Para-Gard [Discontinued] by Integrative Therapeutics

POSSIBLY EFFECTIVE

• Canker sores. Some evidence shows that berberine gel applied to canker sores may reduce pain and the size of the sores, but it has not been compared to conventional treatments. Details: Some clinical research shows that applying a gel containing berberine 5 mg/gram four times daily for 5 days can reduce pain by 26% and ulcer size by 30% when compared with placebo in patients with minor recurrent canker sores. Erythema and exudation also appear to be improved (91955).
• Diabetes. Berberine seems to moderately reduce blood glucose in people with type 2 diabetes; it may provide additional benefit when given with conventional medications. Details: Some clinical research shows that taking berberine 500 mg 2-3 times daily for 2-4 months can reduce glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose (PPG) in subjects with type 2 diabetes when compared with placebo, and may be similarly effective to metformin 500 mg 2-3 times daily or rosiglitazone 4 mg daily (20579,34247,34265,110099). Large meta-analyses show that taking berberine, 0.9-3 grams in 2-3 divided doses daily for 1-11 months, in combination with lifestyle interventions, can reduce FPG by 10-16 mg/dL, PPG by 27-34 mg/dL, and HbA1c by 0.4% to 0.7% when compared with lifestyle interventions alone. Also, taking berberine in combination with oral hypoglycemic drugs appears to lower FPG by 12-19 mg/dL, PPG by 18-24 mg/dL, and HbA1c by 0.6% to 0.9% when compared with hypoglycemic drugs alone (91956,110097). Berberine has also been evaluated in combination with other ingredients. A small clinical study in patients with type 2 diabetes shows that taking berberine 500 mg with Bifidobacterium adolescentis 100 million colony-forming units (CFU) twice daily for 16 weeks reduces FPG by 10 mg/dL, PPG by 28 mg/dL, and HbA1c by 0.22% when compared with placebo (110099). Another clinical study in patients with type 2 diabetes shows that taking berberine 600 mg twice daily with a multi-strain probiotic supplement, containing more than 50 billion CFU, once daily for 12 weeks reduces postprandial cholesterol by 15 mg/dL and postprandial low-density lipoprotein (LDL) cholesterol by 9 mg/dL when compared with placebo. Postprandial triglyceride levels were also improved, while postprandial levels of high-density lipoprotein (HDL) cholesterol were not affected (110100).
• Helicobacter pylori. Oral berberine, when taken with amoxicillin and a proton pump inhibitor (PPI) with or without clarithromycin, might be as effective as bismuth-containing quadruple therapy (BQT), vonoprazan quadruple therapy, and PPI-based triple therapy for eradication of Helicobacter pylori. Details: Most studies evaluate berberine in combination with an antibiotic and acid blocker for the treatment of H. pylori infection. Open-label clinical studies in patients with treatment-naïve H. pylori infection shows that taking berberine 300-500 mg with amoxicillin 1 gram and an acid reducer such as esomeprazole 20 mg, rabeprazole 10 mg, or vonoprazan 20 mg, with or without clarithromycin 500 mg, 2-3 times daily for 14 days is non-inferior to BQT, vonoprazan quadruple therapy (vonoprazan, amoxicillin, clarithromycin, bismuth), and rabeprazole quadruple therapy (rabeprazole, amoxicillin, clarithromycin, bismuth) for H. pylori eradication and clinical symptom improvement. Eradication rates were around 70% to 91% and 69% to 90% in the berberine- and bismuth-containing groups, respectively. BQT is a guideline-recommended treatment regimen for H. pylori eradication (97234,111697). Also, berberine triple therapy appears to be better tolerated when compared with BQT. Quadruple therapy consisted of amoxicillin, rabeprazole, clarithromycin, and bismuth tartrate (110107). A smaller clinical study in patients with H. pylori-associated duodenal ulcers shows that taking berberine 300 mg three times daily for 6 weeks is more effective for eradicating H. pylori than taking ranitidine 150 mg twice daily, but is less effective for promoting ulcer healing (34319).
• Hyperlipidemia. Clinical research shows that taking berberine orally, alone or in combination with other ingredients, reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides in people with hyperlipidemia. Details: Meta-analyses of clinical research in people with hyperlipidemia or nonalcoholic fatty liver disease (NAFLD) show that berberine reduces total cholesterol by 13-32 mg/dL, triglycerides by up to 34 mg/dL, LDL cholesterol by 10-26 mg/dL, and apolipoprotein B by 0.25 g/L when compared with control or lifestyle interventions. However, the meta-analyses conflict on the effect of berberine on HDL cholesterol, with the studies in patients with hyperlipidemia showing that it reduces HDL cholesterol by 2-3 mg/dL while the analysis in patients with NAFLD shows that berberine has no effect on HDL cholesterol when compared with control or lifestyle interventions. (20579,34228,111363,111700,113462). Meta-analyses also show that berberine alone is similarly effective to statins at lowering lipid levels (100983,111362). Administration of berberine in combination with lipid-lowering drugs such as statins lowers total cholesterol by 10-15 mg/dL, LDL cholesterol by up to 9 mg/dL, and triglycerides by up to 30 mg/dL when compared with lipid-lowering drugs alone (91953,91956,99921,100983,111362). The dosage of berberine used most often in these studies was 500 mg twice daily, or 200-500 mg three times daily for 3-24 months. However, one meta-analysis suggests that berberine's effects on lipid levels may be transient, with significant improvements in total cholesterol, LDL cholesterol, and HDL cholesterol lacking in studies lasting 3 or more months (111362). Berberine has also been studied in combination with other supplements. Taking a combination product containing berberine 500 mg, policosanol 10 mg, and red yeast rice 200 mg daily for up to 12 months reduces total and LDL cholesterol levels when compared with placebo or ezetimibe 10 mg (34262,34283,34301). Taking another combination product (Armolipid Plus, Rottapharm S.p.A.) containing berberine, red yeast rice, policosanol, folic acid, coenzyme Q10, and astaxanthin daily for up to 12 months reduces total cholesterol by 10% to 13% and LDL cholesterol by 14% to 21%, and increases HDL cholesterol by 4% to 5% when compared with baseline or placebo. These effects are comparable to those seen with pravastatin 10 mg daily (89438,92142). It is unclear if the benefits of this combination product are due to berberine, other ingredients, or the combination. It is possible that the majority of the therapeutic effect is due to an ingredient in red yeast rice (monacolin K) that is identical to lovastatin.
• Hypertension. Berberine may have added benefits for reducing blood pressure when used in combination with amlodipine. Details: A meta-analysis shows that taking berberine 0.9 grams daily in combination with amlodipine for 2 months reduces systolic blood pressure by 5 mmHg and diastolic blood pressure by 2 mmHg when compared with amlodipine alone (91956).
• Polycystic ovary syndrome (PCOS). Berberine may improve some metabolic characteristics in women with PCOS and insulin resistance. It may also increase live births, although the data are conflicting. Details: Clinical research in patients with PCOS and insulin resistance shows that taking berberine 500-550 mg 2-3 times daily for 3 to 6 months reduces fasting plasma glucose, markers of insulin resistance, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, testosterone levels, body mass index, waist-to-hip ratio, acne severity, and markers of inflammation when compared with placebo or baseline. Berberine also seems to increase high-density lipoprotein (HDL) cholesterol and sex hormone binding globulin (SHBG) levels (34282,91952,111364). Lipid parameters also improved when compared with metformin, as did waist-to-hip ratio, body mass index, and SHBG levels in some, but not all, studies (34282,91952). The effect of berberine on ovulation, pregnancy, and birth rates in women with PCOS is unclear. A meta-analysis of several small, lower quality clinical studies conducted in China in patients with PCOS shows that taking berberine 900 mg daily in combination with other treatments, such as clomiphene or letrozole, for 3 to 6 months improves ovulation and clinical pregnancy rates when compared to medication therapy alone (115725). The validity of these findings is limited by heterogenous methods between clinical trials, including treatment combinations and duration. Additionally, the effect on birth rates was not evaluated. A clinical study, not included in the analysis above, shows that taking berberine 500 mg three times daily for three months prior to controlled ovarian stimulation increases the number of clinical pregnancies and live births by almost two-fold when compared with placebo. These effects are comparable to taking metformin 500 mg three times daily for 3 months (91952). However, other clinical research shows that taking a combination of berberine 1.5 grams daily and letrozole for ovarian stimulation does not increase live birth rates when compared with letrozole alone (97235).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antipsychotic-induced metabolic side effects. It is unclear if oral berberine is beneficial in patients with antipsychotic-induced metabolic side effects. Details: A small clinical study in patients with schizophrenia who developed metabolic syndrome associated with antipsychotic therapy shows that taking berberine 300 mg twice daily for 12 weeks reduces body weight by 1.1 kg, body mass index (BMI) by 0.4 kg/m2, total cholesterol by 22 mg/dL, low-density lipoprotein (LDL) cholesterol by 20 mg/dL, and glycated hemoglobin (HbA1c) by 0.09% when compared with placebo (110103).
• Atrial fibrillation. Limited research suggests that oral berberine might prevent atrial fibrillation shortly after coronary artery bypass graft (CABG) surgery. Details: A small clinical study in Chinese patients who underwent CABG surgery shows that taking berberine 400 mg three times daily for 7 days reduces the risk of postoperative atrial fibrillation by 50% when compared with placebo (110106).
• Biliary disorders. It is unclear if oral berberine is beneficial in patients with biliary disorders. Details: A small clinical study in patients with primary sclerosing cholangitis shows that taking berberine ursodeoxycholate, an ionic salt formulation of berberine and ursodeoxycholic acid, 500-1000 mg twice daily for 6 weeks reduces levels of alkaline phosphatase (ALP), a marker of cholestasis and bile duct injury, when compared with placebo. ALP levels decreased by at least 50% in 7% and 17% of patients taking 500 mg and 1000 mg, respectively, compared with 0% of patients taking placebo (110105).
• Burns. Topical berberine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that topical treatment of second degree burns with an ointment containing berberine, beta-sitosterol, sesame oil, and other ingredients, applied every 4 hours for 20 days, is similar to conventional treatment with silver sulfadiazine cream (13526). It is unclear if this benefit is due to berberine, other ingredients, or the combination.
• Cardiovascular disease (CVD). It is unclear if berberine is beneficial in patients with CVD. Details: A meta-analysis of several small clinical studies in patients with atherosclerosis, ischemic stroke, or coronary heart disease shows that taking berberine alone does not improve lipid levels or markers of atherosclerosis but does reduce markers of inflammation when compared with routine therapy or statins. Additionally, the pooled analysis suggests that berberine reduces stroke severity, as measured by the NIH Stroke Scale, in patients with ischemic stroke (111362). This meta-analysis also shows that, when taken with a statin, berberine improves lipid levels, stroke severity, markers of atherosclerosis, and inflammatory markers when compared with statin therapy alone or routine treatment (111362). The validity of these findings is limited by the overall low-quality of the included studies, with unclear blinding and randomization; significant heterogeneity and differences in patient populations, berberine doses, and treatment durations studied; and concerns related to publication bias.
• Cholera. Although taking a single dose of berberine may be modestly beneficial for reducing stool volume, using berberine daily with tetracycline does not seem to provide added benefit. Details: Some preliminary clinical research shows that a single dose of berberine sulfate 400 mg decreases 24-hour stool volume by a small amount in subjects with cholera when compared with placebo (262). However, taking berberine 200-400 mg daily along with tetracycline 500 mg four times daily does not seem to further enhance the effects of tetracycline in treating cholera-induced diarrhea (34305,34306).
• Colorectal adenoma. Berberine may help prevent adenoma recurrence after polypectomy. Details: Preliminary clinical research in Chinese patients with colorectal adenomas who had undergone complete polypectomy shows that taking berberine 0.3 grams twice daily for 2 years reduces the risk of adenoma recurrence by 22% when compared with placebo (103197). A meta-analysis of this trial and two other small clinical studies in Chinese patients with a history of colorectal adenomas shows that taking berberine 0.1 grams three times daily for 18 months or 0.3 grams twice daily for 2 years reduces the risk of adenoma recurrence by 31% and 25% at years 1 and 2, respectively, when compared with placebo (110101). All available research has been conducted in China; it is unclear whether these results can be applied to other geographic locations.
• Congestive heart failure (CHF). Berberine may provide additional benefit to patients with CHF who are taking conventional medications. Details: Preliminary clinical research in patients with CHF secondary to ischemic or idiopathic dilated cardiomyopathy shows that adding berberine 1.2-2 grams daily for 8 weeks to conventional medications can reduce the frequency and complexity of premature ventricular contractions (PVCs) and reduce mortality when compared with placebo (13520).
• Coronary heart disease (CHD). Oral berberine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in statin-intolerant patients with coronary heart disease treated with a percutaneous intervention (PCI) shows that taking a specific combination product (Armolipid Plus, Rottapharm S.p.A.) containing berberine 500 mg, red yeast rice 200 mg, policosanol 10 mg, folic acid 0.2 mg, coenzyme Q10 2 mg, and astaxanthin 0.5 mg daily for 3 months reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol to a greater extent than ezetimibe 10 mg daily. Combining this specific product with either ezetimibe or a low-dose statin produces additional improvements in all lipid parameters after 3-12 months of treatment when compared with any of the agents alone (97232,97233). It is unclear if the benefits of this combination product are due to berberine, other ingredients, or the combination. Because red yeast rice contains a compound identical to lovastatin (monacolin K), it is likely that the cholesterol-lowering potential of this combination is mainly attributable to the red yeast rice constituent.
• Diarrhea. Limited data suggest that berberine may be helpful for diarrhea caused by bacteria. Details: Some preliminary clinical research shows that a single dose of berberine sulfate 400 mg decreases 24-hour stool volume in subjects with Escherichia coli-induced diarrhea when compared with placebo (262).
• Glaucoma. It is unclear if berberine is beneficial for glaucoma when used as an eye drop. Details: Preliminary clinical research shows that using eye drops containing berberine 2.5 mg and tetrahydrozoline 2.5 mg for 3 days does not reduce intraocular pressure in patients with open angle glaucoma when compared with eye drops containing tetrahydrozoline alone (34304).
• Hepatitis B. It is unclear if berberine is beneficial for improving liver function in people with hepatitis B. Details: Preliminary clinical research shows that taking berberine 1 gram daily for 2 months decreases blood glucose, triglycerides, and markers of liver damage, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), in subjects with type 2 diabetes and hepatitis B when compared with control (34265).
• Hepatitis C. It is unclear if berberine is beneficial for improving liver function in people with this form of hepatitis. Details: Preliminary clinical research shows that taking berberine 1 gram daily for 2 months decreases blood glucose, triglycerides, and markers of liver damage, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), in subjects with type 2 diabetes and hepatitis C when compared with control (34265).
• Impaired glucose tolerance (prediabetes). Small studies suggest that oral berberine may be beneficial in adults with prediabetes. Details: A very small clinical study in adults with overweight and prediabetes shows that taking berberine aqueous root extract (HIMABERB, Pharma Base S.A.) 500 mg 3 times daily for 12 weeks reduces fasting blood glucose by 15 mg/dL, glycated hemoglobin (HbA1c) by 0.7%, and 2-hour oral glucose tolerance test by 28 mg/dL and improves fasting insulin levels and measures of insulin resistance when compared with placebo (111699). The validity of these effects is limited by a very small sample size. Another small clinical study in adults with prediabetes shows that taking berberine phospholipids (Berbevis, Indena, SpA, Italy) 550 mg twice daily for 8 weeks reduces fasting blood glucose by 4 mg/dL and improves insulin levels when compared with placebo (111700).
• Irritable bowel syndrome (IBS). One small clinical study suggests that oral berberine may be beneficial in people with diarrhea-predominant IBS. Details: Preliminary clinical research shows that taking berberine 400 mg twice daily for 8 weeks in patients with diarrhea-predominant IBS reduces the frequency of diarrhea, abdominal pain, and defecation urgency when compared with placebo. Berberine may also improve overall symptom scores and IBS quality of life (97236). Observational research suggests that adding a supplement (Enterofytol PLUS, Tilman SA) providing berberine 200 mg and curcumin 42 mg orally twice daily for 2 months to conventional IBS treatment is associated with improvements in symptoms, such as abdominal discomfort, distension, and stool status, by up to 48% when compared with conventional treatment alone. Use of the supplement was also associated with a 64% reduced need for conventional treatments (113354). It is unclear if this effect is due to berberine, curcumin, or the combination.
• Menopausal symptoms. Oral berberine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of berberine plus soy isoflavones can reduce vasomotor symptoms in menopausal women when compared with taking calcium plus vitamin D (34287). It is not clear if this effect is due to berberine, soy isoflavones, or the combination.
• Metabolic dysfunction-associated steatotic liver disease (MASLD). It is unclear if oral berberine is beneficial in patients with MASLD. Details: A moderate-sized clinical study in adults with MASLD shows that taking berberine extract 500 mg orally three times daily for 12 weeks does not improve markers of liver damage or insulin resistance, fatty liver indices, or most lipid levels when compared with placebo (114769). Also review effectiveness in nonalcoholic fatty liver disease (NAFLD), a similar condition.
• Metabolic syndrome. Berberine may reduce some of the signs and symptoms of metabolic syndrome, but the evidence is weak. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking berberine hydrochloride 500 mg three times daily before meals for 3 months reduces body mass index (BMI) by 0.6 kg/m2, systolic blood pressure (SBP) by 8 mmHg, triglycerides by 18 mg/dL, and serum glucose levels by 2 mg/dL, and can also improve insulin sensitivity, when compared with baseline (91957). The validity of these findings is limited by the lack of a control group. Other preliminary clinical research shows that taking a combination product (Armolipid Plus, Rottapharm S.p.A.) containing berberine 500 mg, red yeast rice 200 mg, policosanol 10 mg, folic acid 0.2 mg, coenzyme Q10 2 mg, and astaxanthin 0.5 mg daily for 18 weeks improves SBP, left ventricular mass, and flow-mediated dilation in patients with metabolic syndrome when compared with control (34289). It is not clear if this effect is due to berberine, the other ingredients, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Oral berberine may improve some measures of liver function and blood lipids in people with NAFLD. Details: A meta-analysis of clinical studies and preliminary clinical research in patients with NAFLD, some with comorbid type 2 diabetes, show that taking berberine 600 mg to 6.35 grams daily, alone or in combination with metformin or lifestyle interventions, for 7 to 22 weeks reduces markers of liver damage, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutamyl transpeptidase (GGT) and improves body mass index (BMI), measures of insulin resistance, and most lipid parameters when compared with control and baseline (34286,113462). Other preliminary clinical research shows that taking berberine 500 mg three times daily for 16 weeks reduces hepatic fat content by 21% when compared with lifestyle modification. Berberine also seems to reduce hepatic fat content, AST, and ALT similarly to pioglitazone 15 mg daily, while reducing body weight, body mass index, and total cholesterol more than pioglitazone (97237). Also review effectiveness in metabolic dysfunction-associated steatotic liver disease (MASLD), a similar condition.
• Obesity. It is unclear if oral berberine is beneficial in patients with obesity. Details: A meta-analysis of 12 small clinical studies, most in patients with various metabolic conditions, shows that taking berberine 300-1500 mg daily for up to 24 months reduces body weight by around 2 kg, body mass index (BMI) by 0.5 kg/m2, and waist circumference by about 1 cm when compared with a control group (104508). However, most of the studies are small, of varying quality, with significant heterogeneity, and likely inadequately powered to detect significant changes. Additionally, none of the studies required patients to have overweight or obesity for inclusion.
• Radiation-induced diarrhea. One small study suggests that oral berberine may reduce diarrhea associated with radiation-induced intestinal damage. Details: Preliminary clinical research shows that taking berberine 300 mg three times daily for 2 weeks can reduce the frequency and severity of radiation-induced intestinal damage and diarrhea in patients receiving abdominal or pelvic radiation therapy when compared with placebo (34263).
• Radiation fibrosis. It is unclear if oral berberine is beneficial for reducing radiation-induced lung damage. Details: Preliminary clinical research shows that taking berberine 20 mg/kg once daily for 6 weeks during radiation therapy reduces the incidence of radiation-induced lung injury and improves lung function in patients treated for NSCLC when compared with placebo (34253).
• Stroke. It is unclear if oral berberine is beneficial in adults with acute ischemic stroke. Details: A meta-analysis of several small clinical studies in adults with acute ischemic stroke shows that taking berberine 0.3-1.0 grams daily for up to 6 months in addition to conventional therapy reduces stroke severity, as measured by the NIH Stroke Scale, improves markers of atherosclerosis and inflammation, and reduces triglycerides and low-density lipoprotein cholesterol when compared with routine therapy as control (111698). The validity of these findings is limited by the overall low quality of the included studies, with unclear blinding and randomization. Other limitations include significant heterogeneity in patient populations, berberine doses, and treatment durations studied.
• Thrombocytopenia. It is unclear if oral berberine is beneficial for improving platelet counts in people with this condition. Details: Preliminary clinical research shows that taking berberine bisulfate 5 mg three times daily before meals for 15 days, either alone or with prednisolone, can increase platelet count in patients with primary or secondary thrombocytopenia when compared with baseline (34317).
• Trachoma. It is unclear if berberine is beneficial for trachoma when administered as eye drops. Details: Preliminary clinical research shows that berberine ophthalmic solution might be useful for treating trachoma, a common cause of blindness in developing countries. Solutions of 0.2% berberine have been applied three times daily for 3-12 weeks, or solutions of 0.5% three times daily for 1-3 weeks (13523,34303,34310,34313).
• Ulcerative colitis. It is unclear if oral or rectal berberine is beneficial for ulcerative colitis. Details: A meta-analysis of several small, lower quality clinical studies in adults with ulcerative colitis shows that taking berberine orally (600-900 mg daily) or rectally (4-6 grams daily) for 3-12 weeks, in addition to mesalamine, improves the rate of patients with complete remission or reduced symptoms, such as bowel movements, blood in stools, or abdominal pain, when compared to mesalamine alone (115724). The validity of these findings is limited by heterogenous methods between clinical trials, including route of administration and treatment duration.
• Ventricular arrhythmias. Limited research suggests that oral berberine might lower the frequency of premature ventricular contractions (PVCs). Details: Data from a meta-analysis of 10 small clinical trials, all conducted in China, shows that taking oral berberine, 0.3-0.6 grams 3 or 4 times daily for 7-30 days has a similar efficacy rate to antiarrhythmic drugs, and a lower incidence of adverse effects, in the management of PVCs. A combination of berberine and antiarrhythmic drugs has a higher efficacy rate and similar adverse effect rate, when compared with antiarrhythmic drugs alone (112947). The quality of this evidence is low. More evidence is needed to rate berberine for these uses.

(Read more about BERBERINE)

POSSIBLY EFFECTIVE

• Atherosclerosis. When used alone or in combination with other ingredients, oral garlic seems to slow the progression of atherosclerosis. Details: Taking low doses of garlic powder (Kwai, Lichtwer Pharma) 300 mg, administered as a single dose or three times daily for up to 4 years, seems to lessen age-related decreases in aortic elasticity (4797,51595). Additionally, taking a specific time-released garlic powder supplement (Allicor, INAT-Farma) 150 mg twice daily for 24 months seems to reduce the rate of atherosclerosis progression, as measured by carotid intima-media thickness, when compared with placebo in males with early evidence of carotid atherosclerosis (88394). Higher doses of 900 mg daily seem to slow development of atherosclerosis in both aortic and femoral arteries when used over a four-year period in females, but not in males (3315,4798). In patients with evidence of coronary artery calcium and a Framingham risk score of greater than 10%, taking aged garlic extract (Kyolic Reserve, Wakunaga) 1200 mg twice daily for 12 months reduces coronary artery calcium progression by 29% when compared with placebo (102670). A meta-analysis also found that garlic powder tablets and aged garlic extract may reduce coronary artery calcium scores when compared with placebo (110721). Some clinical research has investigated the use of garlic in combination with other ingredients. Taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunaga) containing aged garlic extract 250 mg plus vitamin B12 100 mcg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months significantly reduces coronary artery calcium progression and improves vascular function in patients with a Framingham risk score of 10% to 20% without coronary artery disease (88385). In addition, taking a combination product containing aged garlic extract 1200 mg and coenzyme Q10 120 mg daily for one year significantly improves vascular elasticity endothelial function in firefighters facing high degrees of occupational stress (44225).
• Diabetes. Most clinical research suggests that oral garlic, taken alone or in combination with metformin for at least 12 weeks, modestly reduces fasting blood glucose levels in patients with diabetes. It is unclear if garlic improves postprandial glucose levels or glycated hemoglobin (HbA1c). Details: A meta-analysis of results from seven clinical studies in adults with type 2 diabetes shows that taking garlic powder 600-1500 mg daily, garlic oil 8.2 mg daily, or aged garlic extract 1000 mg daily reduces fasting blood glucose levels by about 2 mg/dL when compared with control. The greatest benefit is seen for patients with hyperglycemia at baseline, for interventions lasting at least 12 weeks, and for formulations consisting of garlic powder (96004). Specific garlic formulations used in the reviewed studies have included garlic powder 300 mg 2-3 times daily as tablets (Kwai, Lichtwer Pharmaceuticals) or time-released tablets (Allicor, INAT-Farma) for 4-24 weeks, sometimes in combination with metformin or a sulfonylurea (51396,51463,96004). In one study, when used in combination with metformin, garlic reduced fasting blood glucose levels 70% more than when metformin was used alone (51463). The findings from these studies are in contrast with the results from older meta-analyses, which showed that garlic does not improve glycemic indices or lipid levels in patients with diabetes. Reasons for these discrepancies may relate to the fact that the older analyses included lower quality research (6465,6897). There is insufficient reliable information available to determine if garlic significantly improves postprandial glucose levels or HbA1c (96004). A small clinical trial shows that taking aged garlic extract (Kyolic, Wakunaga) 2400 mg daily for 12 months does not reduce left ventricular myocardial mass, a marker of poor cardiac outcomes, in patients with diabetes. However, this study may have been inadequately powered to detect a difference between groups (102671).
• Endometriosis. Oral garlic seems to improve pain in people with endometriosis. Details: A clinical study in patients with endometriosis shows that taking a tablet containing garlic powder 400 mg, providing allicin 1.1 mg, daily for 3 months along with standard care reduces overall pain scores from baseline by 72%, compared with an increase of 4% from baseline in patients receiving placebo along with standard care (106615).
• Hyperlipidemia. Most research shows that taking oral garlic for at least 8 weeks seems to modestly reduce total and low-density lipoprotein (LDL) cholesterol and slightly increase high-density lipoprotein (HDL) cholesterol in patients with hyperlipidemia. However, evidence is conflicting on whether garlic reduces triglyceride levels. Details: Meta-analyses of clinical studies in patients with hyperlipidemia show that taking garlic daily for 2-12 months reduces total cholesterol by about 15-25 mg/dL, low-density lipoprotein (LDL) cholesterol by about 6-17 mg/dL, and increases high-density lipoprotein (HDL) cholesterol by about 1.5 mg/dL when compared with control (88399,114891). Results regarding triglyceride levels are mixed, with one of these analyses showing a reduction of triglyceride levels of about 15 mg/dL and the other showing no reduction (88399,114891). The impact on lipid levels appears to be more pronounced when garlic is taken for more than 8 weeks and in patients with total and LDL cholesterol levels that are at least borderline high before treatment (88399). Another meta-analysis supports prior findings that taking garlic improves HDL, LDL, and apolipoprotein-A levels while having no impact on triglycerides level. The meta-analysis found that while garlic does not appear to reduce cholesterol in the general population, it may reduce total cholesterol when taken by patients with cardiovascular risk factors (110721). Similarly, a meta-analysis of 17-19 clinical studies in healthy adults and patients with a variety of cardio-metabolic conditions, including hyperlipidemia, shows that taking garlic daily for 1-12 months reduces total cholesterol by about 14 mg/dL, LDL cholesterol by about 8 mg/dL, increases HDL by about 2 mg/dL, but does not reduce triglyceride levels when compared with placebo (114890). Another partially conflicting meta-analysis found that garlic powder reduces total cholesterol, LDL, and triglyceride levels, but has no impact on HDL levels (110720). The majority of available research supports these findings, but conflicting results exist (279,731,732,1873,1875,4782,4783,4784,4785,4786)(4787,4788,4789,4792,4793,4794,4795,4807,6457,6897)(51343,15295,15296,51422,51429,51469,51590,88399,107238)(107352,110721). Whether garlic is beneficial for treating hyperlipidemia may also depend on the specific formulation or product taken. Mixed results have been reported for a variety of specific garlic products, including garlic powder tablets (Kwai, Lichtwer Pharma) 600-900 mg daily in two or more divided doses for 6-16 weeks (279,731,4782,4783,4784,4785,4787,4789,4792,4793)(4795,4807), aged garlic extract (Kyolic, Wakunaga) 1000-7200 mg daily in divided doses for 4-6 months (1873,1875,15295), a garlic powder product (Garlex, Bosch Pharmaceuticals) 300 mg twice daily for 12 weeks (51343), aged black garlic extract (ABG+; PharmActive Biotech Products) 250 mg daily for 6 weeks (108607), and others (732,15295). Subgroup analyses from one meta-analysis suggest that products containing aged garlic extract may be more effective for lowering total cholesterol than garlic powder preparations. If garlic powder preparations are used, total cholesterol levels seem to be lowered to a greater degree in patients taking enteric-coated garlic powder tablets. The opposite trend may be true for reducing LDL cholesterol. Garlic powder tablets seem to reduce LDL cholesterol levels while aged garlic extract does not. However, the few studies that did evaluate the effect of aged garlic extract on LDL cholesterol did so in patients with low baseline LDL cholesterol levels. There is limited evidence on the use of raw garlic or garlic oil products for treating hyperlipidemia (88399). A subgroup analysis from another meta-analysis of clinical studies suggests that garlic oil reduces total and LDL cholesterol more effectively than garlic powder (114891). Taking garlic 1200 mg with fish oil 3 grams daily for 4 weeks or garlic oil 500 mg with fish oil 700 mg daily for 60 days also appears to improve lipid parameters in some patients (4789,4790,51669). Garlic alone may be more effective than garlic plus fish oil for improving LDL cholesterol levels, but the combination may be useful in patients with elevated levels of total cholesterol, LDL cholesterol, and triglycerides (4789).
• Hypertension. Some clinical research suggests that oral garlic seems to modestly reduce blood pressure in hypertensive and normotensive patients. Details: One meta-analysis of clinical studies show that taking garlic can reduce systolic and diastolic blood pressure by about 5 mmHg and 3 mmHg, respectively, in patients with or without hypertension (16605,51414,96007). However, another meta-analysis found that taking garlic may not impact systolic or diastolic blood pressure in patients with coronary artery disease when compared with placebo (110721). When only patients with hypertension are considered, taking garlic can decrease systolic blood pressure by about 7-9 mmHg and diastolic blood pressure by about 4-6 mmHg. These results are limited by the fact that many of the included studies were of low to moderate quality and short duration (96007,96008,96014). Most clinical research appears to support these findings (278,279,1873,51442,88398). However, conflicting results exist (107238,110721). Some garlic formulations evaluated for hypertension have included a specific garlic powder formulation (Kwai, Lichtwer Pharma) 2400 mg as a single dose or 600 mg daily for 12 weeks and a specific aged garlic extract (Garlic High Potency Everyday Formula 112, Wakunaga/Wagner) 960 mg to 7.2 grams daily in up to three divided doses for up to 6 months (278,279,1873,51442,88398). Other doses used in the available research have included garlic tablets 300-1500 mg in divided doses daily for 24 weeks (88386) and garlic oil 500 mg plus fish oil 600 mg daily for 60 days (51669). Hypotensive effects of garlic have also been examined in population research. A large population study found that eating raw garlic at least twice daily is associated with a reduced likelihood of having prehypertension when compared with eating raw garlic three or fewer times per week. However, any significant relationship was eliminated after adjusting for dietary salt, making conclusions difficult (102677).
• Nonalcoholic fatty liver disease (NAFLD). Oral garlic seems to reduce the severity of hepatic steatosis in patients with NAFLD. Details: A meta-analysis including 4 studies with 186 patients with NAFLD found that taking 800-1600 mg of garlic powder daily may reduce aspartate aminotransferase (AST) and alanine transaminase (ALT) and lower the probability of hepatic steatosis by 2.75 times when compared with placebo (110720). Clinical research in patients with NAFLD shows that taking garlic powder reduces the severity of steatosis in 51% to 62% of patients, compared to 16% to 26% of those taking placebo (102681,103470). Doses of garlic included a specific powder (Amin Pharmaceutical Company) 800 mg twice daily for 12 weeks or an enteric-coated powder 400 mg twice daily for 15 weeks (102681,103479). There was also an improvement in most liver enzymes, other than alkaline phosphatase, and the level of low-density lipoprotein (LDL) cholesterol when compared with placebo (102681). In addition, population research shows a 7% reduction in odds of developing NAFLD with each 1 gram of raw garlic per 1000 kcal consumed. However, this association was not observed in females (102673). NAFLD is strongly and independently associated with an increased risk for prehypertension and hypertension. A clinical study in adults with NAFLD and stable diet- or antihypertensive-controlled blood pressure shows that taking an enteric-coated tablet containing garlic powder 400 mg (Amin Pharmaceuticals), providing allicin 1.5 mg, twice daily for 15 weeks reduces systolic blood pressure, diastolic blood pressure, and mean arterial pressure by 8, 3, and 6 mmHg, respectively, when compared with placebo. High-sensitivity C-reactive protein is also reduced by 16% when compared with placebo (106614).
• Periodontitis. Oral aged garlic extract seems to improve some measures of gum health in people with mild to moderate periodontitis. Details: Clinical research in otherwise healthy patients with mild to moderate periodontitis shows that taking a specific aged garlic extract (Kyolic, Wakunaga) orally 1200 mg twice daily for 18 months improves probing pocket depth, but not gingival recession, when compared with placebo (105760). The validity of these findings is limited by the lack of an intention to treat analysis.

POSSIBLY INEFFECTIVE

• Gastric cancer. Oral garlic does not seem to prevent gastric cancer. Details: Clinical research evaluating the effects of taking aged garlic extract for 7 years failed to show a reduced risk of developing gastric cancer up to 22 years later (14447,51470,102016), although there was a reduction in mortality associated with gastric cancer in subjects followed for 12-22 years (5-15 years after stopping the garlic extract) (102016). Also, a prospective, case-control study of 123,484 adults over a 30-year review period suggests that garlic intake, whether obtained from the diet or via supplementation, is not associated with a reduction in the rate of gastric cancer occurrence (97034). However, some research disagrees. One prospective population study suggests that a 1 kg/year increased increment in garlic intake is associated with a 17% reduced risk in gastric cancer incidence over 22 years. Also, consuming at least 3.25 kg yearly is associated with at least a 12% reduced risk when compared with consuming less than 2 kg each year. A sub-analysis suggests that this potential benefit is associated with garlic stalks, rather than garlic bulbs (111764). Meta-analyses of population research, as well as small population studies, have suggested 23% to 51% lower odds of developing gastric cancer with increased dietary garlic intake when compared with never eating garlic (3320,4775,4776,51209,51460,96005,108604). However, these studies have limited external validity.
• Helicobacter pylori. Oral garlic does not seem to be beneficial for Helicobacter pylori eradication. Details: Despite some promising initial laboratory research suggesting activity against Helicobacter pylori, garlic cloves, powder, or oil does not seem to have any beneficial effect when used to treat patients infected with Helicobacter pylori (3322,4761,4762,4763,4765,4774,97034).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral garlic for allergic rhinitis (hay fever), there is insufficient reliable information about the clinical effects of garlic for this condition.
• Alopecia areata. Topical garlic may increase hair growth by a small amount. Details: Preliminary clinical research in adults with alopecia areata shows that applying garlic 5% gel four times daily for 3 months, in addition to topical corticosteroid use, increases hair growth by 18% when compared with placebo plus topical corticosteroid (51386).
• Asthma. Although there has been interest in using oral garlic for asthma, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Athletic performance. It is unclear if oral garlic is beneficial for athletic performance. Details: Preliminary clinical research shows that taking a single dose of garlic 900 mg prior to exercise increases endurance when compared with placebo in young athletes (51623). A small preliminary clinical trial shows that taking garlic extract 1000 mg daily for 4 weeks does not reduce the time to cycle 40 km when compared to placebo (111765).
• Benign prostatic hyperplasia (BPH). It is unclear if oral garlic is beneficial for BPH. Details: In patients with BPH, preliminary clinical research shows that taking aqueous garlic extract 1 mg/kg daily for one month decreases prostate mass and urinary frequency and improves symptom scores and urinary flow rates when compared to baseline (10374). The validity of these findings is limited by the lack of a comparator group.
• Bladder cancer. Although there has been interest in using oral garlic for bladder cancer, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Breast cancer. It is unclear if oral garlic prevents breast cancer. Details: The relationship between garlic intake and risk of breast cancer is unclear. Overall, population research suggests that taking garlic does not seem to decrease the risk of breast cancer. However, when garlic and onions are examined together, there is some evidence of an association with a decreased risk of breast cancer (4779,102674). More research is needed.
• Bronchitis. Although there has been interest in using oral garlic for bronchitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Cardiovascular disease (CVD). It is unclear if oral garlic is beneficial for reducing CVD risk factors in adults with hypercholesterolemia. Details: A clinical crossover study in adults with moderate hypercholesterolemia shows that taking a specific product (ABG+; PharmActive Biotech Products) containing aged black garlic extract 250 mg, standardized to provide S-allyl-L-cysteine 1.25 mg, daily for 6 weeks does not improve blood pressure, glucose or cholesterol levels, or anthropometric measures when compared with placebo. A subgroup analysis in males with elevated diastolic blood pressure at baseline shows that taking this product reduces diastolic blood pressure by 5-mmHg when compared with placebo (108607). It is unclear if garlic is beneficial in patients with existing CVD.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral garlic for CFS, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Colorectal cancer. It is unclear if oral garlic prevents colorectal cancer. Details: Several individual population studies have found that higher dietary intake of garlic is associated with a reduced risk of colorectal cancer (3320,4770,4771,4772). However, results from meta-analyses of population research are mixed (96003,102669). Reasons for the discrepancy seem to relate to the type of population study conducted. A meta-analysis of case-control studies supports a preventative effect of garlic. However, this is not supported when cohort studies are analyzed separately (102669). Case-control studies are prone to recall and selection bias, and some do not account for confounding factors associated with colorectal cancer (96003). Two separate meta-analyses of observational research conducted in various countries have found that consumption of garlic and other allium-containing vegetables (onions, leeks, chives and scallions) is associated with a reduced risk of colorectal cancer; however, subgroup analyses suggest improvement is greatest in studies conducted in Asian countries, modest in those conducted in North America, and absent in those conducted in Europe (108604,108605). The reasons for these differing findings are unclear but may be related to regional differences in dietary habits, such as the use of raw or cooked garlic. Few studies have examined the effects of garlic supplements. While a single preliminary clinical study in patients with confirmed colorectal adenomas shows that taking high-dose aged garlic extract 2.4 mL daily for 12 months reduces the risk of developing new adenomas by 29% when compared with a lower dose of 0.16 mL daily (51320), other studies do not support the use of garlic supplements for this purpose (4773,96003).
• Common cold. Oral garlic might reduce the frequency of the common cold when used prophylactically. Details: Preliminary clinical research shows that taking one capsule of garlic daily for 12 weeks during the winter months reduces the number of self-reported colds by approximately 63% when compared with placebo. The duration of symptoms was also reduced by approximately one day (10787). Also, a small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more common cold episodes compared with 45% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
• Corns. It is unclear if topical garlic is beneficial for corns. Details: Preliminary clinical research in a small number of patients with corns shows that applying a lipid soluble garlic extract topically to corns on the feet twice daily for 10-20 days results in improvement in most patients when compared with baseline (15030). The validity of this finding is limited by the lack of a comparator group.
• Coronary heart disease (CHD). It is unclear if oral garlic is beneficial for CHD. Details: A meta-analysis of preliminary clinical research in adults with CHD shows that taking garlic orally 800-2000 mg daily for 2-48 weeks reduces total cholesterol levels by an average of 16 mg/dL when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. The validity of this study is limited by inclusion of patients with and without dyslipidemia at baseline (107238).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral garlic is beneficial for COVID-19. Details: Clinical research in non-critically ill patients hospitalized with COVID-19 shows that taking garlic extract (Gallecina, Samisaz Pharmaceutical Company, Iran) 90 mg every 8 hours for 5 days or until discharge modestly reduces the proportion of patients requiring supplemental oxygen for at least 1 day when compared with placebo. However, there was no overall effect on clinical status, intensive care admission, or discharge prior to day 6. All patients also took remdesivir (111766). A small preliminary clinical study in patients hospitalized with mild to moderate symptoms of COVID-19 shows that taking garlic essential oil orally 50 mg twice daily before breakfast and dinner for 10 days, in addition to standard COVID-19 treatment, reduces the median duration of fever from 5 to 4 days, cough from 7 to 5 days, and weakness from 9 to 7 days when compared with standard treatment alone. The median time to a negative COVID-19 test decreased from 8 to 7 days (109530). The validity of this study is limited by incomplete randomization, the lack of a placebo comparator, and the exclusion of people with severe symptoms.
• Cystic fibrosis. It is unclear if oral garlic is beneficial for cystic fibrosis. Details: Preliminary clinical research shows that taking garlic oil macerate 625 mg daily for 8 weeks does not improve pulmonary function, symptom scores, or the need for antibiotic therapy when compared with placebo in children with cystic fibrosis and chronic pulmonary infection (51438).
• Dental hypersensitivity. Although there has been interest in using oral garlic for dental hypersensitivity, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Denture stomatitis. It is unclear if topical garlic as a mouthwash is beneficial for denture stomatitis. Details: Preliminary clinical research in patients with oral denture stomatitis shows that using a garlic mouthwash 40 mg/mL three times daily for 4 weeks improves redness when compared to baseline. When compared with nystatin, garlic has a lesser degree of recovery, but better patient satisfaction (51466).
• Diabetic retinopathy. It is unclear if oral garlic is beneficial for diabetic retinopathy. Details: Preliminary research in patients with diabetic retinopathy and macular edema, treated with intravitreal bevacizumab and laser photocoagulation, shows that taking garlic powder 1 gram orally daily for 4 weeks improves the best-corrected visual acuity by 0.18 logMAR (logarithm of the minimum angle of resolution), compared with 0.06 for placebo. It also decreases intraocular pressure by 1 mmHg, compared with 0.3 mmHg for placebo (109529).
• Diarrhea. Although there has been interest in using oral garlic for various types of diarrhea, including travelers' diarrhea and dysentery, there is insufficient reliable information about the clinical effects of garlic for these conditions.
• Dysmenorrhea. Although there has been interest in using oral garlic for dysmenorrhea, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Erectile dysfunction (ED). It is unclear if oral garlic is beneficial for erectile dysfunction. Details: A small clinical study in patients with erectile dysfunction (ED) and poor response to tadalafil shows that adding fresh pressed garlic 5 grams in juice 150 mL twice daily for 4 weeks to a regimen of tadalafil 5 mg daily improves erectile function when compared with placebo plus tadalafil A subgroup analysis suggests that effects are clinically significant in patients with moderate ED but not severe ED (114892).
• Esophageal cancer. It is unclear if oral garlic prevents esophageal cancer. Details: Observational research regarding the use of garlic in preventing esophageal cancer is conflicting. Some evidence suggests that raw garlic consumption does not prevent the development of esophageal cancer (51508). However, other population research suggests that weekly garlic consumption decreases the risk of developing esophageal cancer (51209).
• Exercise-induced muscle soreness. It is unclear if oral garlic is beneficial for exercise-induced muscle soreness. Details: Preliminary clinical research shows that taking allicin, a constituent of garlic, 80 mg daily for 14 days can reduce subjective assessments of exercise-induced muscle soreness in athletes when compared with placebo (51404).
• Fatigue. Although there has been interest in using oral garlic for fatigue, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Familial hypercholesterolemia. Oral garlic does not seem to improve blood lipid levels in children with familial hypercholesterolemia. Details: In children with familial hypercholesterolemia, a small clinical trial shows that taking garlic powdered extract, standardized based on alliin content, does not improve levels of total cholesterol, low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein (a), apolipoprotein B-100, homocysteine, fibrinogen, or blood pressure (4796).
• Fibrocystic breast disease. Oral garlic 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 (Karinat, INAT-Farma), containing garlic powder 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months reduces the severity of breast pain, premenstrual syndrome, and menstruation pain, and can cause regression of palpable symptoms of breast fibromatosis (51317). It is unclear if these effects are due to garlic, other ingredients, or the combination.
• Gastritis. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with gastritis shows that taking a specific combination product (Karinat, INAT-Farma), containing garlic 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months improves digestion, inhibits H. pylori infection, and reduces the risk of precancerous lesion formation when compared with placebo (51308). It is unclear if these effects are due to garlic, other ingredients, or the combination.
• Gout. Although there has been interest in using oral garlic for gout, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Hepatitis. It is unclear if oral garlic is beneficial for hepatitis. Details: Preliminary clinical research shows that taking 3-6 capsules of a product containing garlic oil 50 mg and diphenyl-dimethyl-dicarboxylate 25 mg per capsule daily for 6 weeks improves liver function enzyme levels when compared with placebo in patients with chronic hepatitis (51478). The effects of garlic alone have not been determined.
• Hepatopulmonary syndrome. It is unclear if oral garlic is beneficial for hepatopulmonary syndrome. Details: Preliminary clinical research shows that garlic oil (Garlic Pearls, Ranbaxy, India) 1-2 grams/m² daily in two divided doses for 9-18 months may improve oxygen levels and remission rates when compared with placebo in patients with hepatopulmonary syndrome (51439).
• Influenza. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more influenza-like episodes compared with 36% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
• Lead toxicity. It is unclear if oral garlic is beneficial for lead toxicity. Details: Preliminary clinical research shows that taking garlic powder 400 mg three times daily for 4 weeks reduces blood lead concentration when compared with baseline, but not when compared to treatment with D-penicillamine, in patients with mild to moderate lead poisoning (51467).
• Lung cancer. It is unclear if oral garlic prevents lung cancer. Details: Some population research suggests that eating raw garlic is associated with a reduced odds of developing lung cancer. However, other research suggests that eating garlic or taking garlic supplements is not associated with a reduced risk of lung cancer (4778,103482). Reasons for the discrepancy possibly relate to the type of garlic consumed.
• Metabolic syndrome. Meta-analyses of small studies suggest that oral garlic may improve some metabolic parameters in patients with metabolic syndrome and other metabolic disorders. Details: Two meta-analyses of several small clinical studies in adults with metabolic syndrome or metabolic disorders including hyperlipidemia, hypertension, nonalcoholic fatty liver disease, obesity, and type 2 diabetes show that taking various forms of garlic improves triglycerides, total cholesterol, low-density lipoprotein cholesterol, diastolic blood pressure , measures of insulin resistance, and waist circumference when compared with control. However, the meta-analyses reach conflicting conclusions on whether garlic is beneficial for body mass index, high-density lipoprotein cholesterol, fasting blood glucose, or systolic blood pressure when compared with control. Garlic forms studied in the meta-analyses include raw garlic 5000-20,000 mg, aged garlic extract 240-6000 mg, garlic powder tablets 188-6000 mg, and garlic derivative ajoene 2.34 mg, taken daily for 4 to 36 weeks (113617,113619).
• Mosquito repellent. It is unclear if oral garlic is beneficial as a mosquito repellent. Details: Preliminary clinical research shows that taking a single dose of garlic orally does not seem to effectively repel mosquitos (51322). The effect of long-term garlic administration is unclear.
• Multiple myeloma. It is unclear if oral garlic prevents multiple myeloma. Details: A case-control study comparing a small population of adults with and without multiple myeloma has found that increased intake of garlic in the diet may be associated with a decreased risk of developing multiple myeloma (51476).
• Muscle strength. It is unclear if oral garlic is beneficial for muscle strength. Details: Population research has found that increased consumption of raw garlic is associated with increased hand grip strength in healthy adults. Females consuming raw garlic 2-3 times per week were 23% less likely to have low handgrip strength, defined as being below the 20th percentile, when compared to those who almost never eat garlic. In males, the odds of having low handgrip strength were 34% lower. Eating any raw garlic, even less than once per week, was associated with an increased likelihood for having high grip strength (102678).
• Obesity. It is unclear if oral garlic is beneficial for obesity. Details: Clinical research shows that taking garlic powder (Amin Pharmaceutical Company) 1600 mg daily for 12 weeks does not reduce body weight or body mass index when compared with placebo in overweight or obese patients with nonalcoholic fatty liver disease (NAFLD), although there is a small effect on waist circumference (102681). One small clinical study evaluating garlic in combination with multiple other ingredients shows that the combination (Prograde Metabolism) modestly improves body weight, fat mass, and waist and hip circumference when compared with placebo. The other ingredients include raspberry ketone, caffeine, capsicum extract, ginger root extract, bitter orange fruit, L-theanine, and black pepper fruit (40802). However, it is unclear if this benefit is due to garlic, other ingredients, or the combination.
• Onychomycosis. Although there has been interest in using topical garlic for onychomycosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Oropharyngeal candidiasis. It is unclear if oral garlic is beneficial for oropharyngeal candidiasis. Details: Preliminary clinical research in patients with oral candidiasis shows that applying a topical garlic paste four times daily for 14 days to affected areas can increase the rate of complete eradication of oral lesions by 23% when compared with clotrimazole solution (51330).
• Osteoarthritis. It is unclear if oral garlic is beneficial for osteoarthritis. Details: Preliminary clinical research in overweight and obese females with knee osteoarthritis shows that taking garlic tablets (Nature Made) 500 mg twice daily for 12 weeks modestly reduces pain scores by an additional 15% when compared with placebo (98813).
• Otitis media. Although there has been interest in using topical garlic for otitis media, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Peripheral arterial disease (PAD). Oral garlic seems to improve pain-free walking distance by a small amount in patients with PAD. However, it does not seem to improve blood pressure. Details: In patients with stage II peripheral arterial occlusive disease, a small clinical trial shows that taking garlic (Kwai) 400 mg twice daily for 12 weeks improves pain-free walking distance by about 15 meters. There was no effect on blood pressure or ankle or brachial pressures (4801).
• Polycystic ovary syndrome (PCOS). It is unclear if oral garlic is beneficial for PCOS. Details: Preliminary clinical research in adults with PCOS shows that taking garlic orally 800 mg daily for 8 weeks reduces low-density lipoprotein (LDL) cholesterol levels by approximately 8% when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. Garlic supplementation also modestly reduces body mass index (BMI) and waist circumference in this population. However, there was no change in hip circumference (107238,111763).
• Pre-eclampsia. It is unclear if oral garlic prevents pre-eclampsia during the third trimester. Details: Preliminary clinical research shows that taking a specific garlic extract (Garlet, Cosar Pharmaceutical Company) 800 mg daily during the third trimester of pregnancy does not reduce the risk of developing pre-eclampsia in high-risk patients with first-time pregnancies (9201,51626).
• Premenstrual syndrome (PMS). It is unclear if oral garlic is beneficial for PMS. Details: Preliminary clinical research in adult students with moderate to severe PMS shows that taking a specific garlic supplement (Allium-S, Dineh Pharmaceutical Company) orally 400 mg daily, standardized to contain 1.1 mg allicin, for 3 menstrual cycles improves PMS symptom scores 1.4 times more than placebo. After taking garlic for 3 cycles, 91% of students improved to mild PMS, compared with only 36% in the placebo group (107239).
• Prostate cancer. Observational research on the relationship between garlic intake and prostate cancer risk is conflicting. It is unclear if garlic supplements are beneficial in patients with prostate cancer. Details: Observational research in Chinese males shows that those who eat garlic 2.14 grams/day (about one clove) seem to have a 50% lower risk of developing prostate cancer (9876). Also, a pooled analysis of epidemiological research suggests that garlic consumption may be associated with a 23% decreased odds of developing prostate cancer (88410). A case-control study has also found that garlic, consumed at least twice weekly, may reduce the risk for prostate cancer when compared with lower consumption (4777). However, other population research suggests that garlic consumption has no effect on prostate cancer risk in Iranian males (51454). One very small clinical study in patients with prostate cancer shows that taking garlic extract 1 mg/kg daily for one month might improve prostate specific antigen (PSA) levels, urinary flow, and urinary frequency when compared with baseline (10374). The validity of these findings is limited by the small study size and lack of a comparator group.
• Rheumatoid arthritis (RA). Oral garlic seems to reduce pain by a small amount in patients with RA. Details: Clinical research in females with RA shows that taking dried garlic (Garcin; Goldaru Co.) 500 mg twice daily, providing allicin 5 mg, for 8 weeks reduces pain after activity and improves functional ability by a small amount when compared with placebo. Fatigue and pain were reduced by approximately 13% and tender joint count was reduced by 47% (102680,103481). The long-term effect of garlic supplementation is unclear.
• Scleroderma. It is unclear if oral garlic is beneficial for scleroderma. Details: Clinical research shows that taking garlic 900 mg daily for 7 days does not have an effect on vasomotor function when compared with placebo in females with scleroderma (51374).
• Stress. Although there has been interest in using oral garlic for stress, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tick repellent. It is unclear if oral garlic is beneficial as a tick repellent. Details: Preliminary clinical research shows that taking garlic 1200 mg daily for 8 weeks reduces the number of tick bites when compared with placebo (3318). However, the effect of garlic when compared with commercially available tick repellents is unknown (8027).
• Tinea capitis. Although there has been interest in using topical garlic for tinea capitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tinea corporis. It is unclear if topical garlic is beneficial for tinea corporis. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea corporis (4767).
• Tinea cruris. It is unclear if topical garlic is beneficial for tinea cruris. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea cruris (4767).
• Tinea pedis. It is unclear if topical garlic is beneficial for tinea pedis. Details: Applying a gel containing 1% ajoene, a constituent of garlic, twice daily seems to be more effective than 0.6% ajoene gel, and seems to be as effective as 1% terbinafine (Lamisil) for tinea pedis infections. Sixty days after completing one week of treatment, mycological cure occurred in 100% of patients using 1% ajoene, 72% of patients using 0.6% ajoene , and 94% of those using 1% terbinafine (8019). Additional research suggests that 0.4% ajoene gel twice daily has a 7-day cure rate of around 80% (4766).
• Trichomoniasis. Although there has been interest in using oral garlic for trichomoniasis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tuberculosis. Although there has been interest in using oral garlic for tuberculosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Unstable angina. It is unclear if intravenous garlic is beneficial for unstable angina. Details: Preliminary clinical research in patients with unstable angina shows that giving garlicin, 60 mg by intravenous infusion daily for 10 days improves symptoms by 7% when compared with intravenous nitroglycerin (51244).
• Urinary tract infections (UTIs). Although there has been interest in using oral garlic for UTIs, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Vaginal candidiasis. It is unclear if oral or topical garlic is beneficial for vaginal candidiasis. Details: One small clinical study in asymptomatic patients with culture-positive candida infections shows that taking garlic (Garlicin, Nature's Way) 1050 mg (3 tablets) twice daily for 14 days does not improve vaginal symptoms, candida colony counts, or cases of vaginal candidiasis when compared with placebo (88405). Another small clinical study shows that application of a vaginal cream containing garlic and thyme nightly for 7 nights is as effective as clotrimazole vaginal cream for treating vaginal candidiasis (88387). However, it is unclear if this effect is due to garlic, thyme, or the combination.
• Warts. It is unclear if topical garlic is beneficial for warts. Details: Preliminary clinical research shows that applying a specific lipid-soluble garlic extract topically to warts on the hands twice daily results in wart resolution within 1-2 weeks. An aqueous garlic extract applied twice daily also seems to provide modest improvement, but only after 30-40 days of treatment (15030). The validity of these findings is limited by the lack of a comparator group.
• Wound healing. It is unclear if topical garlic is beneficial for wound healing. Details: Based on patient and physician evaluations, preliminary clinical research shows that applying an ointment containing fresh garlic in petroleum jelly twice daily for 2 weeks results in 80% of surgical wounds healing at a faster rate than those treated with petroleum jelly. Most patients also indicated that the wound treated with garlic experienced less discomfort (102676). More evidence is needed to rate garlic for these uses.

(Read more about GARLIC)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using topical gentian for cancer, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Diabetes. Although there has been interest in using oral gentian for diabetes, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Diarrhea. Although there has been interest in using oral gentian for diarrhea, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Flatulence. Although there has been interest in using oral gentian for flatulence, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Gastritis. Although there has been interest in using oral gentian for gastritis, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Gastroesophageal reflux disease (GERD). Although there has been interest in using oral GERD for diarrhea, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Hypertension. Although there has been interest in using oral gentian for hypertension, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Malaria. Although there has been interest in using oral gentian for malaria, there is insufficient reliable information about the clinical effects of gentian for this purpose.
• Obesity. It is unclear if oral gentian is beneficial for obesity. Details: Preliminary clinical research in healthy adults shows that consuming a pudding containing microencapsulated gentian root extract 1.25 g at breakfast modestly reduces caloric intake over 24 hours, but does not affect self-reported feelings of hunger or fullness, when compared with placebo pudding (96534).
• Rhinosinusitis. Oral gentian has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a specific combination product (SinuComp; Sinupret) that contains gentian root 6 mg , elderflower, verbena, cowslip flower, and sorrel improves the symptoms of acute or chronic sinusitis when compared with placebo (374,379). Observational research in adults with acute rhinosinusitis suggests that taking the same combination product orally three times daily, in addition to topical mometasone furoate nasal spray, for 7 days is associated with lower symptom scores when compared with mometasone nasal spray alone (95907).
• Wound healing. Although there has been interest in using topical gentian for wound healing, there is insufficient reliable information about the clinical effects of gentian for this purpose. More evidence is needed to rate gentian for these uses.

(Read more about GENTIAN)

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about GOLDENSEAL)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Lice. Preliminary clinical research shows that a single application of quassia tincture can kill head lice. However, the single application of quassia tincture resulted in 0.6% reinfestation rate after a week (17492). Researchers suggest that two applications with a one-week interval between them might be more effective.
• Rosacea. Preliminary clinical research in patients with rosacea shows that applying quassia 4% gel twice daily for 45 days reduces flushing, redness, and telangiectasia by approximately 74%, 56%, and 50%, respectively, compared with baseline. A moderate to complete overall improvement occurred in 89% of patients (99995). The validity of these results is limited by a lack of control group.
• Seborrheic dermatitis. Preliminary clinical research shows that applying quassia 4% gel twice daily for 28 days results in complete remission in 29.4% of patients with seborrheic dermatitis. This response rate is higher than the 5.6% and 7.1% response rate for patients using 1% ciclopirox olamine or 2% ketoconazole. At one-month post-treatment, quassia was more effective than the other two treatments for avoiding relapse (99994). However, the lack of placebo group makes conclusions difficult. More evidence is needed to rate quassia for these uses.

(Read more about QUASSIA)

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Sweet Annie sublingual immunotherapy drops seem to be beneficial for preventing or reducing seasonal allergic rhinitis and rhinoconjunctivits symptoms related to Sweet Annie (Artemisia annua) pollen. Details: A large clinical study in adults with Artemisia annua (Sweet Annie) pollen-induced seasonal allergic rhinitis shows that taking sublingual drops of a glycerinated allergen extract of Sweet Annie for 32 weeks, beginning 4 months prior to pollen season, improves combined symptom and rescue medication use scores by 22% when compared with placebo. However, in this study the beneficial effects of Sweet Annie appear to be limited to patients mono-sensitized to its pollen; there was no significant improvement in patients who were also sensitized to other pollens (106441). A smaller clinical study shows that taking these drops beginning as early as 8-9 weeks pre-pollen season modestly improves both symptom and rescue medication scores when compared to a control group receiving only symptomatic drugs. In this study, the beneficial effects occurred in patients mono-sensitized to Artemisia pollen, as well as those patients who were also sensitized to other pollens (109315). The validity of this study is limited by the lack of blinding and placebo-control. A small open-label clinical study in adults with confirmed sensitization to Artemisia annua (Sweet Annie) pollen and a history of seasonal allergic rhinoconjunctivitis shows that taking standardized Sweet Annie sublingual immunotherapy drops combined with pharmacotherapy for a year before allergy season improves rhinoconjunctivitis symptoms and rescue medication use during allergy season when compared with pharmacotherapy alone (112392). Two additional open-label studies also show that Sweet Annie sublingual immunotherapy, given for up to 16 months, improves rhinoconjunctivitis symptoms and rescue medication use for up to 2 allergy seasons when compared with control in individuals who are mono-sensitized to Sweet Annie and in those who are poly-sensitized to Sweet Annie plus a variety of other pollen allergens (112393,112394). All of the aforementioned studies were conducted in China where Sweet Annie is the primary outdoor pollen responsible for seasonal allergic rhinitis and rhinoconjunctivitis (106441,109315,112392,112393,112394). As a result, the applicability of the findings to other geographical regions may be limited.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Malaria. It is unclear if Sweet Annie is beneficial for malaria. Details: Some research shows that consuming Sweet Annie tea orally for 4-7 days might improve symptoms and decrease parasite load in patients with malaria (11055,11058). The Sweet Annie constituent artemisinin is of interest for its antimalarial activity, possibly by inactivating the parasite (3185,11056,11057,11059). Derivatives of the artemisinin constituent are occasionally used as medication in combination with other antimalarial compounds (103258). However, there is some concern that using Sweet Annie tea itself as monotherapy may lead to poor long-term outcomes, as well as resistance to artemisinin derivatives (11055,11059).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if Sweet Annie is beneficial for NAFLD. Details: A clinical study in adults with borderline and mild NAFLD shows that taking an aqueous extract of Sweet Annie 686 mg twice daily for 8 weeks reduces alanine aminotransferase (ALT) concentrations from baseline by a mean of 16 units/L, compared with a reduction of 7 units/L in the placebo group. Aspartate aminotransferase (AST) concentrations and fatigue scores were also improved in those receiving Sweet Annie (106442). However, there have also been reports of liver toxicity with Sweet Annie (16895,103254,103255).
• Osteoarthritis. It is unclear if Sweet Annie is beneficial for osteoarthritis. Details: One small clinical study shows that taking a specific Sweet Annie extract (Arthrem, Promissia Limited) 150 mg twice daily for 12 weeks reduces pain and stiffness and improves function when compared to baseline in patients with osteoarthritis of the hip or knee. However, taking this same extract at a dose of 300 mg twice daily did not produce the same effects (94521). In an extension of this study, the therapeutic effects of taking Sweet Annie 150 mg twice daily were maintained for 6 additional months (94520). However, the validity of these results is limited due to a lack of statistical comparison between the Sweet Annie and placebo groups.
• Rheumatoid arthritis (RA). It is unclear if Sweet Annie is beneficial for RA. Details: Preliminary clinical research in patients with RA shows that taking Sweet Annie 30 grams in warm water once daily for 48 weeks in combination with leflunomide and methotrexate modestly reduces pain, swelling, and tenderness in the joints and increases the cessation of corticosteroids when compared with leflunomide and methotrexate alone (109318). The validity of this study is limited by the lack of a placebo or adequate blinding. More evidence is needed to rate Sweet Annie for these uses.

(Read more about SWEET ANNIE)

POSSIBLY SAFE ...when used orally and appropriately. Berberine has been used safely in doses up to 1.5 grams daily for 6 months (262,13520,20579) (34317,34228,34247,34253,34262,34263,34265,34267,34277,34282), (34283,34286,34287,34289,34293,34301,34305,34306,34319,34325)(99920,99921,103194) or up to 1 gram daily for 24 months (99921,103197). ...when used topically. Berberine ointment has been applied with apparent safety for up to 20 days (13526).

CHILDREN: LIKELY UNSAFE
when used orally in newborns. Berberine can cause kernicterus, particularly in preterm neonates with hyperbilirubinemia (2589). It is unclear if berberine is safe in older children.

PREGNANCY: LIKELY UNSAFE
when used orally. Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589). Also, berberine may stimulate uterine contractions (91951).

LACTATION: LIKELY UNSAFE
when used orally. Berberine can be transferred to the infant through breast milk (2589).

(Read more about BERBERINE)

LIKELY SAFE ...when used orally and appropriately. Garlic has been used safely in clinical studies lasting up to 7 years without reports of significant toxicity (1873,4782,4783,4784,4785,4786,4787,4789,4790,4797)(4798,6457,6897,14447,96008,96009,96014,102016,102670,103479)(107238,107239,107352,108607,110722,111763,114892).

POSSIBLY SAFE ...when used topically. Garlic-containing gels, lipid-soluble garlic extracts, garlic pastes, and garlic mouthwashes have been safely used in clinical research for up to 3 months (4766,4767,8019,15030,51330,51386). ...when used intravaginally. A vaginal cream containing garlic and thyme has been safely used nightly for 7 nights (88387).

POSSIBLY UNSAFE ...when raw garlic is used topically (585). Raw garlic might cause severe skin irritation when applied topically.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Garlic is reported to have abortifacient activity (11020). One study also suggests that garlic constituents are distributed to the amniotic fluid after a single dose of garlic (4828). However, there are no published reports of garlic adversely affecting pregnancy. In clinical research, garlic 800 mg daily was used during the third trimester of pregnancy with no reported adverse outcomes (9201,51626). There is insufficient reliable information available about the safety of topical garlic during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

LACTATION: POSSIBLY UNSAFE
when used orally in amounts greater than those found in foods. Several small studies suggest that garlic constituents are secreted in breast milk, and that nursing infants of mothers consuming garlic are prone to extended nursing (3319,4829,4830). There is insufficient reliable information available about the safety of topical garlic during lactation.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately for up to 8 weeks. Garlic extract 300 mg three times daily has been used with apparent safety for up 8 weeks in children ages 8-18 years (4796). There is insufficient reliable information available about the safety of garlic when used over longer durations or in higher doses.

CHILDREN: POSSIBLY UNSAFE
when raw garlic is used topically. Raw garlic might cause severe skin irritation when applied topically (585,51210).

(Read more about GARLIC)

LIKELY SAFE ...when the root preparations are used in amounts commonly found in foods. Gentian root is categorized by the FDA as a safe food additive flavoring in the US (4912).

POSSIBLY SAFE ...when gentian root is used orally in a specific combination that contains gentian root, elderflower, verbena, cowslip flower, and sorrel (SinuComp, Sinupret) (374,379,95907). There is insufficient reliable information available about the safety of the topical use of gentian.

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of gentian in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about GENTIAN)

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

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

PREGNANCY: LIKELY UNSAFE
when used orally. Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to goldenseal (2589).

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

(Read more about GOLDENSEAL)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Quassia has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used topically and appropriately. A 4% quassia gel has been safely used twice daily for up to 45 days (99995).

POSSIBLY UNSAFE ...when used orally in medicinal amounts. Quassia wood contains cardioactive glycosides (4), but toxicity is likely limited by emetic effects of large doses (4). There is insufficient reliable information available about the safety of rectal use of quassia.

PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally; avoid using. Quassia has cytotoxic and emetic properties (4,18,19). There is insufficient reliable information available about the safety of rectal or topical use during pregnancy or lactation; avoid using.

(Read more about QUASSIA)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Sweet Annie 300 mg daily has been used with apparent safety in studies lasting up to 9 months (11055,94520,94521). Sweet Annie tea, prepared from dried leaves and twigs and consumed in divided doses daily, has been used with apparent safety for up to 7 days (11055,11058). While rare, there is some concern that Sweet Annie might cause liver damage (16895,103254,103255).

POSSIBLY SAFE ...when used sublingually and appropriately, short-term. Sweet Annie up to 2400 biological units daily as sublingual immunotherapy has been used with apparent safety in studies lasting up to 16 months (106441,112392,112393,112394). There is insufficient reliable information available about the safety of Sweet Annie when used topically.

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

(Read more about SWEET ANNIE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, berberine might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details In vitro and in vivo research suggest that berberine can inhibit platelet aggregation (33660,33694). Theoretically, berberine might have additive effects when used with anticoagulant and antiplatelet drugs and increase the risk of bleeding.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, berberine may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Clinical research shows that berberine may lower blood glucose levels (20579,34247,34265,34282,111363). Theoretically, berberine might have additive effects with antidiabetes drugs and increase the risk of hypoglycemia.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, berberine might have additive effects with antihypertensive drugs.  Details Animal research suggests that berberine can have hypotensive effects (33692,34308). Also, a clinical study suggests that taking berberine in combination with amlodipine can lower systolic and diastolic blood pressure when compared with amlodipine alone (91956).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, berberine might increase the sedative effects of CNS depressants.  Details Animal research suggests that berberine may have sedative effects (13519,33650,33664,33692). Theoretically, use of berberine along with CNS depressants might produce additive therapeutic and adverse effects.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = A Berberine can increase serum levels of cyclosporine.  Details Berberine can reduce metabolism and increase serum levels of cyclosporine. Berberine might inhibit cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524,21112,34239).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, berberine might increase serum levels of drugs metabolized by CYP2C9.  Details Preliminary clinical research shows that berberine can inhibit CYP2C9 (34279). Theoretically, taking berberine with drugs metabolized by CYP2C9 might increase drug levels and increase the risk of adverse effects.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, berberine might increase serum levels of drugs metabolized by CYP2D6.  Details In vitro research and preliminary clinical evidence show that berberine can inhibit CYP2D6 (21117,34279,34297). Theoretically, use of berberine with drugs metabolized by CYP2D6 might increase drug levels and increase the risk of adverse effects.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, berberine might increase serum levels of drugs metabolized by CYP3A4.  Details In vitro research and preliminary clinical research show that berberine moderately inhibits CYP3A4 (13524,21114,34279,34297). Theoretically, use of berberine with drugs metabolized by CYP3A4 might increase drug levels and increase the risk of adverse effects.

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, berberine may increase serum levels of dextromethorphan.  Details Preliminary clinical research shows that berberine can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279). This may increase the effects and side effects of dextromethorphan.

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Berberine might reduce the therapeutic effects of losartan by decreasing its conversion to its active form.  Details Preliminary clinical research suggests that berberine can inhibit cytochrome P450 2C9 (CYP2C9) activity and reduce metabolism of losartan (34279).

METFORMIN (Glucophage) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, berberine might increase the therapeutic and adverse effects of metformin.  Details In vitro and animal studies show that berberine can increase the systemic exposure and half-life of metformin, potentially increasing metformin's effects and side effects. This interaction seems to be most apparent when berberine is administered 2 hours prior to metformin. Taking berberine and metformin at the same time does not appear to increase systemic exposure to metformin (103195).

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Berberine can reduce metabolism of midazolam, which might increase the risk of severe adverse effects.  Details Preliminary clinical research shows that berberine can inhibit cytochrome P450 3A4 (CYP3A4) activity and reduce metabolism of midazolam (34279).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Berberine might increase the sedative effect of pentobarbital.  Details Evidence from animal research shows that berberine can prolong pentobarbital-induced sleeping time (13519). Theoretically, combining berberine and pentobarbital might increase the sedative effects of pentobarbital.

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

(Read more about BERBERINE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Garlic may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397,96013).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking garlic with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that garlic and garlic extract lower blood glucose levels in healthy and diabetic individuals (51463,96004,114890).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garlic with antihypertensive drugs might increase the risk of hypotension.  Details In human research, both garlic and garlic extracts have blood pressure-lowering effects (277,278,279,1873,4787,6897,16605,51414,51442,51669)(88386,88398,96007).

ATAZANAVIR (Reyataz) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might decrease levels and effects of atazanavir.  Details In a case report, a patient consuming six stir-fried garlic cloves three times weekly developed suboptimal atazanavir levels and increases in HIV viral load. While the exact cause of this interaction is unclear, there is speculation that garlic might decrease the intestinal absorption of atazanavir or increase its metabolism by inducing cytochrome P450 3A4 (CYP3A4) (88388). Until more is known, advise patients not to consume large amounts of garlic while taking atazanavir.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Garlic might increase levels of drugs metabolized by CYP2E1.  Details Clinical research suggests garlic oil can inhibit the activity of CYP2E1 by 39% (10847). Use garlic oil cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic products containing allicin might induce intestinal CYP3A4 and inhibit hepatic CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.  Details Some human research suggests that garlic may induce INTESTINAL CYP3A4, reducing levels of drugs metabolized by this enzyme. This is primarily based on a study showing that taking a specific allicin-containing garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induced CYP3A4 in the gut mucosa (7027,93578). Another study shows that giving docetaxel intravenously, bypassing the CYP3A4 enzymes in the gut mucosa, along with the same specific garlic product for 12 consecutive days, does not affect docetaxel levels (17221). Conversely, there is concern that garlic may inhibit HEPATIC CYP3A4. In a single case report, increased tacrolimus levels and liver injury occurred in a liver transplant patient after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days (96010). Several other studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

ISONIAZID Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might decrease levels of isoniazid.  Details Animal research suggests that an aqueous extract of garlic reduces isoniazid levels by about 65%. Garlic reduced the maximum concentration (Cmax) and area under the curve (AUC), but not the half-life, of isoniazid. This suggests that garlic extract might inhibit isoniazid absorption across the intestinal mucosa (15031); however, the exact mechanism of this potential interaction is not known.

PROTEASE INHIBITORS (PIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic products containing allicin might decrease levels of PIs.  Details Protease inhibitors are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4, reducing plasma levels of protease inhibitors. This is primarily based on a study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces levels of saquinavir, a PI, by approximately 50%. It is speculated that the allicin constituent induce CYP3A4 in the gut mucosa (7027,93578). Several studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

SAQUINAVIR (Fortovase, Invirase) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic containing allicin might decrease levels of saquinavir.  Details Saquinavir is a substrate of cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4 and cause subtherapeutic levels of saquinavir. This is primarily based on a pharmacokinetic study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induces CYP3A4 in the gut mucosa (7027,93578). Several pharmacokinetic studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506). Until more is known about this potential interaction, use garlic containing allicin cautiously in patients taking saquinavir.

SOFOSBUVIR (Sovaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garlic with sofosbuvir might decrease its effectiveness.  Details Animal research in rats shows that giving aged garlic extract 120 mg/kg orally daily for 14 days decreases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 36%, increases the clearance by 63%, and decreases the plasma concentrations at 1 and 8 hours by 35% and 58%, respectively. This interaction is hypothesized to be due to induction of intestinal P-glycoprotein expression by garlic (109524).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic might increase levels of tacrolimus.  Details In one case report, a liver transplant patient taking tacrolimus experienced increased tacrolimus levels and liver injury after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days. It is speculated that garlic inhibited hepatic cytochrome P450 3A4 (CYP3A4), which increased plasma levels of tacrolimus (96010).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might increase the risk of bleeding with warfarin.  Details Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397). In addition, there is a report of two patients who experienced an increase in a previously stabilized international normalized ratio (INR) with concomitant garlic and warfarin use (51228,51631). However, this report has been subsequently debated due to limited clinical information. Other clinical studies have not identified an effect of garlic on INR, warfarin pharmacokinetics, or bleeding risk (15032,16416). More evidence is needed to determine the safety of using garlic with warfarin.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gentian with antihypertensive drugs might increase the risk of hypotension.  Details In vitro research shows that gentian can cause vasodilation and lower blood pressure (13439,13441).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D In animals, quassia extract reduced levels of fasting glucose (99998). Theoretically, quassia might have additive effects when used with antidiabetes drugs. This might increase the risk of hypoglycemia in some patients. Monitor blood glucose levels closely.  Details Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, metformin (Glucophage), pioglitazone (Actos), rosiglitazone (Avandia), and others.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Overuse of quassia might compound diuretic-induced potassium loss (13). There is some concern that people taking quassia along with potassium depleting diuretics might have an increased risk for hypokalemia. Initiation of potassium supplementation or an increase in potassium supplement dose may be necessary for some patients.  Details Some diuretics that can deplete potassium include chlorothiazide (Diuril), chlorthalidone (Thalitone), furosemide (Lasix), and hydrochlorothiazide (HCTZ, Hydrodiuril, Microzide), and others.

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CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Sweet Annie may alter plasma levels and clinical effects of drugs metabolized by CYP2B6.  Details In vitro research shows that the Sweet Annie constituent artemisinin induces CYP2B6, possibly increasing CYP2B6 activity by 1.6-fold (92501,109316). However, Sweet Annie extract seems to inhibit the activity of CYP2B6 in vitro, suggesting that other constituents of Sweet Annie play a role in its effects on the overall activity of this enzyme (109316). More information is needed to determine whether taking Sweet Annie extract affects the metabolism of CYP2B6 substrates.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Sweet Annie may alter plasma levels and clinical effects of drugs metabolized by CYP3A4.  Details In vitro research shows that the Sweet Annie constituent artemisinin induces CYP3A4, possibly increasing CYP3A4 activity by 1.9-fold (92501). However, Sweet Annie extract seems to inhibit the activity of CYP3A4 in vitro, suggesting that other constituents of Sweet Annie play a role in its effects on the overall activity of this enzyme (109316). More information is needed to determine whether taking Sweet Annie extract affects the metabolism of CYP3A4 substrates.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might have additive adverse hepatotoxic effects.  Details There is some concern that Sweet Annie can adversely affect the liver (16895,103254,103255).

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General ...Orally, berberine is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain and distension, constipation, diarrhea, flatulence, nausea, vomiting.
Intravenously: Facial flushing, painful swelling at the injection site.
Serious Adverse Events (Rare):
Intravenously: Ventricular tachycardia consistent with torsades de pointes.

Cardiovascular ...In four of 12 patients with refractory congestive heart failure, intravenous infusion of berberine at a rate of 0. 2 mg/kg per minute caused ventricular tachycardia consistent with torsades de pointes (33642).

Dermatologic ...When administered intravenously, berberine can cause painful swelling at the injection site or facial flushing (34330). In three of 12 people injected subcutaneously with berberine, permanent hyperpigmentation at the injection site occurred (33698).
Orally, berberine may cause rash, but this event appears to be rare (34285,110106).

Endocrine ...Orally, berberine may cause hypoglycemia (111363).

Gastrointestinal ...Orally, berberine may cause diarrhea, constipation, flatulence, nausea, vomiting, abdominal pain, abdominal distention, gastroesophageal reflux, and bitter taste (33648,33689,34245,34247,34285,91953,99920,99921,103194,103197)(110106,111363,111699,113462,114769).

Hepatic ...Orally, berberine may occasionally cause an increase in transaminases (99921,103194). However, meta-analyses have found no significant effect of berberine on alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (104508,111363).

Musculoskeletal ...Reports of mild muscle pain and muscle weakness have been reported following the use of a combination product containing berberine, policosanol, red yeast rice, folic acid, coenzyme Q10, and astaxanthin (34283). It is unclear if these effects are due to berberine or other constituents.

Neurologic/CNS ...Orally, berberine may cause dizziness, drowsiness, fatigue, and headache (33648,99921,113462).

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General ...Orally, garlic is generally well tolerated. Topically, garlic seems to be well tolerated. Intravenously, there is insufficient reliable information available about adverse effects.
Most Common Adverse Effects:
Orally: Abdominal pain, body odor, flatulence, malodorous breath, and nausea. Allergic reactions in sensitive individuals.
Topically: Burns and dermatitis with fresh garlic.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with garlic.

Dermatologic ...Orally, garlic may cause pruritus (51316,51474,107239), flushing, and acne (107239). Oral intake of a specific garlic product containing allicin (Allimax) has been associated with a case of pruritic rash (51474). Enteric-coated garlic tablets standardized to 1.5% allicin have also been associated with a case of pruritus (51316). Garlic has also been associated with a case of superficial pemphigus in a 49-year-old male with type 2 diabetes (51564). Garlic-induced oral ulcers have also been reported (51467).
Topically, garlic may cause contact dermatitis and urticaria (4833,5004,12635,51258,51265,51375,51403,51412,51459,51483)(51511,51512,51530,51616,51617,51618,111769), as well as contact cheilitis (51384). Fresh garlic may be more likely to elicit a reaction than garlic extract. Most reactions have resolved following withdrawal of garlic therapy. In one case report, applying crushed garlic on the neck to help ease a sore throat resulted in an itchy, burning, erythematous lesion in a young female patient. The lesion healed after one week of treatment with topical antibiotics, steroids, and antihistamine ointments (88390). Cases of occupational eczema or dermatitis have been reported in cooks (51303,51210), food handlers (51292), and caterers (51304). According to one case report, dermatitis appeared in chefs exposed to garlic (15033). Treatment with acitretin 25 mg daily or topical psoralen-ultraviolet A (PUVA) for 12 weeks proved effective in mitigating the symptoms. A 34-year-old female with a history of hand dermatitis and paronychia had a worsening of these conditions after peeling raw garlic. She had a positive skin patch test to fresh, raw garlic but not to any other tested allergens, and the conditions resolved when she avoided contact with garlic (105528). Topically, garlic may also cause chemical burns, usually within 12 hours of application. Second- and third-degree chemical burns have been reported in adults, children, and infants exposed to topical garlic, often as an unintended consequence of using garlic medicinally on the skin (585,4832,51226,51230,51252,51281,51377,51418,51468,51495,51536)(51558,51576,51577,88409,96006). A case of painful blisters on the soles of the feet of a 23-year-old Chinese female has been attributed to chemical burns caused by applying crushed raw garlic for 3 hours (51440). Topically, garlic may also cause hyperpigmentation, ulcers, necrotic lesions, facial flushing, and local irritation (4832,15030,51268,51269,108606). In one case report, applying crushed raw garlic to the palatal mucosa for several minutes to relieve mouth pain resulted in a chemical burn that produced a 3 cm necrotic ulcer in an adult female with trigeminal neuralgia (108606).

Gastrointestinal ...Orally, dehydrated garlic preparations or raw garlic may cause malodorous breath (51438,51444), body odor (732,1873,4784,4793,4795,4798,9201,10787,42692,49769)(51269,51316,51467,51602), abdominal pain or fullness, anorexia, diarrhea, constipation, flatulence, belching, heartburn, nausea, unpleasant taste, reflux, and bowel obstruction (1884,6457,6897,9201,49769,51269,51343,51380,51438,51442)(51450,51457,51466,51471,51474,51520,51593,51602,51623,88398)(88405,111766,114892).
Large quantities of garlic may damage the gastrointestinal tract. In one case report, a patient taking garlic for hypertension reported odynophagia and retrosternal pain after taking garlic without any water the previous day. An esophageal lesion 3 cm in length was detected upon endoscopy. The symptoms resolved 3 days after starting a liquid diet and taking lansoprazole 30 mg twice daily and sucralfate four times daily (88389). One case of bowel obstruction was reported in a 66-year-old male who ingested an entire garlic bulb (51525). Esophageal perforation has been reported in at least 17 individuals who consumed entire garlic cloves. In one case the perforation led to mediastinitis and death (102672).
Garlic has also been associated with eosinophilic infiltration of the gastrointestinal tract. In one case report a 42-year-old female presented with symptoms of eosinophilic gastroenteritis, which included pollinosis, asthma, diarrhea, heart burn, peripheral eosinophilia, and urticaria. After stopping use of garlic and sesame, the patient improved (51441). In a case report of eosinophilic esophagitis, garlic was determined to be the causative agent in a patient with long-standing gastrointestinal symptoms. The patient had attempted to treat upper gastrointestinal symptoms as gastrointestinal reflux disease without success for many years. Skin prick testing showed a positive reaction to garlic, of which the patient noted frequent consumption. Marked symptom improvement was noted within 3 weeks of garlic avoidance (88393).
Intravenously, garlic 1 mg/kg of body weight daily diluted into 500 mL saline and administered over 4 hours has been reported to cause abdominal discomfort, vomiting, diarrhea, nausea, anorexia, flatulence, weight loss, and garlicky body odor (51462).
Clinical research suggests that patients with metabolic syndrome taking 1600 mg of powdered garlic by mouth daily for 3 months may experience improved intestinal transit time when compared with placebo, suggesting that garlic powder may reduce symptoms of constipation (110722).

Genitourinary ...Orally, garlic might cause dysuria, hematuria, or polyuria (51438,51450,51467,113618). In one case, an older male with high dietary and supplemental garlic intake at doses of 300-5400 mg daily for 3-4 years developed severe hematuria with clots after undergoing a minimally invasive prostate procedure (113618).

Hematologic ...Oral use of dietary garlic or supplements containing garlic has caused platelet dysfunction, increased fibrinolytic activity, prolonged bleeding time, retrobulbar hemorrhage (bleeding behind the eye) postoperative bleeding, and spinal epidural hematoma (586,587,4801,4802,11325,51397,51473,51491,51532,51534)(51570,51584,51593,51594,113618). Also, a case of kidney hematoma following extracorporeal shock-wave lithotripsy (SWL) has been reported in a patient with nephrolithiasis who took aged garlic (51630). A case of increased bleeding time that complicated epistaxis management has been reported in a patient taking garlic, aspirin, and milk thistle (51426).
Intravenously, garlic has been associated with the development of thrombophlebitis at the injection site (51462).

Immunologic ...There is a case report of an immediate sensitivity reaction to oral raw garlic, resulting in wheals, in a 31-year-old female. The patient did not react to cooked garlic, and skin prick tests showed allergy only to raw garlic (96015). Researchers note that at least some allergens in raw garlic are heat labile (88392,96012,96015). This suggests that consuming cooked rather than raw garlic may help avoid this reaction in patients allergic to raw garlic. However, different people react to different allergens in garlic. At least some of these allergens are heat stable (96012). While rare, garlic-induced anaphylaxis has been reported (88392,96012).
Topically, allergic contact dermatitis has been reported in case reports (51406,51498,51510,51519,51560).

Musculoskeletal ...Orally, garlic has been associated with individual cases of gout and low back pain (51474,51467), but it is not clear if these adverse events can be attributed to garlic.

Neurologic/CNS ...Orally, dizziness, insomnia, headaches, diaphoresis, fever, chills, somnolence, increased appetite, euphoria, and weight loss have been reported with garlic (15032,42692,51316,51467,51471,51520). In one case, the smell of garlic was identified as a trigger for migraines in a 32-year-old female. The subject reported fortification spectra along with visual spots for a few seconds followed by instantaneous biparietal, crushing level (10/10) headaches upon exposure to the scent of garlic or onion (88404).

Pulmonary/Respiratory ...Garlic exposure, most notably in occupational settings, may cause asthma and other symptoms such as sneezing, nasal obstruction, rhinorrhea, and sinusitis (40661,51218). A case of minor hemoptysis has been reported for one patient with cystic fibrosis following intake of garlic capsules orally once daily for 8 weeks (51438). A 77-year-old female developed pneumonia related to the intake of one whole black garlic clove daily. The cloves were prepared by heating a whole garlic bulb in a pot for one month. Symptoms included dyspnea and coughing, and test results were positive for lymphocyte-induced stimulation by black garlic and raw garlic. The patient required treatment with oral steroids and was told to avoid garlic (96011).

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General ...Orally, gentian root, in combination with other herbs, seems to be generally well tolerated. There is insufficient reliable information available about the adverse effects of gentian when taken as a medicine alone.
Most Common Adverse Effects:
Orally: Allergic skin reactions, gastrointestinal discomfort.

Gastrointestinal ...Orally, gentian root, in combination with other herbs, has been reported to cause gastrointestinal adverse effects (374,379). Gastrointestinal intolerance occurred in patients with cancer-associated anorexia who took gentian tincture 1 mL three times daily, in conjunction with turmeric 1 gram and ginger 1 gram twice daily, for 14 days. Six of 17 patients discontinued the regimen due to nausea, 3 due to vomiting, 2 due to diarrhea, and 2 due to bloating. It is unclear if this gastrointestinal intolerance was caused by gentian, the other herbs, or the patients' predisposing conditions (96263).

Immunologic ...Orally, gentian root, in combination with other herbs, has been reported to cause allergic skin reactions (374,379). It is unclear if these reactions were caused by gentian, the other herbs, or the combination.

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

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

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

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

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

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General ...Orally, quassia can cause mucous membrane irritation, nausea, and vomiting when used in medicinal amounts (4,18). Long-term use can cause vision changes and blindness (18).
Topically, quassia seems to be well tolerated (99995). No adverse effects have been reported.

Gastrointestinal ...Orally, quassia has been reported to cause mucous membrane irritation, nausea, and vomiting when used in medicinal amounts (4,18).

Ocular/Otic ...Orally, long-term use of quassia can cause vision changes and blindness (18).

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General ...Orally, Sweet Annie is generally well-tolerated.
Most Common Adverse Effects:
Orally: Nausea and vomiting.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity.

Gastrointestinal ...Orally, Sweet Annie might cause gastrointestinal upset including nausea and vomiting in some patients (11058,112393).

Hepatic ...Orally, Sweet Annie might cause hepatic adverse effects (16895,103254,103255). In one case, a 52-year-old patient developed hepatitis after taking the Sweet Annie constituent artemisinin 200 mg three times daily for 10 days. The patient developed abdominal pain and dark urine and was found to have elevated liver enzymes consistent with hepatitis. Symptoms resolved within 2 weeks of discontinuing use. Although it is possible this supplement caused liver disease in this patient, it is not certain. In clinical trials evaluating artemisinin, elevated liver enzymes have only been reported in around 0.9% of patients. However, the dose of artemisinin in this case was substantially higher than a typical dose (16895). A case of severe acute cholestatic hepatitis has also been reported in a 51-year-old male who drank Sweet Annie tea daily, prepared using 1.25 grams of Sweet Annie powder, for malaria prophylaxis during a 4-week trip to Ethiopia. Three weeks after his return, he presented with malaise, abdominal discomfort, jaundice, elevated liver enzymes, and markers of cholestasis. The patient was treated with corticosteroids and ursodeoxycholic acid and ultimately recovered (103255).
A series of cases linking the use of a supercritical carbon dioxide extract of Sweet Annie to hepatoxicity has also been reported. Of the 29 reports of adverse hepatic reactions to this extract, 19 patients noted symptoms within 12 weeks of starting the extract, 16 patients experienced jaundice, and 9 patients required hospitalization. Other common symptoms of hepatotoxicity included abdominal pain, vomiting, nausea, fever, headache, anorexia, malaise, fatigue, and lethargy. All but one case involved doses below or up to the extract's recommended dose of 300 mg daily. Upon discontinuation, symptoms resolved completely or were improved in nearly all cases (103254).

Immunologic ...One case of a mild allergic reaction to Sweet Annie tea has been reported. The reaction was characterized by a rash and cough that resolved quickly and did not require treatment (11059). When low doses are taken sublingually by individuals allergic to Sweet Annie, numbness of the tongue and throat itching have been reported (109315,112392,112393,112394).

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