamil (Calan, Isoptin, others), and others.
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Laboratory research suggests that lentinan might increase the activity of cytochrome P450 2C19 (CYP2C19) (103366). So far, this interaction has not been reported in humans. However, watch for a decrease in the levels of drugs metabolized by CYP2C19 in patients taking lentinan.
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Some drugs metabolized by CYP2C19 include proton pump inhibitors including omeprazole (Prilosec), lansoprazole (Prevacid), and pantoprazole (Protonix); diazepam (Valium); carisoprodol (Soma); nelfinavir (Viracept); and others.
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Laboratory research suggests that lentinan might increase the activity of cytochrome P450 2D6 (CYP2D6) (103366). So far, this interaction has not been reported in humans. However, watch for a decrease in the levels of drugs metabolized by CYP2D6 in patients taking lentinan.
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Some drugs metabolized by CYP2D6 include tricyclic antidepressants such as imipramine (Tofranil) and amitriptyline (Elavil); antipsychotics such as haloperidol (Haldol), risperidone (Risperdal), and chlorpromazine (Thorazine); beta-blockers such as propranolol (Inderal), metoprolol (Lopressor, Toprol XL), and carvedilol (Coreg); tamoxifen (Nolvadex); and others.
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Laboratory research suggests that lentinan might increase the activity of cytochrome P450 3A4 (CYP3A4) (103366). So far, this interaction has not been reported in humans. However, watch for a decrease in the levels of drugs metabolized by CYP3A4 in patients taking lentinan.
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Some drugs metabolized by CYP3A4 include lovastatin (Mevacor), ketoconazole (Nizoral), itraconazole (Sporanox), fexofenadine (Allegra), triazolam (Halcion), and numerous others.
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In animal research, lentinan decreases plasma levels of metoprolol. This may be due to induction of cytochrome P450 2D6 (CYP2D6) metabolism (103366).
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In animal research, lentinan decreases plasma levels of midazolam. This may be due to induction of cytochrome P450 3A4 (CYP3A4) metabolism (103366).
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In animal research, lentinan decreases plasma levels of omeprazole. This may be due to induction of cytochrome P450 2C19 (CYP2C19) metabolism (103366).
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In animal research, lentinan decreases plasma levels of phenacetin. This may be due to induction of cytochrome P450 1A2 (CYP1A2) metabolism (103366).
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Theoretically, combining maitake mushroom with antidiabetes drugs might increase the risk of hypoglycemia.
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Clinical research shows that taking maitake mushroom polysaccharide (MMP) can lower blood glucose levels in patients with types 2 diabetes (8188).
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Theoretically, combining maitake mushroom with antihypertensive drugs might increase the risk of hypotension.
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There is limited evidence that maitake mushroom may increase the anticoagulant effects of warfarin.
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In a case report, a patient previously stabilized on warfarin developed an elevated international normalized ratio (INR) of 5.1 after taking maitake mushroom (Grifron-Pro Maitake D-Fraction) 1 drop/kg daily in three divided doses for one week. The elevated INR resolved after holding warfarin for two days, then reducing the dose by 11%. It is thought that the beta-glucan constituent of maitake mushroom might cause warfarin dissociation from proteins, resulting in increased free warfarin levels and increased warfarin effects (17209).
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Theoretically, Oregon grape might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.
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Theoretically, Oregon grape might increase the risk of hypoglycemia when taken with antidiabetes drugs.
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Theoretically, Oregon grape might increase the risk of hypotension when taken with antihypertensive drugs.
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Animal research suggests that berberine, a constituent of Oregon grape, can have hypotensive effects (33692,34308). Also, an analysis of clinical evidence suggests that taking berberine in combination with amlodipine (Norvasc) can lower systolic and diastolic blood pressure when compared with taking amlodipine alone (91956).
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Theoretically, Oregon grape might increase the sedative effects of CNS depressants.
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Theoretically, Oregon grape might increase the effects and adverse effects of cyclosporine.
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Berberine, a constituent of Oregon grape, can reduce metabolism of cyclosporine and increase serum levels. It might inhibit cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524).
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Theoretically, Oregon grape might increase serum levels of drugs metabolized by CYP2C9.
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Preliminary clinical evidence suggests that berberine, a constituent of Oregon grape, can inhibit cytochrome P450 2C9 (CYP2C9) (34279).
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Theoretically, Oregon grape might increase serum levels of drugs metabolized by CYP2D6.
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Theoretically, Oregon grape might increase serum levels of drugs metabolized by CYP3A4.
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Theoretically, Oregon grape might increase serum levels of drugs that are P-glycoprotein (P-gp) substrates.
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In vitro research suggests that Oregon grape extracts inhibit P-gp efflux (112342).
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Theoretically, papaya extract may increase the levels and clinical effects of amiodarone.
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Animal research in rats shows that a single oral dose of papaya extract, as well as multiple doses of papaya extract daily over 14 days, prior to a single dose of amiodarone delays the time to maximum amiodarone concentration. However, only the 14-day papaya extract regimen increases systemic amiodarone exposure by 60% to 70% (93093). This interaction has not been reported in humans.
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Concomitant use of antidiabetic drugs with fermented papaya can produce additive effects. It is unclear if other forms of papaya have the same effect.
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A small low-quality clinical study in patients with type 2 diabetes who are taking glibenclamide shows that taking a fermented papaya preparation 3 grams daily for 2 months decreases fasting and postprandial blood glucose levels when compared to baseline. Additionally, of the 25 patients in the study, 9 required a reduction in glibenclamide dose (67902).
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Theoretically, consuming large quantities of papaya fruit can reduce the clinical effects of levothyroxine.
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In one case-report, a 37-year-old male with a history of thyroidectomy who was stabilized on levothyroxine for 5 years presented with hypothyroidism after consuming 5-6 papaya fruits daily for 14 days during vacation. In a controlled re-challenge test involving 5-6 papayas daily, the patient remained euthyroid for 7 days, but developed mild hypothyroidism after 14 days. Both times, thyroid levels normalized 40-45 days after discontinuing papaya (93087).
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Theoretically, concomitant use of warfarin with papain-containing papaya extract might increase the effects and side effects of warfarin.
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In one case report, a patient previously stable on warfarin was found to have an international normalization ratio (INR) of 7.4, which was attributed to ingestion of a supplement containing papain from papaya extract (613).
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Theoretically, pau d'arco might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.
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In vitro research shows that pau d'arco reduces platelet aggregation and may interfere with vitamin K (18057,68319). One clinical study shows that taking the lapachol constituent of pau d'arco in doses above 1.5 grams daily increases the risk of bleeding (91939). The effects of whole pau d'arco or pau d'arco extract in humans are unclear.
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Pumpkin might reduce excretion and increase levels of lithium.
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Pumpkin is thought to have diuretic properties (92383). Theoretically, this might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.
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Theoretically, rosemary may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, taking rosemary with antidiabetes drugs might increase the risk of hypoglycemia.
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Animal research shows that rosemary extract can decrease blood glucose levels in diabetic models (71821,71923). However, research in humans is conflicting. Although rosemary powder decreased blood glucose levels in healthy adults (105327), no change in blood glucose levels was seen in adults with type 2 diabetes, most of whom were taking antidiabetes drugs (105323,105327).
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Theoretically, rosemary might have additive effects with salicylate-containing drugs such as aspirin.
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Rosemary is reported to contain salicylates (18330).
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Theoretically, rosemary might have additive effects with salicylate-containing drugs such as choline magnesium trisalicylate.
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Rosemary is reported to contain salicylate (18330).
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Theoretically, rosemary might decrease the levels and clinical effects of CYP1A1 substrates.
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Theoretically, rosemary might decrease the levels and clinical effects of CYP1A2 substrates.
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Theoretically, rosemary might have additive effects with salicylate-containing drugs such as salsalate.
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Rosemary is reported to contain salicylate (18330).
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Theoretically, shiitake mushroom might decrease levels of drugs metabolized by CYP2D6.
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Theoretically, taking shiitake mushroom might decrease the effects of immunosuppressive therapy.
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Theoretically, slippery elm may slow the absorption and reduce serum levels of oral drugs.
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Slippery elm inner bark contains mucilage, which may interfere with the absorption of orally administered drugs (19).
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Theoretically, taking turkey tail mushroom with antidiabetes drugs might increase the risk of hypoglycemia.
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Theoretically, the polysaccharide peptide (PSP) component of turkey tail mushroom might increase exposure to cyclophosphamide.
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Some animal research shows that the PSP component of turkey tail mushroom can increase the area under the concentration-time curve (AUC) of cyclophosphamide by 44% to 50% and the half-life by 34% to 43% (96569). This interaction could potentially increase the effects and adverse effects of cyclophosphamide. However, it is not known whether PSP affects the levels of the active metabolites of cyclophosphamide that are responsible for its clinical activity.
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Theoretically, the polysaccharide peptide (PSP) component of turkey tail mushroom might inhibit CYP2C9.
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Laboratory research suggests that the PSP component of turkey tail mushroom dose-dependently inhibits CYP2C9 (94075). Theoretically, taking PSP with drugs metabolized by CYP2C9 might increase drug levels and the risk of adverse effects. However, this has not been reported in humans.
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Theoretically, the polysaccharide peptide (PSP) component of turkey tail mushroom might interfere with the absorption of tamoxifen.
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Animal research suggests that PSP increases the time to reach maximum concentration of a single dose of tamoxifen by about 9.5 hours, or 228%. When repeated doses of tamoxifen were given, the time to reach maximum concentration was increased by about 5.6 hours, or 93%. However, PSP did not affect the maximum concentration or the area under the curve of tamoxifen (108308).
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Theoretically, taking wormwood might interfere with the effects of anticonvulsant drugs.
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Thujone, a constituent of wormwood, has convulsant effects (12816).
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Below is general information about the adverse effects of the known ingredients contained in the product CapraSite. 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, black walnut fruit (nut) is well tolerated.
However, the leaf, bark, and hull of black walnut contain high quantities of tannins, which may cause adverse effects when used orally or topically.
Most Common Adverse Effects:
Orally: The leaf, bark, and hull can cause gastrointestinal upset.
Topically: Hull preparations may cause a temporary yellow or brown discoloration at the site of application. The leaf, bark, and hull can cause skin irritation.
Serious Adverse Effects (Rare):
Orally: The bark may increase the risk for tongue cancer or lip leukoplakia when used long-term.
All routes of administration: Allergic reactions, including anaphylaxis.
Dermatologic ...Topically, black walnut leaf, bark, or hull may have an irritating effect on the skin due to tannin content. Black walnut hull preparations might cause a temporary yellow or brown discoloration of the skin at the site of application (12).
Gastrointestinal ...Orally, black walnut leaf, bark, or hull may cause gastrointestinal upset due to tannin content (12). Also, daily use of the juglone-containing bark of a related species (English walnut) is associated with increased risk of tongue cancer and lip leukoplakia (2,12).
Hepatic ...Orally, black walnut leaf, bark, or hull may cause liver damage if taken for extended periods of time due to tannin content (12).
Immunologic ...Tree nuts, which include black walnuts, can cause allergic reactions in sensitive individuals. Due to the prevalence of this allergy in the general population, tree nuts are classified as a major food allergen in the United States (105410).
Renal ...Orally, black walnut leaf, bark, or hull may cause kidney damage if taken for extended periods of time due to tannin content (12).
General
...Orally, blond psyllium is generally well tolerated.
When used as eye drops, blond psyllium seems to be well tolerated.
Most Common Adverse Effects:
Oral: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, and nausea.
Serious Adverse Effects (Rare):
Oral: Bowel obstruction, esophageal obstruction.
Gastrointestinal ...Orally, blond psyllium can cause transient flatulence, abdominal pain, diarrhea, constipation, dyspepsia, and nausea (1376). Starting with a low dose and slowly titrating to the desired dose can often minimize gastrointestinal side effects. There is some concern that blond psyllium can cause esophageal or bowel obstruction when consumed without water or in patients with swallowing disorders (604,8080,8081,110760). Tell patients to consume plenty of water when taking blond psyllium. Suggest at least 240 mL of fluid for every 3.5-5 grams of seed husk or 7 grams of seed (1376,8080,8081).
Musculoskeletal ...Orally, backache has been reported with the use of psyllium (1376).
Neurologic/CNS ...Orally, headache has been reported with the use of psyllium (1376).
Ocular/Otic ...Ophthalmically, blurred vision or burning haven been reported rarely in patients using eye drops containing blond psyllium mucilage (105274).
Pulmonary/Respiratory ...Orally, rhinitis, increased cough, and sinusitis have been reported with the use of psyllium (1376).
Other
...Some patients can have an allergic response to blond psyllium.
Allergy symptoms include allergic rhinitis, sneezing, conjunctivitis, urticarial rash, itching, flushing, and dyspnea. More serious symptoms include wheezing, facial and body swelling, chest congestion, chest and throat tightness, cough, diarrhea, hypotension, loss of consciousness, and anaphylactic shock. Occupational exposure or repeated ingestion of psyllium can cause sensitization, which can lead to serious allergic reactions (2328,2329,2330,8079,9246,92193). Severe allergic reactions may occur after eating a small quantity of cereal that contains blond psyllium. At least one cereal (Heartwise, Kellogg Co.) has increased the purity of the psyllium it contains, which has decreased the incidence of allergic reactions (9244). A warning of the potential for allergic reactions is on the label of all cereals that contain psyllium (9247). Patients hypersensitive to psyllium usually have marked eosinophilia and an elevated psyllium-specific IgE antibody serum level (2328,2329,92193).
There is concern that individuals allergic to pollen from English plantain weed (Plantain lanceolate) might also react to psyllium husk dust; however, it appears that there is little cross-allergenicity between these plants and is probably mild and of no clinical significance (8057,9244,92193).
Blond psyllium has a tendency to plug feeding tubes. This can be avoided if blond psyllium is mixed with water and pushed through the feeding tube in less than 5 minutes (8423).
General
...Orally, caprylic acid seems to be well tolerated, short-term.
Most Common Adverse Effects:
Orally: Mild abdominal discomfort and change in taste perception.
Topically: Skin irritation.
Dermatologic ...Topically, caprylic acid is irritating to the skin of some people (20277,25076). Orally, a single dose of caprylic acid was associated with the development of a rash under the dressing of an inserted catheter in one patient in a clinical study (97662).
Gastrointestinal ...Orally, caprylic acid may cause mild abdominal discomfort and a change in taste perception (97662).
Neurologic/CNS ...Orally, caprylic acid has rarely been reported to cause mild dizziness, headache, and fatigue (97662).
General ...European barberry is generally well tolerated when consumed in amounts commonly found in food. A thorough evaluation of safety outcomes has not been conducted for the use of larger, medicinal amounts. Topically, European barberry seems to be well tolerated.
Hepatic ...Orally, a case of hepatitis-associated aplastic anemia is reported in an adult male after consuming European barberry 15 drops and nannari root 15 drops twice a day for 2 weeks. The patient presented with lethargy, loss of appetite, and jaundice that progressed to high-grade fevers, chills, rigors, severe pancytopenia, and abnormal liver function tests. Liver biopsy was suggestive of drug-induced liver injury. The patient was hospitalized for multiple infections and symptomatic thrombocytopenia. Despite receiving supportive care, blood transfusions, and corticosteroids, the patient died 7 weeks after diagnosis (110021). The exact reason for this adverse effect is not clear.
General
...Orally, garlic is generally well tolerated.
Topically, garlic seems to be well tolerated. Intravenously, there is insufficient reliable information available about adverse effects.
Most Common Adverse Effects:
Orally: Abdominal pain, body odor, flatulence, malodorous breath, and nausea. Allergic reactions in sensitive individuals.
Topically: Burns and dermatitis with fresh garlic.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with garlic.
Dermatologic
...Orally, garlic may cause pruritus (51316,51474,107239), flushing, and acne (107239).
Oral intake of a specific garlic product containing allicin (Allimax) has been associated with a case of pruritic rash (51474). Enteric-coated garlic tablets standardized to 1.5% allicin have also been associated with a case of pruritus (51316). Garlic has also been associated with a case of superficial pemphigus in a 49-year-old male with type 2 diabetes (51564). Garlic-induced oral ulcers have also been reported (51467).
Topically, garlic may cause contact dermatitis and urticaria (4833,5004,12635,51258,51265,51375,51403,51412,51459,51483)(51511,51512,51530,51616,51617,51618,111769), as well as contact cheilitis (51384). Fresh garlic may be more likely to elicit a reaction than garlic extract. Most reactions have resolved following withdrawal of garlic therapy. In one case report, applying crushed garlic on the neck to help ease a sore throat resulted in an itchy, burning, erythematous lesion in a young female patient. The lesion healed after one week of treatment with topical antibiotics, steroids, and antihistamine ointments (88390). Cases of occupational eczema or dermatitis have been reported in cooks (51303,51210), food handlers (51292), and caterers (51304). According to one case report, dermatitis appeared in chefs exposed to garlic (15033). Treatment with acitretin 25 mg daily or topical psoralen-ultraviolet A (PUVA) for 12 weeks proved effective in mitigating the symptoms. A 34-year-old female with a history of hand dermatitis and paronychia had a worsening of these conditions after peeling raw garlic. She had a positive skin patch test to fresh, raw garlic but not to any other tested allergens, and the conditions resolved when she avoided contact with garlic (105528). Topically, garlic may also cause chemical burns, usually within 12 hours of application. Second- and third-degree chemical burns have been reported in adults, children, and infants exposed to topical garlic, often as an unintended consequence of using garlic medicinally on the skin (585,4832,51226,51230,51252,51281,51377,51418,51468,51495,51536)(51558,51576,51577,88409,96006). A case of painful blisters on the soles of the feet of a 23-year-old Chinese female has been attributed to chemical burns caused by applying crushed raw garlic for 3 hours (51440). Topically, garlic may also cause hyperpigmentation, ulcers, necrotic lesions, facial flushing, and local irritation (4832,15030,51268,51269,108606). In one case report, applying crushed raw garlic to the palatal mucosa for several minutes to relieve mouth pain resulted in a chemical burn that produced a 3 cm necrotic ulcer in an adult female with trigeminal neuralgia (108606).
Gastrointestinal
...Orally, dehydrated garlic preparations or raw garlic may cause malodorous breath (51438,51444), body odor (732,1873,4784,4793,4795,4798,9201,10787,42692,49769)(51269,51316,51467,51602), abdominal pain or fullness, anorexia, diarrhea, constipation, flatulence, belching, heartburn, nausea, unpleasant taste, reflux, and bowel obstruction (1884,6457,6897,9201,49769,51269,51343,51380,51438,51442)(51450,51457,51466,51471,51474,51520,51593,51602,51623,88398)(88405,111766).
Large quantities of garlic may damage the gastrointestinal tract. In one case report, a patient taking garlic for hypertension reported odynophagia and retrosternal pain after taking garlic without any water the previous day. An esophageal lesion 3 cm in length was detected upon endoscopy. The symptoms resolved 3 days after starting a liquid diet and taking lansoprazole 30 mg twice daily and sucralfate four times daily (88389). One case of bowel obstruction was reported in a 66-year-old male who ingested an entire garlic bulb (51525). Esophageal perforation has been reported in at least 17 individuals who consumed entire garlic cloves. In one case the perforation led to mediastinitis and death (102672).
Garlic has also been associated with eosinophilic infiltration of the gastrointestinal tract. In one case report a 42-year-old female presented with symptoms of eosinophilic gastroenteritis, which included pollinosis, asthma, diarrhea, heart burn, peripheral eosinophilia, and urticaria. After stopping use of garlic and sesame, the patient improved (51441). In a case report of eosinophilic esophagitis, garlic was determined to be the causative agent in a patient with long-standing gastrointestinal symptoms. The patient had attempted to treat upper gastrointestinal symptoms as gastrointestinal reflux disease without success for many years. Skin prick testing showed a positive reaction to garlic, of which the patient noted frequent consumption. Marked symptom improvement was noted within 3 weeks of garlic avoidance (88393).
Intravenously, garlic 1 mg/kg of body weight daily diluted into 500 mL saline and administered over 4 hours has been reported to cause abdominal discomfort, vomiting, diarrhea, nausea, anorexia, flatulence, weight loss, and garlicky body odor (51462).
Clinical research suggests that patients with metabolic syndrome taking 1600 mg of powdered garlic by mouth daily for 3 months may experience improved intestinal transit time when compared with placebo, suggesting that garlic powder may reduce symptoms of constipation (110722).
Genitourinary ...Orally, garlic might cause dysuria, hematuria, or polyuria (51438,51450,51467,113618). In one case, an older male with high dietary and supplemental garlic intake at doses of 300-5400 mg daily for 3-4 years developed severe hematuria with clots after undergoing a minimally invasive prostate procedure (113618).
Hematologic
...Oral use of dietary garlic or supplements containing garlic has caused platelet dysfunction, increased fibrinolytic activity, prolonged bleeding time, retrobulbar hemorrhage (bleeding behind the eye) postoperative bleeding, and spinal epidural hematoma (586,587,4801,4802,11325,51397,51473,51491,51532,51534)(51570,51584,51593,51594,113618).
Also, a case of kidney hematoma following extracorporeal shock-wave lithotripsy (SWL) has been reported in a patient with nephrolithiasis who took aged garlic (51630). A case of increased bleeding time that complicated epistaxis management has been reported in a patient taking garlic, aspirin, and milk thistle (51426).
Intravenously, garlic has been associated with the development of thrombophlebitis at the injection site (51462).
Immunologic
...There is a case report of an immediate sensitivity reaction to oral raw garlic, resulting in wheals, in a 31-year-old female.
The patient did not react to cooked garlic, and skin prick tests showed allergy only to raw garlic (96015). Researchers note that at least some allergens in raw garlic are heat labile (88392,96012,96015). This suggests that consuming cooked rather than raw garlic may help avoid this reaction in patients allergic to raw garlic. However, different people react to different allergens in garlic. At least some of these allergens are heat stable (96012). While rare, garlic-induced anaphylaxis has been reported (88392,96012).
Topically, allergic contact dermatitis has been reported in case reports (51406,51498,51510,51519,51560).
Musculoskeletal ...Orally, garlic has been associated with individual cases of gout and low back pain (51474,51467), but it is not clear if these adverse events can be attributed to garlic.
Neurologic/CNS ...Orally, dizziness, insomnia, headaches, diaphoresis, fever, chills, somnolence, increased appetite, euphoria, and weight loss have been reported with garlic (15032,42692,51316,51467,51471,51520). In one case, the smell of garlic was identified as a trigger for migraines in a 32-year-old female. The subject reported fortification spectra along with visual spots for a few seconds followed by instantaneous biparietal, crushing level (10/10) headaches upon exposure to the scent of garlic or onion (88404).
Pulmonary/Respiratory ...Garlic exposure, most notably in occupational settings, may cause asthma and other symptoms such as sneezing, nasal obstruction, rhinorrhea, and sinusitis (40661,51218). A case of minor hemoptysis has been reported for one patient with cystic fibrosis following intake of garlic capsules orally once daily for 8 weeks (51438). A 77-year-old female developed pneumonia related to the intake of one whole black garlic clove daily. The cloves were prepared by heating a whole garlic bulb in a pot for one month. Symptoms included dyspnea and coughing, and test results were positive for lymphocyte-induced stimulation by black garlic and raw garlic. The patient required treatment with oral steroids and was told to avoid garlic (96011).
General
...Orally, ginger is generally well tolerated.
However, higher doses of 5 grams per day increase the risk of side effects and reduce tolerability. Topically, ginger seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal discomfort, burping, diarrhea, heartburn, and a pepper-like irritant effect in the mouth and throat. However, some of these mild symptoms may be reduced by ingesting encapsulated ginger in place of powdered ginger.
Topically: Dermatitis in sensitive individuals.
Cardiovascular ...Orally, use of ginger resulted in mild arrhythmia in one patient in a clinical trial (16306).
Dermatologic
...Orally, ginger can cause hives (17933), as well as bruising and flushing (20316) or rash (20316).
Topically, ginger can cause dermatitis in sensitive individuals (12635,46902).
Gastrointestinal
...Orally, common side effects of ginger include nausea (17933,22602,89898,101761), belching (10380,103359), dry mouth (103359), dry retching (10380), vomiting (10380), burning sensation (10380), oral numbness (22602), abdominal discomfort (5343,89898,96253), heartburn (5343,7624,12472,16306,20316,51845,89894,89895,89898,89899)(101760,101761,101762,111543), diarrhea (5343,101760), constipation (89898,101760,101761), or a transient burning or "chilly hot" sensation of the tongue and throat (52076).
Orally, Number Ten, a specific product composed of rhubarb, ginger, astragalus, red sage, and turmeric, can increase the incidence of loose stools (20346).
Four cases of small bowel obstruction due to ginger bolus have been reported following the ingestion of raw ginger without sufficient mastication (chewing). In each case, the bolus was removed by enterotomy. Ginger is composed of cellulose and therefore is resistant to digestion. It can absorb water, which may cause it to swell and become lodged in narrow areas of the digestive tract (52115).
Genitourinary ...In one clinical trial, some patients reported increased menstrual bleeding while taking a specific ginger extract (Zintoma, Goldaru) 250 mg four times daily orally for 3 days (17931). An "intense" urge to urinate after 30 minutes was reported in two of eight patients given 0.5-1 gram of ginger (7624). However, this effect has not been corroborated elsewhere. Dysuria, flank pain, perineal pain, and urinary stream interruption have been reported in a 43-year-old male who drank ginger tea, containing 2-3 teaspoons of dry ginger, daily over 15 years. The adverse effects persisted for 4 years and were not associated with increases in urinary frequency or urgency. Upon discontinuing ginger, the patient's symptoms began to improve within one week and completely resolved after eight weeks, with no relapses six months later (107902).
Immunologic ...In one case report, a 59-year-old Japanese female with multiple allergic sensitivities developed pruritus and then anaphylactic shock after taking an oral ginger-containing herbal supplement for motion sickness (Keimei Gashinsan, Keimeido). The patient had used this supplement previously for over 20 years with no allergic reaction. The authors theorized the development of a cross-reactivity to ginger after the use of an oral supplement containing zedoary and turmeric, which are also in the Zingiberaceae family (102463).
Neurologic/CNS ...Orally, ginger may cause sedation, drowsiness, or dizziness (16306,17933,51845).
General
...Orally, grapefruit and grapefruit juice are generally well tolerated.
Serious Adverse Effects (Rare):
Orally: Allergic reactions in sensitive individuals have been reported. When large quantities are consumed, arrhythmias, mineralocorticoid excess, QT prolongation, and pseudohyperaldosteronism have been reported. There is also some concern for increased breast cancer risk with grapefruit consumption.
Cardiovascular ...Orally, consumption of pink grapefruit juice 1000 mL can cause QT prolongation and cause arrhythmias in healthy patients and worsen arrhythmias in cardiomyopathy patients (13031,91424).
Endocrine ...Orally, high doses of grapefruit juice have been observed to cause pseudohyperaldosteronism and mineralocorticoid excess (53340,53346).
Gastrointestinal ...In a case report, grapefruit juice held against the teeth resulted in enamel and tooth surface loss (53368).
Immunologic ...Orally, grapefruit can cause allergic sensitization characterized by eosinophilic gastroenteritis, urticaria, and generalized pruritus (53351,53360).
Oncologic ...Preliminary population research shows that postmenopausal adults who consume a quarter or more of a whole grapefruit daily have a 25% to 30% increased risk of developing breast cancer (14858). Grapefruit is a potent inhibitor of cytochrome P450 3A4, which metabolizes estrogen. Consuming large amounts of grapefruit might significantly increase endogenous estrogen levels and therefore increase the risk of breast cancer. More evidence is needed to validate these findings. Until more is known, advise patients to consume grapefruit in moderation.
Renal ...In population research, consumption of 240 mL/day of grapefruit juice is associated with an increased risk of kidney stones (4216,53372).
General
...Orally, lemon is well tolerated in amounts commonly found in foods.
A thorough evaluation of safety outcomes has not been conducted on the use of larger amounts.
Most Common Adverse Effects:
Orally: Epigastralgia and heartburn with the regular consumption of fresh lemon juice.
Dermatologic ...Topically, the application of lemon oil might cause photosensitivity, due to furocoumarin derivative content. This occurs most often in fair-skinned people (11019).
Gastrointestinal ...Orally, fresh lemon juice, taken as 60 mL twice daily, has been reported to cause gastrointestinal disturbances in 37% of patients in one clinical trial, compared with 8% of patients in the placebo group. Specifically, of the patients consuming lemon juice, 21% experienced heartburn and 8% experienced epigastralgia, compared to 1% and 3%, respectively, in the placebo group (107489).
General ...Parenterally and orally, lentinan seems to be well tolerated (96863,34779). Orally, lentinan has been rarely reported to cause rash, diarrhea, and constipation (34779). Parenterally, lentinan has been reported to cause gastrointestinal cramping, rash, myalgia, and fatigue (1107). Mild thrombocytopenia has also been reported in clinical trials (6). Rapid intravenous infusion of lentinan is reported to cause chest tightness and dryness of the throat; these symptoms were not reported to occur with slow drip infusion (1111).
Dermatologic ...Orally and parenterally, lentinan has been reported to cause rash (1107,7267,34779).
Gastrointestinal ...Orally and parenterally, lentinan has been rarely reported to cause diarrhea, nausea, vomiting, and constipation (7267,34779).
Genitourinary ...Parenterally, lentinan has been reported to cause excessive urination (7267).
Hematologic ...Parenterally, lentinan has been reported to cause mild thrombocytopenia (6).
Immunologic ...Parenterally, lentinan has been reported to cause chills, fever, and lymph node swelling (7267).
Musculoskeletal ...Parenterally, lentinan has been reported to cause joint pain and myalgia (1107,7267).
Neurologic/CNS ...Parenterally, lentinan has been reported to cause headache (7267).
Other ...Rapid intravenous infusion of lentinan has been reported to cause chest tightness and dryness of the throat; these symptoms were not reported to occur with slow drip infusion (1111).
General
...Orally, maitake mushroom is generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal effects, including diarrhea and epigastric pain.
Dermatologic ...In a clinical trial, one patient experienced rash and pruritus after two doses of maitake mushroom polysaccharide extract. The allergic reaction cleared without intervention (61239).
Gastrointestinal ...In clinical research of a polysaccharide extract from maitake mushroom, one patient reported nausea (61239) and 2 out of 26 reported epigastric pain (17131). In a clinical trial of a liquid extract from maitake mushroom, 2 out of 21 patients experienced diarrhea, and one experienced nausea. One patient withdrew from the study due to diarrhea (92843).
Immunologic ...In a clinical trial of a liquid extract from maitake mushroom, 4 out of 21 patients experienced eosinophilia (92843).
Musculoskeletal ...In a clinical trial of a polysaccharide extract from maitake mushroom, one patient reported joint swelling (61239).
Pulmonary/Respiratory ...There is one case of occupational hypersensitivity pneumonitis (HP) caused by maitake mushroom spores (61228).
General
...Orally, MCTs can cause significant gastrointestinal upset, especially with higher doses.
Most Common Adverse Effects:
Abdominal discomfort, diarrhea, essential fatty acid deficiency, intestinal gas noises, irritability, nausea, reflux, vomiting. Gastrointestinal disturbances are thought to be associated with higher doses of MCT. Since MCTs are fats, excessive consumption can result in weight gain.
Cardiovascular ...There is some concern that MCTs may further increase the risk for hypertriglyceridemia in some preterm infants due to immature lipoprotein lipase activity in these infants. A case of extremely elevated triglyceride levels of 4,736 mg/dL and associated lipemia retinalis has been reported at 43 weeks post-menstrual age (PMA) for a preterm infant born at 30 weeks' gestational age. It was discovered that the baby had been receiving MCT supplements in addition to breast milk starting at 42 weeks' PMA. MCT supplements were discontinued. One month later triglycerides were reduced to 287 mg/dL, and the retinal vasculature had a normal hue. However, at 2-month follow-up, triglyceride levels were elevated to levels higher than normal for age despite MCT discontinuation. Investigators speculated that a genetic disorder of lipid metabolism may also have contributed to the elevated triglyceride levels in addition to use of MCTs (96330).
Gastrointestinal ...Orally, MCTs can cause significant gastrointestinal upset. Diarrhea is the most commonly reported side effect (11723,93737,93738,101967). Other reported side effects include vomiting, irritability, nausea, reflux, abdominal discomfort, intestinal gas noises, and essential fatty acid deficiency (11723,93738,101967). Taking MCTs with food can reduce these adverse effects (93737). Gastrointestinal disturbances are thought to be associated with higher doses of MCT, such as 85 grams (93731).
Other ...Excessive consumption of MCTs can result in weight gain. MCT oil contains 6-8.5 calories per gram. One tablespoon provides about 14 grams and about 115 calories (11724).
General ...Orally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted. Topically, Oregon grape seems to be well tolerated.
Dermatologic ...Topically, Oregon grape may cause itching, burning, and skin irritation in some patients (854,14000).
Immunologic ...Topically, Oregon grape may cause allergic skin reactions in some patients (854,14000).
General
...Orally, papaya fruit is well tolerated when consumed in food amounts.
Papaya leaf extract seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Nausea and vomiting from papaya leaf extract.
Topically: Burning sensation from unripe papaya.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions.
Dermatologic
...Orally, high doses of papaya might cause yellow skin discoloration.
A case of carotenemia has been reported for a 42-year-old female who consumed 1.5-2 papayas daily for 6 months. The condition resolved when she stopped eating papayas (67929).
Topically, unripe papaya fruit may cause occasional burning sensation when applied to skin ulcers (67856).
Gastrointestinal ...Orally, the leaf extract has been reported to cause nausea and vomiting in clinical research (102799). A case of esophageal perforation has been reported for a previously healthy 27-year-old female who used papain, a constituent of papaya latex, to digest a piece of meat stuck in her esophagus (93083).
Immunologic ...Orally, papain, a constituent of raw, unripe papaya, has been reported to cause allergic reactions in sensitive individuals, including itchy watery eyes, runny nose, sneezing, abdominal cramps, sweating, and diarrhea (6,967). Papaya may also cause hypersensitivity reactions such as systemic contact dermatitis, which occur more commonly in people who are allergic to latex (6197,7853,57635). A case of systemic contact dermatitis has been reported for a 55-year-old female with no prior history of atopic disease or drug allergy after ingesting a throat lozenge containing papaya juice (67942).
Other ...In regions with arsenic-contaminated soil, papaya fruits contain a higher mean concentration of arsenic compared with many other forms of vegetation grown in the regions. Eating papaya from these regions is thought to contribute to higher dietary levels of arsenic (32461,67879).
General ...A thorough evaluation of safety outcomes with pau d'arco has not been conducted. However, taking the lapachol constituent of pau d'arco in doses above 1.5 grams daily is regarded as unsafe.
Gastrointestinal ...Orally, the lapachol constituent of pau d'arco, taken in doses above 1. 5 grams daily, may cause severe nausea, vomiting, and diarrhea (91939).
Hematologic ...Orally, the lapachol constituent of pau d'arco, taken in doses above 1. 5 grams daily, may cause anemia and increased risk of bleeding (91939).
Immunologic ...Occupational exposure to sawdust from the pau d'arco tree and related species may cause asthma and dermatitis. The fresh sawdust can produce erythema and papules which progress to a severe weeping and crusting dermatitis (92184).
Neurologic/CNS ...Orally, the lapachol constituent of pau d'arco, taken in doses above 1. 5 grams daily, may cause dizziness (91939).
General
...Orally, pumpkin products are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal discomfort, diarrhea, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.
Dermatologic ...There are two case reports of adult females developing substantial transient hair loss 1-3 weeks after consumption of a meal containing either bitter-tasting pumpkin or undefined squash. This adverse effect was attributed to a high concentration of cucurbitacin, which is commonly found in wild pumpkins (104535).
Gastrointestinal ...Orally, pumpkin seed oil has been reported to cause mild abdominal discomfort in clinical trials (5093,92378). There are also two case reports of adults developing severe nausea, vomiting, and diarrhea following consumption of a meal containing either bitter-tasting pumpkin or undefined squash. These adverse effects were attributed to a high concentration of cucurbitacin, which is commonly found in wild pumpkins (104535).
Immunologic
...Orally, pumpkin seed oil and pumpkin pulp have been reported to cause anaphylactic reactions in children and adults.
A case review highlights 4 cases of anaphylaxis in children (3 from pumpkin pulp, 1 from pumpkin seeds), and 7 cases in adults (1 from pumpkin flesh, 6 from pumpkin seeds). Symptoms of anaphylaxis include urticaria, angioedema of the lips or face, dyspnea, dysphagia, and oropharyngeal itching and swelling. A case report describes a 2-year-old male presenting with urticaria, swollen lips, and increased dyspnea 10 minutes after ingesting pumpkin seeds. The patient was found to have elevated allergen-specific immunoglobulin E (IgE) and a positive skin-prick test for pumpkin seeds. Symptoms resolved after treatment with epinephrine, systemic glucocorticoids, salbuterol, and antihistamines (107843).
There may also be concern for allergic reaction due to inhalation or topical exposure. One case report describes an 8-year-old child developing anaphylaxis while carving a pumpkin; another highlights that inhalation of pumpkin seed flour may have potentiated anaphylaxis in 3 individuals following the ingestion of pumpkin seeds (107843). Further research is necessary to assess the relationship between anaphylaxis and route of administration.
General ...Orally, rosemary seems to be well tolerated when used in appropriate medicinal amounts. Undiluted rosemary oil or very large quantities of rosemary leaf should not be consumed. Topically and as aromatherapy, rosemary seems to be well tolerated.
Dermatologic ...Topically, rosemary use can lead to photosensitivity, erythema, dermatitis, and cheilitis in hypersensitive individuals (4,6).
Immunologic
...Topically, allergic reactions can occur.
When used in the mouth, lip and gum edema have occurred (101173). When used on the skin, allergic contact dermatitis has occurred, likely due to the constituent carnosol (71715,71924,71926).
Rosemary might also cause occupational asthma. A case of occupational asthma caused by several aromatic herbs including thyme, rosemary, bay leaf, and garlic has been reported. The diagnosis was confirmed by inhalation challenges. Although all of the herbs caused immediate skin reactivity, a radioallergosorbent test (RAST) showed that garlic was the most potent allergen by weight, with rosemary and the other herbs showing less reactivity (783).
Neurologic/CNS ...Orally, the undiluted oil, as well as the camphor constituent of rosemary, might cause seizures (4,5,6,12868).
General
...Orally, shiitake mushroom is generally well tolerated when cooked and consumed as a food.
Most Common Adverse Effects:
Orally: Abdominal discomfort, bloating, diarrhea, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Consumption of raw shiitake mushroom can cause shiitake dermatitis, a skin eruption resembling whiplash marks which can be accompanied by systemic symptoms. Large pieces that have been inadequately chewed can cause intestinal blockage, occasionally requiring surgery.
Dermatologic
...Orally, shiitake mushrooms can cause shiitake dermatitis, a skin eruption that resembles whiplash marks, usually found on the trunk and limbs.
This dermatitis is thought to be a toxic response to lentinan or other compounds found normally in uncooked or inadequately cooked shiitake mushroom. The rash can be made worse by scratching. Symptom onset is usually within hours to days and can persist for 3-4 weeks before resolving on its own. There is some evidence that treatment with steroids alone or with antihistamines might reduce the duration of the rash by a small amount in some people (1148,1152,74782,74806,94236,94237,94238,94240,94241,94243) (94244,94246,94247,94248,94249,94252,94253,94254,94255,94256)(94257,94259,94261,94262,108302,111909,111912,111913). The dermatitis may include small purple spots from broken capillaries, skin plaques, burning, blanching, and pustules (94256,108302). Rarely the rash may look like measles rather than whiplash (94256). Histologically, there may be evidence of dermal and epidermal edema, lymphocyte infiltration, and skin thickening (94256,94257). Other symptoms associated with the dermatitis include fever, aching, malaise, eosinophilia, diarrhea, prickling in the hands, trouble swallowing, conjunctivitis, and pustules with small ulcers in the mouth (94240,94246,94247,94249,94256,94257,108302). It is likely that the dermatitis and other symptoms are due to a delayed type hypersensitivity reaction (94244,94255). Cooking shiitake mushroom generally prevents shiitake dermatitis, although some cases have occurred in people who have consumed cooked sources (94242,94244). It appears that to inactivate lentinan, cooking temperatures of at least 130°C are needed (94243).
Less common is a photosensitivity reaction associated with oral ingestion, which involves rash and pruritus after sun exposure (1148,94241).
Orally, the shiitake mushroom extract AHCC has been reported to cause mild itching (30375).
Gastrointestinal
...Orally, shiitake mushrooms can cause abdominal discomfort, including bloating, nausea, pain, vomiting, and diarrhea (1149,30365,30375,30419,94241).
Gastrointestinal symptoms, such as diarrhea, problems swallowing, or mouth ulcers have been associated with shiitake dermatitis (94241,94256). Consumption of large pieces of shiitake mushroom with inadequate chewing can cause abdominal obstruction that has resulted in death in one case and surgical intervention in two others. In another case, parenteral nutrition was used exclusively until the shiitake mushroom pieces were passed (1147,94260,103160,108303,108304).
Topically, an oral rinse containing shiitake mushroom extract has been associated with teeth sensitivity, teeth staining, and burning in the mouth (94250).
Hematologic ...Ingestion of shiitake mushroom powder 4 grams daily for 10 weeks caused eosinophilia in 5 of 10 healthy humans (1149). Eosinophilia, and leukocytosis or leukopenia have been reported with shiitake dermatitis (94254,94256,94257).
Immunologic ...Allergic contact dermatitis can occur by contact with shiitake hyphae (filaments) (1153,74785,111913). It appears to be more common in growers or others that handle shiitake mushrooms extensively (94241,94259). Contact or inhalation also results in other symptoms of allergy, such as asthma, rhinitis, conjunctivitis, and pneumonia (94241,94249,94258,94259).
Musculoskeletal ...Orally, the shiitake mushroom extract AHCC has been reported to cause foot cramps and difficulty moving hand joints (30365,30416).
Neurologic/CNS
...In patients experiencing shiitake dermatitis, other symptoms may include prickling in the hands (94256).
Malaise has also been reported following oral intake or contact (1151,94240).
Orally, the shiitake mushroom extract AHCC has been reported to cause mild and transient headache (30365).
Ocular/Otic ...Conjunctivitis has been reported rarely in mushroom growers and handlers, or following oral intake in patients with shiitake dermatitis (94241,94256,94259).
Pulmonary/Respiratory ...In mushroom workers, hypersensitivity pneumonitis due to shiitake spore inhalation has occurred. Symptoms include difficulty breathing, chest pain, a dry cough, asthma, and rhinitis (1150,1151,74776,74813,94239,94241,94258,94259).
General ...Orally, slippery elm seems to be well tolerated. A thorough evaluation of safety outcomes with topical use of slippery elm has not been conducted.
Dermatologic ...Topically, slippery elm extracts can cause contact dermatitis. The pollen is an allergen (6). Contact dermatitis and urticaria have been reported after exposure to slippery elm or an oleoresin contained in the slippery elm bark (75131).
General ...Orally, turkey tail mushroom and its PSK component are generally well tolerated. There have been reports of gastrointestinal side effects, hematological abnormalities, liver dysfunction, and palpitations, but these are in patients who received PSK in addition to standard chemotherapy. It is not known if these are due to PSK, the chemotherapy, or both.
Cardiovascular ...Palpitations have occurred when PSK is taken with standard chemotherapy for cancer (1657). It is not clear if this is due to PSK, the chemotherapy, or both.
Dermatologic
...Pigmentation of the nails and erythema have occurred when PSK is taken with standard chemotherapy (1657,1660,70175,94076).
It is not clear if this is due to PSK, the chemotherapy, or both.
Intravaginally, a specific gel (Papilocare, Procare Health) containing turkey tail mushroom with neem, carboxymethyl-beta-glucan, hyaluronic acid, gotu kola, aloe, and alpha-glucan oligosaccharide has been reported to cause vulvovaginal stinging, burning, itching, and candidiasis (108305,111904). The specific role of turkey tail mushroom is unclear.
Gastrointestinal ...Nausea, vomiting, appetite loss, stomach discomfort, diarrhea, constipation, and gastric ulcer have occurred when PSK is taken with standard chemotherapy for cancer (1651,1657,70175,70201,94076). However, one study reported a decreased incidence of gastrointestinal side effects when PSK was taken with chemotherapy (70188,70197).
Hematologic ...Leukopenia, thrombocytopenia, and albuminuria have occurred when PSK is taken with standard chemotherapy (1651,1657,70175,70201,94076). It is not clear if this is due to PSK, the chemotherapy, or both.
Hepatic ...Elevated liver enzymes, liver function impairment, and hepatotoxicity have occurred when PSK is taken with standard chemotherapy (1651,1657,70175,70201,94076). It is not clear if this is due to PSK, the chemotherapy, or both.
Musculoskeletal ...Malaise and fatigue have occurred when PSK is taken with standard chemotherapy (1657,1660,70175,94076). It is not clear if this is due to PSK, the chemotherapy, or both.
Pulmonary/Respiratory ...Coughing has occurred when PSK is taken with standard chemotherapy (1657,1660,70175,94076). It is not clear if this is due to PSK, the chemotherapy, or both.
General
...Wormwood contains thujone, a neurotoxin.
When products containing thujone are used orally in medicinal amounts, wormwood may be unsafe.
Most Common Adverse Effects:
Orally: The oil from wormwood leaves can cause diffuse muscle aches, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: The oil from wormwood leaves can cause acute kidney toxicity, rhabdomyolysis, and seizures.
Dermatologic ...Topically, a single case report describes a sensitivity or first degree chemical burn reaction, with facial pain and erythema, after a 50-year-old adult applied a homemade poultice containing wormwood to the face for an unreported length of time (93466).
Gastrointestinal ...Orally, the oil from wormwood leaves can cause nausea and vomiting (662). Use of a home-prepared wormwood extract has been associated with vomiting and severe diarrhea in an infant (93467).
Hematologic ...Orally, use of a home-prepared wormwood extract has been associated with severe metabolic acidosis in an infant (93467).
Immunologic ...Theoretically, wormwood might cause an allergic reaction in people sensitive to the Asteraceae/Compositae family (12815). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.
Musculoskeletal ...Orally, the oil from wormwood leaves can cause diffuse muscle aches and rhabdomyolysis (662).
Neurologic/CNS ...Orally, the oil from wormwood leaves can cause seizures (662).
Renal ...Orally, the oil from wormwood leaves can cause acute kidney toxicity and acute kidney failure (662).
Other ...Chronic ingestion of absinthe, an alcoholic beverage that contains wormwood extract, has been linked to absinthism. Absinthism was first described in the 1800s when absinthe was at its peak levels of consumption. It has been characterized by addiction, gastrointestinal adverse effects, insomnia, auditory and visual hallucinations, tremors, paralysis, epilepsy, and brain damage. There is also increased risk of psychiatric disease and suicide (662,12814,15008). Increasing thujone concentrations of absinthe increases anxiety and decreases attention in healthy individuals (86541). A case of bradyarrhythmias associated with absinthe intoxication has also been reported (86543). However, there is speculation that some of the symptoms of absinthism originally described might be attributed to adulteration with metals or toxic plants such as calamus and tansy, rather than the ingredients usually used in absinthe drinks (15007). Some researchers also suggest that absinthism is not a unique condition and is indistinguishable from alcohol use disorder. In fact, some evidence suggests that the thujone concentrations in the absinthe formulations from the 1800s were too low to cause significant thujone-related toxicities (15008,15009).
