Candida Liver Care by Kroeger Herb Products Co.

POSSIBLY EFFECTIVE

• Ventilator-associated pneumonia (VAP). Clove mouthwash might reduce the risk of acquiring pneumonia in patients on mechanical ventilation. Details: A large clinical trial in adults in the intensive care unit on mechanical ventilation shows that administration of a clove extract 6.66% mouthwash, 15 mL twice daily for 5 days, results in a 2-fold lower incidence of ventilator-associated pneumonia when compared with chlorhexidine mouthwash (112151).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alveolar osteitis. Although there has been interest in using topical clove for alveolar osteitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Anal fissures. It is unclear if topical clove oil is beneficial in patients with anal fissures. Details: Preliminary clinical research in patients with chronic anal fissures shows that applying clove oil 1% cream for 6 weeks heals fissures in 60% of patients by the 3-month follow-up, compared with only 12% of patients who used topical lidocaine 5% cream and stool softeners (43487).
• Cough. Although there has been interest in using oral clove for cough, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dental plaque. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a specific toothpaste (Sudantha, Link Natural Products Ltd.) containing a combination of clove, Acacia chundra Willd., malabar nut, bullet wood tree, black pepper, Indian beech, gall oak, Terminalia, and ginger twice daily for 12 weeks can reduce dental plaque, bleeding, and bacteria counts in the mouth when compared with placebo (43570). Other clinical research shows that administration of a mouth rinse containing clove, tea tree oil, and basil 10 mL twice daily for 21 days is as effective as a commercially available mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate in reducing dental plaque and gum inflammation (92160). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Diarrhea. Although there has been interest in using oral clove for diarrhea, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dyspepsia. Although there has been interest in using oral clove for dyspepsia, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Flatulence. Although there has been interest in using oral clove for flatulence, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Gingivitis. Although there has been interest in using topical clove for gingivitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Halitosis. Although there has been interest in using oral clove for halitosis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Hangover. It is unclear if oral clove flower extract is beneficial for reducing hangover severity. Details: Preliminary clinical research in a very small number of healthy males with a history of hangovers shows that taking a clove flower bud polyphenol extract 250 mg prior to drinking brandy (42.8% alcohol) decreases hangover severity scores by around 55% when compared with placebo (100597).
• Hyperhidrosis. It is unclear if topical clove oil is beneficial in patients with hyperhidrosis. Details: Preliminary clinical research in patients with hyperhidrosis of the palms shows that topical application of clove oil 45% in liposome base twice daily for 2 weeks improves hyperhidrosis severity and decreases the rate of sweating by around 34% when compared with a saline control (100596). The validity of these findings is limited by a lack of subject randomization.
• Impaired glucose tolerance (prediabetes). It is unclear if oral clove flower extract is beneficial in patients with prediabetes. Details: Preliminary clinical research in a very small number of patients with prediabetes shows that taking a polyphenolic extract from clove flower buds 250 mg daily for 30 days decreases pre-prandial plasma glucose by 14 mg/dL and postprandial plasma glucose by 40 mg/dL when compared to baseline (100595). The validity of these findings is limited by the very small size of the study and the lack of a control group.
• Mosquito repellent. Small clinical studies suggest that topical clove oil may repel mosquitos for up to 4-5 hours. Details: Preliminary clinical research shows that topical application of undiluted clove oil can repel 100% of mosquitoes for up to 4 hours (43427). Other preliminary research shows that topical application of gel containing clove oil 20% can repel 86% to 97% of mosquitoes for 5 hours (43411).
• Nausea and vomiting. Although there has been interest in using oral clove for nausea and vomiting, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Oral mucositis. Although there has been interest in using topical clove for oral mucositis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Pain (acute). It is unclear if topical clove is beneficial in patients with acute pain. Details: Preliminary clinical research shows that topical application of a gel containing ground cloves, applied as 4 grams of gel for 5 minutes prior to dental anesthesia injection, can reduce needle stick pain when compared with placebo. The effect of the clove gel on pain seems to be comparable to benzocaine 20% gel (43448).
• Premature ejaculation. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that administration of a multi-ingredient cream preparation (SS Cream) containing clove flower, Panax ginseng root, Angelica root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, Asiasari root, cinnamon bark, and toad venom to the glans penis, one hour prior to intercourse and washed off immediately before intercourse, increases ejaculatory latency time by over 4-fold when compared with placebo in adults with premature ejaculation (2537). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Pruritus. There is limited evidence on the topical use of clove oil in patients with chronic pruritus. Details: Preliminary clinical research in patients with chronic pruritus shows that applying clove oil 10% in petroleum jelly to the skin twice daily for 2 weeks reduces the daily duration of itching by 48 minutes and improves symptom severity and disability scores when compared with placebo (96950).
• Smoking cessation. Oral clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults in India with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing clove 30 mg, ashwagandha, cowhage, ginger, turmeric, and other herbal extracts (Smotect, Smotect India) twice daily for 3 months reduces the number of cigarettes smoked daily and levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity when compared with placebo (112115). It is unclear if these effects are due to clove, other ingredients, or the combination. More evidence is needed to rate clove for these uses.

(Read more about CLOVE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using oral condurango for cancer, there is insufficient relable information about the clinical effects of condurango for this purpose. More evidence is needed to rate condurango for this use.

(Read more about CONDURANGO)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral eyebright for allergic rhinitis, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Asthenopia (eye strain). Although there has been interest in using topical eyebright for asthenopia, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Blepharitis. Although there has been interest in using topical eyebright for blepharitis, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Cancer. Although there has been interest in using oral eyebright for cancer, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Common cold. Although there has been interest in using oral eyebright for the common cold, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Conjunctivitis. It is unclear if topical eyebright eye drops are beneficial in patients with conjunctivitis. Details: A small observational study shows that applying one drop of eyebright eye drops (WALA Heilmittel GmbH, Eck-walden/Bad Boll) up to five times daily results in complete recovery in about 82% of patients with conjunctivitis after two weeks of treatment (49391). However, due to the lack of a comparator group, it is not clear if this improvement is due to eyebright or to the natural resolution of conjunctivitis symptoms.
• Cough. Although there has been interest in using oral eyebright for cough, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Pharyngitis. Although there has been interest in using oral eyebright for pharyngitis, there is insufficient reliable information about the clinical effects of eyebright for this purpose.
• Rhinosinusitis. Although there has been interest in using oral eyebright for rhinosinusitis, there is insufficient reliable information about the clinical effects of eyebright for this purpose. More evidence is needed to rate eyebright for these uses.

(Read more about EYEBRIGHT)

POSSIBLY INEFFECTIVE

• Urine drug tests. Drinking water with goldenseal or adding goldenseal tea to urine does not appear to cause a false negative urine drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or tetrahydrocannabinol (THC). Details: Goldenseal is often promoted to mask illicit drugs in the urine, but drinking one gallon of water with goldenseal or adding goldenseal tea to urine samples does not seem to cause a false negative immunoassay (EMIT and TDx) for cocaine, amphetamines, barbiturates, benzodiazepines, or opiates. It also does not produce a false negative for Microgenics CEDIA DAU assays for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or THC (260,261,52599). Although adding goldenseal tea to urine samples at 15 grams per liter may produce a false-negative EMIT reading for the presence of THC, the adulteration is obvious due to a brownish color in the urine (52599). Some people also claim that goldenseal can cause a false positive on a drug screen. However, goldenseal does not seem to cause false positives for the fluorescent polarization immunoassay (FPIA) or thin-layer chromatography (TLC) assays for amphetamines, opiates, cocaine, methadone, or their metabolites (2590).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical goldenseal for acne, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral goldenseal for allergic rhinitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Anorexia nervosa. Although there has been interest in using oral goldenseal for anorexia nervosa, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Atopic dermatitis (eczema). Although there has been interest in using topical goldenseal for atopic dermatitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral goldenseal for CFS, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Conjunctivitis. Although there has been interest in using goldenseal as an eye drop for conjunctivitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Dandruff. Although there has been interest in using topical goldenseal for dandruff, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Flatulence. Although there has been interest in using oral goldenseal for flatulence, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Gastritis. Although there has been interest in using oral goldenseal for gastritis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Gingivitis. Although there has been interest in using goldenseal as a mouthwash for gingivitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Hemorrhoids. Although there has been interest in using oral goldenseal for hemorrhoids, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Herpes labialis (cold sores). Although there has been interest in using topical goldenseal for herpes labialis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Menorrhagia. Although there has been interest in using oral goldenseal for menorrhagia, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Otitis media. Although there has been interest in using goldenseal as an ear drop for otitis media, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Peptic ulcers. Although there has been interest in using oral goldenseal for peptic ulcers, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Respiratory tract infections. Although there has been interest in using oral goldenseal for various respiratory tract infections, including influenza, pneumonia, rhinosinusitis, and the common cold, there is insufficient reliable information about the clinical effects of goldenseal for these conditions.
• Tinnitus. Although there has been interest in using goldenseal as an ear drop for tinnitus, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Urinary tract infections (UTIs). Although there has been interest in using oral goldenseal for UTIs, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Uveitis. Although there has been interest in using goldenseal as an eye drop for uveitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Vaginitis. Although there has been interest in using oral goldenseal for vaginitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Wound healing. Although there has been interest in using topical goldenseal for wound healing, there is insufficient reliable information about the clinical effects of goldenseal for this purpose. There is insufficient reliable information available about the effectiveness of goldenseal for its other uses.

(Read more about GOLDENSEAL)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Topical red clover has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in individuals with androgenic alopecia shows that topical application of a combination of red clover flower extract and acetyl tetrapeptide-3 increases the growth phase of hair production by 13% and decreases the resting phase of hair production by 29% when compared to baseline (19540). The validity of these findings is limited by the lack of a comparator group.
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral red clover for BPH, there is insufficient reliable information about the clinical effects of red clover for this condition.
• Breast cancer-related hot flashes. It is unclear if oral red clover is beneficial for reducing hot flashes in patients who have had breast cancer. Details: A small clinical study in breast cancer patients with menopausal symptoms due to tamoxifen therapy shows that taking red clover extract (Promensil Forte) 80 mg daily for 24 months does not reduce menopausal symptoms, including hot flashes, sleep disturbance, and fatigue, any more than placebo (102901).
• Hyperlipidemia. It is unclear if oral red clover is beneficial in patients with hyperlipidemia; research is conflicting. Details: Most clinical trials in adult females with or without elevated cholesterol levels show that taking red clover extracts providing isoflavones 40-120 mg daily for 3 months to 1 year does not reduce total or low-density lipoprotein (LDL) cholesterol, or increase high-density lipoprotein (HDL) cholesterol, when compared with control (3375,8502,11089,11091,17091,19450,19543). However, a meta-analysis of 10 clinical trials in perimenopausal and postmenopausal patients with or without hyperlipidemia shows that red clover decreases total cholesterol by around 11 mg/dL, but does not affect LDL cholesterol, triglyceride, or HDL cholesterol levels, when compared with placebo (102840). This finding is limited by imprecision and inconsistency of the results and the fact that the benefit seems to be mostly attributed to two trials with a high risk of detection and performance bias. When this meta-analysis was repeated without those two trials, red clover supplementation for at least three months still shows a significant, albeit smaller, reduction in total cholesterol of around 4 mg/dL when compared with placebo among post-menopausal individuals. The meta-analysis also shows a small but statistically significant increase in HDL by approximately 1.5 mg/dL and no change in LDL or triglyceride levels (112145). Included studies were of moderate to high quality and lacked heterogeneity.
• Mastalgia. It is unclear if oral red clover is beneficial in patients with mastalgia. Details: One very small study in patients with cyclic mastalgia shows that taking red clover isoflavones (Promensil, Novogen) 40-80 mg daily reduces subjective ratings of breast pain and tenderness. Reductions in pain were 44% with 40 mg and 31% with 80 mg, compared with 13% for placebo (9552).
• Menopausal symptoms. It is unclear if oral red clover is beneficial for menopausal symptoms; research is conflicting and has notable methodological issues. Details: The most recent meta-analysis of 8 small clinical trials in patients with menopausal symptoms suggests that red clover reduces hot flash frequency by an average of 1.7 times when compared with control. The benefit tends to be greater in those with a higher frequency of hot flashes at baseline (5 or more) and when higher doses of red clover isoflavones are used (80 mg or more daily) (105694). However, this finding is limited by imprecision and inconsistency, as well as selective reporting bias in some of the included trials. An older meta-analysis of small, low-quality clinical studies in menopausal patients also suggests that red clover might improve psychological symptoms such as anxiety and depression when compared with control (91525). The most extensively studied product is a specific red clover supplement (Promensil or Melbrosin, Novogen). A meta-analysis of 5 small clinical studies assessing only Promensil shows that taking 80 mg daily for 12 weeks reduces hot flash frequency by 30% to 50%, or by about 3-4 hot flashes per day, when compared with placebo (96731). The validity of these findings is limited by imprecision, inconsistency, and publication bias. Notably, this meta-analysis and all included studies were funded by the supplement manufacturer (8925,10976,10991,17103,19545,96731). In contrast, studies with independent funding sources have not found a benefit with red clover isoflavones 40-120 mg daily for up to 12 months when compared with placebo (10975,17091,19549). Some research has also found benefit for menopausal symptoms when red clover is used in combination with other ingredients. Red clover has been used in combination with black cohosh, dong quai, milk thistle, American ginseng, and Vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months (19552). Red clover isoflavones 37.1 mg have also been used in combination with a probiotic-rich liquid daily for 12 weeks (96730).
• Osteoarthritis. It is unclear if topical red clover is beneficial in patients with osteoarthritis. Details: Preliminary clinical research shows that applying 20 drops of a standardized extract of red clover aerial parts to the knee twice daily for 4 weeks, in addition to taking meloxicam orally, improves subjective measures of pain and function more than using meloxicam plus placebo. However, radiological and laboratory changes were not evaluated (102839).
• Osteoporosis. It is unclear if oral red clover is beneficial in patients with osteoporosis; research is conflicting. Details: One small clinical study in healthy postmenopausal patients shows that taking red clover providing isoflavones 57-85.5 mg daily for 6 months increases bone mineral density (BMD) of the proximal radius and ulna by 3% to 4% (10948). Another clinical study in females ages 49-65 years shows that taking a specific red clover extract (Promensil, Novogen) providing isoflavones 40 mg daily for one year does not increase BMD or bone mineral content (BMC) of the hip, but seems to slightly reduce the loss of lumbar spine BMD and BMC when compared with placebo (6127). However, other research has found no benefit. One clinical study in patients who are at least one year post-menopause and not taking bone preserving medications shows that taking a specific product containing enriched red clover isoflavones (Rimostil [formononetin enriched], Novagen) 50 mg daily for 2 years does not improve BMD of the spine, femoral neck, distal radius, or proximal radius when compared with placebo. However, this study may have been underpowered due to a high drop-out rate (91524). Another small clinical study in perimenopausal and postmenopausal adults shows that taking red clover flowering tops providing isoflavones 120 mg daily for one year does not seem to slow the loss of hip, femoral neck, or lumbar spine BMD when compared with placebo (17091). More evidence is needed to rate red clover for these uses.

(Read more about RED CLOVER)

There is insufficient reliable information available about the effectiveness of yellow dock.

(Read more about YELLOW DOCK)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when clove oil is applied topically (272). A clove oil 1% cream has been applied to the anus with apparent safety for up to 6 weeks (43487). A liposome-based product containing clove oil 45% has been applied to the palms with apparent safety for up to 2 weeks (100596).

LIKELY UNSAFE ...when clove smoke is inhaled. Smoking clove cigarettes can cause respiratory injury (17,43599). ...when clove oil is injected intravenously. This can cause pulmonary edema, hypoxemia, and acute dyspnea (16384). There is insufficient reliable information available about the safety of using clove orally in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when clove oil is taken orally. Ingesting 5-10 mL of undiluted clove oil has been linked to reports of coagulopathy, liver damage, and other serious side effects in infants and children up to 3 years of age (6,17,43385,43395,43419,43457,43652).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (4912). Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of using clove in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about CLOVE)

There is insufficient reliable information available about the safety of condurango.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about CONDURANGO)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Eyebright is listed by the Council of Europe as a natural source of food flavoring (4).

POSSIBLY UNSAFE ...when applied into the eyes. Avoid using due to hygienic concerns; eyebright ophthalmic products may be subject to contamination (8,11). There is insufficient reliable information available about the safety of eyebright when used orally in medicinal amounts.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about EYEBRIGHT)

POSSIBLY SAFE ...when used orally and appropriately as a single dose (260,261). There is insufficient reliable information available about the safety of goldenseal when used as more than a single dose.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of goldenseal can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).

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 goldenseal (2589).

LACTATION:
LIKELY UNSAFE when used orally. Berberine and other harmful constituents can be transferred to the infant through breast milk (2589). Use during lactation can cause kernicterus in the newborn and several resulting fatalities have been reported (2589).

(Read more about GOLDENSEAL)

LIKELY SAFE ...when used orally in amounts commonly used in foods. Red clover has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912,10372).

POSSIBLY SAFE ...when used orally and appropriately in supplemental amounts. Red clover extracts containing up to 80 mg isoflavones have been used with apparent safety in clinical studies lasting up to 2 years (3375,6127,8925,11089,11091,17091,19540,19556,91524,102901,102840). ...when used topically and appropriately. Red clover extracts have been used topically with apparent safety for up to 4 weeks (102839).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in medicinal amounts. Red clover has estrogenic activity (19555); avoid using. There is insufficient reliable information available about the safety of the topical use of red clover during pregnancy and lactation.

(Read more about RED CLOVER)

POSSIBLY SAFE ...when properly prepared and consumed in amounts commonly found in foods. Young leaves must be boiled to remove the oxalate content; death has occurred after consuming uncooked leaves (6,18).

POSSIBLY UNSAFE ...when the uncooked leaves are consumed. Young leaves must be boiled to remove the oxalate content; death has occurred after consuming uncooked leaves (6,18). There is insufficient reliable information available about the safety of properly prepared yellow dock when used orally in medicinal amounts.

PREGNANCY: POSSIBLY UNSAFE
when used orally; avoid using. Yellow dock contains anthraquinone glycosides; unstandardized laxatives are not desirable during pregnancy (4).

LACTATION: POSSIBLY UNSAFE
when used orally; avoid using. Anthraquinones are secreted into breast milk (4,5).

(Read more about YELLOW DOCK)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, clove oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Laboratory research suggests that eugenol, a constituent of clove, has antiplatelet activity (12889,43558,43650,43654). This interaction has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove extracts with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical and laboratory research suggest that polyphenol extracts from clove flower buds might lower blood glucose levels (100595). Dosing adjustments for insulin or oral hypoglycemic agents may be necessary when taken with clove. Monitor blood glucose levels closely.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove may increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that eugenol, the principal constituent of clove, can inhibit CYP1A2 in a dose-dependent manner, (115900). This effect has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove may increase levels of drugs metabolized by CYP2C9.  Details In vitro research shows that eugenol, the principal constituent of clove, inhibits CYP2C9 in a dose-dependent manner (115900). This effect has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove may increase levels of drugs metabolized by CYP2D6.  Details In vitro research shows that eugenol, the principal constituent of clove, can inhibit CYP2D6 in a dose-dependent manner (115900). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove may increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that eugenol, the principal constituent of clove, can inhibit CYP3A4 in a dose-dependent manner (115900). This effect has not been reported in humans.

IBUPROFEN (Advil, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, topical application of clove oil with ibuprofen might increase the absorption and side effects of topical ibuprofen.  Details Laboratory research shows that topical application of clove oil increases the absorption of topical ibuprofen (98854). This interaction has not been reported in humans.

(Read more about CLOVE)

(Read more about CONDURANGO)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, eyebright might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research suggests that eyebright lowers blood glucose levels (49393).

(Read more about EYEBRIGHT)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Goldenseal contains berberine. In vitro and animal research shows that berberine can inhibit platelet aggregation (33660,33694). However, this effect has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the risk of hypoglycemia when used with antidiabetes drugs.  Details Goldenseal contains berberine. Clinical research shows that berberine can lower blood glucose levels (20579,34247,34265,34282). However, this effect has not been reported with goldenseal.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the risk of hypotension when taken with antihypertensive drugs.  Details Goldenseal contains berberine. Animal research shows that berberine can have hypotensive effects (33692,34308). Also, an analysis of clinical research shows that taking berberine in combination with amlodipine can lower systolic and diastolic blood pressure when compared with amlodipine alone (91956). However, this effect has not been reported with goldenseal.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the sedative effects of CNS depressants.  Details Goldenseal contains berberine. Animal research shows that berberine can have sedative effects (13519,33650,33664,33692). However, this effect has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of drugs metabolized by CYP2C9.  Details In vitro research shows that goldenseal root extract can modestly inhibit CYP2C9. This effect may be due to its alkaloid constituents, hydrastine and berberine (21117). However, this effect has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Goldenseal might increase serum levels of drugs metabolized by CYP2D6.  Details Clinical and in vitro research shows that goldenseal can significantly inhibit CYP2D6 enzymes, potentially increasing levels of drugs metabolized by CYP2D6 (13536,16848,35907).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of drugs metabolized by CYP2E1.  Details In vitro research shows that goldenseal root extract can inhibit the activity of CYP2E1 (94140). However, this effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Goldenseal might increase serum levels of drugs metabolized by CYP3A4.  Details Most clinical and in vitro research shows that goldenseal inhibits CYP3A4 enzyme activity and increases serum levels of CYP3A4 substrates, such as midazolam (6450,13536,21117,91740,111725). However, in one small clinical study, goldenseal did not affect the levels of indinavir, a CYP3A4 substrate, in healthy volunteers (10690,93578). This is likely due to the fact that indinavir has a high oral bioavailability, making it an inadequate probe for CYP3A4 interactions (13536,91740) and/or that it is primarily metabolized by hepatic CYP3A, while goldenseal has more potential to inhibit intestinal CYP3A enzyme activity (111725). Both goldenseal extract and its isolated constituents berberine and hydrastine inhibit CYP3A, with hydrastine possibly having more inhibitory potential than berberine (111725).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of dextromethorphan.  Details Goldenseal contains berberine. A small clinical study shows that berberine can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Goldenseal might increase serum levels of digoxin, although this effect is unlikely to be clinically significant.  Details Clinical research shows that goldenseal modestly increases digoxin peak levels by about 14% in healthy volunteers. However, goldenseal does not seem to affect other pharmacokinetic parameters such as area under the curve (AUC) (15132). This suggests that goldenseal does not cause a clinically significant interaction with digoxin. Digoxin is a P-glycoprotein substrate. Some evidence suggests that goldenseal constituents might affect P-glycoprotein; however, it is unclear whether these constituents inhibit or induce P-glycoprotein.

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might decrease the conversion of losartan to its active form.  Details Goldenseal contains berberine. A small clinical study shows that berberine inhibits cytochrome P450 2C9 (CYP2C9) activity and reduces the metabolism of losartan (34279). However, this effect has not been reported with goldenseal.

METFORMIN (Glucophage) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might reduce blood levels of metformin.  Details In vitro research shows that goldenseal extract decreases the bioavailability of metformin, likely by interfering with transport, intestinal permeability, or other processes involved in metformin absorption. It is unclear which, if any, of metformin's transporters are inhibited by goldenseal. Goldenseal does not appear to alter the clearance or half-life of metformin (105764).

OSELTAMIVIR (Tamiflu) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might reduce the therapeutic effects of oseltamivir by decreasing its conversion to its active form.  Details In vitro evidence suggests that goldenseal reduces the formation of the active compound from the prodrug oseltamivir (105765). The mechanism of action and clinical relevance is unclear.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, goldenseal might increase or decrease serum levels of P-glycoprotein (P-gp) substrates.  Details There is conflicting evidence about the effect of goldenseal on P-gp. In vitro research suggests that berberine, a constituent of goldenseal, modestly inhibits P-gp efflux. Other evidence suggests that berberine induces P-gp. In healthy volunteers, goldenseal modestly increases peak levels of the P-gp substrate digoxin by about 14%. However, it does not seem to affect other pharmacokinetic parameters such as area under the curve (AUC) (15132). This suggests that goldenseal is not a potent inhibitor of P-gp-mediated drug efflux. Until more is known, goldenseal should be used cautiously with P-gp substrates.

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the sedative effects of pentobarbital.  Details Animal research shows that berberine, a constituent of goldenseal, can prolong pentobarbital-induced sleeping time (13519). However, this effect has not been reported with goldenseal.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of tacrolimus.  Details Goldenseal contains berberine. In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with tacrolimus 6.5 mg twice daily, intake of berberine 200 mg three times daily increased the blood concentration of tacrolimus from 8 to 22 ng/mL. Following a reduction of tacrolimus dosing to 3 mg daily, blood levels of tacrolimus decreased to 12 ng/mL (91954).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Although some laboratory research suggests that red clover may have anticoagulant and antiplatelet activity, clinical research has not shown this effect.  Details In vitro research suggests that genistein in red clover has antiplatelet effects, and historically, red clover was thought to have anticoagulant effects due to its coumarin content. However, some experts state that this is unlikely as most natural coumarins have not been shown to have anticoagulant effects, and their content in red clover is low (17091,19557,19558,19559). Additionally, some clinical research in postmenopausal patients found no effect on coagulation or prothrombin time with the use of red clover flowering tops 378 mg daily for 12 months or red clover isoflavone (Rimostil) 50 mg daily for 2 years (17091,91524).

CAFFEINE Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, soy might reduce the clearance of caffeine; however, a small clinical study found no effect.  Details Red clover contains genistein. Taking genistein 1 gram daily for 14 days seems to inhibit caffeine clearance and metabolism in healthy females (23582). However, this effect does not seem to occur with the lower amounts of genistein found in red clover. A clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of caffeine (105693).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, red clover might increase levels of drugs metabolized by CYP1A2; however, a small clinical study found no effect.  Details In vitro evidence shows that red clover inhibits CYP1A2 (12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of caffeine, a CYP1A2 probe substrate (105693).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, red clover might increase the levels and clinical effects of drugs metabolized by CYP2C19.  Details In vitro evidence suggests that red clover weakly inhibits CYP2C19 (12479). This interaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, red clover might increase levels of drugs metabolized by CYP2C9; however, a small clinical study found no effect.  Details In vitro evidence suggests that red clover might inhibit CYP2C9 (12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of tolbutamide, a CYP2C9 probe substrate (105693).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, red clover might increase levels of drugs metabolized by CYP3A4; however, a small clinical study found no effect.  Details In vitro evidence shows that red clover might inhibit CYP3A4 isoenzymes (6450,12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of alprazolam, a CYP3A4 probe substrate (105693).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of large amounts of red clover might interfere with estrogen therapy.  Details Red clover contains phytoestrogens which might have estrogenic activity in some people. Theoretically, red clover might compete for estrogen receptors and interfere with estrogen-containing drug therapy (4743,19560,19729).

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, red clover might increase the risk of methotrexate toxicity.  Details In a case report, a 52-year-old female receiving weekly methotrexate injections for psoriasis developed symptoms of methotrexate toxicity, including severe vomiting and epigastric pain, after three days of taking red clover 430 mg daily. Toxicity resolved after red clover was discontinued. However, no liver function tests or methotrexate levels were reported (91522).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the phytoestrogens in red clover might interfere with tamoxifen.  Details In vitro and animal research suggests that genistein, a constituent of red clover, might antagonize the antitumor effects of tamoxifen (8192). However, there is some evidence from an animal study that red clover does not reduce the efficacy of tamoxifen (102901). Until more is known, tell patients taking tamoxifen to avoid red clover.

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DIGOXIN (Lanoxin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, yellow dock might increase the risk of digoxin toxicity when used long-term or in large amount.  Details When yellow dock is used chronically or in large amounts, hypokalemia may occur (4,19). This might increase the toxic effects of digoxin.

DIURETIC DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, yellow dock might increase the risk of hypokalemia when taken with diuretics.  Details When yellow dock is used chronically or in large amounts, hypokalemia may occur (4,19), and overuse of yellow dock might compound diuretic-induced potassium loss (19).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the laxative effects of yellow dock might increase the effects of warfarin, including the risk of bleeding.  Details The anthraquinones in yellow dock have a mild stimulant laxative effect (4,6,12). Consuming excessive amounts can cause diarrhea (6). Diarrhea can increase the effects of warfarin, increase international normalized ratio (INR), and increase the risk of bleeding.

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General ...Orally, clove is well tolerated when consumed as a spice; however, clove oil in doses of only 5-10 mL can be toxic in children. Topically, clove is generally well tolerated. When inhaled or used intravenously, clove may be unsafe.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, dental decay, itching, mucous membrane irritation, tingling, ulcers.
Inhaled: Dental decay, hypertension, itching, tachycardia.
Serious Adverse Effects (Rare):
Orally: Liver failure, respiratory distress.
Inhaled: Pneumonitis, pulmonary edema, respiratory distress.

Cardiovascular ...Smoking clove cigarettes increases heart rate and systolic blood pressure (12892).

Dental ...Population research has found that the risk of dental decay is increased in clove cigarette smokers (43332). Repeated topical application of clove in the mouth can cause gingival damage and skin and mucous membrane irritation (4,272,512). Eugenol, a constituent of clove and a material commonly found in dentistry, has been associated with side effects including gum inflammation and irritation (43365,43373,43522).

Dermatologic ...The American Dental Association has accepted clove for professional use, but not nonprescription use, due to potential damage to soft tissue that may be induced by clove application. In clinical research, small aphthous-like ulcers appeared in the area of the mouth where clove gel was applied in four participants (43448). Skin irritation and stinging have been reported with clove oil application (43338,43626). In a 24-year-old, exposure to a clove oil spill resulted in permanent local anesthesia and anhidrosis, or lack of sweating, at the affected area (43626).

Endocrine ...A case of hypoglycemia and metabolic acidosis have been reported after administration of one teaspoon of clove oil to a seven-month-old infant (43457). A case of electrolyte imbalance following accidental ingestion by a seven-month-old has also been reported (6).

Hematologic ...A case of disseminated intravascular coagulation has been reported in a 2-year-old patient after consuming between 5-10 mL of clove oil. The patient was treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III. On the fifth day, the patient started to improve and made a full recovery (43652).

Hepatic ...There are three cases of hepatic failure occurring in children after ingestion of 5-10 mL of clove oil (43395,43419,43652). Liver injury also occurred in a 3-year-old male (96949). These patients were successfully treated with N-acetylcysteine. The course of liver injury seems to be milder and shorter with early N-acetylcysteine treatment (43395,43419,96949). Another patient, who also presented with disseminated intravascular coagulation, was successfully treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III (43652).

Immunologic ...Contact dermatitis and urticaria has been reported following topical exposure to clove oil or eugenol, a constituent of clove oil (12635,43339,43606,43346).

Neurologic/CNS ...CNS depression has been reported in a 7-month-old who was given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457). A case of confusion and inability to speak has been reported secondary to oral exposure to clove oil and alcohol. The patient required intubation and was successfully treated with thiamine and normal saline (43580). Seizure and coma have been reported in a two-year-old male after ingesting 5-10 mL of clove oil (43652).

Pulmonary/Respiratory ...Clove cigarettes have been associated with throat and chest tightness (43337), pulmonary edema (43618), and fatal aspiration pneumonitis (43599). The causative factor may be clove alone or clove along with other substances found in cigarettes. Clove cigarettes contain significant amounts of nicotine, tar, and carbon monoxide and increase plasma levels of nicotine and exhaled carbon monoxide, which might cause long-term health effects similar to tobacco smoking (12892). According to the American Medical Association, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Also, some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol, which is volatilized into the smoke (43602).
Intravenous injection of clove oil in a 32-year-old female resulted in hypoxia, acute dyspnea, interstitial and alveolar infiltrates, and non-cardiogenic pulmonary edema. The patient was managed with supplemental oxygen and recovered over the next seven days (16384).
Occupational exposure to eugenol, a constituent of clove, has also been reported to cause asthma and rhinitis (43492).

Renal ...Proteinuria and other urinary abnormalities were observed in a seven-month-old infant given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457).

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General ...There is currently a limited amount of information on the adverse effects of condurango.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, including anaphylaxis, in individuals sensitive to latex.

Immunologic ...Orally, condurango bark has been associated with allergic reactions, including anaphylaxis, in individuals sensitive to latex (1500,1501).

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General ...Orally, eyebright is generally well tolerated when used in food amounts. Topically, eyebright might be unsafe due to the potential for contamination.

Gastrointestinal ...Orally, eyebright has been reported to cause nausea and constipation (4).

Genitourinary ...Orally, eyebright has been reported to cause polyuria (4).

Neurologic/CNS ...Orally, eyebright has been reported to cause confusion and headache (4).

Ocular/Otic ...Topically, eyebright has been reported to cause increased ocular pressure, lacrimation, pruritus, redness, swelling of eyelid margins, vision changes, and photophobia when applied to the eyes (4). Ophthalmic eyebright products should be used with caution due to the potential for contamination (8,11).

Pulmonary/Respiratory ...Orally, eyebright has been reported to cause cough, dyspnea, and nasal congestion (4).

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General ...There is limited reliable information available about the safety of goldenseal when used in more than a single dose. Berberine, a constituent of goldenseal, is generally well tolerated when used orally.
Most Common Adverse Effects:
Orally: Berberine, a constituent of goldenseal, can cause abdominal distension, abdominal pain, bitter taste, constipation, diarrhea, flatulence, headache, nausea, and vomiting.

Dermatologic ...Orally, berberine, a constituent of goldenseal, may cause rash. However, this appears to be rare (34285). A case of photosensitivity characterized by pruritic, erythematous rash on sun-exposed skin has been reported in a 32-year-old female taking a combination product containing goldenseal, ginseng, bee pollen, and other ingredients. The rash resolved following discontinuation of the supplement and treatment with corticosteroids (33954). It is not clear if this adverse effect is due to goldenseal, other ingredients, or the combination.

Endocrine ...A case of severe, reversible hypernatremia has been reported in an 11-year-old female with new-onset type 1 diabetes and diabetic ketoacidosis who took a goldenseal supplement (52592).

Gastrointestinal ...Orally, berberine, a constituent of goldenseal, may cause diarrhea, constipation, flatulence, vomiting, abdominal pain, abdominal distention, and bitter taste (33648,33689,34245,34247,34285,91953). Theoretically, these effects may occur in patients taking goldenseal. However, this hasn't been reported in clinical research or case reports.

Neurologic/CNS ...Orally, berberine, a constituent of goldenseal, may cause headache when taken in a dose of 5 mg/kg daily (33648). Theoretically, this may occur with goldenseal, but this hasn't been reported in clinical research or case reports.

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General ...Orally and topically, red clover seems to be well tolerated.
Most Common Adverse Effects:
Orally: Myalgia, nausea, and vaginal spotting.

Dermatologic ...Orally, a specific red clover isoflavone product (Promensil) has been associated with mild cases of psoriasis and thrush, although a direct causal link has not been established (9552).

Gastrointestinal ...Orally, red clover has been reported to cause nausea (8194).

Genitourinary ...In human research, 80 mg, but not 40 mg, of a specific red clover isoflavone product (Promensil) increased the duration of menstrual cycles in patients with mastalgia (9552). Red clover has also been reported to cause vaginal spotting (8194).

Hematologic ...In one case report, a 53-year-old female had a spontaneous subarachnoid hemorrhage associated with the use of an herbal supplement containing red clover, dong quai, and eleuthero. It is not clear if this was due to red clover, another ingredient, the combination of ingredients, or other factors (70419). In another case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis 3 days after taking a combination phytoestrogen product containing red clover 250 mg, wild yam 276 mg, dong quai 100 mg, and black cohosh 250 mg (13155). It is unclear if red clover contributed to this event.

Musculoskeletal ...Orally, red clover has been reported to cause myalgia (8194).

Neurologic/CNS ...Orally, a specific red clover isoflavone product (Medoflavon) has been associated with headache, although with a similar frequency to placebo (19545).

Oncologic ...Due to potential estrogenic effects of red clover isoflavones, there has been some concern that red clover might increase the risk of estrogen-sensitive cancers such as breast cancer or uterine cancer. A meta-analysis of 8 clinical trials suggests that increased intake of red clover- and soy-derived isoflavones may modestly increase mammographic breast density in premenopausal, but not postmenopausal, adults when compared with placebo. However, in a sub-group analysis assessing only isolated red clover isoflavones, there was no change in breast density (70428). Furthermore, a 2015 review by the European Food Safety Authority (EFSA) reported no increase in risk of breast cancer in females taking isoflavone-containing supplements (91725). Similarly, no effect was found on endometrial thickness and histopathological changes in the uterus after up to 36 months of supplementation with 40-120 mg daily of isoflavones from red clover extract (91725).

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General ...Orally, yellow dock seems to be well tolerated when properly prepared and consumed in food amounts. Consuming raw yellow dock leaves or rhizomes may be unsafe.
Serious Adverse Effects (Rare):
Orally: Raw leaves or rhizomes can cause hypocalcemia, kidney stones, and vomiting.

Cardiovascular ...Orally, yellow dock has been linked to ventricular fibrillation and death after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the blood vessels and heart (12). Older or uncooked leaves should be avoided (6).

Dermatologic ...Orally, yellow dock can cause dermatitis when consumed in large amounts (4). Topically, contact with the plant may cause dermatitis in people sensitive to yellow dock (6).

Gastrointestinal ...Orally, vomiting may occur after ingestion of fresh rhizome (18). Consuming excessive amounts can cause diarrhea and nausea (6). Excessive use can also cause abdominal cramps and intestinal atrophy (4). There is one report of a death, preceded by vomiting and diarrhea, after ingestion of 500 grams of yellow dock (17). Older or uncooked leaves should be avoided (6).

Genitourinary ...Orally, yellow dock can cause polyuria when consumed in large amounts (6).

Hematologic ...Orally, in one case report, a 38-year-old female developed immune-mediated thrombocytopenia after consuming a "cleansing" tea containing unknown amounts of yellow dock and burdock. The patient presented with bruising, mild weakness, and fatigue, which started 2-3 days after consuming the tea, and was found to have a platelet count of 5,000 per mcL. Symptoms resolved after platelet transfusion and treatment with oral dexamethasone (108971). It is unclear if these effects were caused by yellow dock, burdock, the combination, or other contributing factors.

Hepatic ...Orally, yellow dock has been linked to liver failure and death after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the liver (12). Older or uncooked leaves should be avoided (6).

Neurologic/CNS ...Orally, yellow dock has been linked to coma and death after ingestion of 500 grams (17). Older or uncooked leaves should be avoided (6).

Pulmonary/Respiratory ...Orally, yellow dock has been linked to respiratory depression and death after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the lungs (12). Older or uncooked leaves should be avoided (6).

Renal ...Orally, yellow dock can cause polyuria when consumed in large amounts (6). There is one report of a death, preceded by kidney failure, after ingestion of 500 grams (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the kidneys. Individuals with a history of kidney stones should use yellow dock cautiously (12). Older or uncooked leaves should be avoided (6).

Other ...Orally, yellow dock can cause hypokalemia when taken in large amounts (4). There is one report of a death, preceded by severe metabolic acidosis, after ingestion of 500 grams of yellow dock (17). Oxalic acid, a constituent of yellow dock, reacts with calcium in plasma, forming insoluble calcium oxalate, which can cause hypocalcemia; the crystals may precipitate in the kidneys, blood vessels, heart, lungs, and liver (12). Older or uncooked leaves should be avoided (6).

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