Kudzu and St. John's Wort Combination by TerraVita

POSSIBLY EFFECTIVE

• Alcohol use disorder. Oral kudzu seems to be beneficial for reducing alcohol consumption in heavy drinkers; however, it may not be beneficial in those with chronic alcohol use disorder. Details: Some research shows that heavy drinkers who take a specific kudzu root extract (Alkontrol-Herbal; NPI-031; Natural Pharmacia International, Inc.) 0.5-1 grams three times daily for 1-4 weeks consume less beer when given an opportunity to drink and may have more abstinent days (13085,92257). Other research shows that binge drinkers who take kudzu extract 2 grams as a single dose 2.5 hours prior to a 90-minute binge drinking episode consume 37% fewer beers than those taking placebo (92258). However, kudzu does not seem to decrease the craving for alcohol (10386,13085,57948,92257). Kudzu extract also does not seem to improve sobriety in people with chronic alcohol use disorder (10386).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there is interest in using oral kudzu for allergic rhinitis, there is insufficient reliable information about the clinical effects of kudzu for this condition.
• Angina. Although there is interest in using the injectable kudzu constituent puerarin for angina, there is insufficient reliable information about the clinical effects of oral kudzu for this condition.
• Angioplasty. Although there is interest in using the injectable kudzu constituent puerarin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), there is insufficient reliable information about the clinical effects of oral kudzu for this condition.
• Athletic performance. Oral kudzu has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in healthy males shows that taking capsules containing kudzu isoflavone extract 180 mg, soybean peptides 600 mg, taurine 200 mg, and ginseng saponins 120 mg daily in two divided doses for 15 days can significantly increase time to exhaustion during exercise when compared with placebo (57945).
• Back pain. Although there is interest in using the injectable kudzu constituent puerarin for back pain, there is insufficient reliable information about the clinical effects of oral kudzu for this condition.
• Cluster headache. Although there is interest in using oral kudzu for cluster headache, there is insufficient reliable information about the clinical effects of kudzu for this condition.
• Coronary heart disease (CHD). Although there is interest in using the injectable kudzu constituent puerarin for CHD, there is insufficient reliable information about the clinical effects of oral kudzu for this condition.
• Diabetes. It is unclear if oral kudzu is beneficial for diabetes. Details: Preliminary clinical research in adults with type 2 diabetes shows that taking oral puerarin, a kudzu constituent, 250 mg three times daily in addition to rosiglitazone 4 mg daily for 12 weeks reduces blood glucose levels and glycated hemoglobin (HbA1c) when compared to baseline (57951). The effect of kudzu alone is unclear. Additionally, the lack of a comparator group limits the validity of this finding.
• Diabetic nephropathy. It is unclear if oral kudzu is beneficial for diabetic nephropathy. Details: Preliminary clinical research in patients with diabetic nephropathy shows that taking puerarin, a kudzu constituent, 250 mg three times daily in addition to rosiglitazone 4 mg daily for 12 weeks improves laboratory measurements of kidney function, including serum creatinine, blood urea nitrogen, and urinary albumin, when compared to baseline (57951). The effect of kudzu alone is unclear. Additionally, the lack of a comparator group limits the validity of this finding.
• Hangover. Although there is interest in using oral kudzu for hangover, there is insufficient reliable information about the clinical effects of kudzu for this condition.
• Heart failure. Although there is interest in using the kudzu constituent puerarin for heart failure, there is insufficient reliable information about the clinical effects of kudzu for this condition.
• Hypertension. It is unclear if oral kudzu is beneficial for hypertension. Details: Preliminary clinical research in adults with hypertension shows that taking kudzu powder 1.5 grams twice daily for 12 weeks decreases systolic blood pressure by 16% and diastolic blood pressure by 12% when compared to baseline (92261). The validity of this finding is limited by the lack of a comparator group.
• Menopausal symptoms. Small clinical studies suggest that oral kudzu may modestly improve menopausal symptoms. Details: Preliminary clinical research shows that taking kudzu 25 mg, 50 mg, or 100 mg daily for 6 months during perimenopause improves climacteric symptoms based on a modified Green climacteric scale when compared with baseline (57890,57942). Other preliminary clinical research in patients with menopausal symptoms shows that taking kudzu extract 0.84-2.52 grams daily for 4 weeks, providing puerarin 113-338 mg daily, modestly reduces overall menopausal symptoms when compared with baseline (108154). The validity of the findings from these studies is limited by the lack of a comparator group. Other clinical research shows that taking kudzu 50 mg daily for 6 months during perimenopause reduces vasomotor symptoms similarly to taking conjugated equine estrogen 0.625 mg with or without medroxyprogesterone acetate 2.5 mg daily (57927).
• Migraine headache. It is unclear if oral kudzu is beneficial for migraine headache. Details: Preliminary clinical research in adults with migraine shows that taking one capsule of kudzu (Kuzik) daily, providing an unspecified dose of kudzu, for 90 days reduces the number of headache attacks per month by about 3, with approximately 50% of patients achieving a 50% reduction in monthly headache days when compared with baseline. There were also modest improvements in disability and medication use (108155). The validity of these findings is limited by the lack of a comparator group.
• Myocardial infarction (MI). Although there is interest in using the injectable kudzu constituent puerarin for MI, there is insufficient reliable information about the clinical effects of oral kudzu for this condition.
• Obesity. It is unclear if oral kudzu is beneficial for obesity. Details: Preliminary clinical research in adults with obesity shows that taking a kudzu extract 300 mg daily for 12 weeks reduces visceral fat and body mass index (BMI) when compared with placebo. However, doses of 200 mg do not seem to be as effective (57954).
• Postmenopausal conditions. It is unclear if oral or intravaginal kudzu is beneficial for postmenopausal conditions. Details: A small clinical study in postmenopausal individuals shows that taking kudzu containing isoflavones 100 mg orally once daily for 3 months improves flexible thinking and attention when compared with control. However, it does not appear to improve total cholesterol, low-density lipoprotein (LDL) cholesterol, or sex hormone levels (11386). Another small clinical study in postmenopausal individuals shows that taking kudzu 20 mg, 30 mg, or 50 mg daily for 24 weeks improves vaginal dryness and pH when compared with baseline, but not when compared with placebo. It also decreases a specific biomarker of bone turnover, called bone alkaline phosphatase, when compared with placebo (57924,57929). It is unclear if this correlates with improved bone density or with a reduced risk of osteoporosis. Kudzu has also been evaluated as an intravaginal gel. One small clinical study shows that applying 0.5 grams of kudzu 6% gel into the vagina every night for 2 weeks, followed by 3 nights each week for 9 weeks, improves vaginal symptoms of dryness, soreness, irritation, and abnormal discharge similarly to conjugated estrogen cream applied on the same schedule. However, kudzu gel is less effective than conjugated estrogen cream for improving overall vaginal health (96740). Another small clinical study of postmenopausal patients shows that applying 0.5 grams of kudzu 6% gel intravaginally every night for 3 weeks increases vaginal arterial blood flow and restores atrophic vaginal tissue when compared with placebo after 12 weeks (110702). In contrast, a similar study shows that applying 0.5 grams of kudzu 5% gel into the vagina every night for 2 weeks, followed by 3 nights each week for 10 weeks, does not improve vaginal symptoms when compared with placebo gel (105521). However, the study may have been inadequately powered to detect a difference between groups.
• Rhinosinusitis. Although there is interest in using oral kudzu for rhinosinusitis, there is insufficient reliable information about the clinical effects of kudzu for this condition.
• Stroke. Although there is interest in using the injectable kudzu constituent puerarin for stroke, there is insufficient reliable information about the clinical effects of oral kudzu for this condition. More evidence is needed to rate kudzu for these uses.

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LIKELY EFFECTIVE

• Depression. Specific formulations of oral St. John's wort are effective for mild or moderate major depressive disorder. St. John's wort may also cause fewer side effects than certain conventional antidepressants. Details: Moderate quality meta-analyses and individual clinical trials show that St. John's wort extracts are more effective than placebo (76057,76140,76143,76271,89669,104036), and likely as effective as low-dose tricyclic antidepressants (6434,76143), tetracyclic antidepressants (76174), and selective serotonin reuptake inhibitors (SSRIs) (76143,76144,96551), including fluoxetine (Prozac) (3550,4897), sertraline (Zoloft) (6400), and paroxetine (Paxil) (13021) for treating depression. However, some of these studies have been critiqued for using lower doses of SSRIs than typical dosing in comparative studies (104037). St. John's wort also seems to have better tolerability and less gastrointestinal, neurologic, and sexual adverse effects than certain conventional antidepressants (104036). Taking St. John's wort extract improves mood and decreases anxiety, somatic symptoms, and insomnia related to mild to severe major depression (3550,4897,6400,13021,13157,76143,104036). Short-term response rates to St. John's wort appear to be between 65% and 100%; however, long-term, the response rates appear to range from 60% to 69% (13156). Most studies have evaluated St. John's wort in adults; however, there is also some evidence that taking St. John's wort 300-1800 mg daily might be effective for depression in children less than 17 years old (4538,10844,76110). There is some concern that St. John's wort may not be effective for severe major depressive disorder necessitating psychiatric care. Two studies in psychiatric care settings showed no benefit of using St. John's wort (5096,10843). Clinical guidelines from the American College of Physicians state that St. John's wort may be as effective and better tolerated than conventional antidepressants for mild to moderate depression (104037). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that St. John's wort is recommended as monotherapy for mild to moderate forms of major depressive disorder (110318). There is no guarantee that people living in the United States can obtain St. John's wort preparations of similar potency and effectiveness as those used in clinical research (104037). The CANMAT Taskforce recommendation is for specific formulations of 3:1 to 7:1 extracts, standardized to approximately 0.2-0.3% hypericin and/or 5-6% hyperforin, in single or divided doses of 600 mg to 1800 mg daily (110318). Most studies have used St. John's wort extracts standardized to hypericin content, usually 0.3%, but extracts standardized to 1% to 4% hyperforin also seem to be effective. Extracts containing hypericin 0.2% to 0.3%, including LI 160 (Lichtwer Pharma) and Remotiv (Zeller) have most often been studied in doses of 300 mg three times daily for up to 6 weeks, or 250 mg twice daily for up to 6 weeks. Extracts containing 3% to 6% hyperforin, including Movana (Pharmaton) and WS 5570 (Schwabe Pharmaceuticals) have most often been studied in doses of 300-600 mg three times daily for 6-26 weeks (761,4538,4630,104036).

POSSIBLY EFFECTIVE

• Menopausal symptoms. Oral St. John's wort seems to be beneficial for patients with menopausal symptoms. Details: Most clinical research shows that taking St. John's wort as a single supplement can reduce menopausal symptoms. A meta-analysis of small clinical trials in menopausal adults shows that taking St. John's wort up to 900 mg daily for up to 16 weeks, alone or in combination with other herbs, reduces frequency and severity of hot flashes when compared with placebo (95510). Some research also suggests that St. John's wort might improve quality of life and psychological symptoms when compared with placebo (76043,76146,89666,95510). St. John's wort has also shown benefit when used in combination with black cohosh (Remifemin Plus, Schaper & Brummer GmbH & Co. KG; Gynoplus, Jin-Yang Pharm; Feramin Q, Dongkook Pharm) (15037,15893,35853,95510), and with Vitex agnus-castus (41482).
• Somatic symptom disorder. Oral St. John's wort seems to be beneficial for patients with somatoform disorder. Details: Two clinical trials in patients with somatoform disorders shows that taking a specific standardized St. John's wort extract (LI 160, Lichtwer Pharma) 600 mg daily seems to reduce symptoms of somatization disorder by 45% after 6 weeks of treatment when compared with placebo (9476,76089).

POSSIBLY INEFFECTIVE

• Burning mouth syndrome. Oral St. John's wort does not appear to reduce pain from burning mouth syndrome. Details: A small clinical study in patients with burning mouth syndrome shows that taking St. John's wort 300 mg (standardized to hypericin 0.3% and hyperforin 3.0%) three times daily for 12 weeks does not alleviate pain when compared to placebo (76133).
• Hepatitis C. St. John's wort contains hypericin. Synthetic hypericin has been studied and shown to be ineffective as an oral drug for hepatitis C. Details: A small clinical study in patients with chronic hepatitis C virus (HCV) infection shows that giving synthetic hypericin 0.05-0.1 mg/kg orally daily does not seem to be effective for reducing viral load and may be unsafe due to the risk for phototoxic reactions (4631).
• HIV/AIDS. St. John's wort contains hypericin. Synthetic hypericin has been studied and shown to be ineffective as an oral and intravenous drug for HIV. Details: A small clinical study in adults infected with HIV shows that giving synthetic hypericin 0.25-0.5 mg/kg, either intravenously 2-3 times weekly or orally every day, as an antiretroviral agent does not seem to be effective and may be unsafe due to the risk for phototoxic reactions, which occurred in about 50% of patients (206).
• Irritable bowel syndrome (IBS). Oral St. John's wort does not seem to improve symptoms in patients with IBS. Details: A small clinical study shows that taking a specific St. John's wort extract (St. John's Wort Extract Extra Strength, Enzymatic Therapy) 450 mg twice daily is no more effective than placebo for reducing symptoms of IBS after 12 weeks of treatment. In fact, patients taking placebo had improved symptoms compared to St. John's wort (16893).
• Peripheral neuropathy. Oral St. John's wort does not seem to relieve pain in patients with peripheral neuropathy. Details: A small clinical study in diabetic and non-diabetic patients with polyneuropathy shows that taking St. John's wort containing 0.9 mg hypericin orally daily for 5 weeks does not seem to relieve most measures of pain when compared with placebo (7047).
• Social anxiety disorder. Oral St. John's wort does not seem to be beneficial for patients with social anxiety disorder. Details: A small clinical study shows that taking St. John's wort 600-1800 mg daily for 12 weeks does not improve social phobia or social anxiety disorder when compared with placebo (76101).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical St. John's wort is beneficial for acne. Details: A small clinical trial in patients with mild to moderate acne treated with photodynamic therapy shows that topical application with 1.5 mL of a St. John's wort 0.5% extract (DR-Light complex; Genicos Co., Ltd, Cheongju, Korea) for 10 minutes for four weekly sessions reduces acne lesion count as effectively as treatment with indole-3-acetic acid (110327).
• Anxiety. Although there is interest in using oral St. John's wort for anxiety, there is insufficient reliable information about the clinical effects of St. John's wort for this condition.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral St. John's wort is beneficial for improving symptoms in children with ADHD. Details: A small clinical study in children ages 6-17 years with ADHD shows that taking a specific St. John's wort extract standardized to 0.3% hypericin, 300 mg three times daily for 8 weeks, does not improve symptoms such as inattentiveness when compared with placebo (17986).
• Brain tumor. St. John's wort contains hypericin. Synthetic hypericin has been studied as an oral drug for malignant brain tumors, with unclear benefit. Details: A small clinical study in patients with malignant gliomas shows that taking synthetic hypericin 0.05-0.5 mg/kg daily orally for up to 3 months was associated with stable disease in 7 of 42 patients and partial response in 2 of 42 patients (76160). However, it is unclear how these outcomes would compare with historical controls or a prospectively enrolled control group.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral St. John's wort for CFS, there is insufficient reliable information about the clinical effects of St. John's wort for this condition.
• Crigler-Najjar syndrome type 2. It is unclear if oral St. John's wort is beneficial for patients with this condition. Details: Crigler-Najjar syndrome type 2 is a rare genetic disorder characterized by the accumulation of bilirubin in the body. One case report of a 24 year-old female with this condition shows that taking St. John's wort (Jarsin LI160, Vifor SA) 300 mg three times daily by mouth for two 8-week periods 18 months apart decreases bilirubin levels by 34%, reduces jaundice, and improves fatigue (95509).
• Fibromyalgia. Although there is interest in using oral St. John's wort for fibromyalgia, there is insufficient reliable information about the clinical effects of St. John's wort for this condition.
• Genital herpes. Topical St. John's wort has only been evaluated in combination with copper sulfate; its effect when used alone is unclear. Details: A clinical study in patients with herpes simplex virus 1 (HSV-1) or 2 (HSV-2) shows that applying a single dose of a specific topical product (Dynamiclear, Global Herbal Supplies Pty Ltd), which contains St. John's wort 0.1% and copper sulfate pentahydrate 5%, helps reduce symptoms such as stinging, burning, erythema, and pain. In fact, the combination product appears to reduce erythema, itching, and pain more than applying acyclovir 5% (Zovirax, Glaxo Smith Kline) five times daily for 7 days (76164).
• Herpes labialis (cold sores). Topical St. John's wort has only been evaluated in combination with copper sulfate; its effect when used alone is unclear. Details: A clinical study in patients with herpes simplex virus 1 (HSV-1) or 2 (HSV-2) shows that applying a single dose of a specific topical product (Dynamiclear, Global Herbal Supplies Pty Ltd), which contains St. John's wort 0.1% and copper sulfate pentahydrate 5%, helps reduce symptoms such as stinging, burning, erythema, and pain. In fact, the combination product appears to reduce erythema, itching, and pain more than applying acyclovir 5% (Zovirax, Glaxo Smith Kline) five times daily for 7 days (76164).
• Mastitis. It is unclear if topical St. John's wort is beneficial for granulomatous mastitis. Details: In patients with idiopathic granulomatous mastitis, persistent or intractable skin lesions may remain after treatment with oral steroids and antibiotics. Preliminary clinical research shows that topical application with St. John's wort oil for two minutes twice daily for 6 weeks reduces the severity of skin lesions in patients with persistent lesions following treatment. After treatment, the success rate, based on clearance or remaining mild symptoms, was 94.1% (110326).
• Memory. It is unclear if oral St. John's wort is beneficial for improving memory in healthy people. Details: A small clinical study in healthy adults shows that taking a specific supplement (Remotiv, Zeller) containing St. John's wort 250 mg, standardized to 0.5 mg of hypericin, by mouth as a single dose, seems to improve short-term memory when compared with baseline. In contrast, the same product containing a higher dose of St. John's wort, 500 mg, seems to worsen memory when compared with baseline (100245). The validity of this finding is limited by the lack of a control group.
• Migraine headache. It is unclear if oral St. John's wort is beneficial for reducing migraine headache. Details: A small low quality clinical study in patients with migraines suggests that adding a specific St. John's wort product (Perforan, Godaru) 160 mg three times daily to sodium valproate 400 mg daily might modestly improve migraine intensity, but not migraine frequency, when compared with sodium valproate alone (89667).
• Obsessive-compulsive disorder (OCD). It is unclear if oral St. John's wort is beneficial for reducing OCD symptoms. Details: There is conflicting evidence about the effectiveness of St. John's wort for OCD. A small open-label study suggests that taking a specific St. John's wort extract standardized to 0.3% hypericin (Alterra, Upsher-Smith Laboratories) 450 mg twice daily for 12 weeks might improve symptoms of OCD when compared to baseline (5075). The validity of this finding is limited by the lack of a control group. A small, higher quality clinical study using a different St. John's wort extract (LI 160, Lichtwer Pharma AG) 600-1800 mg daily for 12 weeks shows that it does not improve symptoms of OCD when compared with placebo (14417). However, this study excluded patients with concomitant depression, so it's unclear if St. John's wort might improve OCD symptoms in patients with depression.
• Polycystic ovary syndrome (PCOS). Oral St. John's wort has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking three tablets containing St. John's wort, licorice root, Ceylon cinnamon, levant berry, peony, and Tribulus daily for 3 months, in addition to lifestyle changes, improves oligomenorrhea by 33% and quality of life by 30% when compared with lifestyle changes alone in adults with PCOS (97216). It is unclear if these effects are due to St. John's wort, other ingredients, or the combination.
• Premenstrual syndrome (PMS). It is unclear if oral St. John's wort is beneficial for patients with PMS. Details: There is conflicting evidence on the effects of St. John's wort for treating PMS, although most evidence suggests benefit. A small clinical study shows that taking a specific St. John's wort extract standardized to contain 0.18% hypericin and 3.38% hyperforin (LI 160, Lichtwer Pharma AG) 450 mg twice daily for two menstrual cycles reduces physical and behavioral PMS symptoms, but not mood or pain, when compared with placebo (76150). Another clinical study shows that taking St. John's wort extract containing hypericin 1.36 mg daily for two menstrual cycles can reduce symptoms of PMS, including anxiety, depression, forgetfulness, crying, headache, and fatigue, when compared with placebo (76159). However, one clinical study shows that taking St. John's wort 600 mg (standardized to contain 1.8 mg of hypericin) does not reduce anxiety or other PMS symptoms when compared with placebo (76104). The conflicting results may be due to differences in St. John's wort formulations and dosages.
• Psoriasis. It is unclear if topical St. John's wort improves symptoms in patients with plaque psoriasis. Details: A small clinical study in patients with mild or moderate plaque psoriasis shows that applying an ointment containing St. John's wort extract 5% twice daily to one side of the body for 4 weeks modestly decreases the severity, thickness, and degree of erythema of psoriasis plaques when compared with applying placebo ointment to the other side of the body (95940).
• Seasonal affective disorder (SAD). It is unclear if oral St. John's wort is beneficial for patients with SAD. Details: Preliminary clinical research shows that St. John's wort extract improves symptoms associated with SAD, including anxiety, decreased libido, and sleep disturbances, when compared with baseline. It may be beneficial when used alone or in combination with light therapy (9686,76175). However, the validity of these findings is limited by the lack of a comparator group.
• Scleroderma. Topical St. John's wort has only been evaluated in combination with neem oil; its effect when used alone is unclear. Details: A small observational study in patients with systemic sclerosis has found that topical application of a specific cream (Holoil, RI.MOS. SRL) containing St. John's wort and neem oil is associated with improved healing, decreased pain, and reduced need for surgical interventions and antibiotics when compared with a control group (102867). It is unknown if these effects are due to St. John's wort, neem, or the combination. Additionally, the validity of these results is limited by a lack of randomization, blinding, and placebo-control.
• Smoking cessation. It is unclear if oral St. John's wort is beneficial for patients trying to quit smoking. Details: A small clinical study in cigarette smokers shows that taking a specific St. John's wort extract (LI-160, Lichtwer Pharma US) 300 mg once or twice daily, starting 1 week before and continuing for 3 months after quitting smoking, is associated with a continuous abstinence rate of 18% at 3 months and 0% at 12 months, suggesting a lack of benefit (14481).
• Wound healing. Topical St. John's wort seems to improve wound healing and wound-related pain for certain types of surgery. Details: A clinical study in patients who have had a Cesarean section shows that applying ointment containing St. John's wort extract 20% three times a day for 16 days improves wound healing and reduces scar formation when compared with placebo ointment (17225). Preliminary clinical research in patients who have had impacted third molars removed shows that using a mouthwash, prepared by macerating the above ground parts of St. John's wort in virgin olive oil, for 60 days is as effective as chlorhexidine gluconate plus benzydamine hydrochloride mouthwash for improving periodontal healing, and reducing swelling, pain, and infectious complications. However, it was also as effective as plain virgin olive oil, suggesting that St. John's wort did not provide additional benefit. 15 mL of each mouthwash was swished for 30 seconds 3 times daily for 7 days (104957). St. John's wort has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with dehisced post-surgical wounds shows that applying a specific aerosol product (1PWD, Kerecis AG) containing St. John's wort and neem oil to wounds during dressing changes does not improve wound healing scores at day 28 but may reduce pain scores when compared with silver-based dressings (alginates or polyurethane foam) (111592). However, this study may have been inadequately powered to detect a difference between groups. It is also unclear if these effects are due to St. John's wort, neem oil, or the combination.
• Tinnitus. St. John's wort has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in adults with tinnitus shows that taking St. John's wort 600 mg and ginkgo biloba daily for 12 weeks does not suppress tinnitus or improve tinnitus-related handicap when compared with ginkgo biloba monotherapy (111513). More evidence is needed to rate St. John's wort for these uses.

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POSSIBLY SAFE ...when used orally and appropriately. Kudzu appears to be safe for up to 4 months (10386,11386,92257). ...when used intravaginally and appropriately. Kudzu 5% to 6% gel has been used with apparent safety for up to 12 weeks (96740,105521,110702).

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

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LIKELY SAFE ...when used orally and appropriately. St. John's wort extracts in doses up to 900 mg daily seem to be safe when used for up to 12 weeks (3547,3550,4835,5096,6400,6434,7047,13021,13156,13157)(14417,76143,76144,89666,89669,95510). Some evidence also shows that St. John's wort can be safely used for over one year (13156,13157,76140), and may have better tolerability than selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) (4897,76153,76143,104036).

POSSIBLY SAFE ...when used topically and appropriately. St. John's wort 0.5% extract seems to be safe when used once weekly for 4 weeks (110327). St. John's wort oil has been used with apparent safely twice daily for 6 weeks (110326). However, topical use of St. John's wort can cause photodermatitis with sun exposure (110318).

POSSIBLY UNSAFE ...when used orally in large doses. St. John's wort extract can be unsafe due to the risk of severe phototoxic skin reactions. Taking 2-4 grams of St. John's wort extract (containing hypericin 5-10 mg) daily appears to increase the risk of photosensitivity (758,4631,7808).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Preliminary population research has found that taking St. John's wort while pregnant is associated with offspring that develop neural tube, urinary, and cardiovascular malformations. Subgroup analyses suggest that these risks may be higher when taking St. John's wort during the first trimester when compared with the second or third trimester. However, more research is needed to confirm these findings (106052). Animal-model research also shows that constituents of St. John's wort might have teratogenic effects (9687,15122). Until more is known, St. John's wort should not be taken during pregnancy.

LACTATION: POSSIBLY UNSAFE
when used orally. Nursing infants of mothers who take St. John's wort have a greater chance of experiencing colic, drowsiness, and lethargy (1377,15122,22418); avoid using.

CHILDREN: POSSIBLY SAFE
when used orally, and appropriately, short-term. St. John's wort extracts in doses up to 300 mg three times daily seem to be safe when used for up to 8 weeks in children aged 6-17 years (4538,17986,76110).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, kudzu may increase the risk of bleeding if used with antiplatelet or anticoagulant drugs.  Details Kudzu isoflavones are reported to have antiplatelet activity (13278,13291).

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking kudzu with antidiabetes drugs might increase the risk of hypoglycemia.  Details Kudzu might lower blood glucose levels and have additive effects in patients treated with antidiabetic agents (13285,13292,57868,57951). The dose of diabetes medications might need to be adjusted.

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking kudzu with caffeine might increase levels of caffeine.  Details In healthy males injected with the kudzu constituent puerarin, caffeine clearance and metabolism is inhibited (23583). This effect has been attributed to inhibition of cytochrome P450 1A2 (CYP1A2) enzyme, which is involved in caffeine metabolism. It is unclear if taking kudzu orally would have this same effect.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, kudzu might alter the effects of estrogen therapy.  Details Some research suggests that kudzu has estrogenic effects (11386,57874,57877). This may enhance or inhibit the effects of estrogen therapy.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might have additive hepatotoxic effects.  Details There is some concern that kudzu can adversely affect the liver (88777,92259,92260,92262).

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking kudzu with methotrexate might increase the risk of methotrexate toxicity.  Details Preclinical research suggests that kudzu extract greatly reduces the elimination and increases the toxicity of methotrexate. Kudzu might inhibit organic anion transporters (OATs) that are responsible for hepatobiliary and renal excretion of anions, similar to the interaction between methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs) (13296).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, kudzu might interfere with tamoxifen activity.  Details Some research suggests that kudzu may have estrogenic effects (11386,110702).

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ALPRAZOLAM (Xanax) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B St. John's wort increases the clearance of alprazolam and decreases its effects.  Details Alprazolam, which is used as a probe for cytochrome P450 3A4 (CYP3A4) activity, has a two-fold increase in clearance when given with St. John's wort. St. John's wort reduces the half-life of alprazolam from 12.4 hours to 6 hours (10830).

AMBRISENTAN (Letairis) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B St. John's wort may increase the clearance of ambristentan and decrease its effects.  Details Clinical research in healthy volunteers shows that taking St. John's wort 900 mg daily decreases the area under the concentration-time curve of ambrisentan 5 mg by 17% to 26%. Ambrisentan clearance was increased by 20% to 35% depending on CYP2C19 genotype. However, these small changes are unlikely to be clinically significant (99511).

AMINOLEVULINIC ACID Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort might have additive phototoxic effects with aminolevulinic acid.  Details Concomitant use with St. John's wort extract may cause synergistic phototoxicity. Delta-aminolevulinic acid can cause a burning erythematous rash and severe swelling of the face, neck, and hands when taken with St. John's wort (9474).

BOCEPREVIR (Victrelis) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B St. John's wort might decrease the levels and clinical effects of boceprevir.  Details Boceprevir increases the maximum concentration and concentration at 8 hours of the St. John's wort constituent, hypericin, by approximately 30%. However, St. John's wort does not significantly change the area under the concentration-time curve or maximum plasma concentration of boceprevir 800 mg three times daily in healthy adults (95507,96552).

BUPROPION (Wellbutrin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort might reduce the levels and effects of bupropion.  Details Clinical research shows that taking St. John's wort 325 mg three times daily for 14 days along with bupropion reduces the area under the concentration-time curve by approximately 14% and increases the clearance of bupropion by approximately 20%. This effect is attributed to the induction of cytochrome P450 2B6 (CYP2B6) by St. John's wort (89662).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B St. John's wort might increase the levels and effects of clopidogrel.  Details Taking St. John's wort with clopidogrel seems to increase the activity of clopidogrel. In clopidogrel non-responders, taking St. John's wort seems to induce metabolism of clopidogrel to its active metabolite by cytochrome P450 enzymes 3A4 and 2C19. This leads to increased antiplatelet activity (13038,89671,96552). Theoretically, this might lead to an increased risk of bleeding in clopidogrel responders.

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D St. John's wort might decrease the levels and clinical effects of clozapine.  Details A case report describes a female with schizophrenia controlled on clozapine who had a return of symptoms when she started taking St. John's wort. The plasma concentration of clozapine was reduced, likely because its clearance was increased due to induction of the cytochrome P450 enzymes 3A4, 1A2, 2C9, and 2C19 by St. John's wort (96552).

CONTRACEPTIVE DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort increases the clearance of contraceptive drugs and reduces their clinical effects.  Details Females taking St. John's wort and oral contraceptives concurrently should use an additional or alternative form of birth control. St. John's wort can decrease norethindrone and ethinyl estradiol levels by 13% to 15%, resulting in breakthrough bleeding, irregular menstrual bleeding, or unplanned pregnancy (11886,11887,13099). Bleeding irregularities usually occur within a week of starting St. John's wort and regular cycles usually return when St. John's wort is discontinued. Unplanned pregnancy has occurred with concurrent use of oral contraceptives and St. John's wort extract (9880). St. John's wort is thought to induce the cytochrome P450 1A2 (CYP1A2), 2C9 (CYP2C9), and 3A4 (CYP3A4) enzymes, which are responsible for metabolism of progestins and estrogens in contraceptives (1292,7809,9204).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of cyclosporine.  Details Concomitant use can decrease plasma cyclosporine levels by 30% to 70% (1234,4826,4831,4834,7808,9596,10628,96552). Using St. John's wort with cyclosporine in patients with heart, kidney, or liver transplants can cause subtherapeutic cyclosporine levels and acute transplant rejection (1234,1293,1301,6112,6435,7808,9596). This interaction has occurred with a St. John's wort extract standardized to 0.3% hypericin and dosed at 300-600 mg per day (6435,10628). Withdrawal of St. John's wort can result in a 64% increase in cyclosporine levels (1234,4513,4826,4831,4834). St. John's wort induces cytochrome P450 3A4 (CYP3A4) and the multi-drug transporter, P-glycoprotein/MDR-1, which increases cyclosporine clearance (1293,1340,9204,9596).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP1A2 substrates.  Details Clinical research shows that St. John's wort induces CYP1A2, but to a lesser extent than CYP3A4 (9204,10848,76163).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP2B6 substrates.  Details Clinical research shows that taking St. John's wort 325 mg three times daily for 14 days along with bupropion, a CYP2B6 substrate, reduces the area under the concentration-time curve by approximately 14% and increases the clearance of bupropion by approximately 20% (89662).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP2C19 substrates.  Details Preliminary clinical research in healthy males shows that taking St. John's wort for 14 days induces CYP2C19 and increases metabolism of mephenytoin (Mesantoin). In patients with wild-type 2C19 (2C19*1/*1) metabolism was almost 4-fold greater in subjects who received St. John's wort compared to placebo. In contrast, patients with 2C19*2/*2 and *2/*3 genotypes did not demonstrate a similar increase in metabolism (17405). Theoretically, St. John's wort might increase metabolism of other CYP2C19 substrates.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the levels of CYP2C9 substrates.  Details There is contradictory research about the effect of St. John's wort on CYP2C9. Some in vitro research shows that St. John's wort induces CYP2C9, but to a lesser extent than CYP3A4 (9204,10848,11889). St. John's wort also induces metabolism of the S-warfarin isomer, which is a CYP2C9 substrate (11890). Other research shows that St. John's wort 300 mg three times daily for 21 days does not significantly affect the pharmacokinetics of a single 400 mg dose of ibuprofen, which is also a CYP2C9 substrate (15546). Until more is known, use St. John's wort cautiously in patients who are taking CYP2C9 substrates.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort increases the metabolism and reduces the levels of CYP3A4 substrates.  Details St. John's wort induces CYP3A4 enzymes and increases metabolism of CYP3A4 substrates (9204,10830,10847,10848,11889,22423,22424,22425,22427,48603). Clinically significant interactions have been reported with St. John's wort products containing hyperforin 1 mg or more (97171).

DIGOXIN (Lanoxin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of digoxin.  Details St. John's wort can reduce the bioavailability, serum levels, and therapeutic effects of digoxin. Taking an extract of St. John's wort 900 mg, containing hyperforin 7.5 mg or more, daily for 10-14 days, can reduce serum digoxin levels by 25% in healthy people. St. John's wort is thought to affect the multidrug transporter, P-glycoprotein, which mediates the absorption and elimination of digoxin and other drugs (382,6473,7808,7810,9204,96552,97171). St. John's wort products providing less than 7.5 mg of hyperforin daily do not appear to affect digoxin levels (97171).

DOCETAXEL (Taxotere) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of docetaxel.  Details Clinical research shows that taking a specific St. John's wort product (Hyperiplant, VSM) 300 mg three times daily for 14 days increases docetaxel clearance by about 14%, resulting in decreased plasma concentrations of docetaxel in cancer patients. This is most likely due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort (89661).

FENTANYL Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, St. John's wort may reduce the levels and clinical effects of fentanyl.  Details Given that St. John's wort induces cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, it is possible that concomitant use of St. John's wort with fentanyl will reduce plasma levels and analgesic activity of fentanyl (96552). However, some clinical research in healthy adults shows that taking St. John's wort (LI-160, Lichtwer Pharma) 300 mg daily for 21 days does not alter the pharmacokinetics or clinical effects of intravenous fentanyl (102868). It is unclear if these findings can be generalized to oral, intranasal, or transdermal fentanyl.

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B St. John's wort may increase the levels and clinical effects of fexofenadine.  Details A single dose of St. John's wort decreases the clearance of fexofenadine and increases its plasma levels. However, the effect of St. John's wort on plasma levels of fexofenadine seems to be lost if dosing is continued for more than 2 weeks (9685). Patients taking fexofenadine and St. John's wort concurrently should be monitored for possible fexofenadine toxicity.

FINASTERIDE (Proscar, Propecia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D St. John's wort may reduce the levels and clinical effects of finasteride.  Details St. John's wort reduces plasma levels of finasteride in healthy male volunteers due to induction of finasteride metabolism via cytochrome P450 3A4 (CYP3A4). The clinical significance of this interaction is not known (96552).

GLICLAZIDE (Diamicron, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort may reduce the levels and clinical effects of gliclazide.  Details Taking St. John's wort decreases the half-life and increases clearance of gliclazide in healthy people (22431).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort may increase the metabolism and reduce the effectiveness of atorvastatin, lovastatin, and rosuvastatin. However, it does not seem to affect pravastatin, pitavastatin, or fluvastatin.  Details Concomitant use of St. John's wort can reduce plasma concentrations of the active simvastatin metabolite, simvastatin hydroxy acid, by 28%. St. John's wort induces intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug transporter. This increases simvastatin clearance. It also increases the clearance of atorvastatin (Lipitor), lovastatin (Mevacor), and rosuvastatin (Crestor). St. John's wort does not seem to affect the plasma concentrations of pravastatin (Pravachol), pitavastatin (Livalo) or fluvastatin (Lescol), which are not substrates of CYP3A4 or P-glycoprotein (10627,96552,97171).

IMATINIB (Gleevec) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A St. John's wort reduces the levels and clinical effects of imatinib.  Details Taking St. John's wort 900 mg daily for 2 weeks reduces the bioavailability and half-life of a single dose of imatinib and decreases its serum levels by 30% in healthy volunteers. This is most likely due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort, which increases clearance of imatinib (11888,96552).

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort may reduce the levels and clinical effects of indinavir.  Details In healthy volunteers, taking St. John's wort concurrently with indinavir reduces plasma concentrations of indinavir by inducing metabolism via cytochrome P450 3A4 (CYP3A4) (96552). Theoretically, this could result in treatment failure and viral resistance.

IRINOTECAN (Camptosar) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A St. John's wort reduces the levels and clinical effects of irinotecan.  Details St. John's wort 900 mg daily for 18 days decreases serum levels of irinotecan by at least 50%. Clearance of the active metabolite of irinotecan, SN-38, is also increased, resulting in a 42% decrease in the area under the concentration-time curve (9206,97171). This is thought to be due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort (7092,96552).

IVABRADINE (Corlanor) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort might reduce the levels and clinical effects of ivabradine.  Details Taking St. John's wort 900 mg containing 7.5 mg of hyperforin daily for 14 days with a single dose of ivabradine causes a 62% reduction in plasma levels of ivabradine. This interaction is thought to be due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort, increasing the metabolism of ivabradine (96552,97171).

KETAMINE (Ketalar) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of ketamine.  Details Taking St. John's wort 300 mg three times daily for 14 days can decrease maximum serum levels of ketamine by around 66% and area under the concentration-time curve of ketamine by 58%. This is most likely due to induction of cytochrome P450 3A4 (CYP3A4) by St. John's wort (89663).

MEPHENYTOIN (Mesantoin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of mephenytoin.  Details Preliminary clinical research in healthy males shows that taking St. John's wort for 14 days induces cytochrome P450 2C19 (CYP2C19) and significantly increases metabolism of mephenytoin (Mesantoin). In people with wild-type 2C19, metabolism was almost 4-fold greater in subjects who received St. John's wort compared to placebo. In contrast, patients with 2C19*2/*2 and *2/*3 genotypes did not demonstrate a similar increase in metabolism (17405).

METHADONE (Dolophine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort might reduce the levels and clinical effects of methadone.  Details St. John's wort might decrease the effectiveness of methadone by reducing its blood concentrations. In one report, two out of four patients on methadone maintenance therapy for addiction experienced methadone withdrawal symptoms after taking St. John's wort 900 mg daily for a median of 31 days. There was a median decrease in blood methadone concentration of 47% (range: 19% to 60%) when compared to baseline (22419).

METHYLPHENIDATE (Concerta, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D St. John's wort might reduce the levels and clinical effects of methylphenidate.  Details St. John's wort might decrease the effectiveness of methylphenidate. In one report, an adult male, stabilized on methylphenidate for attention deficit-hyperactivity disorder (ADHD), experienced increased attention problems and ADHD symptoms after taking St. John's wort 600 mg daily for 4 months. ADHD symptoms improved when St. John's wort was discontinued (15544). The mechanism of this interaction is unknown.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of NNRTIs.  Details St. John's wort increases the oral clearance of nevirapine (Viramune) by 35%. Subtherapeutic concentrations are associated with therapeutic failure, development of viral resistance, and development of drug class resistance. St. John's wort induces intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug transporter (1290,1340,4837,96552).

OMEPRAZOLE (Prilosec) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of omeprazole.  Details Taking St. John's wort, 300 mg orally three times daily for 14 days, reduces serum concentrations of omeprazole by inducing its metabolism via cytochrome P450 (CYP) 2C19 and 3A4. The reduction of omeprazole serum levels is dependent on CYP2C19 genotype, with reductions up to 50% in extensive metabolizers and 38% in poor metabolizers (22440,96552).

OXYCODONE (Oxycontin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of oxycodone.  Details St. John's wort can increase oxycodone metabolism by inducing cytochrome P450 3A4 (CYP3A4), reducing plasma levels and analgesic activity (96552).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of P-glycoprotein substrates.  Details St. John's wort induces P-glycoprotein. P-glycoprotein is a carrier mechanism responsible for transporting drugs and other substances across cell membranes. When P-glycoprotein is induced in the gastrointestinal (GI) tract, it can prevent the absorption of some medications. In addition, induction of p-glycoprotein can decrease entry of drugs into the central nervous system (CNS) and decrease access to other sites of action (382,1340,7810,11722).

PHENOBARBITAL (Luminal) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of phenobarbital.  Details St. John's wort may increase the metabolism of phenobarbital. Plasma concentrations of phenobarbital should be monitored carefully. The dose of phenobarbital may need to be increased when St. John's wort is started and decreased when it is stopped (9204).

PHENPROCOUMON (Marcoumar, others) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of phenprocoumon.  Details St. John's wort appears to increase the metabolism of phenprocoumon (an anticoagulant that is not available in the US) by increasing the activity of the cytochrome P450 2C9 (CYP2C9) enzyme. This may result in decreases in the anticoagulant effect and international normalized ratio (INR) (9204).

PHENYTOIN (Dilantin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of phenytoin.  Details St. John's wort may increase the metabolism of phenytoin. Plasma concentrations of phenytoin should be monitored closely. The dose of phenytoin may need to be increased when St. John's wort is started and decreased when it is stopped (9204).

PHOTOSENSITIZING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might increase the likelihood for photosensitivity reactions when used in combination with photosensitizing drugs.  Details St. John's wort might increase photosensitivity reactions due to its hypericin content (166). However, some clinical research shows that very high doses of St. John's wort are needed to produce phototoxicity in humans (3900,4542,76266).

PROCAINAMIDE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might decrease the levels and clinical effects of procainamide.  Details Animal research shows that taking St. John's wort extract increases the bioavailability of procainamide, but does not increase its metabolism (14865). Whether this interaction is clinically significant in humans is not known.

PROTEASE INHIBITORS (PIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort reduces the levels and clinical effects of PIs.  Details In healthy volunteers, St. John's wort can reduce the plasma concentrations of indinavir (Crixivan) by inducing cytochrome P450 3A4 (CYP3A4). This might result in treatment failure and viral resistance (1290,7808,96552). St. John's wort also induces P-glycoprotein, which can result in decreased intracellular protease inhibitor concentrations and increased elimination (9204).

RESERPINE (Raudixin, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might decrease the effectiveness of reserpine.  Details Animal research shows that St. John's wort can antagonize the effects of reserpine (758).

RIVAROXABAN (Xarelto) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of rivaroxaban.  Details A small pharmacokinetic study in healthy volunteers shows that taking a single dose of rivaroxaban 20 mg after using a specific St. John's wort extract (Jarsin, Vifor SA) 450 mg orally twice daily for 14 days reduces the bioavailability of rivaroxaban by 24% and reduces rivaroxaban's therapeutic inhibition of factor Xa by 20% (104038).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, St. John's wort might inhibit reuptake and increase levels of serotonin, resulting in additive effects with serotonergic drugs.  Details Concomitant use of serotonergic drugs with St. John's wort can lead to increased adverse effects and increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstriction disorders (166,542,3569,8056,110318).

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of tacrolimus.  Details Taking a St. John's wort extract (Jarsin) 600 mg daily significantly decreases tacrolimus serum levels. Dose increases of 60% may be required to maintain therapeutic tacrolimus levels in patients taking St. John's wort. St. John's wort is thought to lower tacrolimus levels by inducing cytochrome P450 3A4 (CYP3A4) enzymes (7095,10329).

THEOPHYLLINE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D St. John's wort might decrease the levels of theophylline, although this effect might not be clinically relevant.  Details St. John's wort does not seem to significantly affect theophylline pharmacokinetics (11802). There is a single case report of a possible interaction with theophylline. A patient who smoked and was taking 11 other drugs experienced an increase in theophylline levels after discontinuation of St. John's wort. This increase has been attributed to a rebounding of theophylline serum levels after St. John's wort was no longer present to induce metabolism via cytochrome P450 1A2 (CYP1A2) (3556,7808,9204). However, studies in healthy volunteers show that St. John's wort is unlikely to affect theophylline to any clinically significant degree (11802).

TRAMADOL (Ultram) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D St. John's wort might decrease the levels and clinical effects of tramadol.  Details St. John's wort can increase tramadol metabolism via induction of cytochrome P450 3A4 (CYP3A4), reducing plasma levels and analgesic activity (96552). Theoretically, concurrent use of St. John's wort with tramadol might also cause additive serotonergic effects (763,6427,8056,8936).

VORICONAZOLE (Vfend) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B St. John's wort might decrease the levels and clinical effects of voriconazole.  Details Clinical research shows that taking St. John's wort with voriconazole reduces voriconazole exposure and increases voriconazole metabolism by approximately 107%. Voriconazole is primarily metabolized by cytochrome P450 (CYP) 2C19, with CYP3A4 and CYP2C9 also involved (89660). St. John's wort induces CYP2C19, CYP3A4, and CYP2C9 (9204,10830,10847,10848,11889,11890,17405,22423,22424,22425)(22427,48603).

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B St. John's wort decreases the levels and clinical effects of warfarin.  Details Taking St. John's wort significantly increases clearance of warfarin, including both its R- and S-isomers (11890,15176). This is likely due to induction of cytochrome P450 (CYP) 1A2 and CYP3A4 (11890). St. John's wort can also significantly decrease International Normalized Ratio (INR) in people taking warfarin (1292). In addition, taking warfarin at the same time as St. John's wort might reduce warfarin bioavailability. When a dried extract is mixed with warfarin in an aqueous medium, up to 30% of warfarin is bound to particles, reducing its absorption (10448).

ZOLPIDEM (Ambien) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B St. John's wort might decrease the levels and clinical effects of zolpidem.  Details In clinical research, concomitant use of zolpidem with St. John's wort decreased zolpidem plasma levels due to induction of its metabolism by cytochrome P450 3A4 (22441,96552). Whether this interaction is clinically significant is not known.

(Read more about ST. JOHN'S WORT)

General ...Orally and intravaginally, kudzu seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Elevated liver transaminases.

Cardiovascular ...Orally, side effects of kudzu reported in clinical trials have included palpitations and chest discomfort; however, these effects did not occur more frequently than with placebo (57924,57927).

Dermatologic ...Orally, a side effect of kudzu reported in one clinical trial has included urticaria; however, this effect did not occur more frequently than with placebo (57924). There is one case report of allergic reaction following use of a combination herbal product (Kakkonto) containing kudzu involving a maculopapular eruption starting on the thighs and spreading over the entire body (13111,57886).

Gastrointestinal ...Orally, some side effects of kudzu reported in clinical trials have included nausea, dyspepsia, and bloating; however, these effects did not occur more frequently than with placebo (57927,57942).

Genitourinary ...Intravaginally, irritation of the vulva has been reported with kudzu gel. These cases were generally mild and transient (110702).

Hematologic ...Intravenously, the kudzu derivative, puerarin, has caused intravascular hemolysis (13298,15025,57947).

Hepatic ...Orally, there are several cases reports of liver injury following use of kudzu involving elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (88777,92260).

Neurologic/CNS ...Orally, a side effect of kudzu reported in one clinical trial has included dizziness; however, this effect did not occur more frequently than with placebo (57924).

Other ...Orally, a side effect of kudzu reported in one clinical trial has included mastodynia; however, this effect did not occur more frequently than with placebo (57942).

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General ...Orally, St. John's wort is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, dizziness, dry mouth, gastrointestinal discomfort (mild), fatigue, headache, insomnia, restlessness, and sedation.
Topically: Skin rash and photodermatitis.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of suicidal ideation and psychosis after taking St. John's wort.

Cardiovascular ...In clinical research, palpitations have been reported for patients taking St. John's wort orally, although the number of these events was higher for the patients taking sertraline (76070). In one case report, an adult female developed recurrent palpitations and supraventricular tachycardia (SVT) within 3 weeks of initiating St. John's wort 300 mg daily. SVT and related symptoms responded to Valsalva maneuvers and did not recur after discontinuing therapy (106051).
Edema has also been reported in clinical research for some patients treated with St. John's wort 900-1500 mg daily for 8 weeks (10843). Cardiovascular collapse following induction of anesthesia has been reported in an otherwise healthy patient who had been taking St. John's wort for 6 months (8931). A case of St. John's wort-induced hypertension has been reported for a 56-year-old patient who used St. John's wort extract 250 mg twice daily for 5 weeks. Blood pressure normalized after discontinuation of treatment (76073). A case of new-onset orthostatic hypotension and light-headedness has been reported for a 70 year-old homebound patient who was taking multiple prescription medications and herbal products, including St. John's wort (76128). When all herbal products were discontinued, these symptoms improved, and the patient experienced improvement in pain control.

Dermatologic ...Both topical and chronic oral use of St. John's wort can cause photodermatitis (206,620,758,4628,4631,6477,13156,17986,76072,76148)(95506,110318). The average threshold dose range for an increased risk of photosensitivity appears to be 1.8-4 grams St. John's wort extract or 5-10 mg hypericin, daily. Lower doses might not cause this effect (4542,7808). For example, a single dose of St. John's wort extract 1800 mg (5.4 mg hypericin) followed by 900 mg (2.7 mg hypericin) daily does not seem to produce skin hypericin concentrations thought to be high enough to cause phototoxicity (3900,4542,76266). Females appear to have a higher risk of dose-related photosensitivity. In a dose-ranging, small clinical trial, almost all of the female participants experienced mild to moderate photosensitivity with paresthesia in sun-exposed skin areas after administration of St. John's wort (Jarsin, Casella Med) 1800 mg daily for 3-6 days. Symptoms resolved about 12-16 days after discontinuation (95506). Male participants reported no adverse effects at this dose, and both genders reported no adverse effects at lower doses. Light or fair-skinned people should employ protective measures against direct sunlight when using St. John's wort either topically or orally (628).
Total body erythroderma without exposure to sunlight, accompanied by burning sensation of the skin, has also been reported (8930). Orally, St. John's wort may cause pruritus or skin rash, although these events seem to occur infrequently (76140,76148,76245). A case of persistent scalp and eyebrow hair loss has been reported for a 24-year-old schizophrenic female who was taking olanzapine plus St. John's wort 900 mg/day orally (7811). Also, a case of surgical site irritation has been reported for a patient who applied ointment containing St. John's wort (17225).

Endocrine ...A case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 67-year-old male with depression has been reported. During a 3-month period, the patient was taking St. John's wort 300 mg daily then increased to 600-900 mg daily with no adverse effects despite a low serum sodium level of 122mEq/L, elevated levels of urine sodium, and urine osmolality suggestive of SIADH. St. John's wort appeared to be the only contributing factor. The patient's sodium level normalized 3 weeks after discontinuation of St. John's wort (95508).

Gastrointestinal ...Orally, St. John's wort may cause dyspepsia, anorexia, diarrhea, nausea, vomiting, and constipation, although these events seems to occur infrequently (4897,13021,17986,76070,76071,76113,76146,76150,76271).

Genitourinary ...Orally, St. John's wort can cause intermenstrual or abnormal menstrual bleeding (1292,76056). However, this effect has occurred in patients who were also taking an oral contraceptive. Changes in menstrual bleeding might be the result of a drug interaction (1292,76056). Also, St. John's wort has been associated with anorgasmia and frequent urination when used orally (10843,76070).
Sexual dysfunction can occur with St. John's wort, but less frequently than with SSRIs (10843). A case of erectile dysfunction and orgasmic delay has been reported for a 49-year-old male after taking St. John's wort orally for one week. Co-administration of sildenafil 25-50 mg prior to sexual activity reversed the sexual dysfunction. Previously, the patient had experienced orgasmic delay, erectile dysfunction, and inhibited sexual desire when taking a selective serotonin reuptake inhibitor (sertraline) (4836).

Hepatic ...A case of acute hepatitis with prolonged cholestasis and features of vanishing bile duct syndrome has been reported for a patient who used tibolone and St. John's wort orally for 10 weeks (76135). A case of jaundice with transaminitis and hyperbilirubinemia has been reported for a 79 year-old female who used St. John's wort and copaiba (95505). Laboratory values normalized 7 weeks after discontinuation of both products.

Musculoskeletal ...Orally, St. John's wort may cause muscle or joint stiffness, tremor, muscle spasms, or pain, although these events appear to occur rarely (76070).

Neurologic/CNS ...St. John's wort may cause headache, dizziness, fatigue, lethargy, or insomnia (5096,13021,76070,76071,76113,76132,76133,76150,89666). Isolated cases of paresthesia have been reported for patients taking St. John's wort (5073). A case of subacute toxic neuropathy has been reported for a 35-year-old female who took St. John's wort 500 mg daily orally for 4 weeks (621).

Ocular/Otic ...There is concern that taking St. John's wort might increase the risk of cataracts. The hypericin constituent of St. John's wort is photoactive and, in the presence of light, may damage lens proteins, leading to cataracts (1296,17088). In population research, people with cataracts were significantly more likely to have used St. John's wort compared to people without cataracts (17088). Ear and labyrinth disorders have been possibly attributed to use of St. John's wort in clinical research, although these events rarely occur (76120).

Psychiatric ...St. John's wort can induce hypomania in depressed patients and mania in depressed patients with occult bipolar disorder (325,3524,3555,3568,10845,76047,76064,76137,110318). Cases of first-episode psychosis have been reported for females who used St. John's wort orally. In both cases, symptoms resolved following discontinuation of St. John's wort and treatment with antipsychotics for several weeks (13015,89664). Also, psychosis and delirium have been reported for a 76-year-old female patient who used St. John's wort for 3 weeks. The patient may have been predisposed to this effect due to undiagnosed dementia (76270). Restlessness, insomnia, panic, and anxiety have been noted for some patients taking St. John's wort orally (5073,13156,76070,76132,76268,76269,89665).
In isolated cases, St. John's wort has been associated with a syndrome consisting of extreme anxiety, confusion, nausea, hypertension, and tachycardia. These symptoms may occur within 2-3 weeks after it is started, in patients with no other predisposing factors. This syndrome has been diagnosed as the serotonin syndrome (6201,7811,110318). In one case, the symptoms began after consuming tyramine-containing foods, including aged cheese and red wine (7812). In an isolated case, a 51-year-old female reported having had suicidal and homicidal thoughts for 9 months while taking vitamin C and a St. John's wort extract. Symptoms disappeared within 3 weeks of discontinuing treatment (76111). A case of decreased libido has been reported for a 42-year-old male with mood and anxiety disorders who had taken St. John's wort orally for 9 months (7312).
St. John's wort has been associated with withdrawal effects similar to those found with conventional antidepressants. Headache, nausea, anorexia, dry mouth, thirst, cold chills, weight loss, dizziness, insomnia, paresthesia, confusion, and fatigue have been reported. Withdrawal effects are most likely to occur within two days after discontinuation but can occur one week or more after stopping treatment in some people. Occurrence of withdrawal symptoms may not be related to dose or duration of use (3569,11801).

Pulmonary/Respiratory ...Orally, St. John's wort may cause sore throat, swollen glands, laryngitis, sinus ache, sweating, and hot flashes, although the frequency of these events appears to be similar to placebo (76150).

Renal ...Orally, St. John's wort has been associated with a case report of acute kidney failure in a 46-year-old female after one dose of homemade St. John's wort tea. Three sessions of hemodialysis were required before there was full recovery (106741). However, causality is unclear since the patient had also been taking diclofenac intermittently for a month prior to developing kidney failure.

Other ...Sjogren's syndrome has been reported in a patient taking herbal supplements including St. John's wort, echinacea, and kava. Echinacea may have been the primary cause, because Sjogren's syndrome is an autoimmune disorder. The role of St. John's wort in causing this syndrome is unclear (10319).

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