Berberine HCL+ by Healths Harmony

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral banaba is beneficial in patients with type 2 diabetes. Details: One preliminary clinical study in patients with type 2 diabetes shows that a specific banaba extract (Glucosol), standardized to corosolic acid 1%, taken as 32 or 48 mg daily for 2 weeks is associated with 10% lower blood glucose levels when compared with placebo (11954). Another preliminary clinical study in patients with type 2 diabetes inadequately controlled by oral antidiabetic agents shows that taking a specific combination product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica) 100 mg daily for 12 weeks reduces glycated hemoglobin (HbA1c) by 0.65% when compared with baseline (92849). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to banaba, Padang cassia, or the combination.
• Impaired glucose tolerance (prediabetes). Oral banaba has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with impaired glucose tolerance shows that taking a specific combination product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica) daily for 12 weeks preserves beta-cell function and insulin release and improves insulin sensitivity, but not 2-hour postprandial glucose levels, when compared with placebo. All patients received 50 mg once daily for 4 weeks, and those considered to be non-responders were titrated up to 100 mg once daily for the remaining 8 weeks (92848). It is unclear if these effects are due to banaba, Padang cassia, or the combination.
• Metabolic syndrome. It is unclear if oral banaba is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that a specific banaba extract (MonoHerb), standardized to corosolic acid 1.13%, taken as 500 mg twice daily for 12 weeks improves systolic blood pressure, fasting blood glucose, triglycerides, and very low-density lipoprotein (VLDL) cholesterol when compared with baseline (108617). The lack of statistical comparison to the placebo group limits the validity of these findings. More evidence is needed to rate banaba for these uses.

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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, and increases high-density lipoprotein (HDL) cholesterol. Details: Meta-analyses of clinical research in people with hyperlipidemia show that berberine can reduce total cholesterol by 21-32 mg/dL, triglycerides by up to 34 mg/dL, LDL cholesterol by 18-26 mg/dL, and apolipoprotein B by 0.25 g/L, as well as increase HDL cholesterol by 2-3 mg/dL, when compared with placebo or lifestyle interventions (20579,34228,111363,111700). 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 pregnancy and birth rates in women with PCOS is unclear. One clinical study 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).
• 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 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: Preliminary clinical research shows that taking berberine 600 mg twice daily for 12 weeks reduces blood lipids and markers of liver damage, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), when compared to baseline in patients with NAFLD and type 2 diabetes (34286). 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).
• 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 of oral berberine is beneficial for improving symptoms of this condition. Details: Preliminary clinical research in a small number of patients with ulcerative colitis taking mesalamine shows that taking berberine 300 mg three times daily for 3 months does not improve clinical symptoms or markers of inflammation when compared with placebo (103194). However, this study primarily focused on safety outcomes and was inadequately powered to detect differences in efficacy.
• 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.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Amenorrhea. Although there is interest in using oral bitter melon for amenorrhea, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Athletic performance. It is unclear if oral bitter melon is beneficial for improving athletic performance. Details: Preliminary clinical research in ten male tennis players taking part in high-intensity training at high temperatures shows that taking bitter melon extract orally, 100 mL six times daily for 4 weeks, improves some biomarkers of fatigue and physical fitness parameters including balance, flexibility, and cardiorespiratory fitness when compared with baseline. Levels of adrenocorticotrophic hormone and cortisol are decreased, suggesting a reduction in oxidative stress (103295,106407). The validity of these results is limited by the lack of a comparator group.
• Constipation. Although there is interest in using oral bitter melon for constipation, there is insufficient reliable information about the clinical effects of bitter melon for this purpose.
• Diabetes. Although some research suggests that bitter melon may improve glycemic control in adults with type 2 diabetes, evidence is conflicting and of limited quality. Details: A meta-analysis of 10 low-quality studies in patients with type 2 diabetes shows that taking bitter melon powdered whole fruits or juice in doses of 0.5 to 12 grams daily for 4-16 weeks reduces fasting blood glucose (FBG) by 13 mg/dL, postprandial glucose by 26 mg/dL, and glycated hemoglobin (HbA1c) by 0.26% when compared with placebo (100632). Another meta-analysis, pooling the results of 7 trials in patients with type 2 diabetes, shows that bitter melon modestly reduces HbA1c by 0.3% and FBG by 14 mg/dL when compared with no treatment, but a separate analysis of 2 other trials shows that bitter melon does not improve either outcome when compared with oral antidiabetic drugs (111503). Additionally, a meta-analysis of 3 clinical trials shows that taking bitter melon 1-6 grams daily for 4-12 weeks does not significantly improve fasting plasma glucose or HbA1c when compared with placebo in patients with type 2 diabetes (92124). Some other clinical research in patients with type 2 diabetes shows that bitter melon fruit, fruit pulp, fruit juice, and extract improve glucose tolerance and insulin secretion, reduce blood glucose levels, and lower HbA1c (34,35,36,38,12530). One clinical study shows that taking powdered bitter melon fruit 2-4 grams daily for 10 weeks lowers HbA1c similarly to glyburide 2.5 mg daily (92126). Reasons for the discrepancies among the evidence are not clear but may relate to the small study sizes, shorter durations of treatment, and varying dosages and formulations of bitter melon.
• Dyspepsia. Although there is interest in using oral bitter melon for dyspepsia, there is insufficient reliable information about the clinical effects of bitter melon for this purpose.
• Genital herpes. Although there is interest in using topical bitter melon for genital herpes, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• HIV/AIDS. Although there is interest in using oral bitter melon for HIV/AIDS, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Impaired glucose tolerance (prediabetes). It is unclear if oral bitter melon is beneficial in patients with prediabetes. Details: A small clinical study in patients with impaired glucose tolerance shows that drinking a beverage containing bitter melon extract 1.25-3 grams as a single dose does not affect blood glucose or insulin response when compared with baseline (97508). A moderate-sized clinical study in adults with prediabetes shows that taking bitter melon (SugarKatcherS52, Kolmar BNH) 800 mg three times daily for 12 weeks reduces blood glucose by 22 mg/dL two hours after oral glucose tolerance test when compared with placebo, but does not improve insulin, C-peptide, or glucagon levels, nor markers of insulin resistance (112372). The validity of these results is limited by the lack of statistical adjustment for multiple comparisons which can lead studies to erroneously show differences between treatment groups (i.e., false positive findings).
• Intestinal parasite infection. Although there is interest in using oral bitter melon for intestinal parasite infection, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Kidney stones (nephrolithiasis). Although there is interest in using oral bitter melon for kidney stones, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Liver disease. Although there is interest in using oral bitter melon for liver disease, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Metabolic syndrome. Although there is interest in using oral bitter melon for metabolic syndrome, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Obesity. It is unclear if oral bitter melon is beneficial for weight loss. Details: A very small clinical study in patients with obesity shows that taking bitter melon 1 gram twice daily for 12 weeks does not reduce body weight, body mass index (BMI), waist circumference, or body fat percentage when compared to baseline. However, when compared with placebo, body weight and BMI were reduced by around 4 kg and 1.6 kg/m², respectively. Patients in the placebo group experienced an increase in these measures (109583).
• Osteoarthritis. It is unclear if oral bitter melon is beneficial in patients with osteoarthritis. Details: A small preliminary clinical study in patients with osteoarthritis shows that taking bitter melon 1500 mg three times daily for 3 months reduces the need for rescue analgesic medications when compared with placebo. However, subjective scores of osteoarthritis symptoms improved similarly in both groups (100631).
• Peptic ulcers. Although there is interest in using oral bitter melon for peptic ulcers, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Polycystic ovary syndrome (PCOS). Although there is interest in using oral bitter melon for PCOS, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Psoriasis. Although there is interest in using oral bitter melon for psoriasis, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Ulcerative colitis. Although there is interest in using oral bitter melon for ulcerative colitis, there is insufficient reliable information about the clinical effects of bitter melon for this condition.
• Wound healing. Although there is interest in using topical bitter melon for wound healing, there is insufficient reliable information about the clinical effects of bitter melon for this purpose. More evidence is needed to rate bitter melon for these uses.

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POSSIBLY SAFE ...when banaba extract is used orally and appropriately, short-term (11954,92848,92849). A specific banaba extract (Glucosol) has been safely used at doses of 32-48 mg daily for 2 weeks (11954). Another specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica) has been safely used at doses up to 100 mg daily for 12 weeks (92848,92849). There is insufficient reliable information available about the safety of banaba extract when used long-term.

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

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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).

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POSSIBLY SAFE ...when the fruit is used orally and appropriately, short-term. Powdered bitter melon fruit 0.5-12 grams daily for up to 4 months has been used (92126,100631,100632,109583). Extracts of bitter melon fruit have also been used safely for up to 3 months (36,15566,106408). There is insufficient reliable information available about long-term use of bitter melon or the safety of bitter melon when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Animal research shows that two proteins isolated from the raw fruit of bitter melon possess abortifacient properties (3724,35719,35722,35728). Also, one animal study shows that bitter melon juice significantly reduces the fertility rate of mice (35728). However, these effects of bitter melon have not been assessed in humans.

LACTATION:
Insufficient reliable information available; avoid using.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of banaba and hypoglycemic drugs might have additive effects.  Details Human and animal research suggests that banaba can lower blood glucose levels (11954,11955,33554,92848,92849).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of banaba and antihypertensive drugs might cause additive effects.  Details Human and animal research suggests that banaba can lower blood pressure (33557,92848,92849).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of banaba with substrates of OATP might reduce the bioavailability of the OATP substrate.  Details In vitro research shows that banaba inhibits OATP, particularly OATP2B1 (35450). OATPs are expressed in the small intestine and liver and are responsible for the absorption of drugs and other compounds.

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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).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking bitter melon with antidiabetes drugs might increase the risk of hypoglycemia.  Details Bitter melon can lower blood glucose levels and might have additive effects when used with antidiabetes drugs (34,35,36,38,8181,12530,92124,92126,92129,100632,111503). This might increase the risk of hypoglycemia in some patients. Monitor blood glucose levels closely.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter melon might increase levels of P-glycoprotein substrates.  Details Bitter melon might inhibit the p-glycoprotein (P-gp) intestinal pump and increase intracellular levels of P-gp substrates. In vitro research in intestinal cells shows that 1-monopalmitin, a constituent of bitter melon, increases levels of daunomycin, a P-gp substrate (97509). Additionally, drinking bitter melon juice has been associated with a case of acute pancreatitis in a patient who had been taking pazopanib, a P-gp substrate, for 8 years. Researchers theorize that inhibition of P-gp led to increased levels of pazopanib, resulting in pazopanib-induced pancreatitis (109581).

PAZOPANIB (Votrient) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter melon might increase levels of pazopanib, potentially increasing the risk of adverse effects.  Details In one case, a 65-year-old patient taking pazopanib for 8 years for renal cell carcinoma experienced signs and symptoms consistent with acute pancreatitis 4 days after drinking bitter melon juice at a dose of 100-150 mL daily. The patient's symptoms, amylase levels, and lipase levels improved upon discontinuation of bitter melon and pazopanib. Pazopanib treatment was re-initiated with no further evidence of pancreatitis. Researchers theorize that inhibition of P-glycoprotein by bitter melon led to increased levels of pazopanib, a P-glycoprotein substrate, resulting in pazopanib-induced pancreatitis (109581).

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General ...Orally, banaba extract appears to be well tolerated.
Most Common Adverse Effects:
Orally: Diaphoresis, dizziness, headache, palpitations, stomach upset, tremor, and weakness have been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if these adverse effects were caused by banaba extract, Padang cassia, or the combination.

Cardiovascular ...Orally, palpitations have been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if this adverse effect was caused by banaba extract, Padang cassia, or the combination (92848).

Gastrointestinal ...Orally, stomach upset has been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if this adverse effect was caused by banaba extract, Padang cassia, or the combination (92849).

Neurologic/CNS ...Orally, dizziness, headache, tremor, and weakness have been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if these adverse effects were caused by banaba extract, Padang cassia, or the combination (92848,92849).

Other ...Orally, diaphoresis has been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if this adverse effect was caused by banaba extract, Padang cassia, or the combination (92849).

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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, and bitter taste (33648,33689,34245,34247,34285,91953,99920,99921,103194,103197)(110106,111363,111699).

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 headache (33648,99921).

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General ...Orally, bitter melon is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal discomfort, constipation, diarrhea, dizziness, fatigue, flatulence, headache, heartburn, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Hypoglycemic coma and seizures (in children).

Dermatologic ...In one clinical study, two out of 31 patients taking bitter melon 4 grams daily experienced skin rash. Reports of skin rashes did not occur for patients taking bitter melon 2 grams daily (92126).

Endocrine ...Two cases of hypoglycemic coma have occurred in children after administration of a bitter melon tea (15568).

Gastrointestinal ...The most common adverse effects associated with bitter melon in clinical studies are gastrointestinal, such as heartburn, anorexia, nausea, vomiting, diarrhea, constipation, flatulence, and abdominal discomfort (92126,100632,100633,106408). In one study, these events occurred in about 3% to 16% of patients taking bitter melon (92126).

Neurologic/CNS ...Headaches, dizziness, and fatigue have been reported after the ingestion of bitter melon (15568,92126,100633,112372). In one clinical study, about 5% of patients taking bitter melon 2-4 grams daily reported dizziness (92126). Two cases of seizures have occurred in children after administration of a bitter melon tea (15568).

Renal ...In one case report, a 60-year-old female was diagnosed with acute interstitial nephritis after a gradual decline in renal function over 9 months. The patient later admitted to taking bitter melon extract 600 mg daily for 3 months followed by 1200 mg daily for 4 months for diabetes. Upon discontinuation of bitter melon and treatment with prednisolone, serum creatinine levels returned to baseline within 3 months (109582).

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