St. John's Tonic Alcohol Free by Village Vitality

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. Although there has been interest in using oral damiana for asthma, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Cognitive function. Although there has been interest in using oral damiana for cognitive function, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Constipation. Although there has been interest in using oral damiana for constipation, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Depression. Although there has been interest in using oral damiana for depression, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Diabetes. Although there has been interest in using oral damiana for diabetes, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Dyspepsia. Although there has been interest in using oral damiana for dyspepsia, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Erectile dysfunction (ED). Oral damiana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized, open-label clinical study in adults with mild-to-moderate ED shows that taking a specific combination supplement (Icarifil, Anvest Health S.p.A) containing damiana 100 mg, panax ginseng, L-carnitine, L-citrulline, tribulus, and other ingredients daily for 3 months improves patient-reported erectile function when compared to baseline. Additionally, taking the supplement with tadalafil improves some, but not all, patient-reported assessments of erectile function when compared with taking tadalafil alone (114989). It is unclear if this effect is due to damiana, other ingredients, or the combination. Additionally, the interpretation of these results is limited by poor methodology, including the use of per-protocol analysis and lack of a placebo group.
• Headache. Although there has been interest in using oral damiana for headache, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Menopausal symptoms. Although there has been interest in using oral damiana for menopausal symptoms, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Obesity. Oral damiana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight adults shows that taking a combination product containing damiana 36 mg, guarana 95 mg, and yerba mate 112 mg, orally three times daily for 45 days increases weight loss when compared with placebo (11866). It is unclear if this effect is due to damiana, other ingredients, or the combination.
• Nocturnal enuresis. Although there has been interest in using oral damiana for nocturnal enuresis, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Sexual dysfunction. Oral damiana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing damiana, L-arginine, Panax ginseng, ginkgo, vitamins, and minerals (ArginMax for Women, Daily Wellness Co.) improves sexual satisfaction and desire, increases orgasm frequency, and reduces vaginal dryness when compared with placebo in females interested in improving their sexual function (46933). It is unclear if this effect is due to damiana, other ingredients, or the combination. More evidence is needed to rate damiana for these uses.

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POSSIBLY EFFECTIVE

• Anxiety. Oral ginkgo seems to modestly reduce anxiety symptoms. Details: Clinical research shows that taking a specific ginkgo extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) for 4 weeks can modestly reduce symptoms of anxiety in a greater percentage of adults with generalized anxiety disorder or adjustment disorder with anxious mood when compared with placebo. After 4 weeks of treatment, a reduction in anxiety rating score of at least 50% was seen in 44% of patients treated with 480 mg daily, 39% of patients treated with 240 mg daily, and 22% of patients treated with placebo (15578). It is unclear whether these effects would persist when taken for longer than 4 weeks. This study was also included in a meta-analysis that performed indirect comparisons of multiple herbs for the treatment of anxiety. This analysis suggests that taking ginkgo may reduce anxiety scores modestly more than kava (110711). However, the interpretation of these results is limited by the small amount of data available for ginkgo.
• Dementia. Oral ginkgo 240 mg seems to improve symptoms of various types of dementia, but lower doses are not always effective. Oral ginkgo does not seem to prevent or slow down the progression of dementia. Details: Most evidence shows that higher doses of a specific ginkgo extract (EGb761) modestly improve symptoms of Alzheimer, vascular, or mixed dementias. Meta-analyses of clinical research in patients with dementia show that taking ginkgo, usually 240 mg daily for 24 weeks, modestly improves cognition and activities of daily living when compared with placebo. When analyses pooled studies testing low-dose (120 mg) and high-dose (240 mg) ginkgo together, the benefit was not always present (87855,87819,87851,87866,88006,89713,102183,102185,102186,103572)(111333). Although most clinical trials show benefit, there are some clinical trials with conflicting findings, suggesting inconsistent and unpredictable effects (16637,87726). There has been some debate about whether ginkgo is more effective in dementia patients who have neuropsychiatric symptoms. Most clinical research shows that this is not the case. However, high-dose ginkgo 240 mg daily seems to modestly relieve most neuropsychiatric symptoms other than psychosis (17717,87794,87897,102185,102187). Few clinical studies compare ginkgo leaf extract to conventional drugs such as cholinesterase inhibitors. Some preliminary comparative studies show that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 160-240 mg daily for 22-24 weeks seems to be comparable to donepezil (Aricept) 5-10 mg daily for mild to moderate Alzheimer disease (14499,87826). Similarly, a clinical study in patients with Alzheimer disease or mild cognitive impairment shows that taking ginkgo extract 150 mg three times daily for 6 months seems to be comparable to donepezil 5 mg daily for improvement of cognitive scores (106611). However, indirect comparisons suggest that ginkgo leaf extract might be less effective than the conventional drugs donepezil, tacrine (Cognex), rivastigmine (Exelon), and other cholinesterase inhibitors (6224,6490,11981,89710). Also, some studies show that taking ginkgo in combination with conventional medications for 12-24 weeks does not improve cognitive scores by a clinically meaningful extent when compared with conventional medications alone (95902,106611). However, a meta-analysis of 17 mostly small, low quality clinical studies in patients with Alzheimer disease, that includes some of these studies, shows that taking ginkgo in combination with donepezil for 3-9 months modestly improves cognitive scores when compared with donepezil alone. Adding ginkgo may also improve activities of daily living scores (111332). Another meta-analysis of mostly small clinical studies in adults with vascular dementia also shows that taking ginkgo extract orally or intravenously daily for 4-12 weeks, in addition to donepezil, moderately improves cognitive scores and functional scores when compared with donepezil alone (114767). However, the validity of these findings is limited by the heterogeneity of the included studies, which utilized various doses and forms of ginkgo. Ginkgo does not appear to be beneficial for preventing or slowing the progression of dementia. Epidemiologic research shows that taking ginkgo extract is not associated with a decreased risk of developing dementia in elderly patients with memory impairment (14812). Three large-scale clinical trials also show that taking ginkgo extract 120 mg twice daily does not reduce the risk of developing all-cause dementia or Alzheimer disease in elderly patients with normal cognitive function or in those with mild cognitive impairment (16634,87848,87904). In addition, taking ginkgo extract does not seem to prevent disease progression in Alzheimer patients (89713). Most of the clinical studies on the effectiveness of ginkgo leaf for dementia have used the standardized extracts EGb 761 (Dr. Willmar Schwabe Pharmaceuticals and Ipsen) and LI 1370 (Lichtwer Pharma). These two extracts are similar and prepared to contain approximately 24% to 25% flavone glycosides and 6% terpene lactones. Other products with similar ingredients include Ginkai (Lichtwer Pharma), Ginkgo 5 (Pharmline), Ginkgold and Ginkgo (Nature's Way), and Quanterra Mental Sharpness (Warner-Lambert).
• Hearing loss. Intravenous ginkgo appears to improve hearing loss when used in conjunction with corticosteroids. The effectiveness of oral ginkgo is unclear. Details: A meta-analysis of randomized controlled trials (RCTs) in adults with sudden hearing loss shows that using intravenous ginkgo leaf extract 40-175 mg daily, in addition to corticosteroids, for 5-14 days increases clinical cure rates by 1.3 times that of corticosteroids alone. Ginkgo leaf in combination with corticosteroids also improved hearing sensitivity (107360). Another meta-analysis of 27 mostly low-quality RCTs in patients with sudden hearing loss, that includes some of the same studies as the prior analysis, shows that adding ginkgo extract to usual care for 1-14 days leads to improvement or no further deterioration in 91% of patients when compared with 75% of patients receiving usual care (111339). However, the interpretation of these results is limited by unclear ginkgo dosing and inclusion of studies that administered ginkgo orally, as an injection, or unknown route. In addition, usual care treatments were not described. In addition, one clinical study in patients with short-term idiopathic hearing loss shows that oral ginkgo leaf extract 120 mg twice daily for 8 weeks might improve hearing recovery rates when compared with ginkgo leaf extract 12 mg twice daily (8543). However, there was a high spontaneous recovery rate in both groups, so it is unclear how much benefit, if any, can be attributed to ginkgo leaf extract.
• Premenstrual syndrome (PMS). Oral ginkgo seems to reduce symptoms of PMS. Details: Taking ginkgo leaf extract orally 80 mg twice daily or 40 mg three times daily seems to produce significant relief in breast tenderness and other physical and psychological symptoms associated with PMS when started during the 16th day of the menstrual cycle and continued until the 5th day of the following cycle for up to two cycles (6229,87839). Specific ginkgo leaf extracts that have been assessed for this condition include Ginko T.D. (Tolidaru Pharmaceuticals) and EGb 761, which is an ingredient in several commercial products including Tebonin (Dr. Willmar Schwabe Pharmaceuticals), Tanakan (Ipsen), and Quanterra Mental Sharpness (Warner-Lambert).
• Schizophrenia. Oral ginkgo seems to reduce total and negative symptoms of schizophrenia, and may be beneficial for reducing antipsychotic-associated adverse effects. Details: Taking a standardized ginkgo leaf extract EGb 761 (Yi Kang Ning, Yang Zi Jiang Pharmaceuticals Ltd.), 120-360 mg orally daily in addition to standard antipsychotic medications (such as olanzapine, clozapine, or haloperidol) for 8-16 weeks, can reduce total and negative symptoms of schizophrenia when compared to treatment with antipsychotic medications alone (87844,95901). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that ginkgo extract at doses of 120-360 mg daily is weakly recommended for adjunctive use in schizophrenia, primarily for negative symptoms (110318). Treatment with ginkgo leaf extract might also reduce anticholinergic side effects such as thirst and constipation and adverse behavioral, cardiovascular, and nerve symptoms associated with antipsychotic treatment (87708,95901). Additional clinical research is needed to determine the role of ginkgo on antipsychotic-associated adverse effects.
• Stroke. Oral and intravenous ginkgo seem to improve recovery from stroke; intravenous ginkgo might be more effective. Details: While some individual studies show conflicting results, meta-analyses of small, low-quality clinical trials in patients recovering from ischemic stroke show that oral or intravenous ginkgo extract along with conventional therapy seems to improve neurologic function and activities of daily living scores, but does not improve quality of life or reduce the risk of recurrent stroke or death, when compared with conventional therapy alone (14435,102883,102884,107452). However, the overall methodological quality of the meta-analyses is described as critically low, with a high risk of bias (113783). One meta-analysis shows that intravenous ginkgo extract is associated with greater improvements in these measures than oral ginkgo extract (102884). Ginkgo diterpene lactone meglumine (GDLM) is a derivative of ginkgo composed of active ingredients ginkgolides A, B, and K that has been investigated for the treatment of acute ischemic stroke both as monotherapy and in combination with thrombolysis. Large clinical trials in adults with moderate acute ischemic stroke show that giving an intravenous infusion of GDLM 25 mg daily, initiated within 48 hours of symptom onset and continuing for up to 14 days, increases the proportion of patients achieving a favorable outcome, defined as a score of 0 or 1 on the modified Rankin Scale (mRS) on day 90, by 15% when compared with placebo. About 62% of patients treated with GDLM show clinically significant improvement in Montreal Cognitive Assessment scores, compared with 56% of those on placebo. The most significant improvements occur in measures of language and visuo-spatial and executive function (111693,113784). Additionally, a meta-analysis shows that combination therapy with GDLM and tissue plasminogen activator (rTPA) is associated with greater improvements than conventional treatments alone or other traditional Chinese herbal medicines that contain ginkgo (i.e. ginaton, danhong, xueshuantong, and shuxuening injections). This specific formulation also appears to be more effective than intravenous ginkgolides or ginkgolide B; however, investigators did not provide a statistical comparison of outcomes between groups, limiting the validity of this finding (108610). Another meta-analysis shows that intravenous administration of ginkgo leaf extract plus dipyridamole 10-40 mL daily for 14-30 days along with conventional therapy also improves neurologic function and activities of daily living when compared with conventional therapy alone (102882). In patients not treated with thrombolytics, a small clinical study in adults in China shows that administering ginkgo diterpene lactone meglumine 25 mg intravenously daily for 14 days, starting within 48 hours after an ischemic stroke, in addition to aspirin 100 mg daily for 90 days, led to improvement in scores related to stroke severity or the degree of disability at 90 days in 94% of patients when compared with 83% of patients treated with aspirin alone (111340). However, the patients in this study had minor or moderate strokes; these results may not apply to patients with more severe strokes. In patients with hemorrhagic stroke, preliminary clinical research shows that daily intravenous administration of ginkgo extract (Taiwan Jisheng Chemical Pharmaceutical Co., Ltd.) 17.5 grams for 2 weeks, in conjunction with routine treatment and intravenous oxiracetam 6 grams, reduces cerebral edema and bleeding and modestly improves recovery of neurological and cognitive function and activities of daily living when compared with oxiracetam plus routine care or routine care alone (103573). A meta-analysis of 19 Chinese clinical trials in patients with hemorrhagic stroke shows that treatment with ginkgo leaf extracts for 7-20 days in combination with standard treatment is associated with lower NIH and Chinese stroke scale scores, lower residual hematoma and cerebral edema volumes, lower serum levels of inflammatory factors, and higher cognitive function and activity of daily living scores, when compared with standard treatment alone, although with considerable heterogeneity in the results (113781).
• Tardive dyskinesia. Oral ginkgo seems to reduce the severity of tardive dyskinesia in schizophrenic patients being treated with antipsychotic medications. Details: Clinical research shows that taking a specific ginkgo extract called EGb 761 (Yi Kang Ning, Yang Zi Jiang Pharmaceuticals Ltd.) 80 mg three times daily for 12 weeks can reduce the severity of tardive dyskinesia by at least 30% when compared with placebo in schizophrenic patients being treated with antipsychotic medications (87864).
• Vascular dementia. Oral ginkgo extract seems to modestly improve scores related to cognitive function in patients with this condition. Details: A meta-analysis of small randomized controlled trials in adults with vascular dementia shows that taking ginkgo extract orally or intravenously daily for 4-12 weeks, in addition to donepezil, moderately improves cognitive scores and functional scores when compared with donepezil alone (114767). However, the results of this study are limited by high heterogeneity. In addition, these trials do not report standard doses of ginkgo. A small clinical study in patients with vascular dementia shows that taking a specific extract of ginkgo EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 240 mg daily for 24 weeks modestly improves scores related to cognitive function, neuropsychiatric symptoms, and activities of daily living when compared with placebo (17191). A preliminary open-label clinical study in patients aged 50 years or older in China shows that taking the same ginkgo extract 240 mg daily for 24 weeks, starting within 7-14 days after an ischemic stroke, modestly improves scores related to cognitive function and mental health, but not neuropsychiatric symptoms, when compared with standard care (111335). However, the patients in this study had minor strokes; these results may not apply to patients with more severe strokes. Ginkgo has also been evaluated in combination with other ingredients to treat vascular dementia. A small clinical study in patients aged 60 years or older with vascular dementia shows that taking a supplement containing extracts of ginkgo, Panax ginseng, and saffron 60 mg three times daily for 16 weeks modestly improves some cognitive function scores, caregiver assessed activities of daily living, and patient-reported quality of life. However, these effects were not maintained after patients stopped taking the supplement (111336).
• Vertigo. Oral ginkgo seems to improve symptoms of vertigo in people with vestibular disorders. It is unclear if it is beneficial for vertigo caused by cerebral arteriosclerosis. Details: Taking ginkgo leaf extract 120-160 mg daily orally seems to improve symptoms of vertigo and equilibrium disorders (5721,6220,6221,107359,108608). There is evidence from two clinical studies that ginkgo leaf extract (EGb 761) for 3 months is significantly more effective than placebo (6220), and possibly as effective as betahistine, for improving vertigo and dizziness caused by vascular vestibular disorders and vestibular disorders of unknown origin (6220,6221). However, adding balance training to treatment with ginkgo leaf extract (EGb 761) orally 80 mg twice daily for 3 months is no better than taking ginkgo leaf extract alone (107359). Ginkgo has also been evaluated in patients with vertigo caused by mild cerebral arteriosclerosis. A clinical study in this population shows that taking oral ginkgo leaf extract (Zhejiang Jiu Xu Pharmaceutical Co, Ltd) 40 mg three times daily for 6 weeks improves scores of traditional Chinese medicine symptom pattern, specifically dizziness, blurry vision, headache, and amnesia, but does not impact Dizziness Handicap Inventory scores, when compared with naoxinqing (NXQ), a standardized herbal product that contains Japanese persimmon leaf extract (108608). The validity of this study is limited due to the lack of comparison to placebo or an accepted conventional treatment.

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Most research shows that oral ginkgo does not improve symptoms of age-related cognitive impairment. Details: While some preliminary clinical research shows a modest benefit of ginkgo leaf extract on memory and cognitive function in patients with age-related memory or thinking impairment (5717,6216,89712), most clinical research shows that taking ginkgo leaf extract orally does not improve memory or attention in elderly individuals with normal mental function (5718,8586,8587,8588,87848). Clinical research also shows that taking a standardized ginkgo leaf extract (Thorne Research Inc.) 240 mg daily for 3.5 years does not reduce the risk of developing age-related cognitive impairment in elderly patients aged 85 years and older who have normal cognitive function (16635).
• Antidepressant-induced sexual dysfunction. Most research shows that oral ginkgo does not improve symptoms of sexual dysfunction in people using antidepressants. Details: Although some preliminary clinical research shows that taking ginkgo leaf extract orally might help sexual dysfunction caused by antidepressant therapy (3965,3967), subsequent research indicates that it not likely to be beneficial (207,3966,3969,10893,14383).
• Cardiovascular disease (CVD). Oral ginkgo does not seem to prevent CVD. Details: A large-scale randomized trial shows that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 240 mg daily orally for an average of 6.1 years does not reduce the risk of myocardial infarction, angina, stroke, CVD-related hospitalization, or mortality in elderly patients when compared with placebo (17402).
• Chemotherapy-related cognitive impairment. Oral ginkgo does not seem to improve symptoms of cognitive impairment in people using chemotherapy. Details: Clinical research shows that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 60 mg twice daily, starting prior to the second cycle of chemotherapy and continuing until one month after chemotherapy completion, does not prevent chemotherapy-related cognitive dysfunction when compared with placebo in chemotherapy-naïve breast cancer patients (89701).
• Hypertension. Oral ginkgo does not seem to reduce blood pressure in older, hypertensive patients. Details: A meta-analysis of low-quality research in subjects with hypertension shows that taking ginkgo orally daily for 4-26 weeks modestly improves systolic and diastolic blood pressure when compared with control (114766). However, the validity of this study is limited by high heterogeneity, differing co-interventions, including known antihypertensives, and differing controls. Other clinical research shows that taking a standardized ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 240 mg daily for up to 6 years does not reduce blood pressure when compared with placebo in hypertensive patients aged 75 years or older (87853).
• Multiple sclerosis (MS). Most research shows that oral ginkgo does not improve symptoms of MS. Details: Most clinical research shows that taking ginkgo leaf extract or ginkgolide B, a constituent of ginkgo leaf extract, does not improve cognition or disability in patients with MS (87739,87787,87903,87947). However, a single preliminary clinical study shows that taking a standardized ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) may improve processing speed when compared with placebo in patients with multiple sclerosis (89705).
• Tinnitus. Most research shows that oral ginkgo does not improve symptoms of tinnitus. Details: Taking ginkgo leaf extract orally does not seem to improve symptoms of tinnitus. Although some studies have shown benefit, the majority of the clinical evidence indicates that ginkgo leaf extract is not consistently effective for patients with tinnitus (221,910,5721,6218,6219,9871,87754,87901,110093,111337)(111513).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral ginkgo is beneficial in AMD. Details: Preliminary clinical research suggests that taking a specific ginkgo leaf extract (EGb 761) 60-240 mg orally in divided doses for up to 6 months might improve symptoms of AMD (6227,6228,11797). There is limited evidence that ginkgo leaf extract might significantly improve distance vision in patients with AMD (6227).
• Aging. Although there has been interest in using oral ginkgo for aging, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Allergic rhinitis (hay fever). Topical ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with seasonal allergic conjunctivitis shows that applying two drops of specific eye drops (Trium, SOOFT) containing ginkgo extract 0.05% and hyaluronic acid 0.15%, three times daily for one month can decrease redness by 80%, discharge by 40%, and swelling by 10% when compared to using eye drops with hyaluronic acid alone (87829).
• Altitude sickness. Research on the use of oral ginkgo for altitude sickness is conflicting. Details: Some research shows that taking ginkgo extract 80-120 mg twice daily for 4 days before the ascent to an altitude of 4300-5400 meters significantly reduces the occurrence of symptoms of acute altitude sickness, including headache, fatigue, dyspnea, nausea, and vomiting, when compared with placebo (6230,87827). A standardized ginkgo leaf extract called EGb 761, 160 mg in two divided doses daily, was used in one of these studies (6230). However, a large-scale trial using a different ginkgo extract (GK501, Pharmaton Natural Health Products) 120 mg twice daily for 1-2 days before the climb from an altitude of 4280 meters to 4928 meters, shows that ginkgo extract has no effect on preventing altitude sickness (11766). Also, another small study suggests that taking ginkgo extract 120 mg twice daily for 3 days before an ascent does not reduce altitude sickness when compared with placebo (87827). The conflicting results may be due to differences in starting baseline altitudes before ascent, duration of the pre-treatment period, or the source of the ginkgo product.
• Angina. Some low-quality evidence suggests that oral ginkgo may reduce angina symptoms when taken in addition to standard of care. Details: A large meta-analysis of variable-quality studies in patients with unstable angina shows that taking ginkgo orally or intravenously for up to 12 weeks modestly improves angina symptoms when compared with control (114768). However, the results of this study are limited by the heterogeneity of included studies, including different control treatments. A small clinical study in patients with stable angina shows that taking ginkgo extract formulated with a polyethylene glycol matrix to improve bioavailability, 315 mg three times daily with standard therapy for 12 weeks, does not improve the overall Seattle Angina Questionnaire score when compared with placebo, although there is a trend towards a reduction in angina attack frequency (113782).
• Asthma. Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that a taking two capsules of a specific combination product (AKL1, AKL International Ltd.) containing ginkgo extract 130 mg/capsule, ginger 100 mg/capsule, and Picrorhiza 270 mg/capsule twice daily for 12 weeks does not improve lung function, respiratory symptoms, or quality of life when compared with placebo in adult patients with asthma (87786).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral ginkgo is beneficial in ADHD. Details: One clinical study shows that taking a standardized ginkgo extract (Ginko T.D., Tolidaru Pharmaceuticals) 80-120 mg daily for 6 weeks is less effective than methylphenidate 20-30 mg daily in children aged 6-14 years with newly diagnosed ADHD. Only 8% of children taking ginkgo extract had at least a 40% improvement in a teacher/parent ADHD rating scale, compared with 64% in children taking methylphenidate (17112). Another clinical study in children aged 6-12 years with ADHD shows that taking the same standardized ginkgo extract 80-120 mg daily in combination with methylphenidate 20-40 mg daily for 6 weeks does not improve parent- or teacher-rated ADHD scores by a clinically meaningful amount when compared with methylphenidate alone (95669). However, one preliminary clinical study shows that taking a specific combination product (AD-fX, CV Technologies) containing ginkgo leaf extract 100 mg, in combination with American ginseng extract 400 mg, in two divided doses for 4 weeks might significantly improve ADHD symptoms such as anxiety, hyperactivity, and impulsivity in children aged 3-17 years (8235). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that ginkgo extract at doses of 80-120 mg daily is not currently recommended for monotherapy or adjunctive use in children with ADHD due to mixed evidence (110318).
• Autism spectrum disorder. It is unclear if oral ginkgo is beneficial in children with autism. Details: A small clinical trial shows that taking a specific ginkgo extract (Ginko T.D., Tolidaru Pharmaceuticals) 80-120 mg daily for 10 weeks along with risperidone 1-3 mg daily does not improve symptoms of autism when compared with risperidone alone in children aged 4-12 years (89708).
• Bronchitis. Although there has been interest in using oral ginkgo for bronchitis, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Chronic fatigue syndrome (CFS). Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with CFS shows that taking ginkgo leaf 120-180 mg in combination with Cistanche tubulosa root 300-450 mg orally daily for 60 days improves fatigue scores by 16% to 19% when compared with placebo. Taking this combination also improved quality of life scores when compared with placebo (107361).
• Chronic kidney disease (CKD). There is limited evidence on the intravenous use of ginkgo leaf extract in adults with hypertensive nephropathy. It has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small meta-analysis in patients with hypertensive nephropathy shows that intravenous administration of 20-30 mL of ginkgo leaf extract and dipyridamole injection once daily for 3-4 weeks along with conventional antihypertensive therapy improves levels of 24-hour urinary total protein, serum creatinine, and blood urea nitrogen by 0.6 grams/dL, 33 mg/dL, and 7 mg/dL, respectively (106610). It is unclear if these effects are due to ginkgo, dipyridamole, or the combination.
• Chronic obstructive pulmonary disease (COPD). Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking two capsules of a specific combination product (AKL1, AKL International Ltd.) containing ginkgo extract, ginger, and Picrorhiza twice daily for 8 weeks does not improve respiratory symptoms when compared with placebo in patients with COPD (89702).
• Cocaine dependence. It is unclear if oral ginkgo is beneficial for maintenance of abstinence from cocaine. Details: A small clinical trial shows that taking a standardized ginkgo leaf extract called EGb 761 in a dose of 120 mg twice daily for 10 weeks does not help maintain abstinence from cocaine use when compared with placebo in cocaine-dependent patients (87723).
• Cognitive function. It is unclear if oral ginkgo is beneficial for cognitive function. Details: Clinical research in healthy adults shows that taking ginkgo leaf extract daily for up to 12 weeks might improve some measures of cognitive function, such as working and long term memory, attention based tasks, speed of information processing, executive function, immediate and delayed recall, and recognition (6214,6215,8236,8544,8585,8588,9759,16635,87788,87879,95668). Doses used in these studies include single doses of ginkgo extract 240-600 mg (6215,8236), a standardized ginkgo extract called EGb 761, 120-240 mg taken once daily or in 2-3 divided doses daily for 4-24 weeks (5717,6216,8585,8588,87879,95668), or another specific ginkgo extract called LI 1370 (Lichtwer Pharma), 120-300 mg daily in three divided doses for 2 days (6214). However, other clinical studies and one clinical review show no significant effect of ginkgo on gait ability, attention, memory, or executive function regardless of participant age, dose, or formulation used (87907,5718,8586,8587,8588,87907,95667). Due to the small number of study participants, significant differences in baseline cognitive function between groups, and variability in outcome measures, no definitive conclusions can be drawn. Larger scale studies are needed to determine the effect of ginkgo on cognitive function in healthy individuals. There is also conflicting evidence about the effect of ginkgo on cognitive function when taken in combination with other products. Some research suggests that taking ginkgo in combination with Panax ginseng or codonopsis enhances memory in healthy young or middle-aged adults, and the combinations might be more effective than the individual products (8591,9759,87758). These studies have used a specific combination product (Ginkoba M/E, Pharmaton SA) containing ginkgo extract 100-600 mg and Panax ginseng 60-360 mg, taken as a single dose or once daily for 12 weeks (8591,9759) or two capsules of a product containing ginkgo extract 40 mg/capsule and Codonopsis 75 mg/capsule daily (87758). However, other clinical research shows that taking ginkgo combined with Panax ginseng (Gincosan, Pharmaton Natural Health Products) or bacopa extract (Ginkgo Brahmi, Blackmore's Ltd.) for up to 12 weeks does not improve cognition when compared with placebo in healthy adults (87767,87748). Similarly, a moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing ginkgo leaf, bacopa, and B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Cognitive impairment. It is unclear if ginkgo is beneficial for cognitive impairment. Details: A clinical study of 500 patients with mild cognitive impairment that is abnormal for their age shows that taking a specific ginkgo standardized extract (EGb761, Tanakan) 40 mg three times daily for 24 months improves scores for cognitive decline, memory, activities of daily living, and depression when compared with baseline (105530). However, it is not clear if these improvements are clinically significant and the validity of the study is limited by the lack of a control group. Cognitive impairment is common side effect of electroconvulsive therapy (ECT). A small clinical study in patients aged 18-60 years with psychiatric disorders undergoing ECT in Iran shows that taking ginkgo (Vitarmonil Co., France) 200 mg after meals, starting 48 hours before initiation of ECT and continuing until the end of ECT sessions, modestly improves scores related to cognitive impairment and memory when compared with placebo (111338). However, it is unclear if these improvements are clinically significant.
• Colorectal cancer. Intravenous ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that adding intravenous ginkgo extract (EGb 761 ONC), 350 mg over 30 minutes on days 1-6 of every 3-week cycle to treatment with 5-fluorouracil 500 mg/m2 daily on days 2-6 of every 3-week cycle for 4 courses of treatment, might reduce disease progression in some patients with metastatic colorectal cancer (9872). However, since the study did not include a control group, it is unclear if the effects of treatment were greater than the effects of 5-fluorouracil alone.
• Cough. Although there has been interest in using oral ginkgo for cough, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Depression. It is unclear if oral ginkgo is beneficial in depression. Details: Preliminary clinical research in elderly patients shows that taking an unknown dose of a specific ginkgo extract (Harbin HaoBo Pharmaceutical Co., Ltd.) in conjunction with citalopram 20 mg daily for 12 weeks improves depression scores by 75% or more in an additional 3% of patients when compared with taking citalopram alone. Taking ginkgo extract with citalopram also produces a faster onset of action when compared to taking citalopram alone. However, it is not clear if these improvements are clinically significant (98811). A meta-analysis of 21 mainly Chinese studies shows that adding ginkgo preparations in various doses to conventional treatment for depression improves Hamilton Depression Scale scores and increases serotonin levels when compared with conventional treatment alone, but there is high heterogeneity in the results (113779).
• Diabetes. Research on the use of oral ginkgo in type 2 diabetes is conflicting. Details: In patients with uncontrolled type 2 diabetes taking metformin, preliminary clinical research shows that taking ginkgo extract (EGb 761) 120 mg for 90 days reduces glycated hemoglobin (HbA1c) levels from an average of 8.6% at baseline to an average of 7.7%. Fasting serum glucose and insulin were also reduced, when compared with baseline, by approximately 20% and 28%, respectively (103574). However, a meta-analysis of 7 clinical studies shows that taking ginkgo is associated with an increase in HbA1c levels, with no effect on fasting serum glucose levels. The only beneficial effect identified in this analysis was an increase in high density lipoprotein (HDL) cholesterol levels (105529). Another meta-analysis of mainly Chinese studies, shows that adding various ginkgo preparations to metformin for 1-3 years does not improve fasting serum glucose, HbA1c, or cholesterol levels, but does reduce blood viscosity and hematocrit while improving dorsalis pedis artery blood flow and ankle brachial index, suggesting a beneficial effect on peripheral arterial disease associated with diabetes (113780).
• Diabetic retinopathy. It is unclear if oral ginkgo is beneficial for this condition. Details: Preliminary clinical research shows that taking a specific ginkgo leaf extract called EGb 761 120 mg daily orally for 6 months improves measures of color vision when compared with placebo in patients with early diabetic retinopathy (6175).
• Dry eye. Ginkgo eye drops have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A nonblinded clinical study in adults undergoing cataract surgery and receiving standard treatment shows that applying a specific, preservative-free eye drop (Trium Free; SOOFT) containing ginkgo extract 0.05% and hyaluronic acid 0.15%, three times daily, beginning the first day after surgery and continued for 4 weeks, reduces dry eye severity and symptoms when compared with standard treatment alone. After 4 weeks, 50% of patients in the standard treatment group reported dry eye symptoms, compared with 16% of patients using ginkgo (108609). The effects of ginkgo in patients with chronic dry eye or dry eye caused by other factors is unclear.
• Dyslexia. It is unclear if oral ginkgo is beneficial for dyslexia in children. Details: Preliminary clinical research shows that taking a standardized ginkgo leaf extract (EGb 761) 80 mg daily for an average of 34 days can help reduce dyslexia when compared to baseline in children aged 5-16 years (87790). The validity of this finding is limited by the lack of a comparator group.
• Fibromyalgia. Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking tablets containing ginkgo extract (Bio-Biloba, Pharma Nord) 200 mg daily in conjunction with capsules containing coenzyme Q10 (Bio Quinone Q10, Pharma Nord) 200 mg daily orally for 84 days improves patient-reported quality of life, such as physical fitness levels, emotional feelings, social activities, overall health, and pain, when compared to baseline (17716). The validity of these findings is limited by the lack of a comparator group.
• Gastric cancer. It is unclear if oral ginkgo is beneficial in gastric cancer. Details: Preliminary clinical research shows that taking carbohydrates from the outer layer of ginkgo fruit 250 mg orally twice daily for 30 days may reduce tumor size in patients with gastric cancer when compared with pre-treatment (87742).
• Glaucoma. It is unclear if oral ginkgo is beneficial in glaucoma. Details: A small observational study has found that taking ginkgo leaf extract 80 mg twice daily for up to 12.3 years is associated with reduced progression of visual field damage in patients with normal tension glaucoma (87900). Furthermore, a small clinical study in patients with normal tension glaucoma shows that taking ginkgo leaf extract 40 mg three times daily for up 4 weeks might improve pre-existing damage and reduce the progression of damage to the visual field (10378). However, conflicting evidence exists. Another small study in patients with newly diagnosed normal tension glaucoma shows that taking a specific ginkgo extract (Ginaton, Dr. Willmar Schwabe Pharmaceuticals) 40 mg three times daily for 4 weeks does not improve damage or progression of glaucoma (89707). Reasons for the discrepancies may be due to the formulation of ginkgo leaf extract used or the severity of glaucoma at baseline.
• Hemorrhoids. Oral ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study shows that taking a combination of ginkgo extract, troxerutin, and heptaminol for one week may decrease some symptoms of hemorrhoids, including bleeding, pain, feelings of incomplete defecation, and discharge when compared to baseline (87751). The validity of these findings is limited by the lack of a comparator group. Additionally, it is unclear if these effects are due to ginkgo, other ingredients, or the combination.
• Hypercholesterolemia. Although there has been interest in using oral ginkgo for hypercholesterolemia, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Intestinal parasite infection. Although there has been interest in using oral ginkgo for intestinal parasite infection, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Lyme disease. Although there has been interest in using oral ginkgo for cognitive dysfunction associated with Lyme disease, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Migraine headache. Oral ginkgolide B, a constituent of ginkgo biloba extract, has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that ginkgolide B (BN52021), a constituent of ginkgo extract, along with coenzyme Q10, riboflavin, and magnesium, taken twice daily for 3 months, may help prevent migraines in school-aged children when compared to baseline (44181,87876). Also, a specific product (Migrasoll, Pharmaval Srl) containing ginkgolide B 60 mg, coenzyme Q10 11 mg, and vitamin B2 8.7 mg, taken twice daily for 4 months, may help prevent migraines in females when compared to baseline (44103). The validity of the findings from these studies is limited by the lack of a comparator group.
• Ovarian cancer. It is unclear if oral ginkgo is beneficial in preventing ovarian cancer. Details: Epidemiological evidence found that use of ginkgo extract for 6 months is associated with a decreased risk for developing ovarian cancer (14813).
• Pancreatic cancer. Intravenous ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that adding a specific intravenous ginkgo extract called EGb 761 ONC 350 mg on days 1-6 of every 3-week cycle to treatment with 5-fluorouracil 500 mg/m2 daily on days 2-6 of every 3-week cycle until disease progression might slow the progression of pancreatic cancer in some patients (87699). However, since the study did not include a control group, it is unclear if the effects of treatment were greater than the effects of 5-fluorouracil alone.
• Parkinson disease. It is unclear if oral ginkgo is beneficial for drug-induced Parkinsonism. Details: Preliminary clinical research in patients with psychiatric diagnoses treated with antipsychotic drugs shows that taking dried ginkgo extract, 80 mg three times daily orally for 3 months, reduces resting tremors, rigidity, bradykinesia, and the severity of motor symptoms when compared with placebo (112945).
• Peripheral arterial disease (PAD). It is unclear if oral ginkgo is beneficial in PAD. Details: Some small clinical studies show that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals and Ipsen) orally increases pain-free walking distance in patients with Fontaine's IIb peripheral arterial occlusive disease and intermittent claudication and might decrease overall peripheral vascular disease (PVD) event incidence, such as surgery or amputation, in elderly patients (3461,6211,6212,6213,17402). Significant benefit has been found with doses as low as 120-160 mg daily (6211). However, there is some evidence that a higher dose of 240 mg daily might be more beneficial in some patients (3461,6212). Although some research is positive, other research shows that taking a specific ginkgo leaf extract called EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) 300 mg daily for 16 weeks does not significantly improve maximum treadmill walking time when compared with placebo in patients with PAD (16638). A reason for this discrepancy may be due to the duration of treatment. A meta-analysis of clinical research shows that taking ginkgo leaf extract does not improve maximum treadmill walking distance when compared with placebo in patients with Fontaine stage II PVD and intermittent claudication when administered for 6-8 weeks or 12-16 weeks, but does increase maximum treadmill walking distance by about 85 meters when administered for at least 24 weeks (89440).
• Pulmonary hypertension. It is unclear if intravenous ginkgo is beneficial in patients with pulmonary hypertension and cor pulmonale. Details: A meta-analysis of 28 small, low-quality clinical trials, including nearly 2500 Chinese patients with pulmonary hypertension and cor pulmonale, shows that intravenous administration of ginkgo leaf extract plus dipyridamole 15-40 mL daily for 1-4 weeks along with conventional therapy increases the total effective rate by 28% and improves various blood gas measures when compared with conventional therapy alone (102881). It is unclear if these effects are due to ginkgo, dipyridamole, or the combination. Large, high-quality clinical trials are needed to confirm these results.
• Quality of life. Some preliminary clinical studies suggest that oral ginkgo might improve quality of life in elderly individuals. Details: A large survey-based study shows that taking a standardized ginkgo leaf extract called LI 1370 (Lichtwer Pharma) 120 mg daily for 4-10 months may improve quality of life measures such as activities of daily living, mood, sleep, and alertness in elderly individuals when compared with control (87715,87760).
• Radiation exposure. It is unclear if intravenous ginkgo is beneficial in people who have been exposed to radiation. Details: Preliminary clinical research shows that taking a standardized ginkgo leaf extract called EGb 761 (Tanakan, Ipsen) 120 mg daily for 2 months might reduce clastogenic factors in the blood of patients who had previously been irradiated. The reduction in clastogenic factors was observed for at least 7 months after initiation of ginkgo in most patients (17719).
• Radiation dermatitis. Topical ginkgo has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a specific cream product (Radioskin 2, Herbalab di Perazza Massimiliano Company) containing ginkgo extract, Aloe vera, and metal esculetina, along with another specific cream product (Radioskin 1) containing alga atlantica and ethylbisiminomethylguaicolo manganese cloruro, may improve skin hydration and reduce skin toxicity associated with radiation therapy in patients with breast cancer (89727). The creams were applied topically 2-3 times daily at least 3 hours before and after radiation treatment from 15 days prior to radiation until one month after completion. It is unclear if these effects are due to ginkgo, other ingredients, or the combination.
• Raynaud syndrome. Evidence for the use of oral ginkgo for flare reduction is conflicting. Details: Some research shows that taking a standardized ginkgo extract (Seredrin, Health Perception Ltd.) 120 mg orally three times daily for 10 weeks can decrease the number of painful attacks per week in patients with Raynaud syndrome (11363). However, other research shows that ginkgo extract is no different than placebo in decreasing the number of attacks in these patients (87888). Also, another study shows that taking ginkgo extract 120 mg daily is less effective than nifedipine SR 30 mg daily orally in decreasing Raynaud syndrome flares (87818).
• Scabies. Although there has been interest in using topical ginkgo for scabies, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Seasonal affective disorder (SAD). It is unclear if oral ginkgo is beneficial for SAD. Details: One small clinical study shows that taking ginkgo leaf extract orally does not seem to prevent winter depression symptoms in patients with SAD when compared with placebo (8233).
• Sexual dysfunction. It is unclear if oral ginkgo is beneficial for sexual dysfunction in females. Details: Some clinical research shows that taking a ginkgo leaf extract 300 mg daily for 8 weeks does not significantly improve sexual function in females with sexual arousal disorder when compared with placebo (16640). However, other preliminary clinical research shows that taking a specific combination product (ArginMax for Women, Daily Wellness Company) containing ginkgo leaf extract, Panax ginseng root extract, damiana leaf extract, L-arginine, multivitamins, and minerals for 4 weeks can improve sexual satisfaction when compared with placebo in females who self-report sexual dysfunction (46933). It is unclear if these effects are due to ginkgo, other ingredients, or the combination.
• Venous thromboembolism (VTE). Although there has been interest in using oral ginkgo for thrombosis, there is insufficient reliable information about the clinical effects of ginkgo for this condition.
• Vitiligo. It is unclear if oral ginkgo is beneficial for reducing vitiligo progression. Details: Preliminary clinical research shows that taking a specific ginkgo extract (Ginkgo Plus, Seroyal) 120 mg in two divided doses daily for up to 6 months reduces the progression of vitiligo vulgaris and lesion size when compared to baseline (17718,87728). The validity of these findings is limited by the lack of a comparator group.
• Wound healing. Although there has been interest in using topical ginkgo for healing of skin sores or chilblains, there is insufficient reliable information about the clinical effects of ginkgo for these conditions. More evidence is needed to rate ginkgo for these uses.

(Read more about GINKGO)

POSSIBLY EFFECTIVE

• Anxiety. Oral kava seems to improve anxiety when taken for at least 5 weeks. Details: Most clinical research shows that kava extracts 150-400 mg, standardized to 70% kavalactones, daily are superior to placebo for relieving symptoms of non-psychotic anxiety (2094,2095,11372,18315,18316,18317,18320,98980), and are possibly comparable to buspirone 10 mg or low-dose benzodiazepines such as oxazepam 30 mg (18314). However, kava may not be effective for improving subthreshold anxiety. A meta-analysis of 3 small clinical studies in patients with subthreshold anxiety shows that taking kava does not improve anxiety symptoms when compared with placebo (110711). Overall, kava's effects appear to be dose-dependent and duration-dependent. One meta-analysis suggests that taking more than 200 mg kavalactones daily tends to be more beneficial for anxiety than taking less than 200 mg kavalactones daily (98980). Some clinical research also suggests that kava extract must be taken for at least 5 weeks to provide a benefit (2094,15046,18314,98980), while single-dose treatments may not be beneficial for acute anxiety (18319). Most studies have used a specific standardized extract (WS 1490, Dr. Willmar Schwabe Pharmaceuticals) 150-300 mg daily. Another specific kava extract (LI 150, Lichtwer Pharma) 400 mg daily has also been used (18314,98980). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) conclude that there is evidence supporting the use of kava for acute or short-term management of general anxiety symptoms but that only products standardized to a sufficient level of kavalactones should be recommended (110318).

POSSIBLY INEFFECTIVE

• Generalized anxiety disorder (GAD). Oral kava doesn't seem to be effective for treating GAD. Details: A meta-analysis of 3 small, low-quality clinical studies in adults with GAD shows that kava extract standardized to 70% kavalactones, providing 140-280 mg kavalactones daily, is no more effective than placebo when used for 4-8 weeks (15130). Additionally, a more recent meta-analysis of 3 moderate-sized clinical trials in patients diagnosed with GAD shows that taking kava does not reduce anxiety when compared with placebo or conventional therapy (110711). While a small clinical trial in adults with GAD shows that taking kava rootstock extract, standardized to provide 120-240 mg of kavalactones daily, for 6 weeks reduces clinician rated anxiety scores when compared with placebo (29663), a large, multi-center clinical trial from the same research group shows that taking kava root extract standardized to 120 mg of kavalactones twice daily for 16 weeks does not reduce anxiety scores when compared with placebo in adults diagnosed with GAD (102086). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends against the use of kava rootstock extracts (standardized to 60-250 mg kavalactones) as either monotherapy or adjunctive therapy in patients with GAD (110318). This recommendation against kava for GAD is based on high quality evidence from a meta-analysis and two additional clinical trials, along with a meta-review of two meta-analyses on the use of kava for GAD (110318,112133).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Benzodiazepine withdrawal. It is unclear if oral kava is beneficial for reducing benzodiazepine withdrawal symptoms. Details: One small clinical study in patients with non-psychotic anxiety shows that titrating a specific kava extract (WS1490, Dr. Willmar Schwabe Pharmaceuticals) up to 300 mg daily over one week while tapering the benzodiazepine over 2 weeks is no more effective than placebo for decreasing benzodiazepine withdrawal symptoms (7325).
• Cancer. It is unclear if oral kava is beneficial in patients with cancer. Details: Epidemiological evidence has found that increasing kava consumption is associated with a lower incidence of cancer (8175).
• Epilepsy. Although there is interest in using oral kava for epilepsy, there is insufficient reliable information about the clinical effects of kava for this condition.
• Insomnia. It is unclear if oral kava is beneficial in patients with insomnia. Details: One small clinical study shows that taking a specific kava extract (WS1490, Dr. Willmar Schwabe Pharmaceuticals) 200 mg standardized to 70% kavalactones daily for 4 weeks reduces sleep disturbances associated with non-psychotic anxiety disorders (18321). However, another internet-based clinical trial in patients with self-reported insomnia associated with anxiety suggests that taking kava in a dose equivalent to 100 mg kavalactones three times daily for 4 weeks does not improve sleep when compared with placebo (15046).
• Menopausal symptoms. It is unclear if oral kava is beneficial for menopausal symptoms. Details: One small clinical study shows that taking kava 100-200 mg standardized to contain 55% kavaina daily for 3 months reduces depression, anxiety, and hot flashes when compared to baseline in perimenopausal patients. However, the changes in depression and hot flashes were not better when compared with the control group that took calcium (18318).
• Myalgia. Although there is interest in using oral kava for myalgia, there is insufficient reliable information about the clinical effects of kava for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral kava for PMS, there is insufficient reliable information about the clinical effects of kava for this condition.
• Sexual arousal. Although there is interest in using oral kava for sexual arousal, there is insufficient reliable information about the clinical effects of kava for this condition.
• Stress. It is unclear if oral kava reduces reactivity to experimental stress. Details: A small study in healthy volunteers shows that taking a single dose of kava (LI 150, Lichtwer Pharma) 120 mg orally might reduce the physiological changes associated with mentally stressful tasks when compared to baseline (9893). More evidence is needed to rate kava for these uses.

(Read more about KAVA)

There is insufficient reliable information available about the effectiveness of pulsatilla.

(Read more about PULSATILLA)

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.
• Osteoarthritis. It is unclear if topical St. John's wort is beneficial for osteoarthritis. Oral St. John's wort is not studied for this use. Details: A moderate-sized clinical study in adults with knee osteoarthritis shows that applying St. John's wort oil (concentration unknown) to the knees three times a day for 21 days improves patient-reported pain, stiffness, and function scores when compared with placebo (olive oil) (113093). However, participants were aware of which treatment they received and were allowed to continue use of analgesics as needed, which limits the validity of this study.
• 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.

(Read more about ST. JOHN'S WORT)

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

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (12,46933,11866).

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

(Read more about DAMIANA)

LIKELY SAFE ...when used orally and appropriately. Standardized ginkgo leaf extracts have been used safely in trials lasting for several weeks up to 6 years (1514,1515,3461,5717,5718,6211,6212,6213,6214,6215)(6216,6222,6223,6224,6225,6490,14383,14499,16634,16635)(16636,16637,17402,17716,17718,87794,87819,87826,87848,87864)(87888,87897,87901,87904,89701,89707,107359,107360). There have been some reports of arrhythmias associated with ginkgo leaf extract. However, it is not yet clear if ginkgo might cause arrhythmia (105253,105254). There is some concern about toxic and carcinogenic effects seen in animals exposed to a ginkgo leaf extract containing 31.2% flavonoids, 15.4% terpenoids, and 10.45 ppm ginkgolic acid, in doses of 100 to 2000 mg/kg five times per week for 2 years (18272). However, the clinical relevance of this data for humans, using typical doses, is unclear. The content of the extract used is not identical to that commonly used in supplement products, and the doses studied are much higher than those typically used by humans. A single dose of 50 mg/kg in rats is estimated to be equivalent to a single dose of about 240 mg in humans (18272).

POSSIBLY SAFE ...when used intravenously, short-term. A standardized ginkgo leaf extract called EGb 761 ONC has been safely administered intravenously for up to 14 days (9871,9872,107360,107452). A Chinese preparation containing ginkgo leaf extract and dipyridamole has been safely administered intravenously for up to 30 days (102881,102882). ...when applied topically, short-term. There was no dermal irritation during a 24-hour patch test using the leaf extract, and no sensitization with repeat applications (112946). When used topically in cosmetics, extracts of ginkgo leaves are reported to be safe, but there is insufficient data to determine the safety of nut and root extracts, and isolated biflavones and terpenoids (112946).

POSSIBLY UNSAFE ...when the roasted seed or crude ginkgo plant is used orally. Consuming more than 10 roasted seeds per day can cause difficulty breathing, weak pulse, seizures, loss of consciousness, and shock (8231,8232). Crude ginkgo plant parts can exceed concentrations of 5 ppm of the toxic ginkgolic acid constituents and can cause severe allergic reactions (5714).

LIKELY UNSAFE ...when the fresh ginkgo seed is used orally. Fresh seeds are toxic and potentially deadly (11296).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is concern that ginkgo might have labor-inducing and hormonal effects. There is also concern that the antiplatelet effects of ginkgo could prolong bleeding time if taken around the time of labor and delivery (15052). Theoretically, ginkgo might adversely affect pregnancy outcome; avoid using during pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term (87790,89708). A specific ginkgo dried extract (Ginko T.D., Tolidaru Pharmaceuticals), has been safely used in doses of 80-120 mg daily for 6 weeks in children aged 6-14 years (17112,95669). Another specific combination product containing ginkgo leaf extract and American ginseng extract (AD-FX, CV Technologies, Canada) has also been safely used in children aged 3-17 years for up to 4 weeks (8235).

CHILDREN: LIKELY UNSAFE
when ginkgo seed is used orally. The fresh seeds have caused seizures and death in children (8231,11296).

(Read more about GINKGO)

POSSIBLY SAFE ...when used orally, short-term. Kava extracts have been used safely in clinical trials under medical supervision for up to 6 months (2093,2094,2095,4032,7325,15046,15130,18314,18316,18318)(18320,29663,29671,98980,102086,112642). Historically, there has been some concern that kava preparations could induce hepatotoxicity and liver failure in patients taking relatively normal doses, short-term. At least 100 cases of liver toxicity following kava use have been reported. Although liver toxicity is more frequently associated with prolonged use of very high doses (6401,57346), in some cases the use of kava for as little as 1-3 months has been associated with the need for liver transplants, and even death (390,7024,7068,7086,7096,17086,57252)(57254,57297). However, some experts question the clinical validity of several of these cases (11369,11371).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is some concern that pyrone constituents in kava can cause loss of uterine tone (19); avoid using.

LACTATION: POSSIBLY UNSAFE
when used orally. There is concern that the toxic pyrone constituents of kava can pass into breast milk (19); avoid using.

(Read more about KAVA)

LIKELY UNSAFE ...when fresh above ground parts are used orally or topically; pulsatilla is a severe local irritant (4). There is insufficient reliable information available about the safety of the use of dried pulsatilla.

PREGNANCY: LIKELY UNSAFE
when used orally. The fresh or dried above ground parts are contraindicated due to abortifacient and teratogenic effects (2,4). ...when the fresh above ground parts are used topically. There is insufficient reliable information available about the safety of topical dried pulsatilla during pregnancy.

LACTATION: LIKELY UNSAFE
when the fresh above ground parts are used for oral or topical use (19). There is insufficient reliable information available about the safety of dried pulsatilla during breast-feeding.

(Read more about PULSATILLA)

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).

(Read more about ST. JOHN'S WORT)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking damiana with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research shows that taking damiana lowers blood glucose level (4,25016).

(Read more about DAMIANA)

ALPRAZOLAM (Xanax) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease the levels and clinical effects of alprazolam.  Details In clinical research, ginkgo extract (Ginkgold) 120 mg twice daily seems to decrease alprazolam levels by about 17%. However, ginkgo does not appear to decrease the elimination half-life of alprazolam. This suggests that ginkgo is more likely to decrease absorption of alprazolam rather than induce hepatic metabolism of alprazolam (11029).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = A Ginkgo has been shown to increase the risk of bleeding in some people when taken with warfarin. Theoretically, ginkgo might increase the risk of bleeding if used with other anticoagulant or antiplatelet drugs.  Details Several pharmacodynamic studies suggest that ginkgo inhibits platelet aggregation. It is thought that the ginkgo constituent, ginkgolide B, displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation (6048,9760). Several case reports have documented serious bleeding events in patients taking ginkgo (244,578,579,8581,13002,13135,13179,13194,14456,87868). However, population and clinical studies have produced mixed results. Some evidence shows that short-term use of ginkgo leaf does not significantly reduce platelet aggregation and blood clotting (87732). A study in healthy males who took a specific ginkgo leaf extract (EGb 761) 160 mg twice daily for 7 days found no change in prothrombin time (12114). An analysis of a large medical record database suggests that ginkgo increases the risk of a bleeding adverse event by 38% when taken concurrently with warfarin (91326). It has been suggested that ginkgo has to be taken for at least 2-3 weeks to have a significant effect on platelet aggregation (14811). However, a meta-analysis of 18 studies using standardized ginkgo extracts, 80-480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT (17179). In addition, a single dose of ginkgo plus clopidogrel (14811) or ticlopidine does not seem to significantly increase bleeding time or platelet aggregation (17111,87846). Also, taking ginkgo leaf extract daily for 8 days in conjunction with rivaroxaban does not affect anti-factor Xa activity; however, this study did not evaluate bleeding time (109526).

ANTICONVULSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might reduce the effectiveness of anticonvulsants.  Details Ginkgo seeds contain ginkgotoxin. Large amounts of ginkgotoxin can cause neurotoxicity and seizure. Ginkgotoxin is present in much larger amounts in ginkgo seeds than leaves (8232). Ginkgo leaf extract contains trace amounts of ginkgotoxin. The amount of ginkgotoxin in ginkgo leaf and leaf extract seems unlikely to cause toxicity (11296). However, there are anecdotal reports of seizure occurring after use of ginkgo leaf both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with antidiabetes drugs might alter the response to antidiabetes drugs.  Details Ginkgo leaf extract seems to alter insulin secretion and metabolism, and might affect blood glucose levels in people with type 2 diabetes (5719,14448,103574). The effect of ginkgo seems to differ depending on the insulin and treatment status of the patient. In diet-controlled diabetes patients with hyperinsulinemia, taking ginkgo does not seem to significantly affect insulin or blood glucose levels. In patients with hyperinsulinemia who are treated with oral hypoglycemic agents, taking ginkgo seems to decrease insulin levels and increase blood glucose following an oral glucose tolerance test. Researchers speculate that this could be due to ginkgo-enhanced hepatic metabolism of insulin. In patients with pancreatic exhaustion, taking ginkgo seems to stimulate pancreatic beta-cells, resulting in increased insulin and C-peptide levels, but with no significant change in blood glucose levels in response to an oral glucose tolerance test (14448).

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease the levels and clinical effects of atorvastatin.  Details In humans, intake of ginkgo extract appears to increase atorvastatin clearance, reducing the area under the curve of atorvastatin by 10% to 14% and the maximum concentration by 29%. However, this interaction does not appear to affect cholesterol synthesis and absorption (89706). Further, a model in rats with hyperlipidemia suggests that administering ginkgo extract does not impact blood levels of atorvastatin and leads to lower total cholesterol, low-density lipoprotein cholesterol, and triglycerides when compared with rats given atorvastatin alone (111331).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, ginkgo might increase levels of drugs metabolized by CYP1A2.  Details Laboratory research suggests that ginkgo leaf extract can mildly inhibit CYP1A2 enzymes (1303,6423,6450). However, clinical research suggests ginkgo might not affect CYP1A2 (10847). Until more is known, use ginkgo cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease levels of drugs metabolized by CYP2C19.  Details Some clinical research shows that a specific ginkgo leaf extract (Remembrance, Herbs Product LTD) 140 mg twice daily can induce CYP2C19 enzymes and potentially decrease levels of drugs metabolized by these enzymes (13108). However, other clinical research shows that taking ginkgo 120 mg twice daily for 12 days has no effect on levels of drugs metabolized by CYP2C19 (87824).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase levels of drugs metabolized by CYP2C9.  Details In vitro, a specific standardized extract of ginkgo leaf (EGb 761) inhibits CYP2C9 activity (11026,12061,14337). The terpenoid (ginkgolides) and flavonoid (quercetin, kaempferol, etc.) constituents seem to be responsible for this effect. Most ginkgo extracts contain some amount of these constituents. Therefore, other ginkgo leaf extracts might also inhibit the CYP2C9 enzyme. However, clinical research suggests that ginkgo might not have a significant effect on CYP2C9 in humans. Ginkgo does not seem to significantly affect the pharmacokinetics of CYP2C9 substrates diclofenac or tolbutamide.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, ginkgo might decrease levels of drugs metabolized by CYP3A4.  Details There is conflicting evidence about whether ginkgo induces or inhibits CYP3A4 (1303,6423,6450,11026,87800,87805,111330). Ginkgo does not appear to affect hepatic CYP3A4 (11029). However, it is not known if ginkgo affects intestinal CYP3A4. Preliminary clinical research suggests that taking ginkgo does not significantly affect levels of donepezil, lopinavir, or ritonavir, which are all CYP3A4 substrates (11027,87800,93578). Other clinical research also suggests ginkgo does not significantly affect CYP3A4 activity (10847). However, there are two case reports of decreased efavirenz concentrations and increased viral load in patients taking ginkgo. It is suspected that terpenoids from the ginkgo extract reduced drug levels by inducing cytochrome P450 3A4 (CYP3A4) (16821,25464).

EFAVIRENZ (Sustiva) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might decrease the levels and clinical effects of efavirenz.  Details There are two case reports of decreased efavirenz concentrations and increased viral load in patients taking ginkgo. In one case, an HIV-positive male experienced over a 50% decrease in efavirenz levels over the course of 14 months while taking ginkgo extract. HIV-1 RNA copies also increased substantially, from less than 50 to more than 1500. It is suspected that terpenoids from the ginkgo extract reduced drug levels by inducing cytochrome P450 3A4 (CYP3A4) (16821). In another case report, a patient stable on antiviral therapy including efavirenz for 10 years, had an increase in viral load from <50 copies/mL to 1350 copies/mL after 2 months of taking a combination of supplements including ginkgo. After stopping ginkgo, the viral load was again controlled with the same antiviral therapy regimen (25464).

IBUPROFEN (Advil, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the risk of bleeding when used with ibuprofen.  Details Ginkgo might have antiplatelet effects and has been associated with several case reports of spontaneous bleeding. In one case, a 71-year-old male had taken a specific ginkgo extract (Gingium, Biocur) 40 mg twice daily for 2.5 years. About 4 weeks after starting ibuprofen 600 mg daily he experienced a fatal intracerebral hemorrhage (13179). However, the antiplatelet effects of ginkgo have been questioned. A meta-analysis and other studies have not found a significant antiplatelet effect with standardized ginkgo extracts, 80 mg to 480 mg taken daily for up to 32 weeks (17179).

NIFEDIPINE (Procardia) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with oral, but not intravenous, nifedipine might increase levels and adverse effects of nifedipine.  Details Animal research and some clinical evidence suggests that taking ginkgo leaf extract orally in combination with oral nifedipine might increase nifedipine levels and cause increased side effects, such as headaches, dizziness, and hot flushes (87764,87765). However, taking ginkgo orally does not seem to affect the pharmacokinetics of intravenous nifedipine (87765).

OMEPRAZOLE (Prilosec) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with omeprazole might decrease the levels and clinical effects of omeprazole.  Details Clinical research shows that a specific ginkgo leaf extract (Remembrance, Herbs Product LTD) 140 mg twice daily can induce cytochrome P450 (CYP) 2C19 enzymes and decrease levels of omeprazole by about 27% to 42% (13108).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ginkgo with P-glycoprotein substrates might increase the levels and adverse effects of these substrates.  Details A small clinical study in healthy volunteers shows that using ginkgo leaf extract 120 mg orally three times daily for 14 days can increase levels of the P-glycoprotein substrate, talinolol, by 36% in healthy male individuals. However, single doses of ginkgo do not have the same effect (87830).

RISPERIDONE (Risperdal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ginkgo with risperidone might increase the levels and adverse effects of risperidone.  Details A single case of priapism has been reported for a 26-year-old male with schizophrenia who used risperidone 3 mg daily along with ginkgo extract 160 mg daily (87796). Risperidone is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4. CYP3A4 activity might be affected by ginkgo. Theoretically, ginkgo may inhibit the metabolism of risperidone and increase the risk of adverse effects.

ROSIGLITAZONE (Avandia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might decrease the levels and clinical effects of rosiglitazone.  Details Animal research shows that ginkgo leaf extract orally 100 or 200 mg/kg daily for 10 days alters the pharmacodynamics of rosiglitazone in a dose-dependent manner. The 100 mg/kg and 200 mg/kg doses reduce the area under the concentration time curve (AUC) of rosiglitazone by 39% and 52%, respectively, and the half-life by 28% and 39%, respectively. It is hypothesized that these changes may be due to induction of cytochrome P450 2C8 by ginkgo (109525).

SEIZURE THRESHOLD LOWERING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ginkgo with drugs that lower the seizure threshold might increase the risk for convulsions.  Details Ginkgo seeds contain ginkgotoxin. Large amounts of ginkgotoxin can cause neurotoxicity and seizure. Ginkgotoxin is present in much larger amounts in ginkgo seeds than leaves (8232). Ginkgo leaf extract contains trace amounts of ginkgotoxin. The amount of ginkgotoxin in ginkgo leaf and leaf extract seems unlikely to cause toxicity (11296). However, there are anecdotal reports of seizure occurring after use of ginkgo leaf both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090,14281).

SIMVASTATIN (Zocor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, ginkgo might decrease the levels and clinical effects of simvastatin.  Details Clinical research shows that taking ginkgo extract can reduce the area under the curve and maximum concentration of simvastatin by 32% to 39%. However, ginkgo extract does not seem to affect the cholesterol-lowering ability of simvastatin (89704).

SOFOSBUVIR (Sovaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the levels and clinical effects of sofosbuvir.  Details Animal research in rats shows that giving a ginkgo extract 25 mg/kg orally daily for 14 days increases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 11%, increases the half-life by 60%, and increases the plasma concentration at 4 hours by 38%. This interaction appears to be related to the inhibition of intestinal P-glycoprotein by ginkgo (109524).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the blood levels of tacrolimus.  Details In vitro evidence suggests that certain biflavonoids in ginkgo leaves (i.e. amentoflavone, ginkgetin, bilobetin) may inhibit the metabolism of tacrolimus by up to 50%. This interaction appears to be time-dependent and due to inhibition of cytochrome P450 (CYP) 3A4 by these bioflavonoids. In rats given tacrolimus 1 mg/kg orally, amentoflavone was shown to increase the area under the concentration time curve (AUC) of tacrolimus by 3.8-fold (111330).

TALINOLOL Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Taking ginkgo with talinolol seems to increase blood levels of talinolol.  Details There is some evidence that using ginkgo leaf extract 120 mg orally three times daily for 14 days can increase levels of talinolol by 36% in healthy male individuals. However, single doses of ginkgo do not seem to affect talinolol pharmacokinetics (87830).

TRAZODONE (Desyrel) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, ginkgo might increase the levels and clinical effects of trazodone.  Details In a case report, an Alzheimer patient taking trazodone 20 mg twice daily and ginkgo leaf extract 80 mg twice daily for four doses became comatose. The coma was reversed by administration of flumazenil (Romazicon). Coma might have been induced by excessive GABA-ergic activity. Ginkgo flavonoids are thought to have GABA-ergic activity and act directly on benzodiazepine receptors. Ginkgo might also increase metabolism of trazodone to active GABA-ergic metabolites, possibly by inducing cytochrome P450 3A4 (CYP3A4) metabolism (6423).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Ginkgo has been shown to increase the risk of bleeding in some people when taken with warfarin.  Details Several pharmacodynamic studies suggest that ginkgo inhibits platelet aggregation. It is thought that the ginkgo constituent, ginkgolide B, displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation (6048,9760). Several case reports have documented serious bleeding events in patients taking ginkgo (244,576,578,579,8581,13002,13135,13179,13194,14456,87868). Information from a medical database suggests that when taken concurrently with warfarin, ginkgo increases the risk of a bleeding adverse event by 38% (91326). There is also some evidence that ginkgo leaf extract can inhibit cytochrome P450 2C9, an enzyme that metabolizes warfarin. This could result in increased warfarin levels (12061). However, population and clinical research has produced mixed results. Clinical research in healthy people suggests that ginkgo has no effect on INR, or the pharmacokinetics or pharmacodynamics of warfarin (12881,15176,87727,87889). A meta-analysis of 18 studies using standardized ginkgo extracts, 80 mg to 480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT (17179). There is also some preliminary clinical research that suggests ginkgo might not significantly increase the effects of warfarin in patients that have a stable INR (11905).

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ALCOHOL (ETHANOL) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = A Combining kava with alcohol may increase the risk of sedation and/or hepatotoxicity.  Details Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Additionally, kava has been associated with over 100 cases of hepatotoxicity. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that alcohol not be used with kava (110318).

CNS DEPRESSANTS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = A Combining kava with CNS depressants can have additive sedative effects.  Details Kava has CNS depressant effects (11373,18316). Concomitant use of kava with other CNS depressants can increase the risk of drowsiness and motor reflex depression (2093,2098). Clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend that CNS depressants, including alcohol and benzodiazepines, not be used with kava (110318).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if kava inhibits CYP1A2; research is conflicting.  Details Although in vitro research and a case report suggest that kava inhibits CYP1A2 (8743,12479,88593), more robust clinical evidence shows that kava has no effect on CYP1A2. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP1A2 activity (13536,98979).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, kava might increase levels of CYP2C19 substrates.  Details In vitro research shows that kava significantly inhibits CYP2C19 enzymes (8743,12479). This effect has not yet 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, kava might increase levels of CYP2C9 substrates.  Details In vitro research shows that kava significantly inhibits CYP2C9 enzymes (8743,12479). This effect has not yet been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if kava inhibits CYP1A2; research is conflicting.  Details In vitro research shows that kava extract significantly inhibits CYP2D6 (8743,12479). However, clinical research shows that kava does not affect the metabolism of CYP2D6 substrates in humans (13536,16848,98979).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Kava might increase levels of CYP2E1 substrates.  Details In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days inhibited the metabolism of CYP2E1 substrates (13536).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if kava inhibits CYP3AA; research is conflicting.  Details Although in vitro research suggests that kava inhibits CYP3A4 (8743,12479), more robust clinical evidence shows that kava has no effect on CYP3A4. In a clinical study in healthy volunteers, taking kava 1000 mg twice daily (containing a daily dose of 138 mg kavalactones) for 28 days had no effect on CYP3A4 activity (13536,98979).

HALOPERIDOL (Haldol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Combining kava and haloperidol might increase the risk of cardiovascular adverse effects and hypoxia.  Details Atrial flutter and hypoxia has been reported for a patient who received intramuscular injections of haloperidol and lorazepam after using kava orally. The side effects were attributed to kava-induced inhibition of CYP2D6, but might also have been related to additive adverse effects with the concomitant use of haloperidol, lorazepam, and kava (88593).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, using kava with hepatotoxic drugs might increase the risk of liver damage.  Details Kava has been linked with over 100 cases of hepatotoxicity. Most cases occur with excessive and prolonged use. There is some concern that kava can adversely affect the liver, especially when used in combination with hepatotoxic drugs (7024,7068,7086,7096,17086,57346).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D It is unclear if kava inhibits P-glycoprotein (P-gp); research is conflicting.  Details In vitro research shows that kava can inhibit P-gp efflux (15131). However, a clinical study in healthy volunteers shows that taking kava standardized to provide 225 mg kavalactones daily for 14 days does not affect the pharmacokinetics of digoxin, a P-gp substrate (15132,98979). It is possible that the use of other P-gp substrates or higher doses of kava might still inhibit P-gp.

ROPINIROLE (Requip) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking kava with ropinirole might increase the risk for dopaminergic toxicity.  Details A case of visual hallucinations and paranoid delusions has been reported for a patient who used kava in combination with ropinirole. The adverse effects were attributed to kava-induced inhibition of CYP1A2, which may have reduced the metabolism of ropinirole, resulting in excessive dopaminergic stimulation (88593).

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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 and in vitro research shows that St. John's wort induces CYP1A2, but to a lesser extent than CYP3A4 (9204,10848,76163,111404).

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 (9204,10830,10847,10848,11889,22423,22424,22425,22427,48603,111404,111644,113094). 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 (166,111644). 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). A small clinical study in healthy adults also shows that taking St. John's wort 300 mg three times daily for 10 days decreases the total systemic exposure to tacrolimus by 27% and 33% after taking a single 5 mg dose of immediate-release or prolonged-release tacrolimus, respectively (113094).

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, adverse effects to damiana seem to be rare; however, a thorough safety evaluation has not been conducted.

Neurologic/CNS ...Orally, 200 grams of damiana extract has caused tetanus-like convulsions and paroxysms resulting in symptoms similar to rabies or strychnine poisoning (4).

(Read more about DAMIANA)

General ...Orally, ginkgo leaf extract is generally well tolerated when used for up to 6 years. However, the seed and crude plant contain toxic constituents and should be avoided.
Intravenously, ginkgo leaf extract seems to be well tolerated when used for up to 30 days.
Topically, no adverse effects have been reported with ginkgo as a single ingredient. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Dizziness, gastrointestinal symptoms, headache.
Serious Adverse Effects (Rare):
Orally: Arrhythmia, bleeding, Stevens-Johnson syndrome.

Cardiovascular ...Cardiac arrhythmias suspected to be related to ginkgo have been reported. Internationally, there are at least 162 reports from 18 countries, with 34% of cases considered serious, involving five deaths and four life-threatening events. Additionally, a report from Canada found that 10 out of 15 cases of arrhythmia were considered serious. Ginkgo was the only suspect ingredient in 57% of all international reports, with symptoms generally presenting within days of initiation. The most common symptoms included palpitations, tachycardia, bradycardia, syncope, and loss of consciousness. Most cases were reported to be related to oral use of ginkgo leaf products; however, some cases were associated with oral use of the seed, and others with intravenous or intramuscular use of the leaf. Documented discontinuation of ginkgo led to recovery in approximately 84% of cases where ginkgo was the sole suspect. Despite these findings, ginkgo cannot be confirmed as the causal agent. It is possible that these reports are confounded by underlying co-morbidities. Of the reported cases, the main reason for ginkgo use was tinnitus, a symptom commonly associated with pre-existing arrhythmias (105253,105254). Despite this large number of reports, only three cases of cardiac arrhythmia have been published in the literature (105253,105254). In one case, frequent nocturnal episodes of paroxysmal atrial fibrillation were reported for a 35-year-old female taking ginkgo extract 240 mg daily orally for 2 months. Arrythmias ceased following discontinuation of ginkgo (87884).
Increases in blood pressure were commonly reported with ginkgo in a safety database analysis; however, information on the magnitude of the increase was limited, and reports included both oral and intravenous administration (115628).
In one clinical trial, the rate of ischemic stroke and transient ischemic attacks was significantly higher in patients taking ginkgo extract orally when compared with placebo (16635). It is unclear if these events were due to ginkgo, other factors, or a combination.

Dermatologic ...Topically, ginkgo fruit pulp can cause contact dermatitis, with intense itching, edema, papules, and pustules which take 7-10 days to resolve after stopping contact (112946).

Gastrointestinal ...Orally, ginkgo extract may cause mild gastrointestinal discomfort or pain (3965,8543,17112,87818,87858), nausea and vomiting (8543,17112,87728,87844,87858), diarrhea (87844), dry mouth (17112), and constipation (5719,87787). However, post-market surveillance suggests that the incidence of these events is relatively low, occurring in less than 2% of patients (88007).
Fresh ginkgo seeds can cause stomach ache, nausea, vomiting, or diarrhea. Ingesting roasted seeds in amounts larger than the normal food amounts of 8-10 seeds per day, or long-term, can also cause these same adverse reactions (8231,8232).

Genitourinary ...Orally, ginkgo extract has been reported to cause blood in the urine (87858,115628).

Hematologic ...Spontaneous bleeding is one of the most concerning potential side effects associated with ginkgo. There are several published case reports linking ginkgo to episodes of minor to severe bleeding; however, not all case reports clearly establish ginkgo as the cause of bleeding. In most cases, other bleeding risk factors were also present including taking other medications or natural medicines, old age, liver cirrhosis, recent surgery, and other conditions. In most cases, bleeding occurred after several weeks or months of taking ginkgo (13135). Large-scale clinical trials and a meta-analysis evaluating standardized ginkgo leaf extracts show that the incidence of bleeding in patients taking ginkgo is not significantly higher than in those taking placebo (16634,16635,17179,17402).
There are several case reports of intracerebral bleeding. Some of these cases resulted in permanent neurological damage and one case resulted in death (244,578,8581,13135,13179,14456,87868,87977).
There are at least 4 cases of ocular bleeding including spontaneous hyphema (bleeding from the iris into the anterior part of the eye) and retrobulbar hemorrhage associated with ginkgo use (579,10450,13135).
There are also cases of surgical and post-surgical complications in patients using ginkgo. Retrobulbar hemorrhage (bleeding behind the eye) during cataract surgery has been associated with ginkgo use (10450). Excessive postoperative bleeding requiring transfusion has also occurred following laparoscopic surgery in a patient who had been taking ginkgo leaf extract (887). There have also been two cases of excessive bleeding during surgery and post-surgical hematoma in patients undergoing rhytidoplasty and blepharoplasty (13002). In another case, an elderly patient taking ginkgo experienced excessive postoperative bleeding following total hip arthroplasty (13194). In another case, use of ginkgo following liver transplantation surgery was associated with subphrenic hematoma requiring evacuation by laparotomy. The patient also subsequently experienced vitreous hemorrhage (14315). In another case, an elderly patient who had taken ginkgo chronically experienced excessive post-operative bleeding following an ambulatory surgical procedure (14453).
In another case, an elderly man experienced nose bleeds and ecchymosis following use of ginkgo. One case of diffuse alveolar hemorrhage in a female taking ginkgo and ginseng for over one year has been reported (95670). These instances of bleeding stopped when ginkgo was discontinued, and recurred when the patient started taking ginkgo again (13135).
Persistent bleeding has also occurred following dental surgery (87862) and laparoscopic cholecystectomy (88000). Nosebleed has also been reported as an adverse effect in a clinical trial (87813).

Immunologic ...Orally, ginkgo leaf extract can cause allergic skin reactions in some patients (14449,15578,112946). In one case, a patient developed acute generalized exanthematous pustulosis 48 hours after taking a single-ingredient ginkgo product. The rash resolved within 10 days after discontinuing ginkgo (14449). In another case, progressive erythema of the face, neck, trunk, and extremities occurred after two 60 mg oral doses of ginkgo extract (112946). There is also a case of Stevens-Johnson syndrome following a second administration of a preparation containing ginkgo leaf extract, choline, vitamin B6, and vitamin B12 (208). In another case, systemic edema and severe arthralgia was reported after contact with a ginkgo tree nut and manifested as multifocal lymphadenopathy associated with an allergic reaction on PET/CT scan imaging (95672).

Musculoskeletal ...Edema has been reported for three patients treated with ginkgo extract 40 mg orally three times daily (87818).

Neurologic/CNS ...Orally, ginkgo extract may cause headache (6220,8543,87818), dizziness (5719,87818), increased desire to sleep (87839,115628), and sedation (10893) in some patients. In addition, although ginkgo leaf and ginkgo leaf extract contain only small amounts of ginkgotoxin, there are anecdotal reports of seizure occurring after use of ginkgo leaf preparations both in patients without a history of seizure disorder and in those with previously well-controlled epilepsy (7030,7090,11296,14281).

Ocular/Otic ...Orally, ginkgo may cause tinnitus is some patients (8543,115628).
Topically, eye drops containing ginkgo extract and hyaluronic acid may cause stinging sensations in some people (87829).

Psychiatric ...Orally, ginkgo has been associated with a single case of mood dysregulation. A 50-year-old female with schizophrenia developed irritability, difficulty controlling anger, and agitation after one week of taking ginkgo 80 mg twice daily. The mood changes resolved within 2-3 days of discontinuation. When ginkgo was re-trialed at a later date, the same symptoms reappeared, and again dissipated after discontinuation of the ginkgo product. The relationship between ginkgo and mood dysregulation was considered to be "probable" based on the Naranjo adverse drug reaction probability scale (96763); however, the exact mechanism by which ginkgo may have affected mood regulation is unknown.

(Read more about GINKGO)

General ...Orally, kava seems to be well tolerated.
Most Common Adverse Effects:
Orally: Drowsiness, dry mouth, dizziness, gastrointestinal upset, headache, memory problems, tremor.
Serious Adverse Effects (Rare):
Orally: There have been over 100 reported cases of hepatotoxicity and a few reported cases of rhabdomyolysis.

Cardiovascular ...Long-term use of very large amounts of kava, especially in high doses (400 mg kava pyrones daily), has been associated with overall poor health including symptoms of low body weight, reduced protein levels, puffy face, hematuria, increased red blood cell volume, decreased platelets and lymphocytes, and possibly pulmonary hypertension (4032,6402). Tachycardia and electrocardiogram (ECG) abnormalities (tall P waves) have been reported in heavy kava users (6402).

Dermatologic ...Orally, kava can cause allergic skin reactions, including sebotropic eruptions, delayed-type hypersensitivity, or urticarial eruption (4032,11370,28489,57277,57325,57343,114683). In one case of kava-associated urticarial eruption, biopsy revealed neutrophilic sebaceous glands with lymphocytic infiltrate (114683). Chronic use of high doses of kava has also been associated with kava dermopathy, which consists of reddened eyes; dry, scaly, flaky skin; and temporary yellow discoloration of the skin, hair, and nails (6240,6401,8414,8417,11370,28485,57342). This pellagra-like syndrome is unresponsive to niacinamide treatment (6240,7728,11370). The cause is unknown, but may relate to interference with cholesterol metabolism (6240). Kava's adverse effects on liver function might also contribute to kava dermopathy (6401,8417). Kava dermopathy usually occurs within three months to one year of regular kava use, and resolves when the kava dose is decreased or discontinued (6401,8414). Kava dose should be decreased or discontinued if kava dermopathy occurs (6401). In addition to kava cessation, oral or topical corticosteroids have been described as treatment options in some cases of kava associated dermatitis (114683).

Gastrointestinal ...Orally, kava may cause gastrointestinal upset, nausea, or dry mouth (2093,2094,4032,11370,18316,57228,57343).

Hematologic ...Orally, chronic use of very high doses of kava has been associated with increased red blood cell volume, reduced platelet volume, reduced lymphocyte counts, and reduced serum albumin (6402,57258). Hematuria has also been reported anecdotally (6402).

Hepatic ...Since the early 2000's, hepatotoxicity has been a particular concern with kava. Worldwide, there have been at least 100 reported cases of hepatotoxicity following use of kava products (7024,7068,7086,7096,11795,17086)(57252,57254,57297). However, some experts question the clinical validity of several of these cases (11369,11371). Some cases were reported multiple times and in some cases it was unlikely that kava was the causative agent (7068,57253).
In susceptible patients, symptoms can show up after as little as 3-4 weeks of kava use. Symptoms include yellowed skin (jaundice), fatigue, and dark urine (7024,7068). Liver function tests can be elevated after 3-8 weeks of use, possibly followed by hepatomegaly and onset of encephalopathy (7024). Kava has also been reported to exacerbate hepatitis in patients with a history of recurrent hepatitis (390). However, in many cases, symptoms seem to resolve spontaneously, and liver function tests usually normalize within eight weeks (390,7068).
Liver toxicity is more frequently associated with prolonged use of very high doses (6401,57346). But there is some concern that even short-term use of kava in typical doses might cause acute hepatitis in some patients, including severe hepatocellular necrosis. The use of kava for as little as 1-3 months has resulted in need for liver transplant and death, although these events are rare (7024,7068,7086,7096,17086).
There is some speculation that the type of extraction method could be responsible for these rare cases of hepatotoxicity (17086). The "Pacific kava paradox" holds that while the alcohol and acetone extracts of kava used for commercial products cause liver toxicity, the traditional kava rhizome preparation mixed with water might not be toxic (11794,17086). However, a more recent analysis reports cases of hepatotoxicity from the aqueous kava extract and suggests that kava's hepatotoxic effects may be due to contaminants such as mold (29676). Other suggested causes of hepatotoxicity include quality of the kava plant, concomitant medications, large doses and prolonged use, and toxic constituents and metabolites of kava (57300,88532).
Some commercial kava extracts contain parts of the stems and other aerial parts in addition to the rhizome, and it has been suggested that a constituent called pipermethysine, which is only found in these aerial parts, might be partly responsible for hepatotoxicity (17086). Other constituents of kava which might contribute to hepatotoxicity are kavalactones, which are metabolized by cytochrome P450 (CYP450) enzymes in the liver. Reactive metabolites are produced which conjugate with glutathione, and might deplete glutathione in a similar manner to acetaminophen (17086). Increased levels of gamma-glutamyl transferase, involved in the production of glutathione, have been reported in chronic kava users (17086). One of the enzymes involved in production of reactive metabolites from kavalactones is cytochrome P450 2E1 (CYP2E1), which is induced by chronic alcohol intake. Alcohol may also compete for other enzymes which clear kavalactone metabolites from the body. This might explain the observation that alcohol ingestion seems to increase the risk of hepatotoxicity with kava (7068,17086).
There is also speculation that "poor metabolizers" or those patients with deficiency in the cytochrome P450 2D6 (CYP2D6) isoenzyme, which occurs in up to 10% of people of European descent, may be at increased risk for hepatotoxic effects from kava (7068). This deficiency has not been found in Pacific Islanders. However, this theory has not been confirmed.
Due to the concerns regarding the potential hepatotoxicity of kava, kava supplements were withdrawn from European and Canadian markets in 2002 (7086). However, many of the market withdrawals of kava have been lifted after re-evaluation of kava suggested that the risk of hepatotoxicity was minimal (91593,91594,91615). Still, clinical practice guidelines from a joint taskforce of the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend exercising caution when using kava in patients with preexisting liver issues (110318). Until more is known, tell patients to use kava cautiously and recommend liver function tests for routine users or those with underlying liver disease.

Immunologic ...Sjögren syndrome has been associated with an herbal supplement containing kava, echinacea, and St. John's wort. Echinacea may have been the primary cause, because Sjögren syndrome is an autoimmune disorder. The role of kava in this syndrome is unclear (10319).

Musculoskeletal ...Kava has been linked with reports of rhabdomyolysis. A 34-year-old man who consumed kava tea several times a week developed rhabdomyolysis with a peak creatine kinase level of 32,500 units/liter (18212). However, there is speculation that this might have been due to product impurities rather than kava itself. Another case report describes rhabdomyolysis with myoglobinuria and a creatine kinase level of 100,500 units/liter in a 29-year-old man who had taken kava in combination with guarana and ginkgo biloba (18213).
Cases of ataxia and tremors have been reported in patients taking single doses of kava powder 205 grams (11373).

Neurologic/CNS ...Orally, kava may cause headache, dizziness, and drowsiness (4032,6402,11370,11372,11373,18316,112642). It might also cause extrapyramidal side effects such as involuntary oral and lingual reflexes, twisting movements of the head and trunk, tremors, and other parkinsonian-like symptoms possibly due to dopamine antagonism (534,4055,7727,8415,102086). In one clinical trial, patients taking a kava supplement providing 120 mg of kavalactones twice daily for 16 weeks had a 3.2-fold greater risk of experiencing tremors when compared with patients taking placebo (102086). Theoretically, kava may worsen symptoms in patients with Parkinson disease or precipitate Parkinson-like symptoms in certain patients (4055,7727). Unlike benzodiazepines, kava is not thought to be associated with impaired cognitive function (2097,2098,11373,57332,57333). However, one clinical trial shows that taking a kava supplement providing 120 mg of kavalactones twice daily for 16 weeks increases the risk for memory impairment by 55% when compared with placebo (102086).
Orally, kava may reduce alertness and impair motor coordination in a dose-dependent manner. Some preliminary reports have noted a decline in accuracy of visual attention and slower reaction times after kava ingestion, particularly at higher doses and in combination with alcohol (11373,95926). Population research has also found that ingesting large amounts of kava tea (typically 50 times higher than what is used medicinally in the US) within a 12-hour period before driving increases the odds of being involved in a serious motor vehicle crash resulting in death or serious injury by almost 5-fold when compared to not drinking kava tea (95927). Use of normal doses of kava may also affect the ability to drive or operate machinery, and driving under the influence (DUI) citations have been issued to individuals observed driving erratically after drinking large amounts of kava tea (535). However, in computer-based driving simulator tests, there are no reported adverse effects of kava on performance (95926). Additionally, other research shows that consuming over 4400 mg of kavalactones over a 6-hour kava session does not seem to impair alertness or attention when compared with non-kava drinkers (103867). Similar research using a specific psychometric tool (Brain Gauge) shows that consuming approximately 3680 mg of kavalactones in a 6-hour kava session seems to impair temporal order judgment, which is associated with the brain's ability to track the order of events, when compared with non-kava drinkers. However, it does not seem to impact cognitive domains related to focus, accuracy, timing perception, plasticity, or fatigue when compared with non-kava drinkers (110435).

Ocular/Otic ...Orally, high doses of kava may cause eye irritation (7728). There is one case report of impaired accommodation and convergence, increased pupil diameter, and oculomotor disturbance following a single dose of kava (9920).

Psychiatric ...Apathy has been associated with traditional use of kava at high doses (57313).

Pulmonary/Respiratory ...Orally, kava may cause shortness of breath, possibly due to pulmonary hypertension (6402).

Renal ...Orally, kava may cause acute urinary retention (57349).

(Read more about KAVA)

General ...Orally, fresh pulsatilla is a toxic gastrointestinal irritant (4,19). It can also cause kidney and urinary tract irritation (2).
Topically, contact with the fresh plant can cause skin irritation, mucous membrane irritation, itching, and pustule formation known as ranunculus dermatitis (2). Allergic reactions to pulsatilla volatile oil have been documented with patch tests (4).
Inhalation of pulsatilla volatile oil may cause nasal mucosal and conjunctival irritation (4).

Dermatologic ...Topically, contact with the fresh plant can cause skin irritation, mucous membrane irritation, itching, and pustule formation known as ranunculus dermatitis (2).

Gastrointestinal ...Orally, fresh pulsatilla is a toxic gastrointestinal irritant (4,19).

Genitourinary ...Orally, fresh pulsatilla can cause urinary tract irritation (2).

Immunologic ...Topically, allergic reactions to the protoanemonin-containing volatile oil of pulsatilla have been documented with patch tests (4).

Ocular/Otic ...Inhalation of the protoanemonin-containing volatile oil of pulsatilla may cause conjunctival irritation (4).

Pulmonary/Respiratory ...Inhalation of the protoanemonin-containing volatile oil of pulsatilla may cause nasal mucosal irritation (4).

Renal ...Orally, fresh pulsatilla can cause kidney irritation (2).

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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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