Professional Series Prostectin by Advanced Orthomolecular Research (AOR)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Amenorrhea. Although there has been interest in using oral Angelica archangelica for amenorrhea, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition.
• Anxiety. Although there has been interest in using oral Angelica archangelica for anxiety, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition.
• Cognitive impairment. Oral Angelica archangelica has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients aged 65-85 years with mild cognitive impairment, taking Angelica archangelica extract 20 mg combined with ferulic acid 100 mg (Feru-Guard, Glovia Co. Ltd.) twice daily for 24 weeks improves scores on the Mini-Mental State Examination when compared with placebo (106409).
• Cough. Although there has been interest in using oral Angelica archangelica for cough, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition.
• Dementia. Although there has been interest in using oral Angelica archangelica for dementia, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition.
• Dyspepsia. Oral Angelica archangelica has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A specific combination product (Iberogast, Medical Futures, Inc) containing Angelica archangelica root, peppermint leaf, clown's mustard plant, German chamomile flowers, caraway fruit, licorice root, milk thistle fruit, celandine herb, and lemon balm leaves seems to improve symptoms of dyspepsia. A meta-analysis of studies using this combination shows that taking 1 mL orally three times daily for 4 weeks reduces the severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089).
• Flatulence. Although there has been interest in using oral Angelica archangelica for flatulence, there is insufficient reliable information about the clinical effects of Angelica archangelica for this purpose.
• Insomnia. Although there has been interest in using oral Angelica archangelica for insomnia, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition.
• Nocturia. It is unclear if oral Angelica archangelica is beneficial in patients with nocturia. Details: Clinical research shows that taking a specific Angelica archangelica leaf extract (SagaPro, SagaMedica) 2 tablets daily for 8 weeks does not improve overall nocturia symptoms, including the number of overnight voids or the volume of urine. However, in individuals with a decreased bladder capacity, the number of voids per hour decreases by 43%, compared to 26% with placebo (92461).
• Rheumatoid arthritis (RA). Although there has been interest in using oral Angelica archangelica for RA, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition.
• Smoking cessation. It is unclear if inhaling the aroma of Angelica archangelica root essential oil is beneficial for people wanting to stop use of tobacco. Details: Preliminary clinical research in patients addicted to dipping, chewing, or smoking tobacco shows that placing a drop of Angelica archangelica root essential oil on tissue paper and inhaling for 2 minutes at least three times a day for 3 days reduces nicotine cravings when compared with baseline (90502). The validity of these results is limited by the lack of a comparator group.
• Stroke. Although there has been interest in using oral Angelica archangelica for stroke, there is insufficient reliable information about the clinical effects of Angelica archangelica for this condition. More evidence is needed to rate Angelica archangelica for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol-related liver disease. Preliminary clinical research in habitual alcohol drinkers with early alcohol-related liver disease shows that taking ashitaba extract 500 mg twice daily for 12 weeks does not improve fatigue or reduce liver enzyme levels when compared with placebo. However, in heavy drinkers consuming 20 or more cans of beer or 12 or more glasses of wine per week, ashitaba extract reduces gamma-glutamyl transferase levels when compared with placebo (100594). More evidence is needed to rate ashitaba for this use.

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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 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)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). Although there is interest in using oral dong quai for atopic dermatitis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Chronic kidney disease (CKD). There is limited evidence on the use of dong quai in patients with CKD. Details: A large propensity score-matched observational study over 15 years in Taiwanese adults with CKD suggests that taking dong quai is associated with a 5.1% risk of end-stage renal disease (ESRD) and 38% risk of overall mortality when compared with 7% and 56%, respectively, in controls. Higher cumulative doses (i.e., 15 grams or more) and longer duration of exposure (i.e., > 60 days) are also associated with fewer ESRD events (112362). However, the interpretation of these findings is limited by the lack of exact dosage information and retrospective study design.
• Coronary heart disease (CHD). Intravenous dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with CHD shows that injecting 20 mL of an intravenous solution containing dong quai, ginseng, and astragalus (Yi-qi Huo-xue Injection) daily for 2 weeks reduces the frequency and severity of angina episodes when compared with placebo. It also seems to increase exercise tolerance and improve left ventricular function when compared with placebo (33046). It is unclear if these benefits are due to dong quai, other ingredients, or the combination.
• Dysmenorrhea. Although there is interest in using oral dong quai for dysmenorrhea, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Hypertension. Although there is interest in using oral dong quai for hypertension, there is insufficient reliable information about the clinical effects of dong quai for this purpose.
• Idiopathic interstitial pneumonia. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of 17 studies conducted in China in patients with idiopathic interstitial pneumonia concludes that adding traditional Chinese medicine combinations containing dong quai root and astragalus root to treatment with conventional medicines improves pulmonary function index, six-minute walking distance, and the Borg scale of perceived exertion when compared with conventional treatment alone (103618). The included studies are of low quality, include a range of treatment durations from 1-12 months, and vary in the conventional medicines and Chinese herb combinations used. The doses of dong quai used were not stated.
• Infertility. Although there is interest in using oral dong quai for infertility, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Iron deficiency anemia. Although there is interest in using oral dong quai for iron deficiency anemia, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Menopausal symptoms. There is inconsistent and contradictory evidence about the effect of dong quai on menopausal symptoms. Benefits have only been seen when it is used in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research shows that taking dong quai, 1.5 grams three times daily for 24 weeks, does not affect menopausal symptoms (738). Other clinical research shows that dong quai improves menopausal symptoms when used in combination with other constituents. In one clinical trial, taking five chewable tablets of a specific combination of dong quai and chamomile (Climex) daily for 12 weeks reduced the frequency and severity of hot flushes when compared with placebo (48445). In another trial, taking a combination providing dong quai 75 mg, along with American ginseng, black cohosh, milk thistle, red clover, and vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months reduces menopausal symptoms, including the number and intensity of hot flushes, the number of night sweats, and sleep quality (19552). Taking another combination product containing dong quai, burdock root, licorice root, motherwort, and Mexican wild yam root, 500 mg three times daily for 3 months, also reduces menopausal symptoms when compared with placebo (48522). It is unclear if the beneficial effects in these studies were due to dong quai, other ingredients, or a combination of ingredients.
• Migraine headache. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with menstrual migraine shows that taking a combination of soy isoflavones 60 mg, dong quai 100 mg, and black cohosh 50 mg daily for 24 weeks reduces the frequency of attacks when compared with placebo (35797). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
• Osteoporosis. Although there is interest in using oral dong quai for osteoporosis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Peptic ulcers. Although there is interest in using oral dong quai for peptic ulcers, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Premature ejaculation. Topical dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In one preliminary clinical trial in patients with premature ejaculation, a multi-ingredient cream preparation (SS Cream) containing dong quai, Panax ginseng root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, clove flower, Asiasari root, cinnamon bark, and toad venom was applied to the glans penis 1 hour prior to intercourse and washed off immediately before intercourse. Patients using the cream had significantly improved ejaculatory latency when compared with placebo cream (2537). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
• Premenstrual syndrome (PMS). Although there is interest in using oral dong quai for PMS, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Psoriasis. Although there is interest in using oral dong quai for psoriasis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Pulmonary hypertension. Preliminary clinical research shows that intravenous dong quai may be effective in patients with pulmonary hypertension. Details: Some preliminary clinical research in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension shows that intravenous administration of 250 mL of a solution containing dong quai 25%, once daily for 5-10 days, reduces pulmonary arterial pressure and pulmonary vascular resistance when compared to baseline (48438,48442,48443). The validity of these findings is limited by the lack of comparator groups.
• Rheumatoid arthritis (RA). Although there is interest in using oral dong quai for RA, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Stroke. Preliminary evidence does not support the use of intravenous dong quai for acute ischemic stroke. Details: Preliminary clinical research in patients with acute ischemic stroke shows that administering 200 mL of a solution containing dong quai 25% intravenously daily for 20 days does not improve neurological symptoms when compared with dextran-40 (48483). More evidence is needed to rate dong quai for these uses.

(Read more about DONG QUAI)

POSSIBLY EFFECTIVE

• Prostate cancer. Early findings suggests that oral lycopene might have a small benefit in preventing the development or recurrence of prostate cancer. Details: While some observational studies have found a reduced risk for prostate cancer from increased dietary lycopene intake (2405,2406,7772,7773,7895,12878,60304,60448,109432), others have found no significant association (34635,60334,60449,60457,60547). The most recent meta-analysis of these and other observational studies has found an overall modest benefit, suggesting that the risk of developing prostate cancer decreases by 1% for each additional 2 mg of daily dietary lycopene intake, and decreases by 3.5% for each 10 mcg/dL increase in plasma lycopene levels (98824). A subgroup analysis of some population research also suggests that the benefits from increased dietary lycopene may be limited to non-Hispanic White subjects (109432). Furthermore, a small clinical study in patients at high risk for developing prostate cancer with high-grade prostate intraepithelial neoplasia shows that taking lycopene (Lyc-O-Mato, LycoRed Natural Product Industries) 4 mg twice daily for one year might delay progression to prostate cancer when compared with no supplementation (14126). Numerous small heterogeneous studies have examined the effect of lycopene on serum prostate specific antigen (PSA) levels. One meta-analysis of 6 controlled clinical trials in patients with non-metastatic prostate cancer or prostatic intraepithelial neoplasia shows that taking lycopene 15-45 mg daily for 4 months does not reduce PSA levels when compared with control. However, in patients with a higher baseline PSA of over 6.5 mg/L, lycopene supplementation seems to reduce PSA levels when compared with control (105573). Other small, uncontrolled studies in patients in remission or with recurrent or metastatic prostate cancer suggest that taking lycopene (LycoRed, Jagsonpal Pharmaceuticals; Lyc-O-Mato, LycoRed Natural Product Industries Ltd.) 10-30 mg daily, or tomato products providing a mean of 43 mg lycopene daily, for 3-6 months reduces PSA levels when compared to baseline (60353,60397,60403,60417). Lycopene might also be beneficial in patients receiving surgical interventions. Small clinical studies in patients receiving orchiectomy for metastatic prostate cancer or radical prostatectomy show that taking lycopene 4 mg daily for 6 months or 30 mg daily for 3 weeks seems to reduce and normalize PSA levels when compared with baseline or control (7771,60328,60342). However, not all research has been positive. Two small clinical studies in patients with relapsed or androgen-independent prostate cancer show that taking lycopene 15-120 mg daily for up to one year does not affect PSA levels when compared with baseline (60372,60384). Many of these findings are limited due to a lack of a placebo control.

POSSIBLY INEFFECTIVE

• Bladder cancer. Dietary lycopene does not seem to affect the risk of bladder cancer. Details: Epidemiological research and population studies have not established a link between dietary intake of lycopene or lycopene serum levels and the risk of bladder cancer (2407,60411,60496,60533).
• Diabetes. Increased dietary lycopene intake does not seem to reduce the risk of diabetes or diabetic complications. Details: Population research has found that increasing intake of dietary lycopene does not decrease the risk of developing type 2 diabetes (14004,14361). Other epidemiological research in patients with type 2 diabetes has found that an increased serum concentration of lycopene is not associated with reduced cardiovascular mortality over 14 years (109768).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral lycopene is beneficial in patients with AMD; the available evidence is conflicting. Details: Some observational research has found that lycopene serum levels in the lowest quintile are associated with an almost two-fold increased risk for AMD when compared with levels in the highest quintile (6110). However, other population research has found no association between lycopene serum levels or dietary lycopene intake and the risk of developing AMD (5922,10902,14007,60585).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if dietary lycopene helps to prevent ALS. Details: Population research has found that the highest quintile of total dietary carotenoid intake is associated with a 25% lower risk of ALS when compared with the lowest quintile. However, no association was found for lycopene intake alone (90412).
• Asthma. It is unclear if oral lycopene reduces asthma exacerbations or prevents asthma. Details: Some preliminary clinical research in adults with stable asthma shows that taking a specific tomato extract product (Lyc-O-Mato, LycoRed Natural Products Industries, Ltd.) providing lycopene 15 mg three times daily orally for up to 14 weeks does not reduce asthma exacerbations when compared with placebo (60482). However, other observational research has found that a higher dietary intake of lycopene is associated with at least a 20% lower odds of having asthma when compared with a lower dietary intake (109765). The effects of lycopene supplements are unclear.
• Atherosclerosis. It is unclear if oral lycopene is beneficial in patients with atherosclerosis. Details: Some observational research has found that higher serum lycopene levels are associated with a lesser degree of aortic or carotid atherosclerosis (1446,60329,60463). Some observational research has also found that higher serum lycopene levels are associated with a lower risk of coronary heart disease and myocardial infarction in people with atherosclerosis (7897,60538). However, there does not seem to be a link between serum lycopene levels and the risk of ischemic stroke (1449).
• Benign prostatic hyperplasia (BPH). Small studies suggest that lycopene products might improve BPH symptoms. Details: While epidemiological evidence has not found an association between dietary lycopene and the development of BPH (60365), clinical research suggests that lycopene might improve BPH-related symptoms. One small clinical study in patients with BPH shows that taking lycopene (LycoVit powder, BASF) 15 mg daily for 6 months slows the progression of BPH and improves symptom scores when compared to baseline (60399). This finding is limited by the lack a statistical comparison to the control group. Research also suggests that combination products containing lycopene might improve BPH symptoms. These products have combined lycopene 2.1 mg with pumpkin seed oil 160 mg, small-flowered willow herb 500 mg, pygeum 15 grams, and saw palmetto 660 mg (ProstateEZE Max, Caruso's Natural Health) once daily for 3 months (92164); and lycopene 5 mg with saw palmetto 320 mg and selenium 50 mcg (Profluss, KonPharma) daily for 1 year (90354).
• Brain tumor. It is unclear if oral lycopene is beneficial for various types of brain tumor. Details: A small clinical study in patients with glioblastoma multiforme or anaplastic astrocytoma shows that taking lycopene 8 mg orally daily for 3 months does not improve the response to radiotherapy and paclitaxel when compared with placebo (60441).
• Breast cancer. It is unclear if oral lycopene reduces the risk of breast cancer. Details: Some observational research has found that higher levels of lycopene in the blood and breast adipose tissue are associated with reduced breast cancer risk (10132,34634,60549,60555). However, other epidemiological research has found that neither dietary lycopene intake nor lycopene serum levels are associated with breast cancer risk (10823,15751,60344,60468,60541). Also, some population research has found that there is a possible relationship between low serum lycopene levels and an increased risk of breast cancer in Black females, but not White females (60325).
• Cardiovascular disease (CVD). It is unclear if oral lycopene reduces the risk of CVD. Details: Most epidemiological research has found that higher serum levels of lycopene and increased dietary lycopene intake are associated with modestly reduced risk of adverse cardiovascular events, including reduced incidence of coronary heart disease, myocardial infarction, stroke, and mortality (7897,9594,10418,15749,60538,102178,109434). However, evidence from clinical trials shows that lycopene may not improve most risk factors for CVD. Meta-analyses of clinical research in healthy adults or patients with at least one cardiovascular risk factor show that taking lycopene 1.44 to 75 mg daily does not improve blood pressure, lipid levels, or endothelial function when compared with control (95777,105575). These findings are limited by the heterogeneity of the included trials.
• Cataracts. It is unclear if oral lycopene is beneficial for reducing the risk of cataracts. Details: One epidemiological study has found that serum lycopene levels are inversely associated with the risk of developing cataracts (60203). However, other population studies have found no association between lycopene serum levels or dietary intake of lycopene and the development of cataracts (3219,3220,60299).
• Cervical cancer. It is unclear if oral lycopene reduces the risk of cervical cancer. Details: Epidemiological research has found that higher serum lycopene levels or higher dietary lycopene intake is associated with a reduced risk of cervical intraepithelial neoplasia and invasive cervical cancer (60429,60430,60439,60566). However, other studies have not shown this association (60388,60517,60521).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with prostatitis and chronic pelvic pain syndrome shows that taking a specific combination of lycopene 5 mg with selenium 50 mcg and saw palmetto 320 mg (Profluss, KonPharma) daily for 8 weeks reduces pain scores by 52%, compared with a 26% reduction with saw palmetto alone (60442). It is unclear if this effect is due to lycopene, the other ingredients, or the combination.
• Cognitive function. It is unclear if oral lycopene is beneficial for improving cognitive function and memory. Details: Observational research in healthy adults has found that consuming more lycopene in the diet over 22 years is associated with lower odds of poor cognitive function (104468).
• Colorectal cancer. It is unclear if lycopene reduces the risk for colorectal cancer; the available research is conflicting. Details: Some population research has found that the highest tertile of dietary lycopene intake is associated with a 50% reduced risk for colorectal cancer when compared with the lowest tertile (2407,38845). However, other epidemiological research has found no association between dietary lycopene intake and the risk of colorectal cancer, regardless of smoking status, drinking status, geographical location, gender, and tumor location (3962,34542,95778).
• Esophageal cancer. It is unclear if oral lycopene is beneficial for preventing esophageal cancer. Details: A meta-analysis of population research has found that high dietary intake of lycopene is associated with a 25% reduced odds of developing esophageal squamous cell carcinoma when compared with low dietary intake of lycopene (91159).
• Exercise-induced asthma. It is unclear if oral lycopene is beneficial for preventing exacerbations of exercise-induced asthma. Details: One very small clinical trial in children and adults with exercise-induced asthma shows that taking a specific tomato extract product (Lyc-O-Mato, LycoRed Natural Products Industries, Ltd.) providing lycopene 30 mg daily for 1 week seems to reduce the incidence of exercise-induced asthma exacerbations, but does not improve certain measures of lung function, when compared to baseline (7898). However, another very small study in adolescent athletes with exercise-induced asthma shows that taking the same product and dose for 1 week does not improve post-exercise lung function or reduce exacerbations when compared with placebo (60358). This study may have been underpowered to detect a difference between groups.
• Exercise-induced muscle damage. Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adult long-distance runners shows that taking a combination product (Lycored Ltd.) containing lycopene 5 mg, other carotenoids 4 mg, folic acid 0.1 mg, tocopherols 4 mg, and rosemary extract orally once daily for 4 weeks reduces muscle damage associated with a 2-hour run when compared with placebo (98825).
• Gastric cancer. It is unclear if oral lycopene reduces the risk of gastric cancer. Details: Preliminary observational research in adult males has found that high dietary intake of lycopene is associated with 0.87 lower odds of having stomach cancer when compared with low dietary intake (109436).
• Gingivitis. Small studies suggest that ingesting or injecting oral lycopene products might improve gingivitis. Details: Preliminary clinical research shows that taking a specific oral lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 8 mg daily for 2 weeks, or receiving a single injection of lycopene gel 2 mg into the gums, reduces gingivitis when compared with placebo (60400,60473). However, using a combination product (Lycotas, Intas Pharmaceuticals) containing lycopene 2 mg, vitamin C 50 mg, vitamin A 2500 units, zinc sulfate 20.6 mg, and chromium picolinate 75 mcg orally twice daily for 2 weeks does not improve moderate gingivitis or mild to moderate periodontitis when compared with placebo in people who have also undergone scaling and root planning (92172).
• Helicobacter pylori. It is unclear if oral lycopene helps to eradicate H. pylori. Details: A small clinical study in patients diagnosed with H. pylori shows that adding lycopene 30 mg daily for 1 month to standard therapy with metronidazole, amoxicillin, omeprazole, and bismuth does not increase the rate of H. pylori elimination when compared with standard therapy alone (60480).
• Human papillomavirus (HPV). It is unclear if oral lycopene is beneficial in patients with HPV. Details: Epidemiological research in females has found that higher plasma levels of lycopene are associated with a faster rate of oncogenic HPV clearance, with an average of 8.5 months, when compared with lower levels of plasma lycopene, with an average of 11-12 months (12177).
• Hyperlipidemia. Most research shows that oral lycopene doesn't reduce low-density lipoprotein (LDL) cholesterol levels; however, effects on other lipid levels are unclear. Details: A subgroup meta-analysis of 3 small clinical studies in adults with hyperlipidemia shows that taking lycopene 7-15 mg daily or tomato juice containing lycopene 2.5 mg 4 times weekly for 8 weeks does not improve LDL cholesterol levels when compared with control (105575). Another subgroup meta-analysis of 9 studies in adults without hyperlipidemia shows that consuming lycopene, in supplements or in tomato products, also does not seem to reduce LDL cholesterol levels when compared with both active and inactive controls (105575). This finding is limited by the heterogeneity of interventions and patient populations. In contrast, one small clinical study in Japanese patients with borderline high cholesterol shows that taking 50 grams of a semi-dried tomato containing lycopene 22-27.8 mg daily for 12 weeks modestly reduces LDL cholesterol levels, but does not affect high-density lipoprotein (HDL) cholesterol levels, when compared with taking 50 grams of tomato without lycopene (102180). Subgroup meta-analyses also show that taking lycopene does not reduce triglyceride levels or improve HDL cholesterol levels (105575). However, a meta-analysis of 14 small clinical trials including healthy subjects and subjects with metabolic disorders shows that taking lycopene 6-75 mg orally daily for 1 week to 6 months moderately improves both HDL cholesterol and triglyceride levels when compared with control. A subgroup analysis suggests lycopene may improve lipid levels in unhealthy, but not healthy, subjects. However, the validity of this study is limited by high heterogeneity and the exclusion of LDL cholesterol levels from the analysis (109431). Also, a clinical study in patents with ischemic heart failure shows that taking lycopene 25 mg daily for 8 weeks modestly reduces levels of triglycerides (109773). In postmenopausal females, taking a specific lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 4 mg orally twice daily for 6 months also modestly increases triglyceride levels (109694). However, there was no effect on other lipid levels in either of these studies (109694,109773).
• Hypertension. Small clinical studies suggest that some lycopene products might reduce blood pressure in patients with hypertension. However, lycopene does not seem to reduce the risk for hypertension. Details: Observational research has found no link between serum lycopene levels and the risk for hypertension (60419). Additionally, lycopene supplements do not seem to reduce blood pressure in patients without hypertension or with pre-hypertension (42079,105572,105575). However, some clinical research suggests that lycopene may be beneficial for lowering blood pressure in people with hypertension. A network meta-analysis of 4 small clinical trials in patients with hypertension shows that taking standardized tomato extract containing lycopene 10-30 mg daily for 4-12 weeks reduces systolic and diastolic blood pressure by about 8 mmHg and 4 mmHg, respectively, when compared with placebo. This benefit was not seen with supplements containing only lycopene or tomato products without standardized lycopene content (105572). Specific tomato extract products (Lyc-O-Mato or Tomato Nutrient Complex, LycoRed, Ltd.), were used in some studies (60415,102182).
• Lung cancer. It is unclear if oral lycopene is beneficial in patients with lung cancer. Details: Some epidemiological research has found that higher dietary lycopene intake or serum levels are linked to a decreased risk of lung cancer (2595,60332,60363,60550). However, other epidemiological research has found no association between dietary intake or blood levels of lycopene and lung cancer risk (60316,60520,60522,60554).
• Male infertility. It is unclear if oral lycopene is beneficial in male patients with infertility. Details: A small clinical study in males with idiopathic infertility shows that taking lycopene 2 mg orally twice daily for 3 months improves sperm concentration, motility, and morphology when compared with baseline (60340). The validity of this finding is limited by the lack of a control group.
• Melasma. Topical lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with melasma shows that applying a sunscreen cream containing lycopene 0.05% and wheat bran extract 3.45% twice daily for 12 weeks seems to modestly reduce the severity of melasma, but not the area of affected skin, when compared with a placebo cream (105569).
• Menopausal symptoms. Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with menopausal symptoms shows that taking a specific oral combination of lycopene with calcium, vitamin D3, astaxanthin, and citrus bioflavonoids (Cor.Con. International) daily for 8 weeks reduces hot flashes, incontinence, joint pain, anxiety, and depression when compared with no treatment (19198). It is not clear if this effect is due to lycopene, other ingredients, or the combination.
• Obesity. It is unclear if a diet high in lycopene helps to reduce weight. Details: A small clinical study in obese adults shows that ingesting a drink with a carrot paste containing lycopene 7.6-8.6 mg, along with either high-lutein kale paste or low-lutein cabbage paste, daily for 8 weeks does not reduce body weight or waist circumference, but seems to modestly reduce the amount of visceral fat, when compared with baseline (105574). This finding is limited due to a lack of comparison to the control group, which consumed a carrot paste containing no lycopene.
• Oral leukoplakia. It is unclear if oral lycopene is beneficial in patients with oral leukoplakia. Details: A small clinical study in patients with oral leukoplakia shows that taking a specific lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 2-4 mg orally twice daily for 3 months improves clinical and histological symptoms in a dose-dependent manner when compared with placebo (15748). Preliminary clinical research also shows that taking lycopene 6 mg, along with vitamin E 400 IU and selenium 200 mcg twice daily, for 3 months has a large beneficial effect on lesion size when compared with placebo (109772).
• Oral submucous fibrosis. Small studies suggest that oral lycopene might slightly improve mouth opening in patients with oral submucous fibrosis. It is unclear if lycopene reduces pain or burning sensation. Details: A meta-analysis of 5 small clinical studies in patients with oral submucous fibrosis, usually from chewing betel nuts and/or tobacco, shows that taking lycopene 4-8 mg twice daily for 1-3 months seems to improve maximal mouth opening, but not pain, when compared with control (105570). Clinical studies reported an average mouth opening increase of 3.5-4 mm when compared to baseline (60381,98823,102181). It is unclear if this improvement is clinically significant. Furthermore, although two clinical studies using specific tomato extracts (LycoRed, Jagsonpal Pharmaceuticals; MintovitL by Obsurge Biotech Limited) show that lycopene also reduces the burning sensation in the mouth (98823,102181), the meta-analysis did not confirm this benefit (105570). All of the available studies have been conducted in India and Saudi Arabia; it is unclear if these results are generalizable to other locations.
• Osteoporosis. It is unclear if oral lycopene reduces the risk of osteoporosis. Details: Population research in adults at least 50 years of age has found that high dietary intake of lycopene is not associated with bone mineral density or osteoporosis risk when compared with low dietary intake (107289).
• Ovarian cancer. It is unclear if oral lycopene reduces the risk of ovarian cancer. Details: Some epidemiological evidence has found that a diet rich in carotenoids, including lycopene, is associated with a decreased risk of premenopausal ovarian cancer (10133). However, other epidemiological research has found no association (60373,60534).
• Overall mortality. It is unclear if oral lycopene reduces the risk of overall mortality. Details: Preliminary observational research in adults undergoing cancer screening has found that moderate dietary intake of lycopene, defined as 5.61-8.43 mg daily, is associated with a lower risk of overall mortality and cardiovascular disease-related mortality when compared with low dietary intake of lycopene, defined as less than 2.79 mg daily. However, higher dietary intake of lycopene of 8.44 mg or greater was not associated with mortality risk (109434).
• Pancreatic cancer. It is unclear if oral lycopene helps to prevent pancreatic cancer. Details: Epidemiological research has found that high dietary intake of lycopene is associated with a reduced risk of pancreatic cancer. Intake in the highest quartile was associated with a 31% reduction in risk when compared with the lowest quartile (15750).
• Parkinson disease. It is unclear if oral lycopene helps to prevent Parkinson disease. Details: Epidemiological research has found that neither dietary intake nor blood levels of lycopene is associated with the risk of developing Parkinson disease (91164).
• Polymorphous light eruption (PMLE). Oral lycopene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with PMLE shows that taking a combination of lycopene 2.5 mg, beta-carotene 4.7 mg, and Lactobacillus johnsonii 500 million CFU (Inneov Sun Sensitivity, Laboratoires Innéov) daily for 12 weeks reduces skin lesion severity after a single exposure to light when compared with placebo (90276). It is not clear if this effect is due to lycopene, other ingredients, or the combination.
• Pre-eclampsia. It is unclear if oral lycopene is beneficial in patients with pre-eclampsia. Details: Epidemiological research has found that the highest intake of lycopene during pregnancy is associated with 45% reduced odds of having pre-eclampsia when compared with the lowest intake (109762). However, results from clinical research are mixed. One clinical study in healthy primigravidae shows that taking a specific oral lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) 2 mg twice daily, starting between weeks' 16 and 20 of pregnancy and continuing until delivery, lowers mean diastolic blood pressure and reduces the incidence of pre-eclampsia, intra-uterine growth retardation, and preterm labor when compared with placebo (60337). However, another clinical study in this same population shows that taking this same lycopene supplement only once daily, starting between weeks' 12 and 20 of pregnancy, does not reduce the incidence of pre-eclampsia when compared with placebo. Furthermore, the rates of preterm labor and low birth weight were higher in those taking lycopene when compared with placebo (60428). The reasons for these conflicting findings are unclear; larger, high-quality studies are needed to clarify these findings.
• Renal cell carcinoma. It is unclear if oral lycopene reduces the risk for renal cell carcinoma. Details: Observational research has found no association between dietary lycopene intake and the risk of developing renal cell carcinoma (60379).
• Sunburn. Small studies suggest that consuming tomato paste with oral lycopene might prevent sunburn. Details: Small clinical studies in healthy volunteers shows that taking lycopene 10-16 mg daily for 12 weeks, in the form of tomato paste or a tomato extract (Lyc-O-Mato), may provide some protection against experimentally-induced sunburn when compared to baseline or control (23012,60324,60452). More evidence is needed to rate lycopene for these uses.

(Read more about LYCOPENE)

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Intranasal resveratrol seems to be beneficial for reducing allergic rhinitis symptoms in adults and children. Details: Some clinical research shows that intranasal resveratrol with carboxymethyl-beta-glucan can improve symptoms of allergic rhinitis (91332,97339). One clinical study in adults with allergic rhinitis shows that using an intranasal spray containing resveratrol 0.1% three times daily for 4 weeks reduces nasal symptoms and improves quality of life scores when compared with placebo (97339). A study in children aged 4-17 years with pollen-induced allergic rhinitis shows that using an intranasal spray containing resveratrol 0.05% three times daily for 2 months improves itching, sneezing, runny nose, and nasal obstruction and reduces use of rescue medication when compared with placebo (91332).
• Obesity. Oral resveratrol seems to be beneficial for weight loss in individuals with overweight or obesity. However, it is unlikely to be beneficial for improving most metabolic parameters in this population. Details: A meta-analysis of 28 clinical trials shows that taking resveratrol modestly decreases body weight by 0.5 kg, body mass index (BMI) by 0.17 kg/m2, and waist circumference by 0.8 cm when compared with placebo or no intervention. This analysis included studies of individuals with normal weight, overweight, and obesity, with or without type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, or other chronic conditions. A subgroup analysis suggests that individuals with obesity have a greater response to resveratrol. In these individuals, taking resveratrol 8-3000 mg daily resulted in an average weight reduction of 1.15 kg and a BMI reduction of 0.3 kg/m2 when compared with placebo. The greatest impact on body weight and BMI occurred with resveratrol doses of no more than 500 mg daily and treatment durations of at least 3 months (100696). However, it is unclear whether any improvements are clinically significant.

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Oral resveratrol does not seem to be beneficial for CVD prevention. Details: Population research suggests that a higher dietary intake of resveratrol is not associated with a reduced risk of CVD when compared with a lower dietary intake (91334). Also, a meta-analysis of clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides in patients at high risk for CVD (91333). While one preliminary clinical study shows that taking resveratrol 10 mg daily for 3 months improves left ventricular function by about 1% and endothelial function when compared to baseline in patients with a history of myocardial infarction and coronary artery disease, the improvements are very small and blood pressure and markers of inflammation do not appear to be improved (91330).
• Hypercholesterolemia. Oral resveratrol does not seem to be beneficial for hypercholesterolemia. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving blood lipids when compared with placebo in patients with hypercholesterolemia. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), angina, and dyslipidemia (105181). Although there was a small reduction in total cholesterol levels of approximately 7 mg/dL, resveratrol did not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (105181). Also, an analysis of results from clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides in patients at high risk for cardiovascular disease (91333). Also, clinical research in healthy humans shows that taking resveratrol 500 mg orally daily for 30 days increases levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B (112944). Another meta-analysis identified more promising results; however, any effect on blood lipids may not be considered clinically significant. This meta-analysis included 17 clinical studies enrolling 968 participants with dyslipidemia, type 2 diabetes, coronary artery disease, overweight or obesity, or stroke. Resveratrol reduced total cholesterol by approximately 10 mg/dL, LDL by approximately 6 mg/dL, and triglycerides by approximately 9 mg/dL, but did not improve HDL, when compared with placebo. However, most of the included studies were small and utilized heterogenous dosing regimens, with doses ranging from 10-3000 mg daily for 4-48 weeks (110020).
• Metabolic syndrome. Oral resveratrol does not seem to be beneficial for metabolic syndrome. Details: A meta-analysis of clinical research shows that taking resveratrol does not improve blood pressure when compared with placebo in patients with metabolic syndrome or related disorders (102513). A similar meta-analysis shows that taking resveratrol does not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or liver enzymes. There was a small reduction in total cholesterol levels of approximately 7 mg/dL (105181). However, only 3-4 of the papers included in these meta-analyses, which included 28-31 publications, evaluated patients with metabolic syndrome. The remainder included patients with related conditions, such as overweight/obesity, type 2 diabetes, or nonalcoholic fatty liver disease (NAFLD). The mainly small or preliminary clinical studies that did evaluate patients with metabolic syndrome all show that taking resveratrol 100-1000 mg daily for 12-16 weeks does not improve blood pressure, glucose control, or plasma lipids (91331,95828,102513,105181). However, one preliminary clinical trial shows that taking resveratrol 500 mg three times daily for 3 months reduces body weight by about 4 kg, body mass index (BMI) by 1.3 kg/m2, fat mass by 2.4 kg, and waist circumference by 4 cm when compared to baseline (91331). The validity of these findings is limited by the lack of a comparator group. Also, a moderate-sized clinical trial of adults with metabolic syndrome shows that taking resveratrol 300 mg and delta-tocotrienols 500 mg daily for 24 weeks improves body weight, waist circumference, blood pressure, fasting blood glucose, triglycerides, total and HDL cholesterol, and markers of inflammation and oxidative stress when compared with placebo (112144). It is unclear if these effects are due to resveratrol, delta-tocotrienols, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Oral resveratrol does not seem to be beneficial for most metabolic symptoms of NAFLD. It is unclear if oral resveratrol is beneficial for improving steatosis. Details: Although some individual studies disagree, meta-analyses reviewing 4-6 preliminary clinical studies show that taking resveratrol does not affect liver enzyme levels, insulin resistance, blood pressure, blood lipids, body mass index (BMI), or abdominal size when compared with placebo in patients with NAFLD (95826,99048,105184). Most trials have studied doses of 300-3000 mg daily for 2-3 months; one study used resveratrol 500 mg 3 times daily for 6 months (95826,98911,99048,105184). However, one meta-analysis shows that taking resveratrol might have a small effect on levels of the inflammatory mediators C-reactive protein and tumor necrosis factor (TNF)-alpha (105184). It is not clear if resveratrol might reduce steatosis in patients with NAFLD. One preliminary clinical study shows that taking resveratrol 3000 mg daily in two divided doses for 8 weeks does not improve steatosis when compared to baseline in males with NAFLD (91327). However, another preliminary clinical study in adults with NAFLD shows that taking resveratrol 500 mg daily for 3 months, while following an energy-balanced diet and exercising, improves steatosis, but not fibrosis, insulin resistance, lipid levels, or body composition, when compared with lifestyle modifications alone (91328). The difference in these findings might be due to small study sizes, the duration of therapy, or the gender of the included patients.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical resveratrol is beneficial for acne. Details: Preliminary clinical research shows that applying a gel containing trans-resveratrol 1 mcg per gram to facial skin for 60 days reduces the severity of acne by about 54%, compared to only 6% for control gel (71064).
• Age-related cognitive decline. It is unclear if oral resveratrol is beneficial for age-related cognitive decline. Details: One small clinical study shows that taking resveratrol 75 mg twice daily for 14 weeks modestly improves cognitive performance and memory after menopause, but not executive function or learning, when compared with placebo (95827). Another small clinical study in healthy, older adults shows that taking resveratrol 200 mg daily for 26 weeks improves memory retention, but not delayed recall or word recognition, when compared with placebo. In this study, resveratrol capsules were formulated to also contain 320 mg of quercetin to enhance the absorption of resveratrol (102511). It is unclear if resveratrol alone would result in similar effects. Despite these positive results, conflicting research exists. A small clinical study in sedentary, overweight, elderly adults shows that taking resveratrol 300 mg daily for 90 days does not improve measures of cognitive function such as psychomotor speed, attention, executive function, learning, or memory when compared with placebo. Taking a higher dose of 1000 mg daily for 90 days modestly improves psychomotor speed, but no other cognitive measures, in these patients (98907). Another small clinical study in healthy elderly adults shows that taking resveratrol 200 mg daily for 26 weeks does not improve verbal memory when compared with placebo (98909).
• Aging skin. Although there has been interest in using oral resveratrol for aging skin, there is insufficient reliable information about the clinical effects of resveratrol for this purpose.
• Alzheimer disease. It is unclear if oral resveratrol is beneficial for improving symptoms of Alzheimer disease. Details: A meta-analysis of small clinical studies in patients with Alzheimer disease shows that taking resveratrol or trans-resveratrol up to 500 mg daily for 12 to 52 weeks improves the ability to perform activities of daily living but does not change cognitive function when compared with placebo (114517).
• Beta-thalassemia. It is unclear if oral resveratrol is beneficial for beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia intermedia shows that taking micronized trans-resveratrol (Xian Tianxingjian Natural Bio-Products CO., LTD) 2000 mg with piperine (Bioprex Co.) 40 mg, with or without hydroxyurea 8-15 mg/kg, daily for 6 months does not improve hemoglobin levels or affect the need for blood transfusion when compared with taking placebo with or without hydroxyurea (98908).
• Cancer. It is unclear if dietary resveratrol is beneficial for cancer prevention. Details: Population research has found that a higher dietary intake of resveratrol is not associated with a reduced risk of cancer when compared to lower dietary intake (91334).
• Chronic obstructive pulmonary disease (COPD). Oral resveratrol 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 resveratrol 10 mg, vitamin C 180 mg, zinc 15 mg, and flavonoids 160 mg daily for 20 days followed by 10 days without supplementation, repeated for three cycles, modestly reduces symptoms of cough and sputum production in patients with mild-to-moderate COPD when compared with control (71130). It is not clear if these effects are due to resveratrol, the other ingredients, or the combination.
• Cognitive function. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy young adults shows that taking a specific supplement (Transmax by BiotiviaTM) containing trans-resveratrol 500 mg and piperine 10 mg daily for 28 days does not improve most measures of cognitive performance when compared with placebo (95834).
• Cognitive impairment. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in a small number of patients with mild cognitive impairment shows that taking resveratrol 200 mg and quercetin 350 mg daily for 26 weeks does not improve learning and memory performance when compared with placebo (102512). However, given the small sample size, it is possible this study was inadequately powered to detect significant changes in these cognitive measures.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral resveratrol is beneficial for COVID-19. Details: A small clinical trial in outpatients with COVID-19 shows that taking resveratrol (Vita-Age) 1 gram four times daily, for 7-15 days based on symptom duration, does not reduce the rate of hospitalization, emergency room visits, or pneumonia when compared with placebo. All patients also received a single dose of Vitamin D3 (109164). This study may have been inadequately powered to detect differences between groups.
• Diabetes. Some research shows that oral resveratrol is beneficial for improving glycemic indices in patients with type 2 diabetes. However, more research is needed to determine the most effective dose or the patient population most likely to benefit. Details: Although results from individual clinical studies have been mixed (91329,95825,95832,100695,109165,109167,109170), meta-analyses of clinical research show that resveratrol modestly reduces blood glucose and glycated hemoglobin (HbA1c) levels in patients with diabetes. Studies lasted 4-24 weeks and many included patients treated with antidiabetes medications, including metformin. However, these meta-analyses have yielded differing findings regarding effective doses (91329,109165,109167,109170). One meta-analysis of clinical research in individuals aged 45 years and older shows that doses of 250-1000 mg daily modestly reduce levels of fasting blood glucose, insulin, and HbA1c, as well as insulin resistance, when compared with placebo. Doses of up to 250 mg daily are generally ineffective, and only one study used doses greater than 1000 mg daily. Although sub-analyses suggest that these benefits may be limited to individuals aged 45-59 years, the number of studies in older individuals is small and findings are unclear (109165). A second meta-analysis in adults with type 2 diabetes suggests that resveratrol doses of at least 500 mg daily were necessary for reducing levels of fasting blood glucose and insulin, as well as insulin resistance (109167). A third meta-analysis, which also included Chinese language publications, shows that doses of resveratrol of at least 1000 mg daily are needed for improved glycemic control (109170). Some studies have used a specific resveratrol product (Biotivia Bioceuticals, International SrL) (95825). Although the reasons for discrepancies between individual clinical trials are not clear, it is possible that conflicting results are related to baseline blood glucose control. Resveratrol has shown benefit in patients with diabetes that is not well-controlled at baseline (HbA1c of 8% or higher) (91329), while results are mixed in patients with diabetes that is at least moderately well-controlled prior to supplementation (HbA1c of 7% or lower) (95825,100695). It is also possible that the differences may relate to the technique used to measure outcomes. For instance, resveratrol appears to improve insulin resistance when measured by the Stumvoll insulin sensitivity index, but not by the gold-standard hyperinsulinemic-euglycemic clamp technique (95832). Resveratrol has also been evaluated for improving blood pressure, blood lipid, and liver transaminase levels in patients with type 2 diabetes. Meta-analyses of clinical trials show that resveratrol has a small, but likely clinically insignificant, effect on systolic blood pressure when compared with placebo. Two meta-analyses show similar findings for diastolic blood pressure; however, some research suggests that any benefits are limited to doses of at least 500 mg daily (102513,109167,109170). Most meta-analyses of clinical research show that resveratrol does not improve blood lipid levels (105181,109167,109170) or liver transaminase levels (105181) when compared with placebo. Other clinical research in patients with overweight and type 2 diabetes shows that taking resveratrol 1000 mg daily for 8 weeks does not affect hepatic steatosis or cardiovascular risk indices when compared with placebo (109169).
• Diabetic nephropathy. It is unclear if oral resveratrol is beneficial for diabetic nephropathy. Details: Preliminary clinical research in patients with diabetic nephropathy shows that taking resveratrol 500 mg plus losartan 12.5 mg daily for 90 days can reduce urinary albumin-to-creatinine ratios, but not serum creatinine levels or glomerular filtration rates, when compared with taking placebo and losartan. When compared to baseline, the urinary albumin-to-creatinine ratio decreased by 46 mg/gram with resveratrol and increased by 25 mg/gram with placebo (100695).
• Hypertension. It is unclear if oral resveratrol is beneficial for lowering blood pressure. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving systolic or diastolic blood pressure when compared with placebo in patients with hypertension. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), stroke, and dyslipidemia (102513). More research is needed in patients with hypertension.
• Migraine headache. It is unclear if oral resveratrol is beneficial for treating migraine headache. Details: A small clinical crossover study in patients with hormonal migraine headaches shows that taking resveratrol (Veri-te Resveratrol, Evolva SA) 75 mg twice daily for 3 months does not affect headache frequency, severity, or disability when compared with placebo (109166). However, this study did not include a wash-out period between treatments, introducing the potential for carry-over effects.
• Mitochondrial myopathies. It is unclear if oral resveratrol is beneficial for increasing exercise tolerance in patients with mitochondrial myopathies. Details: A very small clinical trial in adults with mitochondrial myopathies shows that taking resveratrol (Veri-te resveratrol) 500 mg twice daily for 8 weeks does not improve exercise capacity when compared with placebo (109162). This study may have been inadequately powered to detect differences between groups.
• Osteoarthritis. It is unclear if oral resveratrol is beneficial for osteoarthritis. Details: A small clinical study in patients with mild or moderate knee osteoarthritis receiving physical therapy and meloxicam 15 mg daily shows that adding resveratrol 500 mg daily for 90 days improves pain, function, and stiffness when compared with adding placebo (98910).
• Osteopenia. It is unclear if oral resveratrol is beneficial for improving bone mineral density (BMD). Details: A meta-analysis of clinical research shows that taking resveratrol at doses of up to 1500 mg daily for 1-12 months does not increase BMD or alter bone biomarkers when compared with placebo (109163). The studies in this meta-analysis included various populations, such as postmenopausal or overweight individuals, or patients with type 2 diabetes or metabolic syndrome. However, a clinical study in healthy, postmenopausal females shows that taking fermented soy 200 mg, containing resveratrol 25 mg and equol 10mg, orally daily for 12 months increases whole-body BMD when compared with placebo. Levels of markers of bone formation, including osteocalcin and bone-specific alkaline phosphatase, are increased, and the level of deoxypyridinoline, a marker of bone resorption, is decreased (112942).
• Periodontitis. It is unclear if oral resveratrol is beneficial for periodontitis. Details: A small clinical study in individuals with chronic moderate-to-severe periodontitis who recently received non-surgical treatment for periodontitis shows that taking resveratrol 480 mg daily for 4 weeks improves plaque index when compared with placebo, but resveratrol does not seem to improve other markers of periodontitis, including pocket depth, bleeding index, clinical attachment loss, or salivary markers of inflammation (112135). The study may have been inadequately powered and too short in duration to detect a difference between the groups.
• Peritoneal dialysis. It is unclear if oral resveratrol can improve outcomes with peritoneal dialysis. Details: One clinical study shows that taking trans-resveratrol 150 mg or 450 mg daily for 12 weeks increases ultrafiltration rate and volume when compared with placebo in patients on peritoneal dialysis. The effect appears to be dose-dependent (95830).
• Polycystic ovary syndrome (PCOS). It is unclear if oral resveratrol is beneficial for PCOS. Details: Clinical research in patients with PCOS shows that taking resveratrol 1000 mg daily for 3 months results in a regular menstruation cycle length in 77% of individuals, compared with 52% of those taking placebo. The occurrence of hair loss was reduced by about 50%; however, there was no effect on hormone, metabolic, or lipid profiles. There was also a small increase in fat mass and decrease in fat-free mass, although the clinical relevance of these changes is unclear (109131). A small clinical trial in adults with PCOS shows that taking micronized trans-resveratrol (RevGenetics) 1500 mg daily for 3 months decreases levels of testosterone, but does not improve weight, lipid levels, insulin sensitivity, acne, or hirsutism, when compared with placebo (95823). A meta-analysis of 4 controlled trials of resveratrol, taken orally in doses of 800-1500 mg daily for 40 days to 3 months, shows reductions in levels of testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate when compared with placebo, but no effect on follicle stimulating hormone, prolactin, thyroid stimulating hormone, C-reactive protein, insulin, sex hormone binding globulin, lipids, acne, or pregnancy rates (112943).
• Rheumatoid arthritis (RA). It is unclear if oral resveratrol is beneficial for RA. Details: A small clinical study shows that adding resveratrol 1 gram orally once daily as adjunct therapy to antirheumatic drugs for 2 months reduces the number of tender and swollen joints, as well as biomarkers of inflammation. It is not known whether resveratrol reduces joint damage when assessed using conventional radiography. Also, the most effective combination of resveratrol and antirheumatic drug is not known, since the patients in this study were taking different antirheumatic drugs at variable doses (95706).
• Sciatica. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with sciatica secondary to a herniated disk shows that taking a combination of resveratrol 50 mg with alpha-lipoic acid, acetyl-L-carnitine, and cholecalciferol orally once daily for 30 days, concurrently with a physiotherapy protocol, reduces pain and disability, and improves quality of life when compared with the physiotherapy protocol alone (112933). It is unclear if the effects are due to resveratrol, other ingredients, or the combination.
• Ulcerative colitis. It is unclear if oral resveratrol is beneficial for ulcerative colitis. Details: Preliminary clinical research shows that taking trans-resveratrol (Sumabe Company) 500 mg daily for 6 weeks reduces subjective measures of disease activity and improves quality of life measures when compared with placebo in patients with mild to moderate active ulcerative colitis (95831). However, a small clinical trial in patients with mild to moderate active ulcerative colitis shows that taking resveratrol (VeNatura Resveratrol Supplement) 250 mg twice daily for 8 weeks, while following the Mediterranean diet, is not more effective for improving ulcerative colitis symptom severity than following the Mediterranean diet without supplemental resveratrol (113339). More evidence is needed to rate resveratrol for these uses.

(Read more about RESVERATROL)

LIKELY EFFECTIVE

• Selenium deficiency. Oral selenium is effective for the treatment and prevention of selenium deficiency. Details: Selenium supplementation is effective for reversing symptoms of selenium deficiency, as well as for preventing the development of selenium deficiency (4844,90357).

POSSIBLY EFFECTIVE

• Autoimmune thyroiditis. Oral selenium seems to improve autoimmune thyroiditis in adults, but the evidence of benefit in children is conflicting. Details: A meta-analysis of mostly small, low-quality clinical and observational studies in children and adults with Hashimoto thyroiditis shows that taking selenium 83 mcg, selenomethionine 50 mcg or 200 mcg, or selenium 83 mcg with myoinositol 600 mg daily for 3 to 6 months reduces thyroid peroxidase antibody (TPOAb) levels and thyroglobulin antibody (TgAb) levels after 6 months of treatment when compared with baseline or placebo. However, there was no change in thyroid antibody levels at 3 months, suggesting a longer duration of 6 months is needed to sufficiently reduce serum antibody levels. Additionally, subgroup analysis suggests that patients with higher baseline thyroid antibody levels might benefit more from selenium supplementation compared to those with lower baseline thyroid antibody levels (113645). The validity of these effects is limited by high heterogeneity between baseline thyroid antibody levels amongst the included studies. Additionally, clinical research in adults with thyroiditis shows that taking selenium up to 200 mcg daily in combination with levothyroxine reduces TPOAbs by about 6% to 30% more than placebo after 3-12 months of treatment (9797,17510,17511,17512,17513,17515,17516,97943,104424). Selenium also seems to improve measures of quality of life such as feelings of well-being and mood (17515). Doses under 200 mcg daily might not be as effective (17512); selenomethionine might be more effective than sodium selenite (97943). Some research shows that selenium might be more effective in patients with more severe disease activity and less effective in patients with only moderate disease activity (9797,17513,17515). Also, selenium might not reduce TPOAbs in patients newly diagnosed with thyroiditis not receiving concurrent levothyroxine (97943). There is no reliable evidence about the effect of selenium on thyroid function or thyroid morphology. Despite positive findings in adults, most clinical research in children suggests that taking selenium 50-200 mcg daily for 3-12 months does not significantly improve TPOAb, TgAb, or thyroid echogenicity (17514,90362).
• Kashin-Beck disease. Selenium seems to help prevent Kashin-Beck disease, but does not improve symptoms in patients with existing disease. Details: A meta-analysis of prospective studies conducted in China shows that adding salt enriched with selenium to the diet of healthy children for up to 4 years reduces the odds of developing Kashin-Beck disease by 84% when compared with the use of iodine salt. Additionally, in children with Kashin-Beck disease, adding salt enriched with selenium to the diet might help heal metaphyseal lesions (97945). However, selenium does not seem to improve symptoms in those with existing disease. A clinical trial in children with Kashin-Beck disease shows that selenium supplementation does not improve joint pain or mobility when compared with placebo (55941).
• Pre-eclampsia. Oral selenium might reduce the risk of pre-eclampsia in pregnant patients. Details: A meta-analysis of three low-quality clinical trials in pregnant patients shows that taking selenium 60-100 mcg daily for up to 6 months reduces the risk of pre-eclampsia by 72% when compared with placebo. Additionally, a meta-analysis of population research has found that the risk of pre-eclampsia is higher in pregnant patients with low selenium levels. Selenium levels were about 6.5 mcg/L lower in those who developed pre-eclampsia compared with those who did not (97946).

POSSIBLY INEFFECTIVE

• Asthma. Oral selenium does not seem to improve asthma symptoms. Details: Epidemiological research has found that plasma selenium concentration is not associated with asthma (74422). Also, clinical research in patients with asthma shows that taking selenium 100 mcg daily for 14-24 weeks does not improve symptoms, lung function, use of rescue inhalers, or quality of life when compared with placebo (74490,74387).
• Atopic dermatitis (eczema). Oral selenium-enriched yeast does not seem to improve eczema symptoms. Details: A small clinical study in patients with eczema shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not improve symptom severity when compared with placebo (74456).
• Cardiovascular disease (CVD). Most research shows that oral selenium does not reduce the risk of CVD. Details: Meta-analyses of clinical trials in patients with and without risk factors for CVD show that taking selenium alone or with other supplements for up to 8 years does not reduce the risk of CVD mortality or fatal and non-fatal CVD events (90360,97078). When reported, patients in these studies all had adequate plasma selenium levels at baseline (90360).
• Colorectal cancer. Oral selenium does not seem to prevent cancer of the colon and rectum. Details: Epidemiological research has found no association between serum concentrations of selenium and the risk of developing colorectal cancer (74321,97085). Also, meta-analyses of clinical research, as well as individual clinical trials, show that taking selenium 100-200 mcg daily, alone or in combination with other vitamins and minerals, does not reduce the risk of colorectal cancer when compared with control (16707,34676,90361,97092).
• Dyslipidemia. Most research shows that oral selenium supplementation does not improve cholesterol levels. Details: A meta-analysis of 11 clinical studies in adults with dyslipidemia shows that taking selenium 50-300 mcg daily for 8-24 weeks does not increase high-density lipoprotein (HDL) cholesterol levels or decrease total or low-density lipoprotein (LDL) cholesterol levels when compared with placebo. Taking selenium might modestly improve triglyceride levels, but this improvement is unlikely to be considered clinically significant (99662). Another meta-analysis of 21 mostly small, low-quality clinical studies, some of which were included in the prior meta-analysis, shows that taking various forms of selenium may modestly decrease total cholesterol levels, but does not improve triglycerides, LDL, or HDL cholesterol when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which assessed various selenium dosing regimens and enrolled healthy patients or those with various cardiovascular and non-cardiovascular conditions.
• Low birth weight. Oral or intravenous selenium supplementation does not improve outcomes in low birth weight infants. Details: Low selenium levels have been documented in low birth weight infants. However, selenium supplementation, orally or intravenously, does not appear to improve most outcomes in low birth weight infants. Clinical research shows that administering selenium, either as 7-10 mcg/kg daily parenterally or 5 mcg/kg daily orally, does not improve oxygen dependency or reduce the risk of death in low birth weight infants when compared with placebo. However, supplementation decreases the incidence of sepsis by up to 33% (74288,97083).
• Lung cancer. Oral selenium does not reduce lung cancer risk in most patients. Details: While a large cohort study suggests that increased dietary intake of selenium is associated with a lower risk of lung cancer, supplemental selenium does not appear to have the same effect. Additionally, a meta-analysis of three large clinical trials of over 20,000 patients, including patients with resected stage I non-small-cell lung cancer, shows that taking selenium 200-400 mcg daily for up to 5 years does not reduce the risk of lung cancer when compared with control (92912,97092). A secondary analysis of one of these studies found that selenium supplementation might reduce lung cancer risk in people with selenium levels below 105 ng/mL (9798). Also, a large study in healthy Chinese patients shows no benefit of using selenium in combination with other nutrients for over 5 years when compared with control (34539).
• Nonmelanoma skin cancer. Oral selenium does not reduce the risk of nonmelanoma skin cancer and has been linked to increased risk in some patients. Details: Epidemiological research has found that higher selenium intake is not associated with a reduced risk of nonmelanoma skin cancer (97085). Furthermore, clinical research shows that taking selenium orally 200 mcg daily does not reduce the risk of basal cell carcinoma when compared with control (2664,10687). In addition, some evidence shows that daily selenium supplementation might increase the risk of squamous cell carcinoma and total non-melanoma skin cancer (10687).
• Prostate cancer. Oral selenium does not seem to reduce prostate cancer risk. Details: Population studies have found that higher serum or toenail selenium levels are associated with a decreased risk of prostate cancer (8734,8735,8736,92911,10263). However, clinical research does not support this finding. A meta-analysis of 5 large clinical trials of over 20,000 patients shows that selenium 200-400 mcg daily for up to 5 years does not reduce the risk of prostate cancer when compared with control (97092). A 7-14 year follow-up study of one of these trials shows there was still no reduction of prostate cancer risk (17688). Selenium has also shown no benefit when used in combination with other supplements. In a large-scale clinical study (SU.VI.MAX), taking selenium 100 mcg in combination with vitamin C, vitamin E, beta-carotene, and zinc did not reduce prostate cancer risk (14135). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and prostate cancer risk, stating that it is highly unlikely that selenium supplements reduce the risk of prostate cancer (102373).
• Psoriasis. Oral selenium does not seem to reduce psoriasis severity. Details: Clinical research shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not reduce the severity of psoriasis when compared with placebo (74460).
• Sepsis. Intravenous selenium does not appear to improve outcomes in septic adults. Details: Earlier meta-analyses of clinical trials in septic adults showed that parenteral administration of selenium, along with routine nutritional interventions, reduces the risk of mortality by 11% to 27% when compared with placebo (90347,92907,92910). However, a more recent meta-analysis, which includes a large, multi-center study of over 1000 cases, shows that parenteral selenium does not reduce mortality in septic adults at 28, 90, or 180 days when compared with placebo (99658). Enteral selenium with other nutrients has been studied for sepsis in children. Clinical research in children shows that taking enteral selenium 40-400 mcg daily with zinc, glutamine, and IV metoclopramide is no more effective than whey protein for reducing time to first episode of nosocomial infection or sepsis in the intensive care unit (ICU). However, the selenium combination treatment might reduce the risk for sepsis in immunocompromised pediatric patients (86095).

LIKELY INEFFECTIVE

• Bladder cancer. Despite promising initial research, oral selenium does not seem to prevent the development, recurrence, or progression of bladder cancer. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and bladder cancer risk based on two small studies. However, the FDA determined that it is highly uncertain that selenium supplements reduce the risk of bladder cancer (102373). Since then, most available research has not confirmed an association between selenium and bladder cancer risk. Epidemiological and clinical research suggests that selenium supplementation is not associated with a reduced risk of bladder cancer and does not prevent recurrence, slow progression, or improve overall survival in patients with bladder cancer (97085). One moderate-sized clinical study shows that taking selenium 200 mcg daily with or without vitamin E 200-400 IU daily for 7 years does not prevent bladder cancer in older males (90352). Another small clinical study shows that taking selenium yeast 200 mcg daily for 3 years does not prevent the recurrence of bladder cancer when compared with placebo in patients that had undergone a transurethral resection for non-invasive bladder cancer (97087). These findings are supported by another moderate-sized clinical study in adults with non-invasive bladder cancer which shows that taking selenium 200 mcg with or without vitamin E 200 IU daily for a median of 1.5 years does not prevent recurrence, slow bladder cancer progression, or improve overall survival when compared with placebo over a median follow-up period of 5.5 years (114116).
• Diabetes. Increased intake of selenium, either in the diet or as a supplement, is associated with an increased risk for developing type 2 diabetes. It is unclear if oral selenium is beneficial in patients with type 2 diabetes. Details: Observational research suggests that high serum selenium levels, high dietary selenium intake, and selenium supplementation are each linked to an increased risk of developing diabetes (97091,99661). Consuming more than the recommended dietary allowance (RDA) of selenium daily is associated with an increased risk of developing diabetes when compared with consuming less than the RDA (99661). However, the effect of short-term selenium supplementation in patients with diabetes is unclear. Two meta-analyses of clinical studies in adults with various health conditions show that taking supplemental selenium as selenium yeast, sodium selenite, or selenomethionine in doses of 100-960 mcg daily for 4 to 96 weeks reduces serum and fasting insulin levels and increases measures of insulin sensitivity but does not lower fasting blood glucose or glycated hemoglobin (HbA1c) when compared with placebo. Additionally, selenium supplementation does not reduce total or low-density lipoprotein (LDL) cholesterol or triglycerides but may improve high-density lipoprotein (HDL) cholesterol (110593). However, the validity of the findings from the meta-analyses is limited by the heterogeneity of the included studies, which enrolled healthy adults and patients with diabetes, gestational diabetes, cardiovascular disease, heart failure, obesity, polycystic ovary syndrome (PCOS), cancer, and Alzheimer disease.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral selenium reduces the risk of cognitive decline in older adults. Details: A cross-sectional study in elderly Americans has found that lower blood levels of selenium are associated with a greater risk of poor cognitive scores when compared with higher levels (104426).
• Alcohol-related liver disease. Although there is interest in using oral selenium for alcohol-related liver disease, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral selenium for allergic rhinitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Alzheimer disease. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with Alzheimer disease shows that taking selenium 200 mcg with a probiotic daily for 12 weeks improves cognitive function as measured by the Mini-Mental State Examination (MMSE) when compared with placebo. However, when selenium 200 mcg was taken alone, no improvement in cognitive function over placebo was found, so it is unclear whether the improvements in cognitive function are due to the probiotics or the combination of ingredients (113659). Another very small clinical study in adults with mild-to-moderate Alzheimer disease shows that taking supranutritional selenium 30 mg daily for 12 weeks does not change cognitive measures, cerebrospinal fluid biomarkers, or neuroimaging biomarkers of Alzheimer disease progression when compared with placebo or nutritional selenium doses. However, the control group showed worsened diffusivity imaging markers indicative of deterioration of axonal structure integrity, while no such decline was noted in supranutritional selenium neuroimaging (113660).
• Androgenic alopecia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing selenium, hydrolyzed collagen, taurine, cysteine, methionine, and iron (GFM Oral, Cantabria Labs) daily for 12 weeks daily along with conventional therapy, consisting primarily of finasteride or minoxidil, improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to selenium, other ingredients, or the combination.
• Arsenic poisoning. It is unclear if oral selenized yeast is beneficial for patients that were exposed to high levels of arsenic in the environment. Details: A small clinical study in Chinese people environmentally exposed to high concentrations of arsenic shows that taking selenized yeast providing 100-200 mcg of selenium daily for 14 months decreases the concentration of arsenic and symptoms of toxicity when compared with placebo (7831).
• Benign prostatic hyperplasia (BPH). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in men with BPH shows that taking selenium 240 mcg plus silymarin 570 mg daily for 6 months reduces lower urinary tract symptoms when compared with placebo (88155). Another clinical study in men with BPH shows that taking tamsulosin 0.4 mg plus a specific product containing selenium, saw palmetto, and lycopene (Profluss, Ayanda AS) daily for one year improves lower urinary tract symptoms and urodynamic parameters when compared with tamsulosin-alone (90354). It is unclear if these effects are due to selenium, other ingredients, or the combinations.
• Burns. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with burns on 46% of their body surface suggest that taking a combination of copper 2.5-3.1 mg, selenium 315-380 mcg, and zinc 26.2-31.4 mg daily reduces the incidence of hospital-acquired pneumonia, but does not seem to improve wound healing, hospital stay, or mortality, when compared with placebo (6520,74382). Another very small clinical study in burn patients suggests that taking copper 4.5 mg, selenium 190 mcg, and zinc 40 mg daily reduces the duration of hospitalization, but does not have an effect on recovery and wound treatment requirements, when compared with standard dietary doses of these nutrients (74485).
• Cancer. Selenium does not seem to reduce the risk of cancer in most people, but it might be beneficial in those with low selenium levels and in men. Details: Meta-analyses of clinical research and several clinical studies show that selenium supplementation does not reduce the incidence of cancer or cancer-related mortality when compared with control (14109,34538,74414,97078,97092). In clinical studies, selenium 100-400 mcg taken daily for 2-7.5 years with or without additional antioxidants did not reduce overall cancer risk (14109,34538,74414). However, most evidence did not assess baseline selenium levels. Other evidence suggests that selenium may have a benefit in men and in people with lower selenium levels. Epidemiological research has found that selenium intake at the recommended daily allowance (RDA) of 55 mcg or higher is associated with decreased cancer incidence and cancer mortality, especially in men (97085,103164). However, this research suggests that cancer risk was also influenced by age, body mass index, and smoking status (103164). Some clinical research also suggests that taking selenium might decrease the risk of cancer, when only men are considered (14109). An older meta-analysis of clinical research suggests that selenium was particularly beneficial in patients with lower baseline levels of selenium and in patients at high risk for cancer (90350). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim stating that consumption of selenium may produce anticarcinogenic effects and reduce the risk for certain forms of cancer. However, the FDA has determined that the evidence is limited and inconclusive (102374).
• Cataracts. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An ancillary clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for around 5.6 years does not reduce the risk of age-related cataracts in men when compared with placebo (92902).
• Cervical dysplasia. It is unclear if oral selenized yeast is beneficial for patients with cervical dysplasia of mild severity. Details: A small clinical study in patients with cervical intraepithelial neoplasia grade 1 (CIN1) shows that taking yeast containing selenium 200 mcg daily for 6 months resulted in regression of CIN1 in 88% of participants, compared with regression in only 55% of participants taking placebo (97944).
• Chemotherapy-induced nephrotoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-induced nephrotoxicity when compared with a placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral selenium for CFS, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Cirrhosis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with primary biliary cirrhosis shows that taking a combination of selenium, vitamin A, vitamin C, vitamin E, methionine, and coenzyme Q10 for 12 weeks does not improve fatigue or any other disease-related symptoms when compared with placebo (34494).
• Cisplatin-associated ototoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-associated hearing loss when compared with placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
• Colorectal adenoma. It is unclear if oral selenium prevents recurrence of adenomas in the colon and rectum. Details: A large clinical study in patients with a history of colorectal adenomas shows that taking a specific selenium supplement (SelenoExcell High Selenium Yeast, Cypress Systems) 200 mcg daily for about 33 months does not reduce adenoma recurrence when compared with placebo. However, in a sub-group of patients with advanced adenomas at baseline, selenium seems to reduce risk of recurrence by 18% when compared with placebo (97091). Some research also shows that taking selenium in combination with zinc, and vitamins A, C, and E reduces adenoma recurrence when compared with placebo (92903). It is not clear any benefit is due to selenium, other nutrients, or the combination.
• Congestive heart failure (CHF). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in elderly patients with heart failure living in Sweden shows that taking a specific selenium supplement (SelenoPrecise, Pharma Nord) 200 mcg plus a specific coenzyme Q10 supplement (Bio-Quinon, Pharma Nord) 200 mg daily for about 4 years reduces the risk of cardiovascular mortality by about 55% when compared with placebo (92904). The risk reduction seems to be most pronounced in patients with lower selenium levels (97906). Furthermore, at 10- and 12-year follow-ups, cardiovascular mortality in the treatment group continued to be 49% and 41% lower, respectively, when compared with placebo (96546,97466). It is unclear if the benefit can be attributed to selenium, coenzyme Q10, or the combination.
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral selenized yeast is beneficial for patients undergoing CABG surgery. Details: A small clinical study in patients undergoing CABG surgery shows that taking selenium 200 mcg daily as selenium yeast for 4 weeks improves glycemic control, lipid levels, and markers of inflammation when compared with placebo (103163). It is not known whether this influences the outcome or complications of CABG surgery.
• Critical illness (trauma). Evidence on the use of intravenous selenium in critically ill patients is conflicting. Details: The most recent meta-analysis of 24 clinical trials in critically ill patients shows that intravenous selenium does not improve survival over 6 months, shorten hospital stay, or reduce intensive care unit (ICU) stay, infectious complications, development of acute kidney failure, or duration of mechanical ventilation when compared with control. Also, length of ICU stay was increased by about 4.5-fold in patients receiving selenium in doses of more than 1000 mcg daily (109086). These findings are similar to those of a meta-analysis of 21 randomized controlled trials in critically ill patients from 2016 which shows that intravenous selenium given alone or with other nutrients does not improve mortality, duration of hospital stay, or kidney function when compared with control (97090). However, another recent meta-analysis of 19 clinical trials in critically ill patients shows that intravenous selenium reduces total mortality by 14% and shortens hospital stay by about 2 days when compared with control, without affecting ICU stay, duration of mechanical ventilation, or mortality over 28 days (101345). The reasons for these discrepancies are not clear and do not seem to be completely explained by differences in doses or durations of selenium (109086). Some reasons for the discrepancies might include differing analytic methods used in meta-analyses, as well as variations in forms of selenium, concomitant treatments, and specific patient populations. One sub-analysis shows that, when limited to randomized controlled trials examining the effect of selenium supplementation in patients sustaining traumatic injury, the odds of mortality was reduced by about 26% and duration of ICU and hospital stay were modestly reduced. There was no effect on infectious complications (109090).
• Dementia. It is unclear if oral selenium prevents dementia or reduces symptoms. Details: Observational research has found that taking selenium 200 mcg daily for 4 years does not decrease the incidence of dementia in men 60 years or older (93570). However, the follow-up period may not have been long enough to reliably detect the effect of selenium on the development of dementia. Also, the screening method used to detect new cases of dementia may have failed to identify individuals presenting with only the initial symptomatic stages of the disease (93570,93571).
• Depression. It is unclear if oral selenium is beneficial for the treatment of prevention of depression. Details: A meta-analysis of observational research has found no difference in serum levels of selenium between patients with or without depression. In addition, serum levels of selenium do not correlate with depression scores (109091). A meta-analysis of clinical research shows that selenium supplementation, usually 100-200 mcg daily, modestly reduces symptoms of depression; however, at least one of the three studies included in this meta-analysis investigated the effects of selenium in patients with postpartum depression, specifically (109091). These meta-analyses are limited by the quality of included research and the small number of available studies.
• Diabetic nephropathy. It is unclear if oral selenium alleviates diabetic nephropathy symptoms. Details: A small clinical study in patients with diabetic nephropathy shows that taking selenium (Nature Made) 200 mcg daily for 12 weeks does not improve kidney markers such as blood urea nitrogen or serum creatinine when compared with placebo (97084).
• Dilated cardiomyopathy. There is limited evidence on the oral use of selenium in patients with Keshan disease and peripartum cardiomyopathy. Details: Observational research in patients with a specific type of dilated cardiomyopathy called Keshan disease and congestive heart failure has found that selenium supplementation is associated with a 61% decreased risk of cardiac death when compared with no supplementation (101346). A small clinical study in patients with peripartum cardiomyopathy and selenium deficiency shows that taking selenium 200 mcg daily for 3 months does not seem to improve heart failure symptoms or left ventricle systolic function, or prevent death, when compared with no treatment (104420).
• Esophageal cancer. Limited research suggests that oral selenium does not reduce esophageal cancer risk. Details: Low quality clinical research suggests that taking selenium supplements alone or with other vitamins does not decrease the risk of esophageal cancer when compared with control (4679,12185).
• Gastric cancer. Oral selenium has only been evaluated in combination with other ingredients and in a specific patient population; its effect when used alone and in other populations is unclear. Details: Population research in Chinese patients has found that high levels of selenium are associated with lower risk of gastric cancer and cancer mortality (97948). However, clinical research does not agree. A large clinical study in patients residing in China shows that taking selenium 37.5 mcg in combination with vitamin C 250 mg and vitamin E 100 IU twice daily for about 7.3 years does not reduce the risk of developing gastric cancer or precancerous gastric lesions when compared with placebo. This combination treatment was not associated with reduced gastric cancer incidence or mortality at the 14-year follow-up of this study (14447,51470). Another clinical study in healthy Chinese adults also shows that taking a combination of selenium 50 mcg, vitamin E 30 mg, and beta-carotene 15 mg daily for 5.2 years does not reduce the risk of gastric cancer when compared with control (4679). It is unclear if these findings are generalizable to populations in geographic locations other than China.
• Graves' ophthalmopathy. It is unclear if oral selenium is beneficial for Graves' ophthalmopathy. Details: A small clinical trial in adults with Graves' ophthalmopathy shows that taking selenium 100 mcg twice daily for 6 months is modestly beneficial for reducing disease activity, based on signs and symptoms including pain, swelling, and redness, when compared with placebo (109085).
• Hepatitis C. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with hepatitis C shows that taking a combination of selenium 200 mcg, vitamin C 500 mcg, and vitamin E 945 IU daily for 6 months does not have an effect on levels of alanine aminotransferase or viral load when compared with placebo (74377).
• HIV/AIDS. It is unclear if oral selenium improves outcomes in patients with HIV. Details: Clinical trials in HIV-positive men and women, most receiving anti-retroviral therapy (ART), shows that taking selenium 200 mcg daily for up to 2 years can reduce HIV-1 viral load, increase CD4 cell counts, and lower the risk of hospitalizations when compared with placebo (15266,74314). However, not all research agrees. Two small clinical trials in HIV-positive patients taking ART shows that taking selenium 100-200 mcg daily for 6-12 months does not reduce the risk for opportunistic infections and does not increase CD4 counts when compared with control (7830,104417). Furthermore, selenium does not seem to benefit patients that are not receiving conventional ART. A large clinical study in HIV-infected pregnant patients in Tanzania with poor access to ART shows that taking selenium 200 mcg daily with prenatal vitamins until 6 months after delivery, does not improve progression of HIV nor pregnancy outcomes when compared with no selenium supplementation (74419). Another large clinical study in HIV-infected and ART-naïve patients in Botswana shows that taking selenium 200 mcg daily for 24 months does not slow HIV progression when compared with placebo (92905).
• Hypertension. It is unclear if oral selenium improves blood pressure. Some evidence suggests selenium supplementation may slightly increase systolic blood pressure. Details: A meta-analysis of 5 small clinical studies in adults with various health conditions shows that taking selenium or selenium yeast 100-200 mcg/day for 6-12 weeks may increase systolic blood pressure by about 2 mmHg but does not impact diastolic blood pressure when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with preeclampsia, gestational diabetes, obesity, or heart failure. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
• Hyperthyroidism. It is unclear if oral selenium alleviates symptoms in patients with Graves' disease. Details: A small clinical study in patients with Graves' hyperthyroidism shows that taking sodium selenite 300 mcg daily in addition to treatment with methimazole for 24 weeks does not affect symptoms or recurrence rates when compared with placebo plus methimazole (97089). Oral selenium has also been studied in combination with other supplements. A small preliminary clinical trial in patients with newly diagnosed Graves' disease and low levels of selenium and vitamin D shows that taking selenium 100 mcg daily for 180 days along with vitamin D as cholecalciferol 7000 IU weekly for 270 days, in addition to methimazole, modestly reduces levels of serum free thyroxine and improves quality of life when compared with methimazole alone. However, taking selenium and vitamin D did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
• Hypothyroidism. It is unclear if oral selenium improves thyroid hormone balance in elderly individuals, pregnant patients, or patients with subclinical hypothyroidism. In patients with iodine deficiency, selenium supplementation may be harmful. Details: Low selenium levels or selenium deficiency seems to reduce conversion of thyroxine (T4) to triiodothyronine (T3). However, clinical research in healthy elderly patients is conflicting. Although one study shows that taking selenium 100 mcg daily for 3 months increases conversion of T4 to T3 when compared with placebo (17508), a larger study shows that taking selenium 100-300 mcg daily for 6 months does not impact conversion of T4 to T3 when compared with placebo (17509). Additionally, taking selenium can worsen hypothyroidism in people with iodine deficiency. People who are iodine- and selenium-deficient should not receive selenium supplements without concomitant iodine. In these individuals, selenium increases conversion of T4 to T3, but the thyroid gland lacks iodine to synthesize more T4 (1664,14563,14564,14565,17508). Selenium does not have a significant effect on thyroid function when iodine intake is adequate (1664,4844). In pregnant patients with hypothyroidism, clinical research shows that taking selenium does not reduce complications such as pre-eclampsia or preterm birth. However, selenium might improve postpartum thyroid function and decrease the risk of postpartum thyroiditis (17507). Also, taking selenium 200 mcg daily during pregnancy seems to reduce the risk of developing postpartum thyroid dysfunction and permanent hypothyroidism by 41% and 42%, respectively, when compared with placebo in euthyroid pregnant patients who are positive for thyroid peroxidase antibodies (74391). Selenium supplementation has also been studied for subclinical hypothyroidism. Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking selenium 83 mcg daily and myo-inositol 600 mg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared with baseline. Selenium and myo-inositol supplementation also reduced patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to selenium, myo-inositol, or the combination.
• Influenza. Although there is interest in using oral selenium for influenza, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Kidney failure. It is unclear if oral selenium is beneficial for improving lipid parameters in patients on hemodialysis. Details: Selenium levels may be low in patients undergoing chronic hemodialysis, and supplementation might be needed (1805,11053). However, clinical research in patients on hemodialysis shows that taking selenium daily for 3 months does not improve the lipid profile when compared with taking placebo (109095).
• Lichen planus. It is unclear if topical or oral selenium alleviates oral lichen planus symptoms. Details: A small clinical study in patients with oral lichen planus shows that applying a selenium hydrogel (selenomethionine 14 mcg/gram) twice daily for 6 weeks seems to significantly reduce pain at a 12 week follow-up, but not immediately after use, when compared with applying topical corticosteroids and antifungal agents 2-4 times daily. Taking oral selenium 200 mcg twice daily for 6 weeks seems to be no different than the topical corticosteroids and antifungal treatment at both time points (104422).
• Liver cancer. It is unclear if oral selenium reduces liver cancer risk. Details: Preliminary clinical research in China suggest that taking selenium 200 mcg daily for 2-5 years can reduce the incidence of liver cancer when compared with control (74389). The benefit of selenium on prevention of liver cancer in Western countries is unknown.
• Lymphedema. It is unclear if oral selenium reduces lymphedema complications. Details: Preliminary clinical research in patients with secondary lymphedema after breast cancer surgery shows that taking a sodium selenite solution 1000 mcg daily for 1 week followed by 300 mcg daily for 2 weeks and then 200 mcg daily for a total of 15 weeks might reduce recurrence of erysipelas, a type of bacterial skin infection, when compared with placebo (15334).
• Male infertility. It is unclear if oral selenium, used alone or in combination with other antioxidants, improves pregnancy or live birth rates for couples with idiopathic male infertility. Details: Meta-analyses of 2-3 clinical trials in males with infertility show that taking selenium, alone or in combination with other antioxidants, for 12-26 weeks modestly improves sperm count and motility, but does not improve sperm morphology, when compared with placebo. Pregnancy rates and live birth rates were only studied in one clinical trial each, with no statistical evidence of benefit (109094,111459). However, the included studies may have been inadequately powered to detect a difference between groups. Studies included in the analysis used selenium 26-200 mcg daily for 3-26 weeks, either alone or in combination with vitamin A 1 mg, vitamin C 10 mg, and vitamin E 15 mg; vitamin E 400 IU and folic acid 5 mg; lycopene 6 mg, vitamin E 400 IU, vitamin C 100 mg, zinc 25 mg, folate 0.5 mg, and garlic 1000 mg; or N-acetyl-cysteine 600 mg (74526,74493,102968,109094,111459). Selenium has also been evaluated in combination with other ingredients. A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing selenium 50 mcg, vitamin B12, L-carnitine, acetyl L-carnitine, citric acid, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus, AltaSigma) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. However, improvements in sperm morphology were lacking. Furthermore, patients with more severe varicocele seem to benefit most (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to selenium, other ingredients, or the combination.
• Mercury toxicity. It is unclear if oral selenium improves clearance of mercury and reduces symptoms of toxicity. Details: A small clinical trial in Chinese adults environmentally exposed to high concentrations of mercury shows that taking selenium-enriched yeast, containing selenium 100 mcg, daily for 3 months increases urinary excretion of mercury when compared with control (90351).
• Muscular dystrophy. There is limited evidence on the oral use of selenium in Duchenne muscular dystrophy. Details: Preliminary clinical research suggests that supplementation with sodium selenite 1 mg daily for 6 months does not improve disease activity in patients with muscular dystrophy (74455).
• Obesity. It is unclear if oral selenium is beneficial for weight reduction. Details: A small clinical study in adults with obesity shows that taking selenium 240 mcg daily and following a low-calorie diet for 3 months does not reduce body weight when compared with following a low-calorie diet alone (104416). Additionally, a very small clinical study in adults with overweight or obesity shows that taking L-selenomethionine 200 mcg and zinc gluconate 25 mg once daily for 8 weeks does not improve body mass index (BMI), total body fat, or fat free mass when compared with placebo (111448).
• Oral mucositis. It is unclear if oral selenium is beneficial for reducing oral mucositis in patients undergoing radiotherapy. Details: A small clinical study in patients with head and neck cancers shows that taking selenium 200 mcg twice daily for the duration of radiation therapy does not seem to reduce the incidence or severity of oral mucositis when compared with placebo (104421). It is unclear if other doses or routes of administration might be beneficial.
• Osteoarthritis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis shows that taking a specific selenium-containing combination supplement (Selenium-ACE) does not improve most clinical symptoms when compared with placebo (74449).
• Ovarian cancer. It is unclear if oral selenium reduces ovarian cancer risk. Details: Epidemiological research has found that there is no association between dietary selenium intake and the risk of developing ovarian cancer (74342).
• Overall mortality. Although oral selenium does not seem to reduce overall mortality risk in most patients, it might have benefit in patients with low nutrient intake. Details: Meta-analyses of clinical research show that selenium supplementation, alone or in combination with other micronutrients, does not reduce all-cause mortality when compared with placebo (15305,90360,97078). Selenium might also not be beneficial when used in combination with non-nutrient supplements. An additional large clinical study in elderly patients in Sweden shows that taking selenium 200 mcg daily plus coenzyme Q10 100 mg twice daily for around 5 years does not reduce the risk of all-cause mortality when compared with placebo. The baseline selenium status of these patients is unclear (92904). Despite these results, some evidence suggests that selenium used with other nutrients might have benefit in patients with low nutrient intake. In a large clinical study, selenium in combination with zinc, vitamin C, vitamin E, and beta-carotene lowered all-cause mortality risk in men, but not women, when compared with control (14109). Researchers speculate that this result occurred because men have a lower intake of dietary antioxidants than women. Another large clinical study in Chinese patients with chronically low nutrient intake shows that taking selenium with beta-carotene and vitamin E decreases stroke mortality, cancer mortality, and total mortality when compared with control (2673).
• Pancreatic cancer. It is unclear if oral selenium reduces pancreatic cancer risk. Details: Some epidemiological research has found that increased selenium intake is associated with a 34% lower risk of pancreatic cancer (97093). However, other observational research has found no association (101342).
• Pancreatitis. Although there is interest in using oral selenium for pancreatitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
• Periodontitis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing selenium 30 mcg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, vitamin C, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal measures such as bleeding on probing, gingival recession, plaque index, or inflammation when compared with placebo (111708).
• Polycystic ovary syndrome (PCOS). It is unclear if oral selenium is beneficial for PCOS. Details: Most available research addressing the effects of selenium on the hormonal, metabolic, and reproductive symptoms associated with PCOS is conflicting. Meta-analyses of small clinical studies and a small clinical study in adults with PCOS show that taking selenium 200 mcg daily for 8-12 weeks might reduce total testosterone and dehydroepiandrosterone (DHEA) levels but does not seem to improve other hormone levels when compared with placebo (109096,113653,113654,113657). Additionally, a small clinical study in patients with PCOS shows that taking selenium yeast or selenium (Nature Made) 200 mcg daily for 8 weeks reduces the severity of alopecia, acne, and hirsutism when compared with placebo (109096). Research is conflicting whether selenium improves lipid profiles, glycemic indices, insulin metabolism, or anthropometric measures (109096,110596,113642,113654,113657). The effect of selenium on pregnancy outcomes in patients with PCOS who are undergoing or candidates for in vitro fertilization (IVF) is unclear. A small clinical study in patients with PCOS shows that taking selenium (Nature Made) 200 mcg daily for 8 weeks results in a significantly higher pregnancy rate of 19%, compared with 3% in those taking placebo (109096). However, another very small clinical study of the same population and dosing regimen shows that selenium does not improve IVF outcomes including pregnancy rate, endometrial thickness, number of oocytes retrieved, fertilization rate, or number of embryos when compared with placebo (113640). Selenium has also been studied in combination with other ingredients. A small clinical study in adults with PCOS shows that taking selenium 200 mcg daily for 12 weeks, along with a combination probiotic product, modestly improves subjective scores of depression, anxiety, and stress when compared with placebo. Taking this combination also modestly reduces total testosterone levels and subjective ratings of hirsutism when compared with placebo (99659). It is unclear if these effects are due to selenium, the probiotic, or the combination.
• Postoperative recovery. It is unclear if intravenous sodium selenite reduces morbidity and mortality in cardiac surgery patients. Details: A very large clinical study in adults undergoing high-risk cardiac surgery with cardiopulmonary bypass or cardioplegic arrest shows that administering intravenous high-dose sodium selenite 2000 mcg/L perioperatively, 2000 mcg/L immediately postoperatively, and then 1000 mcg/L daily in the intensive care unit (ICU) for up to 10 days does not increase the number of days alive or the number of days without persistent organ dysfunction over 30 days after surgery when compared with placebo. Additionally, intravenous sodium selenite does not reduce 30-day or 6-month mortality, intensive care unit (ICU) or hospital length of stay, or hospital readmission rates when compared with placebo (113651).
• Postpartum depression. It is unclear if oral selenium is beneficial for postpartum depression. Details: A meta-analysis of two observational studies has found that a high selenium intake is associated with a modestly reduced risk of postpartum depression. The effect of selenium supplementation on symptoms of postpartum depression is unclear. One moderate-sized clinical trial included in this publication shows that taking selenium reduces symptoms of postpartum depression (109091).
• Pregnancy-induced hypertension. It is unclear if oral selenium reduces the development of hypertension during pregnancy. Details: A small clinical study in pregnant patients shows that drinking a dietary liquid containing selenium 100 mcg daily for 6-8 weeks seems to decrease the incidence of pregnancy-induced hypertension when compared with placebo (74481).
• Premature rupture of membranes (PROM). It is unclear if oral selenium during pregnancy prevents PROM. Details: One clinical trial shows that taking selenium 100 mcg daily from the first trimester of pregnancy until delivery significantly reduces the incidence of PROM to 13%, compared to 34% with placebo (109097).
• Radiation-induced diarrhea. It is unclear if oral selenium reduces diarrhea in patients receiving radiation therapy for cancer. Details: A small clinical study in patients with cervical or endometrial cancer shows that taking selenium 500 mcg on days of radiation therapy and 300 mcg on days without radiation therapy reduces the incidence of radiation-induced diarrhea to 20.5%, compared to 44.5% in the control group not taking selenium. This benefit appears to be more pronounced in patients receiving a larger (>1302 mL) planning target volume of radiation (90355).
• Rheumatoid arthritis (RA). It is unclear if oral selenium reduces RA symptoms. Details: A small clinical study in patients with RA suggests that taking selenized yeast, providing selenium 200 mcg, daily for 90 days does not improve objective measures of RA when compared with placebo. However, there might be small improvements in quality of life measures (9763). Another small clinical study in Iranian patients with moderate to severe RA shows that taking selenium 200 mcg twice daily for 12 weeks in addition to standard treatment reduces patient-reported disease activity, difficulty in performing activities of daily living, and pain severity but does not change the number of tender or swollen joints, erythrocyte sedimentation rate, or disease activity as measured by Disease Activity Score of 28 Joints (DAS28) when compared with placebo (113648).
• Schizophrenia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with schizophrenia shows that taking a combination of selenium (Nature Made) 200 mcg and a combination probiotic mixture (LactoCare, Zisttakhmir Company) daily for 12 weeks modestly improves general positive and negative symptoms of schizophrenia, but not positive or negative scores, when compared with placebo. There were also modest improvements in levels of high-sensitivity C-reactive protein (CRP), fasting glucose, insulin resistance, and insulin sensitivity, but not lipid parameters (109087).
• Seborrheic dermatitis. It is unclear if topical selenium disulfide shampoo is beneficial for seborrheic dermatitis. Details: A very large observational study in adults with dandruff or seborrheic dermatitis suggests that applying selenium disulfide-based shampoo 2-3 times weekly for 4 weeks improves scalp condition and reduces flaking, erythema, and irritation when compared to baseline (113652). The validity of the results is limited by the observational nature of the study and lack of comparator group. A small clinical study in adults with moderate-to-severe seborrheic dermatitis shows that applying selenium disulfide-based 1% shampoo to the scalp once weekly for 8 weeks after a 2-week treatment with corticosteroid and salicylic acid combination therapy reduces relapse rate, erythema, pruritis, adherent dandruff, and total dandruff but does not improve non-adherent dandruff when compared with a placebo shampoo (113646).
• Statin-induced myopathy. Small clinical studies suggest that oral selenium may not improve symptoms of myopathy in patients taking statins. Details: Small clinical studies in patients with statin-induced myopathy suggests that taking selenium (SelenoPrecise, Pharma Nord) 200 mcg daily with or without coenzyme Q10 for 3 months does not improve myopathy symptoms when compared with placebo (92908,92909).
• Stroke. It is unclear if intravenous selenium improves neurological outcomes following a stroke. Details: A small clinical trial in patients with a recent first ischemic stroke shows that intravenous sodium selenite pentahydrate (Selenase, Biosyn, Arzenitmittel GmbH) 2000 mcg after admission and then 1000 mcg daily for 5 days modestly improves some, but not all, measures of neurological deficits when compared with placebo (109088). Another small clinical trial in patients with a recent ischemic stroke shows that the same intervention improves some neurological outcome measures on day 7 or at an earlier discharge, but benefits were not maintained at 3 months (109093). The effects of oral selenium on neurological outcomes following a stroke have not been investigated.
• Subarachnoid hemorrhage. Intravenous selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized study in adults with aneurysmal subarachnoid hemorrhage shows that administering intravenous selenium 800 mcg and acetylcysteine 1000 mg twice daily starting within 24 hours of admission for 14 days reduces total days spent in the intensive care unit but does not change neurological outcomes, time to reach target sedation, duration of hospital stay, or need for tracheostomy when compared with intravenous placebo. Additionally, no change in radiological outcomes including hematoma or perihematomal edema volume, midline shifting, or the incidence of radiological vasospasm, angioplasty for vasospasm, or hydrocephalus was observed when compared with placebo (113644). It is unclear whether this effect is due to selenium, acetylcysteine, or the combination.
• Succinylcholine-induced myalgia. It is unclear if oral selenium is beneficial for preventing succinylcholine-induced postoperative myalgia. Details: Clinical research in patients receiving succinylcholine for a sinuscopy shows that taking a single dose of selenium 200 mcg 2 hours before anesthesia induction modestly decreases the incidence of postoperative myalgia at 24 hours. In those taking selenium, 95% of patients had no postoperative myalgia, compared with 77.5% of those taking placebo. Postoperative analgesia requirements were also modestly reduced; however, there was no difference in overall pain or the incidence of muscle twitching (109089).
• Thyroid cancer. It is unclear if oral selenium reduces the risk of thyroid cancer in most patients. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and thyroid cancer risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that selenium supplements reduce the risk of thyroid cancer (102373). More recent observational research in postmenopausal individuals using data from the Women's Health Initiative has found that selenium intake at or above the recommended daily allowance from dietary sources or supplements is not associated with a decreased risk of thyroid cancer (110590).
• Ulcerative colitis. It is unclear if oral selenium is beneficial for ulcerative colitis. Details: A small clinical study in Iranian adults with mild-to-moderate ulcerative colitis shows that taking selenomethionine 200 mcg daily for 10 weeks in addition to standard therapy improves disease activity and quality of life and increases the percentage of patients with clinical improvement and clinical remission when compared with placebo (113643). Selenium has also been evaluated in combination with other ingredients. A clinical study in patients with ulcerative colitis shows that taking a liquid supplement containing a combination of selenium, fish oil, fructo-oligosaccharides, acacia, vitamin E, and vitamin C daily for 6 months does not improve disease activity scores when compared with placebo. However, taking the combination supplement seems to reduce the need for oral prednisone for symptom control (13757). More evidence is needed to rate selenium for these uses.

(Read more about SELENIUM)

EFFECTIVE

• Zinc deficiency. Orally or intravenously, zinc is effective for treating and preventing zinc deficiency. Details: Taking zinc orally or intravenously prevents and treats zinc deficiency (2619). However, routine zinc supplementation is not recommended (403). Zinc deficiency requiring supplementation may occur in patients with severe diarrhea, malabsorption syndromes, liver cirrhosis, and alcoholism; after major surgery, renal failure, and dialysis; or during long-term administration of total parenteral nutrition (3900,24321). Zinc supplementation (136 mg of elemental zinc per day) in patients with cirrhosis and zinc deficiency seems to improve liver function and glucose tolerance, possibly by increasing insulin-like growth factor (8624,87520).

LIKELY EFFECTIVE

• Diarrhea. Oral zinc reduces duration and severity of acute diarrhea in malnourished children. Doses of 5-20 mg seem to be effective, while 5-10 mg daily is less likely to cause vomiting. Details: Most research, including meta-analyses and over 30 clinical trials, show that taking zinc orally reduces the duration and severity of acute and persistent diarrhea in malnourished or zinc-deficient children, but not in well-nourished children (87236,96074). Most studies have been conducted in Bangladesh and India, so it is unclear if these findings are generalizable to other geographic locations. The most comprehensive meta-analysis of clinical studies in children older than 6 months shows that zinc supplementation reduces the duration of acute diarrhea by about 11 hours and the duration of persistent diarrhea by about 16 hours when compared with placebo. However, zinc does not seem to reduce the duration of acute diarrhea in children younger than 6 months. Zinc supplementation seems to have the greatest benefit in children with clear malnutrition and diarrhea. In these children, zinc reduces diarrhea duration by about 26 hours and reduces the risk of diarrhea persisting through days 3, 5, and 7 by 18% to 24% when compared with placebo. There was no clear benefit of using zinc in a specific dose or salt form. The most common dose of zinc was 20 mg daily and salt forms included zinc sulfate, gluconate, and acetate (96074). Also, a large clinical trial in children with acute diarrhea shows that taking zinc 5 or 10 mg daily for 14 days is non-inferior to taking 20 mg. Furthermore, zinc 5 or 10 mg results in a respective 29% and 19% lower risk of vomiting within the first 30 minutes when compared with zinc 20 mg (104045). It's unclear whether zinc supplementation reduces mortality in children with diarrhea. A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of mortality from diarrhea by 15% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). However, many studies were conducted in hospitals where rates of mortality are low and were not adequately powered to determine whether zinc has an effect on mortality in children with acute diarrhea (87210,96074,106239).
• Wilson disease. Taking zinc orally improves symptoms of this condition. Details: Zinc acetate (Galzin) is an FDA-approved orphan drug for treating this condition. Zinc blocks copper absorption and increases copper elimination in the stool of people with Wilson disease (2692,2693,87327). Small clinical studies suggest that taking zinc after 8 weeks of treatment with tetrathiomolybdate alone can improve Kayser-Fleischer rings, urine copper levels, and neurological symptoms for up to 6 years post-treatment (63588,87491).

POSSIBLY EFFECTIVE

• Acne. Orally, zinc might help to reduce symptoms of acne. However, it's unclear how oral zinc compares to conventional acne treatments. Topical zinc doesn't seem to be beneficial if used alone. Details: Observational research has found that people with acne seem to have lower zinc levels in the serum and skin (104056). A meta-analysis of small, low quality clinical trials suggests that taking zinc sulfate or zinc gluconate 137-300 mg 2-3 times daily by mouth can modestly improve acne when compared with placebo (104056). However, not all individual trials show benefit (87002,104056). So far, it is not clear how oral zinc compares to other treatments. Trials comparing zinc sulfate with various tetracyclines have yielded conflicting results (6505,6506,86946,106233). One large open-label clinical trial shows that taking zinc sulfate 200 mg twice daily for 12 weeks is at least as effective as lymecycline 300 mg daily for reducing acne severity. Quality of life related to acne was modestly improved in the patients using zinc sulfate (106233). However, in another clinical trial, a 3-month treatment of oral zinc gluconate 30 mg daily reduced the number of acne lesions from baseline, but was not as effective as minocycline (86946). When applied topically, clinical research shows that zinc does not help treat acne when compared with placebo (87297,104056). However, when used in combination with erythromycin, topical zinc seems to result in improvement (819,820,2687,2688).
• Acrodermatitis enteropathica. Oral zinc seems to improve symptoms of this rare genetic disorder. Details: Multiple case reports have found that taking oral zinc seems to help improve symptoms of acrodermatitis enteropathica, a rare disorder (821,2689,2690,2691). One case report in a female with necrolytic acral erythema and hepatitis C suggests that adding oral zinc sulfate 225 mg twice daily to interferon alfa-2b for 6 months contributed to resolving all lesions. Necrolytic acral erythema is categorized in the family of necrolytic erythemas that includes acrodermatitis enteropathica (6192).
• Age-related macular degeneration (AMD). Oral zinc, especially in combination with antioxidant vitamins, seems to slow the progression of AMD. Details: Clinical research shows that taking elemental zinc 80 mg plus vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily reduces the odds of progression to advanced AMD by 28%. In patients with more severe AMD, this combination reduced the odds of progression to advanced AMD by 34%. This combination also reduced the odds of visual acuity loss by 27% in patients with severe AMD (7303,11326). However, there is contradictory evidence about the effects of zinc plus antioxidants on visual acuity loss or the progression to advanced AMD in low-risk patients with AMD (6583,6584,7303). Some clinical evidence shows that, when taken without antioxidant vitamins, zinc supplementation does not slow the progression of existing AMD (6580,90069). However, a subgroup analysis of results from a large clinical trial that included patients with intermediate or advanced AMD suggests that the effect of zinc on AMD progression might vary depending on a patient's genetic predisposition. Complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) are two genes for which specific variations (i.e., risk alleles) have been associated with an increased risk of AMD. Results from the retrospective subgroup analysis suggest that zinc supplementation may DECREASE the progression of AMD in patients with ARMS2 risk alleles and INCREASE the progression of AMD in patients with CFH risk alleles (90193). However, some experts question the results from this analysis due to the retrospective nature of the study (93045). Another retrospective analysis of similar data found that only zinc plus antioxidants, but not zinc alone, was beneficial for slowing the progression of AMD, regardless of the patient's genotype (93046). Consequently, the American Academy of Ophthalmology does not currently recommend routine genetic screening to determine which patients would benefit from zinc, antioxidants, or the combination. Instead, patients with intermediate or advanced AMD are recommended to take an antioxidant and zinc supplement similar to those used in the Age-Related Eye Disease Study (AREDS) and the Age-Related Eye Disease Study 2 (AREDS2) (93047). Large scale population studies suggest that increasing dietary intake of zinc might reduce the risk of developing AMD (6579,14257).
• Child growth. Oral zinc seems to increase growth when taken by children and improve infant growth in the first year of life when taken by pregnant adults. Details: A meta-analysis of 8 clinical studies in healthy children over 2 years old shows that taking supplemental zinc 5-15 mg daily for 6-56 weeks modestly increases height and weight when compared with placebo. This analysis also shows that taking zinc may improve height for age, but not weight for age when compared with placebo (112474). Most of these studies were conducted in developing countries; results may not apply elsewhere. Another clinical study in pregnant adults in Peru shows that taking zinc 15 mg daily in addition to iron and folic acid, starting during the first or second trimester and continuing up to one month after delivery, modestly improves growth measures of infants at one year when compared with taking iron and folic acid alone. Improved growth measures include body weight, calf and chest circumference, and calf muscle area (87130).
• Common cold. Oral zinc seems to help treat cold symptoms in adults. However, it is unclear if zinc is beneficial for common cold prevention. Details: Using zinc oral lozenges seems to be beneficial in helping TREAT the common cold in adults. The majority of clinical trials and analyses of clinical research show a significant decrease in the duration of symptoms of the common cold when adults take zinc gluconate or zinc acetate lozenges providing 9-24 mg of elemental zinc per dose. It is recommended that lozenges be taken every 2 hours while awake, starting within 48 hours of symptom onset for a total daily dose of at least 75 mg in order to attain a mean cold duration reduction of 3 days (333,334,335,337,6703,6705,87501,92212,106902). However, not all studies have been positive (333,338,339,6522,6700,87512). The reasons for these different findings are not clear, but might be due to differences in zinc formulations and doses and study methodologies. In some cases, flavoring agents such as citric acid, mannitol, and sorbitol might chelate zinc and decrease zinc ionization. Since ionization is thought to be necessary for zinc activity, a decrease in zinc ionization could decrease effectiveness (300,340,6522). Some of the positive studies have also been criticized for inadequately blinding the unpleasant, distinctive taste of zinc (6522,6706). Allergy and smoking status do not appear to impact the efficacy of zinc acetate lozenges (92212). Overall, zinc products may be beneficial for modestly reducing the duration of symptoms of the common cold in adults, but adverse effects such as bad taste and nausea may limit their usefulness (18216). There is conflicting evidence for the use of oral zinc products to PREVENT colds. Some clinical research suggests that taking zinc prophylactically does not prevent the common cold in adults (10780,10784) or children (341). However, other clinical research suggests that administering zinc gluconate lozenges can reduce the incidence of colds in children and adolescents (10803,86972). In a meta-analysis of 28 randomized controlled trials with a total of 5446 participants, oral zinc prevented 5 viral upper respiratory tract infections per 100 person months of zinc use when compared with placebo, with a number needed to treat (NNT) of 20 (106902). Intranasal zinc is not recommended for the prevention or treatment of the common cold due to the risk for anosmia. See the Adverse Effects section for more information. Some research shows that zinc nasal spray (as a sulfate, gluconate emulsion, or gluconium gel) reduces the severity and duration of cold symptoms; however, other research has found no effect (6471,8628,8629,10247,87035). Zinc nasal spray does not seem to prevent experimentally-induced colds (8628).
• Coronavirus disease 2019 (COVID-19). While oral zinc does not seem to speed recovery from COVID-19 in non-hospitalized patients, an analysis of a small number of studies suggests that oral or intravenous zinc might reduce the risk of death in hospitalized patients with COVID-19. Details: A small observational study in patients with COVID-19 has found that lower serum zinc levels are associated with worse clinical outcomes, such as admission to the intensive care unit (ICU) and death, when compared with higher zinc levels (105681). Another small observational study has found that 96% of patients with confirmed COVID-19 were zinc-deficient based on plasma levels of zinc, and that these patients had lower plasma zinc levels than a group of individuals without COVID-19. However, plasma zinc concentrations were only weakly correlated with length of hospital stay and there was no correlation with morbidity or mortality (106236). One clinical study in adult outpatients with COVID-19 shows that taking zinc gluconate 50 mg daily at bedtime, alone or with vitamin C (ascorbic acid) 8000 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). This study was terminated prior to complete enrollment due to a lack of effect with zinc and/or vitamin C supplementation. Limitations of this study include a lack of placebo control and blinding. Zinc supplementation also does not appear to enhance the clinical efficacy of hydroxychloroquine in patients with confirmed COVID-19 infection. Taking zinc sulfate 220 mg twice daily during a 6-day course of hydroxychloroquine does not improve the clinical recovery rate, reduce the mortality rate, or reduce the need for mechanical ventilation when compared with hydroxychloroquine alone (104818). Other research has evaluated zinc in hospitalized patients. Multiple meta-analyses of small and low-quality clinical studies, including randomized controlled trials and retrospective studies, involving hospitalized patients with COVID-19 shows that supplementation with oral or intravenous zinc is associated with a 29% to 43% reduction in the odds of in-hospital mortality when compared with control (109451,110631). However, in one meta-analysis, the odds of 30-day mortality were not different between groups (110631). These meta-analyses did not elevate the most effective form, dose, frequency, or duration of zinc supplementation (109451,110631). Additionally, a retrospective study in adults admitted to the ICU with COVID-19 has found that those who received oral zinc sulfate, 220 mg daily for a median of 11 days, had a lower 30-day mortality rate when compared with those who did not receive zinc. However, there was no difference in hospital length of stay or in-hospital mortality (106903).
• Depression. Oral zinc seems to be beneficial when used in combination with antidepressant treatments. Details: Population research has found that higher zinc levels and higher dietary intake of zinc are associated with a 28% lower incidence of depression (90227,97139,104057). Oral zinc seems to be beneficial as an adjunct therapy in depression. A meta-analysis of small, low-quality studies in patients with major depression shows that taking zinc in addition to antidepressant therapy is associated with modestly improved depression symptoms when compared with antidepressant therapy alone (104044). Clinical studies used zinc doses of 7-25 mg daily for up to 12 weeks (86985,90221,104044). One small clinical study also shows that adding zinc to imipramine therapy might improve depression that was previously resistant to antidepressant treatment (87158). One clinical guideline also provisionally recommends use of zinc 25 mg elemental orally daily to treat patients with depression based on low-quality evidence. This guideline recommends use of chelated or picolinate zinc products over other forms of zinc (110318).
• Diabetes. Oral zinc might modestly improve glycemic control in some patients. Details: A meta-analysis of 12 clinical studies in patients with diabetes shows that taking zinc supplements reduces fasting blood glucose by up to 20 mg/dL and glycated hemoglobin (HbA1c) by 0.35% when compared with control. However, when only high quality studies were included, the reduction in fasting blood glucose dropped to 12 mg/dL. Zinc seems to only have glycemic benefit in patients living in the Eastern hemisphere, and not the Western hemisphere. Also, glucose reduction seems to be higher with inorganic zinc formulations at doses of at least 30 mg daily taken for at least one month (104080). Zinc has also been evaluated for improving lipid parameters in patients with diabetes. A meta-analysis of nine studies in patients with diabetes shows that taking zinc reduces triglycerides by 17 mg/dL, but does not seem to affect low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol levels, when compared with placebo (104041). The findings from these meta-analyses are limited by the high heterogeneity and small size of the included studies. Zinc has also been studied for gestational diabetes. Some clinical research in patients with gestational diabetes shows that taking zinc gluconate for 6 weeks, starting at 24-28 weeks' gestation, reduces fasting plasma glucose levels by about 10% and improves insulin resistance by 14% when compared to baseline (96072). However, taking zinc gluconate does not reduce the need for caesarean section or insulin therapy, or improve infant outcomes, such as size or health at birth, in these patients (96073).
• Diaper rash. Topical and oral zinc seem to reduce the incidence and severity of diaper rash in infants. Details: Clinical research shows that administering oral zinc gluconate 10 mg daily for 4 months can reduce the incidence of diaper rash in infants when compared with placebo (87281). Other clinical research shows that applying 47% zinc oxide paste to affected areas for 5 days can improve the healing of diaper rash. However, the effect of zinc oxide paste is inferior to eosin 2% solution (86918).
• Gingivitis. Topical zinc seems to reduce the development of gingivitis. Details: While some clinical research shows that zinc, in combination with triclosan, does not prevent plaque and gingivitis (24093,87020), most clinical research shows that using zinc toothpaste or mouthwash, alone or in combination with triclosan, can prevent plaque accumulation, gingivitis, or the formation of calculus (6523,6524,6525,6526,6527,6528,6529,87418,87507). However, most studies used zinc citrate in combination with triclosan, which is not available in the US (6523). For treating existing plaque, calculus, and gingivitis, some clinical research suggests that using zinc citrate 0.5% toothpaste three times daily for 3 months reduces calculus scores by 14% when compared with placebo (87205). However, other evidence suggests that stannous fluoride 0.454% toothpaste is more effective than zinc citrate 0.75% toothpaste for reducing plaque levels (87136).
• Halitosis. Oral zinc seems to reduce halitosis when taken as a gum, mouth rinse, or candy. Details: Clinical research shows that chewing zinc-containing gum reduces volatile sulfur compounds and related odor levels when compared with placebo gum in patients with moderate to severe halitosis (87538). Clinical research also shows that using one of two mouth rinses (Halita, which contains 0.05% chlorhexidine and 0.14% zinc lactate, or Meridol, which contains 0.025% fluoride plus 0.2% zinc lactate) improves breath odor and volatile sulfur compounds by approximately two-fold when compared with mouth rinse containing only 0.05% fluoride or chlorhexidine 0.12% (90206). Additional clinical research shows that sucking a candy containing abrasive substances and zinc gluconate 0.5% or candy containing abrasive substances plus zinc 0.25% and propolis 1% improves breath malodor two- to three-fold when compared with sucking placebo candy (90196).
• Herpes labialis (cold sores). Topical zinc seems to reduce the severity and duration of cold sores. Details: Applying zinc topically seems to help treat herpes simplex infection (6538,6539,8623,11051). Zinc sulfate seems to reduce the severity and duration of symptoms in both orolabial and genital herpes (6538,6539). Zinc oxide (0.3%) in combination with glycine cream applied topically every 2 hours to facial and circumoral herpes seems to reduce symptoms such as blistering, soreness, itching, and tingling. It can also reduce the duration of lesions from 6.5 days to 5 days when treatment is begun within 24 hours of onset of symptoms (8623). A specific combination product containing zinc oxide and L-lysine plus 14 other ingredients (Super Lysine Plus +) also seems to help decrease symptoms and duration of herpes lesions when applied topically every 2 hours (11051). However, zinc may not be effective for recurrent herpes simplex infections. In one clinical study, applying zinc sulfate 0.0025% or 0.05% solution to affected areas did not reduce the frequency, severity, or duration of herpes episodes when compared with a placebo solution in patients experiencing more than five episodes per year (87330).
• Hypogeusia. Oral zinc might improve taste disturbance and taste acuity in people with hypogeusia of various etiologies. Details: A meta-analysis of low-quality studies in patients with taste disorders that are idiopathic or due to zinc deficiency shows that taking oral zinc modestly improves taste acuity when compared with placebo (104055). Studies tested zinc gluconate, zinc sulfate, zinc acetate, and zinc-carnosine as Polaprezinc (Promac, Zeria Pharmaceutical Co., Ltd.), containing 17-68 mg elemental zinc, daily for up to 12 weeks (104055). Zinc also might improve hypogeusia conditions unrelated to zinc deficiency, such as gustin/carbonic anhydrase VI deficiency, captopril-induced taste disturbances, hypogeusia due to chronic renal failure, and post-traumatic olfactory disorder (6543,6544,104055). It also seems be beneficial in radiation-induced dysgeusia. A meta-analysis of three small clinical trials shows that oral zinc reduces the risk of radiation-induced dysgeusia by 28%, but does not improve taste acuity when compared with placebo (104043). However, patients with hypogeusia from other causes may not benefit. Zinc supplementation does not seem to improve taste perception when compared with placebo in patients with acetazolamide-induced taste dysfunction or chemotherapy-induced taste dysfunction (87388,90214).
• Leishmania lesions. Oral zinc and intralesional injections of zinc might improve healing of these lesions. Details: Clinical research shows that taking zinc sulfate 2.5-10 mg/kg orally in three divided doses daily, improves the cure rate of cutaneous leishmania lesions after 45 days when compared with no treatment (86935). Other clinical research shows that intralesional injections of zinc sulfate 2% solution for 6 weeks improves cure rates of cutaneous leishmania lesions when compared with no treatment (6587). However, intralesional injections with zinc sulfate solution does not appear to be more effective than intralesional injections of meglumine antimoniate (Glucantime), hypertonic saline, or sodium stibogluconate (6587,86996,87008).
• Leprosy. Oral zinc seems to be beneficial when used in combination with anti-leprosy drugs. Details: Zinc levels appear to be reduced in people with leprosy. Early clinical research suggests that the addition of zinc improves tolerance of the anti-leprosy drug regimen and might allow for lowering or eliminating steroid doses in erythema nodosum leprosum, a severe form of leprosy (6534,6535,6536,6537).
• Low birth weight. Oral zinc supplementation seems to improve growth in low birth weight infants. Whether oral zinc can improve other outcomes, including mortality, is unclear. Taking oral zinc during pregnancy does not seem to reduce the risk of having a low birth weight infant. Details: While there is some mixed evidence regarding the effects of zinc supplementation on weight gain and length in infants born with low birth weight (87172,87452,90229), a meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, increases weight by around 380 grams, length by around 3 cm, and head circumference by around 0.6 cm when compared with control (109455). There is also mixed evidence regarding the effect of zinc supplementation on other outcomes in low birth weight infants. A large clinical trial in full-term, underweight infants aged 1-6 months in developing countries shows that adding zinc to nutritional supplementation reduces the risk of mortality by about 68% when compared with nutritional supplementation not containing zinc (8920). A small clinical trial in very low birth weight preterm infants born in an industrialized country shows that adding zinc to multivitamin supplementation appears to reduce the occurrence of necrotizing enterocolitis and mortality. However, adding zinc does not appear to prevent late-onset sepsis, bronchopulmonary dysplasia, or retinopathy of prematurity (90229). A meta-analysis of these trials and two other studies in low birth weight infants shows that supplementation with zinc reduces the risk of all-cause mortality by 52% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). Another small clinical study in low birth weight and preterm infants born in a developing country shows that zinc supplementation seems to improve alertness and attention when compared with placebo (97140). However, a meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, does not improve mental or psychomotor development or reduce the risk of mortality, hospitalization, acute respiratory infection, or sepsis when compared with control (109455). Some of these discrepant findings may be due to differences in patient populations (hospitalized, non-hospitalized), milk sources (breastfed, formula-fed, or both), and duration of follow-up. The effect of zinc intake or supplementation during pregnancy has also been evaluated. Population research has found that low dietary intake of zinc during pregnancy is associated with low birth weight in infants; similarly, zinc supplementation is associated with increased infant weight at birth (87471,105678). However, a meta-analysis and a large clinical study show that zinc supplementation during pregnancy does not reduce the risk of having a low birth weight infant (97142,105679). Reasons for the discrepancies may be due to differing zinc status prior to supplementation. Also, numerous factors contribute to the risk of low birth weight, which may confound research on the use of zinc supplementation alone.
• Peptic ulcers. Oral zinc seems to treat and prevent peptic ulcers. Details: Taking zinc orally seems to help treat and prevent peptic ulcers (6588,6589,6591). Some clinical research shows that zinc acexamate improves peptic ulcers when compared with placebo (6589,87285), and seems to be as effective as H2-receptor antagonist drugs (6589,87533). It is not known if other zinc salts are effective.
• Pneumonia. Oral zinc might reduce the risk for pneumonia in children, but it doesn't seem to improve symptoms in children that already have pneumonia. Details: A meta-analysis of four clinical studies shows that giving zinc supplements to children, ages 3 months to 5 years living in developing countries, some of whom were undernourished, reduces the risk of pneumonia incidence by 21% when compared with placebo (104047). Another meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of pneumonia mortality by 21% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). The research on TREATING existing pneumonia in children is inconsistent. Most meta-analyses and clinical studies in children ages 2 months to 5 years with severe pneumonia show that taking elemental zinc in addition to antibiotic therapy does not improve symptom resolution or the time to recovery when compared with antibiotic therapy alone. Zinc also does not seem to reduce mortality in these patients (87248,90197,96080,98131,104042). However, two clinical studies in children in the same age group with pneumonia suggest that adding zinc to standard antibiotic therapy improves symptom resolution and decreases hospital stay when compared with placebo (11052,87242). Reasons for these discrepancies are not clear, but may be related to zinc status prior to treatment.
• Prematurity. Analyses of clinical studies suggest that oral zinc improves growth in premature infants. Whether zinc improves development or reduces the risk of mortality in these patients is unclear. Details: A meta-analysis of small clinical trials in hospitalized infants born prematurely suggests that receiving enteral zinc supplementation at a dose of up to 10 mg daily reduces mortality and might improve short-term weight gain when compared with placebo (105687). Another meta-analysis of small clinical studies in preterm infants shows that adding zinc to formula or to a multivitamin seems to modestly increase infant weight and height and improve motor development when compared with control (105676). A larger meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, increases weight by around 380 grams, length by around 3 cm, and head circumference by around 0.6 cm when compared with control. However, zinc supplementation did not improve mental or psychomotor development or reduce the risk of mortality, hospitalization, acute respiratory infection, or sepsis when compared with control (109455). These analyses are limited by imprecision as well as a high risk of bias in some of the included studies. Some of the discrepant findings may be due to differences in patient populations (hospitalized, non-hospitalized), milk sources (breastfed, formula-fed, or both), and duration of follow-up.
• Pressure ulcers. Topical zinc paste seems to work as a skin barrier and improve pressure ulcer healing. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying zinc oxide paste to pressure ulcers daily for 8 weeks reduces necrotic tissue and decreases the surface area of skin pressure ulcers similarly to using a topical streptokinase-streptodornase product (Varidase) (87331). Other small clinical studies show that applying zinc oxide paste to pressure ulcers daily for 8-12 weeks improves healing similarly to a hydrocolloid dressing (Duoderm) (87181) or a specific barrier film product (Cavilon No Sting Barrier Film) (87017). Oral zinc has been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients shows that administering an oral nutritional supplement enriched with zinc, L-arginine, and vitamin C improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, zinc, L-arginine, and vitamin C daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Sickle cell disease. Oral zinc seems to improve symptoms of sickle cell disease in patients with zinc deficiency. Details: Taking zinc orally seems to help reduce symptoms of sickle cell disease in people with zinc deficiency (6594,6595,6596,8626,87343). Taking zinc supplements also seems to decrease the occurrence rate of sickle-cell crises and infections (6594,6596,90228). Additionally, zinc might reduce the number of hospitalizations for sickle cell crises, although the severity of the crises that do develop is not necessarily decreased by taking zinc supplements (6594,6596). In prepubertal children and adolescents with homozygous sickle cell disease, taking zinc seems to improve growth, height, and weight gain (8626,87403).
• Warts. Oral and topical zinc seem to improve the cure rate of cutaneous warts. Details: A small clinical study suggests that applying zinc sulfate 10% solution three times daily for 4 weeks improves plane warts, but not common warts, when compared with distilled water (87094). Another small clinical study suggests that applying topical zinc oxide 20% ointment twice daily for up to 3 months seems to have a similar cure rate as ointment containing salicylic acid 15% with lactic acid 15% (87082). Taking zinc orally may also be effective in treating warts (87227). A meta-analysis of low quality clinical studies shows that taking zinc sulfate orally improves the odds of curing cutaneous warts nearly 17-fold when compared with respective controls (87227). Preliminary clinical research in adults treated with cryotherapy for anogenital warts shows that taking zinc gluconate 30 mg orally three times daily for 2 months does not reduce the number of warts when compared with placebo (111445).

POSSIBLY INEFFECTIVE

• Alopecia areata. Oral zinc does not seem to improve symptoms of this condition. Details: Although there is preliminary evidence that suggests zinc in combination with biotin might be helpful for alopecia areata (6932), most studies indicate that zinc is not effective for alopecia areata, alopecia totalis, or alopecia universalis (6931,6932).
• Cystic fibrosis. Oral zinc does not improve cystic fibrosis symptoms or progression. Details: Clinical research shows that taking supplements providing 30-90 mg of elemental zinc for 6 weeks to one year does not improve lung function when compared with placebo in children and adolescents with cystic fibrosis (87066,87113,96079). One clinical study also shows that taking elemental zinc for one year does not reduce the number of days requiring oral or intravenous antibiotics for pulmonary infections (96079). However, one study shows that taking zinc can reduce the number of days of oral antibiotic use when compared with placebo (87113).
• HIV/AIDS. Oral zinc does not seem to improve outcomes in patients with HIV. Details: Clinical research in adult HIV patients with normal or low zinc levels shows that taking elemental zinc 12-15 mg daily orally for 18 months along with antiretroviral therapy does not improve viral load, CD4/8 counts, or mortality when compared with placebo (87036,87216,105686). In children with HIV-1, clinical research shows that administering zinc sulfate, providing 10 mg elemental zinc, daily for 6 months does not improve mortality, viral load, or CD4 counts when compared with placebo (82377).
• HIV/AIDS-related pregnancy complications. Oral zinc does not prevent pregnancy complications related to HIV infection. Details: Adding zinc 25 mg orally during pregnancy does not seem to reduce parent-to-child vertical transmission of HIV, infant mortality, birth weight, or gestational period in HIV-infected females with low zinc levels (11054,87034). Also, one clinical study in HIV-1-infected pregnant patients suggests that supplemental zinc can increase the risk of wasting, as assessed by weight and mid-upper arm circumference, by 170% when compared with placebo (87034).
• HIV/AIDS-related wasting. Oral zinc does not seem to improve HIV-related wasting syndrome. Details: A clinical study in patients with HIV-related wasting syndrome shows that taking zinc orally in combination with vitamins and albendazole does not seem to improve diarrhea or mortality when compared with taking albendazole alone (6564).
• Infant development. Oral zinc does not seem to improve infant mental and psychomotor development. Details: Clinical research, including a meta-analysis of eight studies, shows that giving zinc to infants or children at high risk for zinc deficiency does not improve mental and psychomotor development when compared with placebo (87013,90209). In another meta-analysis of studies in children whose baseline zinc status was not specified, there was no beneficial effect of zinc supplementation on mental or psychomotor development at 6 or 12 months of age (104817).
• Inflammatory bowel disease (IBD). Oral zinc does not improve symptoms of IBD. Details: Some clinical research shows that taking zinc orally does not seem to help treat IBD (6913,6915,6916).
• Influenza. Oral zinc does not seem to reduce the risk for influenza. Details: Supplemental zinc seems to improve cell-mediated immune response in elderly people (824), but it does not seem to have a significant effect on antibody response and incidence of influenza infection after the vaccine (6553,6563). Additionally, zinc supplementation in patients on hemodialysis, who have a high risk of zinc deficiency, does not seem to improve response to influenza vaccine (10809). Taking zinc supplements orally is unlikely to improve immune function in people without risk factors for zinc deficiency (10789). However, there is preliminary evidence that suggests zinc along with selenium might reduce the incidence of infections in institutionalized older patients (8921).
• Otitis media. Oral zinc does not prevent otitis media in children. Details: A meta-analysis of clinical research shows that taking elemental zinc 3-70 mg daily for up to 24 months does not prevent the occurrence of ear infections in children from low- or middle-income countries (87258).
• Pre-eclampsia. Oral zinc taken prenatally does not seem to be beneficial for pre-eclampsia prevention. Details: A meta-analysis and a large clinical study show that zinc supplementation during pregnancy does not reduce the risk of pre-eclampsia when compared with placebo (97142,105679).
• Prostate cancer. Oral zinc does not reduce the risk for prostate cancer or prostate cancer-related mortality. Details: Some epidemiological research has found an inverse relationship between dietary zinc intake and prostate cancer (96075). Also some clinical research shows that taking zinc 20 mg in combination with vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, and selenium 100 mcg daily for an average of 8 years might reduce the risk of prostate cancer in men with normal PSA levels; however, it does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). However, some evidence raises concern that zinc might actually INCREASE the risk of prostate cancer. A large-scale population study found that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study shows that men who take a multivitamin more than seven times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). Despite these studies suggesting the potential for adverse effects of zinc, a meta-analysis of mainly population research has found that there is no association between zinc intake and the risk of prostate cancer (96075).
• Psoriasis. Oral zinc does not reduce the severity of psoriasis symptoms. Details: Zinc epidermal levels are reportedly lower in people with psoriasis (6509). However, taking zinc orally does not seem to help treat psoriasis (6513,6514,6912,87363). Zinc supplementation has no effect on the psoriasis area and severity index (6513,6514).
• Rheumatoid arthritis (RA). Oral zinc does not treat symptoms of RA. Details: Multiple clinical studies in patients with RA show that taking zinc orally does not improve function or symptoms when compared with baseline or control (6517,6518,6519,87406).
• Sexual dysfunction. Oral zinc does not improve sexual function in males with chronic kidney disease (CKD). Details: Clinical research shows that zinc supplementation does not improve sexual activity or libido when compared with placebo in males with sexual dysfunction secondary to CKD (6708,6568,87220,87386,87416). In fact, one clinical study shows that taking zinc can decrease the frequency of intercourse by 76% when compared with placebo in patients with CKD-related sexual dysfunction (87220).
• Tinnitus. Oral zinc does not improve severity of tinnitus or reduce tinnitus-related disability. Details: A meta-analysis of three small clinical trials in adults with tinnitus shows that taking elemental zinc 50 mg daily for up to 16 weeks does not improve tinnitus severity, or disability from tinnitus when compared with placebo (104051).

LIKELY INEFFECTIVE

• Malaria. Oral zinc does not prevent or treat malaria in undernourished children or pregnant adults in developing countries. Details: A meta-analysis of clinical research in children or pregnant adults shows that taking zinc orally, alone or in combination with other supplements, for does not reduce the risk of malaria parasitemia (111444). A large multi-country study in zinc-deficient preschool children with acute malaria shows that taking zinc supplements does not affect fever, parasitemia, or hemoglobin when compared with placebo (10246). An even larger clinical study of over 40,000 children with malaria aged 1-36 months shows that taking zinc 5-10 mg daily orally for approximately 17 months does not reduce mortality when compared with placebo (87078). Zinc supplements also do not appear to protect against infection by Plasmodium falciparum (8638,87235,86937). However, one small study in children with low and high levels of parasitemia shows that taking zinc 10 mg daily for 46 weeks may lower the incidence of fever episodes by 38% and 69%, respectively, when compared with placebo (86937).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral zinc is beneficial in patients with age-related cognitive decline. Details: An epidemiological study based on elderly adults enrolled in the National Health and Nutrition Examination Survey (NHANES) has found that taking zinc may improve cognition in a non-linear manner. Daily doses below 9 mg and 8 mg in males and females, respectively, showed a positive association with cognitive function, but doses above that level showed no association. Additionally, high intake of both zinc and selenium was associated with improved cognition in females, but not in males (108446). Dietary intake was collected from two patient-reported 24-hour recalls and cognition was only measured once, limiting the validity of these findings.
• Alcohol-related liver disease. It is unclear if oral zinc is beneficial in patients with alcoholic-related liver cirrhosis. Details: A small clinical study in patients with alcoholic liver cirrhosis shows that taking zinc sulfate 600 mg daily for 6 weeks improves liver function, based on increased alkaline phosphatase activity and reduced serum bilirubin, when compared to baseline (87325).
• Anorexia nervosa. Oral zinc seems to improve weight gain in people with anorexia nervosa. Details: Anorexia nervosa might be linked with zinc deficiency. Small clinical trials in adolescents and adults with anorexia nervosa show that oral zinc supplements might help increase weight gain and improve depressive symptoms when compared with placebo (6905,6906).
• Arsenic poisoning. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking zinc 4 mg in combination with spirulina extract 500 mg daily for 16 weeks can decrease skin manifestations and reduce arsenic levels in the urine and in hair of patients with chronic arsenic poisoning (18301).
• Asthenopia (eye strain). Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults without dry eye disease shows that taking a specific combination product containing zinc 10 mg, L-carnitine 50 mg, elderberry fruit extract 300 mg, currant 100 mg, and Eleutherococcus root 50 mg (Meramirt CM) orally once daily for 1 month improves measures of eye strain and contrast sensitivity when compared to baseline. Improvements in these measures were lacking in the control group (111295). Statistical comparison between the two groups was not reported. It is unclear if these effects are due to zinc, other ingredients, or the combination.
• Athletic performance. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of zinc 90 mg, magnesium 1350 mg, and vitamin B6 31.5 mg orally for 3 nights at bedtime does not improve grip strength, squat, or bench press performance when compared with placebo (113655).
• Atopic dermatitis (eczema). It is unclear if oral zinc is beneficial for alleviating eczema in children. Details: A small clinical study in children with eczema shows that taking zinc sulfate 185.4 mg orally daily for 8 weeks does not appear to improve the surface area affected and degree of erythema, symptom scores of itch and sleep disturbance, or topical steroid use when compared with placebo. Also, plasma zinc levels appear to be normal in children with eczema (6911).
• Attention deficit-hyperactivity disorder (ADHD). Oral zinc might improve certain symptoms in children with ADHD. Details: Observational research has found that lower serum zinc levels are both more prevalent in children with ADHD and are linked to worsened response to stimulant therapy (9965,9966,9967). Based on this evidence, there is some interest in using zinc to improve symptoms in children with ADHD. A meta-analysis of six small clinical trials shows that although taking zinc modestly improves overall symptoms of ADHD when compared with placebo, there is no effect on hyperactivity or inattention when these outcomes are examined separately. The sub-analyses conducted for these two separate outcomes included only 3 studies. Most, but not all, of the included studies were conducted in children also receiving methylphenidate treatment (106240). Elemental zinc, usually as sulfate, was typically used in doses of 10-40 mg daily for 6-12 weeks (11350,12060,106240). There is some evidence that zinc could be most helpful in children with a high body mass index (BMI), low zinc levels, and low free fatty acid levels (11350). It is unclear if zinc is beneficial in children who are not already taking stimulant medications. One clinical guideline also provisionally recommends against use of oral zinc to treat patient with ADHD based on low-quality evidence (110318).
• Autism spectrum disorder. It is unclear if oral zinc is beneficial in children with autism spectrum disorder. Details: One small clinical study conducted in children with autism spectrum disorder shows that taking zinc 15-30 mg orally, alone or as add-on therapy to amphetamine, does not improve attention deficit hyperactivity disorder (ADHD) symptoms when compared with placebo (98711). However, the optimal mg/kg dose of amphetamine was shown to be 37% lower for those children also taking zinc 15 mg twice daily when compared with those taking placebo (98711).
• Autoimmune thyroiditis. It is unclear if oral zinc is beneficial in children with autoimmune thyroiditis. Details: A small clinical study in children aged 3-18 years with autoimmune thyroiditis shows that taking zinc acetate 25 mg daily in addition to standard therapy for 12 weeks does not change thyroid auto-antibody levels, thyroid function tests, or oxidative stress markers when compared with standard therapy alone. However, subjects taking zinc did not require escalation in levothyroxine doses when compared with the control group control group, which did require levothyroxine dose escalation (113661).
• Behcet disease. It is unclear if oral zinc is beneficial in patients with Behcet disease. Details: A small clinical trial in patients with Behcet disease shows that taking zinc gluconate 30 mg daily for 12 weeks does not improve disease activity scores, quality of life, or measures of inflammation when compared with placebo (109453).
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral zinc for BPH, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Beta-thalassemia. It is unclear if oral zinc is beneficial in patients with beta-thalassemia major. Details: A small clinical study in children recently diagnosed with beta-thalassemia major shows that initiating zinc sulfate in addition to standard blood transfusions increases linear growth rate when compared with transfusions alone (87329). Another small clinical study in adult and pediatric patients with thalassemia major and low bone mass shows that taking zinc 25 mg daily (as zinc sulfate) for 18 months improves whole-body bone mineral content, as well as hip and spine bone mineral density, by small amounts when compared with placebo (90208).
• Brain tumor. It is unclear if dietary zinc is beneficial for reducing the risk for brain cancer. Details: Population research has found that zinc intake is not associated with a reduced risk of developing brain cancer (87098).
• Breast cancer. It is unclear if increased dietary zinc intake is beneficial for reducing the risk for breast cancer. Details: Population research has found that neither zinc intake nor blood levels of zinc are associated with a reduced risk of breast cancer (106229).
• Bronchiolitis. It is unclear if oral zinc is beneficial for viral bronchiolitis in infants and children. Details: A small clinical study in children 2 years or younger with acute viral bronchiolitis shows that taking elemental zinc 10-20 mg as zinc sulfate for 5 days improves clinical recovery and reduces the duration of hospital stay by almost one day when compared with placebo. After 72 hours, 98% of infants and children taking zinc were considered fully recovered, compared to only 52% of infants taking placebo (96076).
• Burning mouth syndrome. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with burning mouth syndrome shows that taking zinc 15 mg and vitamin C 35 mg once daily, along with a vitamin B complex twice daily, for 30 days modestly decreases pain and burning when compared to baseline (105195). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefit is due to zinc, other vitamins, or the combination.
• Burns. Intravenous zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. The effects of oral zinc for burn healing are unclear. Details: Administering zinc intravenously in combination with other minerals seems to improve the outcomes of burn patients. Supplementation with zinc, copper, and selenium appears to improve wound healing, reduce pulmonary infections, and shorten intensive care unit stay in patients with serious burns (6520,87085). The effect of supplementation with zinc alone is unclear.
• Canker sores. It is unclear if oral zinc is beneficial in patients with canker sores. Details: Evidence for the use of zinc in canker sores is conflicting. A small clinical crossover study in patients with recurrent canker sores shows that taking zinc sulfate 660 mg daily for 3 months does not improve the size or frequency of canker sore ulcers when compared with control (6592). However, another clinical study in patients with recurrent sores and low or normal zinc levels shows that taking zinc sulfate 220 mg daily for 1 month reduces recurrence of sores when compared with placebo (86964). Reasons for conflicting results are unclear. Zinc might be beneficial when used in a muco-adhesive formulation. A small clinical study in patients with canker sores shows that taking a muco-adhesive zinc sulfate 5 mg tablet three times daily for 7 days reduces pain and speeds up healing when compared with placebo (104048).
• Cataracts. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking zinc orally in combination with antioxidant vitamins does not seem to help treat or prevent cataracts. Taking elemental zinc 80 mg plus vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily does not seem to have any effect on the development or progression of age-related lens opacities (cataracts) or the need for cataract surgery in well-nourished people 55-80 years of age. However, it is unknown whether earlier intervention and/or a longer period of treatment with supplements would have any effect on cataracts (7304).
• Chemotherapy-induced acral erythema. It is unclear if oral zinc reduces the severity of acral erythema induced in patients treated with the vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment regorafenib. Details: A small study in patients with metastatic colorectal cancer undergoing treatment with regorafenib shows that taking zinc gluconate 78 mg twice daily reduces the proportion of patients with more severe acral erythema when compared with control. Though there is no association in the zinc treatment group, lower serum zinc levels seem to correlate with more severe acral erythema in the control group, suggesting a possible role of zinc deficiency in the pathogenesis of acral erythema (112472). The validity of this study is limited by the lack of blinding.
• Chemotherapy-related fatigue. It is unclear if oral zinc improves symptoms in patients with fatigue due to chemotherapy. Details: A small clinical study in patients undergoing 4 or more cycles of chemotherapy for colorectal cancer shows that taking zinc 70 mg daily for 16 weeks does not improve fatigue or quality of life when compared with placebo (97141).
• Chronic fatigue syndrome (CFS). Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females with CFS shows that taking zinc 10 mg as zinc sulfate plus melatonin 1 mg daily for 16 weeks modestly reduces self-reported symptoms of physical fatigue when compared with placebo. However, there was no effect on cognitive or psychological symptoms, sleep, or symptoms of anxiety or depression (106241). This study may not have been adequately powered to detect differences between groups.
• Cirrhosis. It is unclear if zinc is beneficial for reducing cirrhosis-related mortality. Details: A meta-analysis of four small clinical trials shows that zinc supplementation does not seem to reduce mortality in patients with cirrhosis when compared with control (104054). This finding is limited due to the heterogeneity and small size of the available studies.
• Cognitive function. It is unclear if zinc is beneficial for cognitive function. Details: A very small clinical study in adults with overweight and obesity shows that taking supplemental zinc 30 mg daily for 12 weeks improves some measures of cognitive function and executive processing but does not improve verbal fluency when compared with placebo (112471). Zinc has also been evaluated in combination with other ingredients. A small clinical trial in healthy adults shows that taking a specific product containing a combination of zinc 9 mg, Lactobacillus helveticus, Lactiplantibacillus plantarum, Bifidobacterium longum, and other ingredients (Puraflor, GSK Consumer Healthcare, Milano, Italy) orally daily for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923).
• Colorectal adenoma. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking a combination supplement containing zinc 30 mg, selenium 200 mcg (as l-selenomethionine), vitamin A 2 mg (as retinol), vitamin C 180 mg, and vitamin E 30 mg (as D-a-tocopherol acetate) by mouth daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by approximately 40% when compared with placebo (92903). It is not clear if the benefit is due to zinc, other supplements, or the combination.
• Colorectal cancer. It is unclear if oral zinc is beneficial for reducing colorectal cancer risk. Details: Population research has found that increased intake of zinc is associated with a 17% to 20% reduced risk of colorectal cancer (90213,90220).
• Congenital heart disease. It is unclear if oral zinc is beneficial for reducing the risk of congenital heart defects. Details: An observational study in pregnant adults has found that consuming the recommended nutritional intake of zinc may be associated with a lower risk of total congenital heart defects in infants, including atrial and ventricular septal defects, when compared with low zinc intake. This association appears to persist despite copper or selenium intake (108445).
• Critical illness (trauma). It is unclear if oral zinc is beneficial for critically ill patients. Details: A meta-analysis of two small randomized clinical trials in adults with head trauma shows that supplementing zinc, given as 120 mg elemental zinc orally daily or 12 mg elemental zinc intravenously daily for 15 days to 3 months, regardless of serum zinc levels, does not improve the risk of 30-day mortality when compared with control (111290). However, the study may have been inadequately powered to detect a difference between groups.
• Dementia. Although there is interest in using oral zinc for dementia, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Diabetic foot ulcers. Although there is interest in using oral zinc for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Diabetic neuropathy. It is unclear if oral zinc is beneficial in patients with diabetic neuropathy. Details: A small clinical study in patients with poorly-controlled diabetic neuropathy shows that taking zinc sulfate 660 mg daily for 6 weeks improves motor nerve conduction velocity and reduces fasting and postprandial blood sugar when compared to baseline (86933). The validity of this finding is limited by the lack of statistical comparison to the control group.
• Down syndrome. It is unclear if oral zinc is beneficial for improving immune function in people with this condition. Details: A very small clinical study in Down syndrome patients with zinc deficiency shows that taking zinc sulfate 1 mg/kg daily for 2 months seems to improve immune function and reduce recurrent infections when compared with baseline (87289). The validity of this finding is limited by the lack of a control group. Another small clinical study in children with Down syndrome shows that zinc 25-50 mg daily for 6 months does not improve immune function when compared with placebo (87278). Reasons for the discrepancies may be related to the dose of zinc or zinc status at baseline.
• Dysmenorrhea. It is unclear if oral zinc is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research in females aged 13 to 21 years with primary dysmenorrhea shows that taking zinc sulfate 40 mg orally daily for the first 3 days of menstruation for three cycles reduces mean pain scores by 51% when compared with placebo (111446).
• Epilepsy. There is limited evidence on the oral use of zinc in children with intractable seizures. Details: A small clinical study in children with intractable epilepsy shows that taking elemental zinc 1 mg/kg daily as zinc sulfate heptahydrate for 6 months reduces seizures when compared with placebo. About 31% of children taking zinc experienced a 50% decrease in seizure frequency, compared to only 5% of children taking placebo (96078).
• Erectile dysfunction (ED). It is unclear if oral zinc is beneficial in patients with erectile dysfunction. Details: A moderate-sized, open-label clinical study in adults with mild-to-moderate ED shows that taking a specific combination supplement (Icarifil, Anvest Health S.p.A) containing zinc 15 mg, L-carnitine, L-citrulline, tribulus, and other ingredients daily for 3 months improves patient-reported erectile function when compared to baseline. Additionally, taking the supplement with tadalafil improves some, but not all, patient-reported assessments of erectile function when compared with taking tadalafil alone (114989). It is unclear if this effect is due to zinc, other ingredients, or the combination. Additionally, the interpretation of these results is limited by poor methodology, including the use of per-protocol analysis and lack of a placebo group.
• Esophageal cancer. It is unclear if oral zinc is beneficial for esophageal cancer prevention. Details: Population research in Chinese and Iranian patients has found that low intake of zinc is associated with an increased risk of esophageal squamous cell cancer (17205,87059). However, other population research in patients from America, Europe, or Asia has found that dietary zinc intake is not associated with esophageal cancer risk (90213).
• Fatigue. It is unclear if oral zinc is beneficial for reducing fatigue in older individuals. Details: A clinical study in adults 50 years and older, some with below-normal levels of zinc at baseline, shows that taking zinc 30 mg daily for 70 days improves subjective fatigue when compared with no intervention (105675). The validity of this finding is limited due to a lack of placebo control and potential performance bias. Additionally, it is unclear whether baseline zinc status alters the benefits of zinc supplementation.
• Fecal incontinence. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with fecal incontinence shows that topically applying an ointment containing zinc sulfate 1% and aluminum sulfate 5% to the anal canal mucosa three times daily for 4 weeks improves symptoms approximately twice as much as a placebo ointment. Quality of life related to the incontinence also improved (90219).
• Gastric cancer. It is unclear if dietary zinc is beneficial for gastric cancer prevention. Details: Population research has found that increased dietary zinc intake is not associated with a decreased risk of gastric cancer (90213).
• Head and neck cancer. It is unclear if oral zinc improves survival in patients with head and neck cancers. Details: Preliminary clinical research in patients with head and neck cancers shows that zinc supplementation does not improve disease-free or metastasis-free survival rates after 3 years when compared with placebo (87103).
• Hepatic encephalopathy. It is unclear if oral zinc is beneficial for reducing the severity of hepatic encephalopathy or preventing recurrence. Details: A meta-analysis of small clinical studies, as well as some individual clinical studies, show that short-term zinc supplementation improves cognitive function and possibly quality of life in patients with hepatic encephalopathy. These findings are based on results from the number connection test and other tests (87377,90202,106227). One study in patients with minimal hepatic encephalopathy used zinc bisglycinate 75 mg three times daily, providing elemental zinc 45 mg daily for 12 weeks (106227). However, other preliminary clinical research shows that short-term zinc supplementation does not improve hepatic encephalopathy severity when compared with placebo when assessed using Conn's index, which includes evaluation of mental state, asterixis (flapping tremor), number connection test, electroencephalogram (EEG) record, and plasma ammonia (87144). Also, a meta-analysis of clinical research shows that zinc sulfate supplementation does not reduce encephalopathy recurrence (90202). Based on these results, zinc supplementation may marginally improve cognitive function in hepatic encephalopathy patients, but it does not appear to improve disease severity or reduce the risk of recurrence.
• HIV/AIDS-related diarrhea. It is unclear if oral zinc is beneficial for preventing diarrhea in adult HIV patients. Details: Short-term zinc supplementation does not appear to TREAT diarrhea in adult HIV patients with persistent diarrhea. Clinical research shows that taking zinc 50 mg twice daily for 7 days does not reduce the duration of HIV-related diarrhea when compared with placebo (87055). However, zinc supplementation may help PREVENT HIV-related diarrhea when administered long-term. Clinical research shows that taking elemental zinc 12-15 mg daily for 18 months reduces the rate of diarrhea by about half when compared with placebo in adult HIV patients with zinc deficiency (87216). In HIV-infected children, clinical research shows that taking elemental zinc 10 mg daily for 6 months can reduce the occurrence of diarrhea by 49% when compared with placebo (82377). However, administering zinc in combination with vitamin A until 2 years of age does not reduce the occurrence of diarrhea when compared with vitamin A alone in HIV-infected children (82417).
• HIV/AIDS-related opportunistic infections. It is unclear if oral zinc is beneficial in opportunistic infections in patients with HIV/AIDs. Details: A small clinical study in patients with AIDS shows that taking zinc supplements orally in combination with zidovudine (AZT, Retrovir) might reduce opportunistic infections of Pneumocystis carinii and Candida when compared with taking zidovudine without zinc (6566).
• Human papillomavirus (HPV). It is unclear if oral zinc is beneficial for preventing relapse in patients with vulvar warts or for treating HPV infections and cervical lesions in patients with abnormal cervical cytology. Details: One small clinical study in patients with vulvar warts shows that taking zinc sulfate 400 mg daily for 8 weeks in addition to topical treatments including podophyllin 20%, imiquimod 5%, or cryotherapy, does not affect the duration of response, but does reduce the relapse rate by approximately 66% after 6 months, when compared with topical treatments alone (90190). Additionally, a small, open-label study in zinc-sufficient females with HPV shows that taking zinc sulfate 220 mg twice daily for 3 months reduces the odds of persistent HPV infection by 87% and improves the resolution of pre-existing cervical lesions when compared with no treatment (109456).
• Hypertension. It is unclear if oral zinc reduces blood pressure in normotensive or hypertensive patients. Details: A meta-analysis of small clinical trials shows that taking zinc reduces systolic blood pressure by about 1.5 mmHg, but does not reduce diastolic blood pressure, when compared with placebo. Response did not differ with the dosage of zinc or duration of supplementation. Only one study evaluated patients with hypertension; other patient populations included those with type 2 diabetes, diabetic retinopathy, pre-diabetes, obesity, polycystic ovary syndrome (PCOS), and patients on dialysis (104052). More research in patients with hypertension is needed to determine if zinc is beneficial in this population.
• Impaired glucose tolerance (prediabetes). While some conflicting evidence exists, several small clinical studies suggest that oral zinc may improve glycemic control in patients with prediabetes. Details: A meta-analysis of three low-quality studies in patients with prediabetes suggests that taking zinc sulfate 20-30 mg, alone or in combination with lysine and vitamin C, for 6-12 months reduces fasting blood glucose and postprandial glucose when compared with control (105682). Furthermore, a small clinical study in patients with prediabetes shows that taking zinc gluconate 30 mg daily for 90 days improves glycemic parameters when compared with placebo. All study participants were also instructed to increase physical activity and start a calorie-restricted diet (105391). However, another small clinical study in patients with prediabetes shows that taking zinc gluconate 30 mg daily for 12 months does not improve glycemic parameters when compared with placebo (109454). The available research has been conducted in Sri Lanka, Bangladesh, Iran, and Australia; it is unclear if these findings are generalizable to other geographic locations.
• Intestinal parasite infection. It is unclear if oral zinc is beneficial in patients with intestinal parasitic infections. Details: Zinc supplementation may help TREAT infection from Schistosoma mansoniin, but not other parasites, in children in developing countries. Results from one clinical study show that taking oral zinc sulfate 30-50 mg for 12 months reduces the intensity of Schistosoma mansoniin infection in children, as measured by number of eggs per gram in feces, when compared with placebo (87495). However, supplementation with zinc does not appear to reduce the intensity of Ascaris lumbricoides, Trichiuris trichura, nor Giardia lamblia infection in children (6586). Furthermore, preliminary clinical research suggests that supplementation with zinc may increase the duration of Entamoeba histolytica infection in children (87099). There are also inconsistent results regarding the effects of zinc in PREVENTING intestinal parasite infections. Some clinical research shows that taking zinc in combination with vitamin A reduces the incidence of Giardia lamblia infections when compared with placebo (87099). However, zinc supplementation does not appear to prevent intestinal infections by Ascaris lumbricoides, Schistosoma haematobium, nor Schistosoma mansoniin (87099,87495).
• Kidney failure. It is unclear if oral zinc is beneficial for patients on hemodialysis who have resistance to erythropoiesis-stimulating agents (ESAs). Details: Zinc deficiency is thought to play a role in ESA-resistant anemia in patients with kidney failure. A small clinical trial in patients on hemodialysis with low zinc levels shows that taking zinc acetate hydrate, usually 25mg or 50 mg daily, for 12 months increases plasma levels of zinc and modestly reduces the required weekly dose of ESAs when compared with placebo. However, there was no effect on hemoglobin levels (109781).
• Leukemia. It is unclear if oral zinc is beneficial for improving weight maintenance in children and adolescents with leukemia. Details: A small clinical study in children and adolescents with acute leukemia shows that taking zinc 2 mg/kg (as an amino acid salt) in two divided doses daily for 60 days doubles weight gain and reduces infection rate by approximately 60% when compared with placebo. However, zinc supplementation does not appear to improve nutritional status (90204).
• Liver cancer. It is unclear if oral zinc is beneficial for preventing hepatocellular carcinoma (HCC). Details: In patients treated for hepatitis C, the presence of hepatic fibrosis increases the risk for development of HCC, and is also associated with low plasma zinc levels. In a retrospective analysis of patients with a sustained virological response to hepatitis C therapy, those taking oral zinc supplements for at least 6 months had approximately half the risk of developing HCC when compared with those not taking zinc. Maintaining a serum zinc level above 90 mcg/dL seems to reduce the risk for HCC (106904).
• Lung cancer. It is unclear if increased dietary zinc intake is beneficial for reducing the risk of lung cancer. Details: Population research suggests that the highest dietary intake of zinc is associated with a 32% reduced risk of lung cancer when compared with the lowest intake (106235). Additionally, another large epidemiological cancer screening trial with a mean follow-up of 12.2 years suggests that dietary intake of zinc is protective against lung cancer, with the highest quartile of dietary intake showing the greatest benefit. However, this protective effect was not found for supplemental intake of zinc (112096).
• Male infertility. It is unclear if oral zinc is beneficial for infertility in males. Details: Some preliminary clinical research shows that taking zinc sulfate 66 mg daily increases sperm count, testosterone levels, and the incidence of pregnancy in idiopathic infertile men with low testosterone levels (9334,87430). Another clinical study shows that taking zinc sulfate 66 mg daily can improve sperm morphology by approximately 33% when compared to baseline in men with a grade III varicocele (90194). However, not all research agrees. One clinical study shows that taking elemental zinc 30 mg with folic acid 5 mg daily for 6 months does not improve sperm morphology or pregnancy rates when compared with placebo in infertile men (102085). It is possible the lower dose used in this study was insufficient to produce the beneficial effects observed in earlier research. Zinc supplementation has also been studied as part of combination therapy. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, vitamin C 90 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvements in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296). There is also interest in using zinc to improve results of in vitro fertilization (IVF). A small clinical study in couples undergoing IVF suggests that infertile male partners who take a specific combination product (Menevit) containing zinc and other antioxidants seem to have an increased rate of viable pregnancies when compared with placebo (87087). However, it's unclear if the benefit can be attributed to zinc, other antioxidants, or the combination.
• Melasma. It is unclear if topical zinc reduces melasma severity. Details: A small clinical study shows that applying a topical solution containing zinc sulfate 10% once daily for 2 months is less effective at reducing melasma severity when compared with hydroquinone 4% (90232).
• Menopausal symptoms. It is unclear if oral zinc improves sexual function after menopause. Details: A single clinical trial shows that taking zinc sulfate 110 mg daily for 6 weeks modestly improves testosterone levels and sexual function, including desire, arousal, satisfaction, and pain, after menopause when compared with placebo (106228).
• Migraine headache. It is unclear if oral zinc is beneficial in patients with migraine. Details: Two small clinical studies in patients with migraine show that taking zinc sulfate 200 mg or zinc gluconate 15 mg daily for 8-12 weeks modestly reduces migraine severity and frequency when compared with placebo (104040,105684). Both studies were conducted in Iran; it is unclear if these findings are generalizable to other geographic locations.
• Nasopharyngeal cancer. It is unclear if oral zinc is beneficial in patients with this type of cancer. Details: A small clinical study in patients with locally advanced nasopharyngeal cancer shows that zinc supplementation 75 mg daily for 2 months may improve disease-free survival rates after 5 years when compared with placebo (87163).
• Neonatal jaundice. It is unclear if oral zinc is beneficial for neonatal jaundice. Details: There is contradictory evidence about the effects of oral zinc in infants with hyperbilirubinemia. Two small clinical studies in infants with idiopathic neonatal hyperbilirubinemia show that receiving oral zinc sulfate 5 mg twice daily for 5-7 days does not affect levels of total bilirubin, the required duration of phototherapy, or the duration of hospitalization, when compared with placebo (90212,104814). However, a larger clinical trial in preterm infants receiving phototherapy and zinc 1.2 mg/kg daily as zinc sulfate heptahydrate, via either orogastric or nasogastric tube for 10 days, serum bilirubin levels were modestly decreased only on days 8-10 when compared with phototherapy alone (106242). Additionally, a second larger clinical trial in infants with idiopathic hyperbilirubinemia shows that receiving oral zinc sulfate (Zinc sulfate, Ramofarmin Company) 1 mg/kg daily for 3 days reduces total bilirubin levels and duration of phototherapy when compared with placebo; additionally length of hospitalization is reduced by less than 1 day (115631). The reason for these discrepant findings is unclear but may be attributed to variations in baseline characteristics, treatment duration, and dose.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral zinc is beneficial in patients with NAFLD. Details: A small clinical study in patients with NAFLD shows that following a calorie-restricted diet and taking zinc 30 mg daily for 12 weeks reduces certain liver enzymes, but does not improve steatosis or reduce weight, when compared with taking placebo and following a calorie-restricted diet (104046).
• Non-Hodgkin lymphoma. It is unclear if oral zinc is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that higher dietary intake of zinc is associated with a 42% decreased odds of developing non-Hodgkin lymphoma (87048).
• Obesity. Small studies suggest that oral zinc does not reduce weight or calorie intake in people with overweight or obesity. Details: A very small clinical study in adults with overweight or obesity shows that taking supplemental zinc 30 mg daily for 12 weeks does not reduce body weight, body mass index (BMI), calorie intake, or macronutrient intake when compared with placebo (112471). Additionally, clinical research in adults with overweight or obesity shows that taking zinc gluconate 25 mg and L-selenomethionine 200 mcg once daily for 8 weeks does not improve BMI, total body fat, or fat free mass when compared with placebo (111448).
• Obsessive-compulsive disorder (OCD). It is unclear if oral zinc reduces symptoms in patients with OCD. Details: A small clinical study in patients with OCD shows that taking zinc sulfate 200 mg twice daily with fluoxetine 20 mg daily for 8 weeks modestly reduces the severity of OCD symptoms when compared with taking placebo with fluoxetine (90223).
• Oral mucositis. It is unclear if oral or topical zinc prevents oral mucositis due to chemotherapy. Some small clinical studies suggest that oral zinc might prevent mucositis due to radiotherapy. Details: Two small clinical studies in adults with leukemia and other cancers shows that taking zinc sulfate 220 mg three times daily for 14 days or until the end of chemotherapy treatment reduces oral mucositis and pain intensity when compared with placebo (90191,98132). However, smaller doses have not shown benefit. A small clinical study in children and adolescents with leukemia shows that taking zinc 2 mg/kg daily (up to 60 mg daily) in two divided doses does not affect chemotherapy-induced mucositis when compared with placebo (90204). An unblinded clinical study in children and adolescents aged 8-16 years with recently diagnosed leukemia shows that taking zinc gluconate 50 mg (7 mg elemental zinc) daily does not significantly reduce the incidence or duration of oral mucositis when compared with a control group not receiving zinc (104816). Zinc also doesn't seem to be beneficial with high-dose chemotherapy. A small clinical study in adolescents and adults receiving high-dose chemotherapy prior to undergoing hematopoietic stem cell transplantation (HSCT) suggests that taking zinc sulfate 220 mg (50 mg elemental zinc) twice daily, beginning one day prior to the chemotherapy regimen and continuing for 3 weeks, does not affect the severity, duration, or onset of mucositis when compared with placebo (90215). Other preliminary clinical research in children aged 3-18 years receiving chemotherapy for leukemia or other cancer also shows that taking zinc 1 mg/kg orally daily for 14 days, beginning on the first day of chemotherapy, does not reduce the incidence or severity of mucositis when compared with placebo (111447). Topical zinc has also been investigated for radiation-induced or chemotherapy-induced oral mucositis. In two clinical studies, using 7.5 mL of a mouthwash containing zinc chloride 0.2% twice for 2 minutes every 8 hours for 3 weeks modestly reduces the incidence and severity of oral mucositis, and improves quality of life, when compared with a placebo mouthwash (106232,109690). In one study, the average patient weight was higher in the group using the mouthwash containing zinc (106232). Other preliminary clinical research in adults with head and neck cancer undergoing radiotherapy treatment, consisting of at least 30 Gy radiation exposure shows that using zinc sulfate 1% mouthwash, 5 mL three times daily for 6 weeks, beginning on the first day of radiation therapy, moderately improves oral mucositis severity and pain scores when compared with chlorhexidine 0.2% or placebo mouthwash (111291). Taking zinc orally might be beneficial in radiation-induced oral mucositis. A small clinical study in patients with head and neck tumors shows that taking zinc sulfate, providing 150 mg elemental zinc, daily starting at the first day of radiation therapy and ending at 6 weeks, reduces the severity of mucositis and prolongs the onset of mucositis when compared with placebo (86981). Another clinical study in patients with head and neck cancer shows that taking zinc sulfate 150 mg daily during and after chemoradiotherapy treatment, consisting of a total 69.5 Gy radiation exposure and cisplatin 40 mg/m2 weekly, is associated with less severe mucositis when compared with placebo (105677).
• Osteoporosis. It is unclear if oral zinc improves bone density in patients with osteoporosis. Details: Population research has found that reduced zinc intake and lower zinc serum levels seem to be associated with lower bone mineral density (BMD) (6920,14410). In elderly patients with at least marginal zinc deficiency who are taking standard therapy for osteoporosis, preliminary clinical research shows that taking zinc acetate dihydrate (Nobelzin, Nobelpharma) providing elemental zinc 25 mg twice daily for 12 months increases BMD when compared with baseline. Increases in serum zinc were associated with improvements in BMD. However, it is unclear if increases in BMD were significant when compared with placebo (106230). It is also unclear if zinc improves BMD in patients without zinc deficiency. A small clinical study in healthy postmenopausal adults suggests that taking zinc in combination with copper, manganese, and calcium might slow bone loss when compared with placebo (1994). It is not clear if this effect is due to zinc, other ingredients, or the combination.
• Overall mortality. It is unclear if oral zinc reduces overall mortality in young children. Details: A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc in daily doses of at least 10 mg reduces the risk of all-cause mortality by 16% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation. The risk of mortality was reduced by 54% when children took zinc for up to one year, but overall mortality was not reduced in studies lasting at least one year (106239).
• Periodontitis. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a combination supplement containing zinc 3.75 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin C, and vitamin E twice daily for 8 weeks in addition to standard nonsurgical therapy does not reduce periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation when compared with placebo (111708).
• Polycystic ovary syndrome (PCOS). It is unclear if oral zinc is beneficial in patients with PCOS. Details: A small clinical study in adults taking metformin for PCOS shows that also taking zinc sulfate 220 mg (50 mg elemental zinc) daily for 8 weeks improves hair loss and facial growth, but not acne, when compared with placebo (96071).
• Postoperative sore throat. It is unclear if oral zinc is beneficial for postoperative sore throat. Details: Clinical research shows that dissolving a lozenge containing zinc 40 mg as zinc sulfate in the mouth in the 30 minutes before surgery involving endotracheal intubation reduces the incidence of postoperative sore throat by 58% when compared with placebo lozenges. It also seems to reduce the severity of postoperative sore throat that does occur (97138). Other clinical research in adults undergoing a procedure that required endotracheal intubation shows that using a preoperative 30-mL gargle containing zinc 40 mg does not affect sore throat scores when compared with magnesium sulphate 250 mg or budesonide 200 mcg gargles (114763).
• Postpartum depression. It is unclear if oral zinc prevents postpartum depression after a Cesarean section (C-section). Details: A small observational study in pregnant patients with anemia who underwent C-section has found that taking zinc sulfate 100 mg daily for 4 days after surgery is associated with a 75% reduction in the odds of developing postpartum depression when compared with no supplementation (109452).
• Premenstrual syndrome (PMS). It is unclear if oral zinc improves symptoms in patients with PMS. Details: A small clinical study in female college students shows that taking elemental zinc 30 mg daily for 3 months improves quality of life, but not quality of sleep, when compared with placebo (104049).
• Preterm labor. It is unclear if oral zinc reduces the risk of preterm labor. Details: Observational research has found that low dietary intake of zinc during pregnancy is associated with an increased likelihood of preterm deliveries (87471). Also, most meta-analyses of clinical research show that taking zinc supplements during pregnancy modestly reduces the risk of preterm birth (106231). However, one large meta-analysis of 22 clinical studies shows that zinc supplementation during pregnancy seems to have little or no benefit for reducing the risk of preterm birth when compared with control (105679). Zinc supplementation also does not seem to reduce the risk of stillbirth, neonatal death, spontaneous abortion, or premature rupture of membranes (97142,105679,106231).
• Prostatitis. It is unclear if oral zinc improves symptoms in men with chronic prostatitis. Details: A clinical study in men with chronic prostatitis shows that taking zinc sulfate 220 mg daily along with prazosin 2 mg daily for 12 weeks does not improve difficulty urinating or quality of life, but does seem to improve pain, when compared with prazosin alone (90210). The validity of this study was limited by a significant dropout rate.
• Pruritus. There is limited evidence on the oral use of zinc for reducing pruritis in hemodialysis patients. Details: A small clinical study in end-stage renal disease patients with hemodialysis-associated pruritus shows that taking zinc sulfate 220 mg twice daily for 2 months reduces pruritus severity when compared with placebo (90218).
• Psoriatic arthritis. It is unclear if oral zinc improves psoriatic arthritis symptoms. Details: Two small clinical trials in patients with psoriatic arthritis show that taking zinc orally, alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), does not seem to reduce pain or improve function when compared with control (6514,6515).
• Respiratory tract infections. It is unclear if oral zinc reduces respiratory tract infections in children. Details: An open-label study in children aged 6 months to 5 years with zinc deficiency shows that taking zinc sulfate 20 mg orally once daily for 2 weeks reduces the number of episodes and the mean duration of upper and lower respiratory tract infections over 6 months of follow-up when compared with the 6 months prior to zinc supplementation (104815). The validity of this finding is limited by the lack of a comparator group.
• Rosacea. It is unclear of oral zinc improves symptoms of rosacea or quality of life. Details: A small clinical trial shows that taking zinc sulfate 440 mg in two divided doses daily for 90 days does not improve quality of life or symptoms associated with rosacea when compared with placebo (90195).
• Seizures. It is unclear if oral zinc reduces recurrent febrile seizures in children. Details: Although some individual preliminary clinical research disagrees (96069), a meta-analysis of generally low-quality research in children under 5 years of age with a previous febrile seizure shows that taking zinc sulfate 1-2 mg/kg or 20 mg daily for 6-12 months does not reduce febrile seizure recurrence when compared with placebo (106237). Also, a small clinical study shows that taking zinc does not increase the time to first febrile seizure recurrence (96069).
• Sepsis. It is unclear if oral zinc is beneficial in pediatric or adult patients with sepsis. Details: A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of sepsis mortality by 57% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). Also, a small clinical study in newborns with sepsis shows that giving zinc sulfate monohydrate 3 mg/kg twice daily for 10 days along with antibiotics reduces the likelihood of neurological abnormalities, such as those related to posture, behavior, and reflexes, by 70% when compared with antibiotics alone. Mortality and length of hospital stay were not improved, but the study may have been inadequately powered to detect a difference in these parameters (96077). Another study in preterm infants with late-onset sepsis (developing at least 72 hours after birth), shows that giving 1.4 mg/kg elemental zinc daily orally for 10 days in addition to antibiotics reduces the number of infants with unresolved sepsis at 10 days, and reduces C-reactive protein and procalcitonin levels, when compared with giving antibiotics alone (104819). A meta-analysis of small clinical studies in infants less than 4 months old shows that administering zinc 1-3 mg/kg daily for 1-18 weeks may reduce the rate of infant mortality and treatment failure when compared with placebo or control, but does not seem to prevent sepsis or improve sepsis-related mortality (108444). Additionally, zinc has been evaluated in adults. A single-center observational study in adults with sepsis found that administering zinc orally or enterally in various doses, ranging from less than 15 mg to greater than 50 mg daily, does not improve survival rates or reduce the length of stay in the intensive care unit (115630).
• Shigellosis. It is unclear if oral zinc is beneficial in patients with acute shigellosis from food poisoning. Details: A small clinical study in malnourished children with acute shigellosis (food poisoning) shows that administering a multivitamin syrup containing elemental zinc 20 mg daily for 2 weeks, in addition to standard treatment, can improve recovery time and reduce the number of diarrhea episodes when compared with multivitamin syrup without elemental zinc (87088).
• Sleep deprivation. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of zinc 90 mg, magnesium 1350 mg, and vitamin B6 31.5 mg orally for 3 nights at bedtime does not change sleep quality, subjective sleepiness, mood, or fatigue when compared with placebo (113655).
• Substance use disorder. It is unclear if oral zinc is beneficial for substance use disorder. Details: Preliminary clinical research in adults with opioid use disorder that were being treated with methadone shows that taking zinc sulfate, containing 12 mg zinc, orally daily for 3 months moderately improves relapse prevention scores, including drug use and drug craving scores, when compared with control. Taking zinc also modestly improved stress and anxiety scores (111293).
• Tonsillopharyngitis. It is unclear if oral zinc is beneficial in patients with tonsillopharyngitis. Details: A moderate-sized, open-label clinical study in pediatric patients aged 3 to 10 years with acute tonsillopharyngitis shows that taking a specific combination solution (PediaFlù, Pediatrica S.r.l.) containing zinc (age dependent doses ranging from 2 to 4 mg), honey, propolis, and pelargonium sidoides daily for 6 days along with standard of care reduces tonsilitis severity scores when compared with standard care alone; however, this improvement is not clinically significant. (115632). It is not clear if these effects are due to zinc, other ingredients, or the combination.
• Traumatic brain injury (TBI). There is limited evidence on the parenteral use of zinc for closed head injury. Details: A small clinical study shows that administering zinc parenterally immediately following severe closed head injury seems to improve the rate of neurological recovery when compared with standard therapy (2696).
• Tuberculosis. It is unclear if oral zinc can improve outcomes in patients receiving tuberculosis treatment. Details: Low levels of zinc are common in patients with tuberculosis. In patients newly diagnosed with tuberculosis and using anti-tuberculosis treatment, some clinical research shows that taking zinc 50 mg daily as zinc sulfate for 6 months increases the number of patients with negative sputum smears by 50% to 80% within the first 6 weeks of treatment when compared with placebo. However, there were no differences in the number of patients with negative smears after this time point. There were also improvements in some liver function enzyme levels after 2 months, but not 6 months, when compared with placebo (106238). However, other clinical research shows that taking zinc 15-90 mg daily for 2-6 months does not improve cure rates or sputum smear conversions when compared with placebo. However, when combined with vitamin A, serum levels of vitamin A, zinc, and hemoglobin were modestly improved and there was a modest increase in sputum smear conversions (109754).
• Urinary tract infections (UTIs). It is unclear if oral zinc is beneficial in children with UTI. Details: A low-quality, clinical study in children aged 3-12 years hospitalized for a UTI and receiving intravenous antibiotic treatment shows that taking zinc 1 mg/kg daily for 14 days reduces the duration of dysuria, urinary frequency, and urgency when compared with intravenous antibiotics alone. Zinc does not improve fever or the time to negative urine culture (96081). However, this study did not demonstrate that treatment groups were equal at baseline.
• Venous leg ulcers. It is unclear if oral or topical zinc is beneficial for leg ulcer healing. Details: Two small studies in elderly patients with leg ulcers suggest that using a zinc saline solution on a wound dressing or applying zinc oxide to a dressing might improve healing of leg ulcers (2694,6901). However, oral zinc supplementation does not seem to be beneficial. A meta-analysis of four small clinical trials in patients with venous leg ulcers shows that taking zinc orally does not improve healing when compared with placebo (104079).
• Vertigo. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with benign paroxysmal positional vertigo with serum 25-hydroxyvitamin D levels less than 20 ng/mL shows that taking a specific combination product containing zinc 7.5 mg, alpha-lipoic acid 600 mg, L-carnosine 165 mg, curcumin 100 mg, piperine 1 mg, cholecalciferol 800 units, vitamin B2 0.8 mg, and vitamin B6 1 mg (Vertistop D, Difass) orally daily for 6 months moderately reduces the number of vertigo relapse episodes when compared with control. However, in patients with serum 25-hydroxyvitamin D levels greater than 20 ng/mL that took a specific combination product containing zinc 7.5 mg, alanine 600 mg, L-carnosine 165 mg, curcumin 100 mg and piperine 1 mg (Vertistop L, Difass) orally daily for 6 months there was no difference in relapse episodes when compared with control (111294). It is unclear if this effect is due to zinc, other ingredients, or the combination.
• Water warts. It is unclear if oral zinc is beneficial for the treatment of water warts in children. Details: In children with water warts, preliminary clinical research shows that taking zinc sulfate heptahydrate (as Zinco syrup) for 2 months results in lesion resolution in 70% of patients when compared with baseline. Lesion resolution occurred in an additional 13% of patients in the month after treatment completion, with no recurrence in any of these children over the next 9 months. Zinc 3 mg daily was used in children up to 3 years of age, and 5 mg daily was used in older children (106234). Due to the lack of a comparator group, it is unclear if these outcomes are due to zinc or the natural resolution of the condition.
• Wound healing. Topical zinc might be beneficial for the healing of uncomplicated wounds. Details: A small clinical study shows that applying zinc chloride solution, standardized to contain zinc 20 mcg/mL, twice daily improves wound healing when compared with saline solution in patients with uncomplicated, skin wounds. However, when zinc is administered as a component of an insulin product (Humulin, Eli Lilly and Company), it seems to be more effective than zinc chloride alone (90192).
• Wrinkled skin. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A topical preparation containing 10% vitamin C as L-ascorbic acid and acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months seems to improve fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). More evidence is needed to rate zinc for these uses.

(Read more about ZINC)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Angelica archangelica has Generally Recognized as Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of Angelica archangelica when used orally or topically for medicinal purposes.

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

(Read more about ANGELICA ARCHANGELICA)

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. An ashitaba extract has been used with apparent safety in doses of 500 mg twice daily for 12 weeks (100594). There is insufficient reliable information available about the safety of ashitaba 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 used orally and appropriately. Dong quai has been used with apparent safety in a dose of 4.5 grams daily for 24 weeks, or in combination with other ingredients in doses of up to 150 mg daily for up to 6 months (19552,35797). ...when used intravenously as a 25% solution, in a dose of 200-250 mL daily for up to 20 days (48438,48442,48443,48483).

POSSIBLY UNSAFE ...when used orally in large amounts, long-term. Theoretically, long-term use of large amounts of dong quai could be harmful. Dong quai contains several constituents such as bergapten, safrole, and isosafrole that are considered carcinogenic (7162). There is insufficient reliable information available about the safety of dong quai when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Dong quai has uterine stimulant and relaxant effects (8142); theoretically, it could adversely affect pregnancy. Observational research has found that intake of An-Tai-Yin, an herbal combination product containing dong quai and parsley, during the first trimester is associated with an increased risk of congenital malformations of the musculoskeletal system, connective tissue, and eyes (15129).

LACTATION:
Insufficient reliable information available; avoid use.

(Read more about DONG QUAI)

LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods (2406,7772,7773). ...when used orally in supplemental doses. Lycopene supplements have been used safely in doses of 15-45 mg daily for 4 to 6 months (60389,60399,60482,102180,102182,109431). Some limited evidence suggests that 120 mg daily is safe for up to one year (60372).

PREGNANCY: LIKELY SAFE
when consumed in amounts commonly found in foods. There is insufficient reliable information available about the safety of lycopene supplements during pregnancy. Small, low-quality clinical studies have shown conflicting results about the safety of using lycopene 2-4 mg daily during pregnancy (60337,60428).

LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods. There is insufficient reliable information available about the safety of lycopene supplements during lactation; avoid using in amounts greater than those typically found in foods.

(Read more about LYCOPENE)

LIKELY SAFE ...when used in amounts found in foods (2030).

POSSIBLY SAFE ...when taken orally in doses of up to 1500 mg daily for up to 3 months (71066,71097,91328,91331,95825,95833,98910,100695,105183,109163,109167). Higher doses of 2000-3000 mg daily have been well tolerated when taken for 2-6 months, but are more likely to cause gastrointestinal side effects (91327,98908). ...when used topically for up to 30 days (71064). ...when used as an intranasal spray for up to 4 weeks (97339).

CHILDREN: LIKELY SAFE
when used in amounts found in foods.

CHILDREN: POSSIBLY SAFE
when used as an intranasal spray for up to 2 months in children 4 years of age and older (91332). There is insufficient reliable information available about the safety of resveratrol when used by mouth in larger amounts as medicine.

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods (2030). Resveratrol is found in grape skins, grape juice, wine, and other food sources. However, wine should not be used as a source of resveratrol during pregnancy and lactation.

(Read more about RESVERATROL)

LIKELY SAFE ...when used orally and appropriately. Selenium appears to be safe when taken short-term in amounts below the tolerable upper intake level (UL) of 400 mcg daily (4844,7830,7831,7836,7841,9724,9797,14447,17510,17511)(17512,17513,17515,17516,97087,97943,109085); however, there is concern that taking selenium long-term might not be safe. Some evidence shows that consuming a diet containing more than the recommended dietary allowance (RDA) of selenium, which is 55 mcg daily for most adults, is associated with an increased risk for developing type 2 diabetes (99661). Some evidence also shows that taking a selenium supplement 200 mcg daily for an average of 3-8 years increases the risk of developing type 2 diabetes (97091,99661). Higher serum levels of selenium are also associated with an increased risk of developing diabetes and increased mortality (16710,99661). ...when used intravenously. Selenium, as selenious acid, is an FDA-approved drug. Sodium selenite intravenous infusions up to 1000 mcg daily have been safely used for up to 28 days (90347,92910).

POSSIBLY UNSAFE ...when used orally in high doses or long-term. Doses above 400 mcg daily can increase the risk of developing selenium toxicity (4844,7825). Additionally, some evidence shows that consuming a diet containing more than the recommended dietary allowance (RDA) of selenium, which is 55 mcg daily for most adults, is associated with an increased risk for developing type 2 diabetes (99661). There is also concern that taking a selenium supplement 200 mcg daily long-term, for an average of 3-8 years, increases the risk of developing type 2 diabetes (99661). Higher serum levels of selenium are also associated with an increased risk of developing diabetes and increased mortality (16710,99661).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Selenium seems to be safe when used short-term in doses below the tolerable upper intake level (UL) of 45 mcg daily for infants up to age 6 months, 60 mcg daily for infants 7 to 12 months, 40-90 mcg daily for children 1 to 3 years, 100-150 mcg daily for children 4 to 8 years, 200-280 mcg daily for children 9 to 13 years, and 400 mcg daily for children age 14 years and older (4844,86095); however, there is some concern that long-term use might not be safe. ...when used via a nasogastric tube in premature infants (7835,9764).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately. Selenium appears to be safe when used short-term in amounts that do not exceed the tolerable upper intake level (UL) of 400 mcg daily (4844,17507,74419,74481,74391); however, there is concern that long-term use might not be safe.

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. Doses above 400 mcg daily may cause significant toxicity (4844).

LACTATION: POSSIBLY SAFE
when used orally and appropriately. Selenium appears to be safe when used short-term in amounts that do not exceed the tolerable upper intake level (UL) of 400 mcg daily when taken short-term (4844,74467); however, there is concern that long-term use might not be safe.

LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Doses above 400 mcg daily may cause significant toxicity (4844,7838). ...when used orally in HIV-positive women. Selenium supplementation in HIV-positive women not taking highly active antiretroviral therapy may increase HIV-1 levels in breast milk (90358).

(Read more about SELENIUM)

LIKELY SAFE ...when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 40 mg daily (7135). ...when used topically and appropriately (2688,6538,6539,7135,8623,11051,111291).

POSSIBLY SAFE ...when used orally and appropriately in doses higher than the tolerable upper intake level (UL). Because the UL of zinc is based on regular daily intake, short-term excursions above 40 mg daily are not likely to be harmful. In fact, there is some evidence that doses of elemental zinc as high as 80 mg daily in combination with copper 2 mg can be used safely for approximately 6 years without significant adverse effects (7303,8622,92212). However, there is some concern that doses higher than the UL of 40 mg daily might decrease copper absorption and result in anemia (7135).

POSSIBLY UNSAFE ...when used intranasally. Case reports and animal research suggest that intranasal zinc might cause permanent anosmia or loss of sense of smell (11155,11156,11703,11704,11705,11706,11707,16800,16801,17083). Several hundred reports of anosmia have been submitted to the US Food and Drug Administration (FDA) and the manufacturer of some intranasal zinc products (Zicam) (16800,16801). Advise patients not to use intranasal zinc products.

LIKELY UNSAFE ...when taken orally in excessive amounts. Ingestion of 10-30 grams of zinc sulfate can be lethal in adults (7135). Chronic intake of 450-1600 mg daily can cause multiple forms of anemia, copper deficiency, and myeloneuropathies (7135,17092,17093,112473). This has been reported with use of zinc-containing denture adhesives in amounts exceeding the labeled directions, such as several times a day for several years (17092,17093). Advise patients to follow the label directions on denture adhesives that contain zinc.

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135). Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL for children is based on age: 4 mg daily for 0-6 months, 5 mg daily for 7-12 months, 7 mg daily for 1-3 years, 12 mg daily for 4-8 years, 23 mg daily for 9-13 years, and 34 mg daily for 14-18 years (7135,97140).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Taking amounts greater than the UL can cause sideroblastic anemia and copper deficiency (7135). ...when used topically on damaged skin. An infant treated with 10% zinc oxide ointment for severe diaper rash with perianal erosions developed hyperzincemia. Absorption seemed to occur mainly via the erosions; plasma levels dropped after the erosions healed despite continued use of the ointment (106905).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during pregnancy in those 14-18 years of age and 40 mg daily in those 19-50 years of age (7135).

PREGNANCY: LIKELY UNSAFE
when used orally in doses exceeding the UL (7135).

LACTATION: LIKELY SAFE
when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during lactation in those 14-18 years of age, and 40 mg daily for those 19-50 years of age (7135).

LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher doses can cause zinc-induced copper deficiency in nursing infants (7135).

(Read more about ZINC)

(Read more about ANGELICA ARCHANGELICA)

(Read more about ASHITABA)

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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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dong quai may increase the risk of bleeding when used with anticoagulant or antiplatelet drugs; however, research is conflicting.  Details Animal studies suggest that dong quai has antithrombin activity and inhibits platelet aggregation due to its coumarin components (6048,10057,96137). Additionally, some case reports in humans suggest that dong quai can increase the anticoagulant effects of warfarin (3526,6048,23310,48439). However, clinical research in healthy adults shows that taking 1 gram of dong quai root daily for 3 weeks does not significantly inhibit platelet aggregation or cause bleeding (96137). Until more is known, use dong quai with caution in patients taking antiplatelet/anticoagulant drugs.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dong quai may reduce the effects of estrogens.  Details Dong quai has estrogenic effects (6180,7860,15108,15535,48459). Theoretically, concomitant use of large amounts of dong quai might interfere with hormone replacement therapy due to competition for estrogen receptors.

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Dong quai may increase the risk of bleeding when used with warfarin.  Details Case reports suggest that concomitant use of dong quai with warfarin can increase the anticoagulant effects of warfarin and increase the risk of bleeding (3526,6048,23310,48439). In one case, after 4 weeks of taking dong quai 565 mg once or twice daily, the international normalized ratio (INR) increased to 4.9. The INR normalized 4 weeks after discontinuation of dong quai (3526).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking lycopene with anticoagulant or antiplatelet drugs might increase the risk of bleeding.  Details In vitro research shows that lycopene has antiplatelet effects (60360,60375,92177).

(Read more about LYCOPENE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Resveratrol may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Resveratrol seems to have antiplatelet effects (2949,2950,2951,2952,2961,70813,70828,70831,70892,70968,71106).

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A1.  Details In vitro research shows that resveratrol can inhibit CYP1A1 enzymes (70811,70862). However, this interaction has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that resveratrol can inhibit CYP1A2 enzymes (21733). However, this interaction has not been reported in humans.

CYTOCHROME P450 1B1 (CYP1B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1B1.  Details In vitro research shows that resveratrol can inhibit CYP1B1 enzymes (70834). However, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP2C19.  Details In vitro research shows that resveratrol can inhibit CYP2C19 enzymes (70896). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Resveratrol might increase levels of drugs metabolized by CYP2E1.  Details In vitro research suggests that resveratrol inhibits CYP2E1 isoenzyme (7864,70896). Also, a pharmacokinetic study shows that taking resveratrol 500 mg daily for 10 days prior to taking a single dose of chlorzoxazone 250 mg increases the maximum concentration of chlorzoxazone by about 54%, the area under the curve of chlorzoxazone by about 72%, and the half-life of chlorzoxazone by about 35% (95824). Chlorzoxazone is used as a probe drug for CYP2E1.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that resveratrol can inhibit the CYP3A4 enzyme (7864,70896). However, clinical research shows that taking resveratrol 3000 mg daily for 8 weeks does not necessitate dose adjustments to medications metabolized by CYP3A4 (91327).

(Read more about RESVERATROL)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Selenium may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Clinical research suggests that taking selenium 10 mcg/kg/day can increase bleeding times by increasing prostacyclin production, which inhibits platelet activity (14540). Other clinical research suggests that taking selenium 75 mcg daily, in combination with ascorbic acid 600 mg, alpha-tocopherol 300 mg, and beta-carotene 27 mg, reduces platelet aggregation (74406).

BARBITURATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, selenium might prolong the sedating effects of barbiturates.  Details Laboratory research suggests that selenium can inhibit the hepatic metabolism of barbiturates (14601,14602). Selenium seems to prolong the sedative effect of pentobarbital in animal models (14601).

CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Contraceptive drugs might increase levels of selenium, although the clinical significance of this effect is unclear.  Details Some research suggests that oral contraceptives increase serum selenium levels in women taking oral contraceptives; however, other research shows no change in selenium levels (14544,14545,14546,101343). It is suggested that an increase could be due to increased carrier proteins, indicating a redistribution of selenium rather than a change in total body selenium (14545).

GOLD SALTS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Gold salts might interfere with selenium activity in tissues.  Details Gold forms complexes with selenium, altering its tissue distribution. Theoretically, this might prevent the normal activity of selenium and produce effects equivalent to deficiency (14547,14548).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, selenium supplementation may reduce the effectiveness of immunosuppressant therapy.  Details In vitro research and preliminary clinical evidence suggests that selenium may stimulate the immune system (74483,74445).

NIACIN Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = A Selenium might reduce the beneficial effects of niacin on high-density lipoprotein (HDL) levels.  Details A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as selenium, or to the combination. It also is not known whether it will occur in other patient populations.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, selenium might interfere with warfarin activity.  Details Animal research suggests that selenium can increase warfarin activity. Selenium might interact with warfarin by displacing it from albumin binding sites, reducing its metabolism in the liver, or by decreasing production of vitamin K-dependent clotting factors (14541). Selenium can also prolong bleeding times in humans by increasing prostacyclin production, which inhibits platelet activity (14540).

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AMILORIDE (Midamor) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Amiloride can modestly reduce zinc excretion and increase zinc levels.  Details Clinical research shows that amiloride can reduce urinary zinc excretion, especially at doses of 10 mg per day or more. This zinc-sparing effect can help to counteract zinc losses caused by thiazide diuretics, but it is unlikely to cause zinc toxicity at usual amiloride doses (830,11626,11627,11634). The other potassium-sparing diuretics, spironolactone (Aldactone) and triamterene (Dyrenium), do not seem to have a zinc-sparing effect.

ATAZANAVIR (Reyataz) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Zinc modestly reduces levels of atazanavir, although this effect does not seem to be clinically significant.  Details Clinical research shows that zinc might decrease serum atazanavir levels by chelating with atazanavir in the gut and preventing its absorption (93578). Although a single dose of zinc sulfate (Solvazinc tablets) 125 mg orally does not affect atazanavir concentrations in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate 125 mg daily for 2 weeks reduces plasma levels of atazanavir by about 22% in these patients. However, despite this decrease, atazanavir levels still remain at high enough concentrations for the prevention of HIV virus replication (90216).

CEPHALEXIN (Keflex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc might decrease cephalexin levels by chelating with cephalexin in the gut and preventing its absorption.  Details A pharmacokinetic study shows that zinc sulfate 250 mg taken concomitantly with cephalexin 500 mg decreases peak levels of cephalexin by 31% and reduces the exposure to cephalexin by 27%. Also, taking zinc sulfate 3 hours before cephalexin decreases peak levels of cephalexin by 11% and reduces the exposure to cephalexin by 18%. By decreasing cephalexin levels, zinc might increase the risk of treatment failure. This effect does not occur when zinc is taken 3 hours after the cephalexin dose (94163). To avoid an interaction, advise patients take zinc sulfate 3 hours after taking cephalexin.

CISPLATIN (Platinol-AQ) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, zinc might interfere with the therapeutic effects of cisplatin.  Details Animal research suggests that zinc stimulates tumor cell production of the protein metallothionein, which binds and inactivates cisplatin (11624,11625). It is not known whether zinc supplements or high dietary zinc intake can cause clinically significant interference with cisplatin therapy. Cisplatin might also increase zinc excretion.

INTEGRASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking zinc along with integrase inhibitors might decrease the levels and clinical effects of these drugs.  Details Zinc is a divalent cation. Pharmacokinetic studies have shown that other divalent cations such as calcium and iron can decrease blood levels of the integrase inhibitor dolutegravir through chelation (93578,93579).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc might reduce the levels and clinical effects of penicillamine.  Details By forming an insoluble complex with penicillamine, zinc interferes with penicillamine absorption and activity. Zinc supplements reduce the efficacy of low-dose penicillamine (0.5-1 gram/day), but do not seem to affect higher doses (1-2.75 gram/day), provided dosing times are separated (2678,4534,11605). Advise patients to take zinc and penicillamine at least 2 hours apart.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc can decrease the levels and clinical effects of quinolones antibiotics.  Details Quinolones form complexes with zinc in the gastrointestinal tract, reducing absorption of both the quinolone and zinc if taken at the same time (828,2682,3046,11600). Advise patients to take these drugs at least 2 hours before, or 4-6 hours after, zinc supplements.

RITONAVIR (Norvir) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Zinc modestly reduces levels of ritonavir.  Details Clinical research shows that zinc might reduce serum ritonavir levels by chelating with ritonavir in the gut and preventing its absorption (93578). In patients with HIV, ritonavir is taken with atazanavir to prevent the metabolism and increase the effects of atazanavir. A pharmacokinetic study shows that, in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate (Solvazinc tablets) 125 mg as a single dose or as multiple daily doses for 2 weeks reduces plasma levels of ritonavir by about 16% (90216). However, atazanavir levels still remains high enough to prevent HIV virus replication. Therefore, the decrease in ritonavir levels is not likely to be clinically significant.

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Zinc might reduce levels of tetracycline antibiotics.  Details Tetracyclines form complexes with zinc in the gastrointestinal tract, which can reduce absorption of both the tetracycline and zinc when taken at the same time (3046,4945). Taking zinc sulfate 200 mg with tetracycline reduces absorption of the antibiotic by 30% to 40% (11615). Demeclocycline and minocycline cause a similar interaction (4945). However, doxycycline does not seem to interact significantly with zinc (11615). Advise patients to take tetracyclines at least 2 hours before, or 4-6 hours after, zinc supplements to avoid any interactions.

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General ...Orally, Angelica archangelica is generally well tolerated in food amounts. There is limited information available about the adverse effects of Angelica archangelica when used as medicine.
Most Common Adverse Effects:
Orally: Constipation, photosensitivity.

Dermatologic ...Orally or topically, Angelica archangelica might cause photosensitivity reactions (13406). Patients who take Angelica archangelica orally or apply it topically should be advised to avoid prolonged exposure to the sun. Some constituents of the leaves have a strong irritant effect on the skin and mucous membranes, referred to as "angelica dermatitis" (18).

Gastrointestinal ...Orally, Angelica archangelica has been reported to cause constipation in one out of 21 patients taking a specific Angelica archangelica leaf extract (SagaPro, SagaMedica) (92461).

(Read more about ANGELICA ARCHANGELICA)

General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

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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).

(Read more about BERBERINE)

General ...Orally, dong quai is generally well-tolerated.
Most Common Adverse Effects:
Orally: Burping and flatulence.
Intravenously: Headache.

Cardiovascular ...Orally, dong quai might cause hypertension; according to one case report, a parent and breastfed infant experienced hypertension (195/85 mmHg and 115/69 mmHg, respectively) after the parent consumed a soup containing dong quai root (48428).

Dermatologic ...Dong quai contains psoralens that may cause photosensitivity and photodermatitis (10054,10057,48461).

Endocrine ...In a case report, a male developed gynecomastia after ingesting dong quai tablets (48504).

Gastrointestinal ...Orally, burping and gas may occur with dong quai (738).

Hematologic ...In one case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis three days after taking a phytoestrogen preparation containing dong quai 100 mg, black cohosh 250 mg, wild Mexican yam 276 mg, and red clover 250 mg (13155). It is unclear if dong quai contributed to this event.

Neurologic/CNS ...Dong quai given orally or by injection may be associated with headache (738,48438).

Oncologic ...Dong quai contains constituents that are carcinogenic; however, whether these constituents are present in concentrations large enough to cause cancer with long-term or high-dose use is unknown (7162).

Pulmonary/Respiratory ...A pharmacist experienced allergic asthma and rhinitis after occupational exposure to dong quai and other herbs (48435).

(Read more about DONG QUAI)

General ...Orally, lycopene is generally well tolerated.
Most Common Adverse Effects:
Orally: Mild gastrointestinal complaints, skin rash.

Cardiovascular ...A case of chest pain has been reported in a pregnant patient who was taking a specific lycopene product (LycoRed, Jagsonpal Pharmaceuticals) 2 mg daily (60428). The role of lycopene in this event has not been determined.

Dermatologic ...Orally, lycopene supplements have been reported to cause allergic skin reactions in some clinical studies (60409,60417). Skin rash also occurred in a pregnant patient who was taking a specific lycopene product (LycoRed, Jagsonpal Pharmaceuticals) (60428).
There is at least one case report of carotenoderma, with a yellow-orange coloration in the stratum corneum of the skin, in a 26-year-old female who consumed 20-30 cherry tomatoes and 180 mL tomato juice, as well as other carotenoid-rich foods, daily for up to 10 years. Plasma levels of carotenoids, mainly lycopene, were elevated (109774).

Gastrointestinal ...Orally, gastrointestinal side effects associated with use of lycopene supplements include diarrhea, flatulence, abdominal distension, nausea, vomiting, dyspepsia, and anorexia (60372,60384,60417,60433,60464).

(Read more about LYCOPENE)

General ...In foods, resveratrol is well tolerated. When used orally in higher doses, as well as topically or intranasally, resveratrol seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal discomfort, and loose stools.

Dermatologic ...Orally, there is one case of a pruritic skin rash that occurred in a clinical trial. The rash resolved two weeks after stopping resveratrol (109163).
Topically, a case of allergic contact dermatitis has been reported after applying a facial cream (Resveratrol BE, Skinceuticals) containing aqueous resveratrol 1% in combination with Baikal skullcap root extract 0.5%. Patch testing identified a positive reaction to both ingredients (110024).

Gastrointestinal ...Orally, mild gastrointestinal discomfort with increased diarrhea or loose stools has been reported, especially when resveratrol is taken in doses of 2. 5-5 grams daily (71042,71052,91327,95830,109163,109164,109167).

Hematologic ...In one clinical study, a patient developed severe febrile leukopenia and thrombocytopenia after taking oral resveratrol 500 mg three times daily for 10 days. Upon re-exposure to resveratrol, febrile leukopenia recurred (109163).

Musculoskeletal ...Orally, resveratrol has been associated with muscle cramps in patients on peritoneal dialysis. The causality of this adverse effect has not been established (95830).

Neurologic/CNS ...Orally, resveratrol has been associated with headache, fatigue, and memory loss in patients on peritoneal dialysis. The causality of these adverse effects has not been established (95830).

(Read more about RESVERATROL)

General ...Orally, selenium is generally well-tolerated when used in doses that do not exceed the tolerable upper intake level (UL) of 400 mcg daily. Intravenously, selenium is generally well-tolerated.
Most Common Adverse Effects:
Orally: Gastric discomfort, headache, and rash. Excessive amounts can cause alopecia, dermatitis, fatigue, nail changes, nausea and vomiting, and weight loss.
Serious Adverse Effects (Rare):
Orally: Excessive ingestion has led to cases of multi-organ failure and death.

Dermatologic ...Excess selenium can produce selenosis in humans, affecting liver, skin, nails, and hair (74304,74326,74397,74495,90360,113660) as well as dermatitis (74304). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer (10687). Mild skin rash has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).

Endocrine ...Multiple clinical studies have found an association between increased intake of selenium, either in the diet or as a supplement, and the risk for type 2 diabetes (97091,99661). One meta-analysis shows that a selenium plasma level of 90 mcg/L or 140 mcg/L is associated with a 50% or 260% increased risk for developing type 2 diabetes, respectively, when compared with plasma levels below 90 mcg/L. Additionally, consuming selenium in amounts exceeding the recommended dietary allowance (RDA) is associated with an increased risk of developing diabetes when compared with consuming less than the RDA daily. Also, taking selenium 200 mcg daily as a supplement is associated with an 11% increased risk for diabetes when compared with a placebo supplement (99661).
Hypothyroidism, secondary to iodine deficiency, has been reported as a result of selenium intravenous administration (14563,14565). One large human clinical trial suggested a possible increased risk of type 2 diabetes mellitus in the selenium group (16707).

Gastrointestinal ...In human research, nausea, vomiting, and liver dysfunction has been reported as a result of high selenium exposure (74439,74376,113660). Mild gastric discomfort has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).

Genitourinary ...The effect of selenium supplementation on semen parameters is unclear. In human research, selenium supplementation may reduce sperm motility (9729); however, follow-up research reported no effect on sperm motility or any other semen quality parameter (74441).

Musculoskeletal ...Chronic selenium exposure of 30 mg daily for up to 24 weeks may cause arthralgia, myalgia, and muscle spasms (113660).

Neurologic/CNS ...Chronic exposure to organic and inorganic selenium may cause neurotoxicity, particularly motor neuron degeneration, leading to an increased risk of amyotrophic lateral sclerosis (ALS) (74304). Headache has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months and in patients taking sodium selenate 30 mg daily for up to 24 weeks (97943,113660).

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General ...Orally, zinc is well tolerated in doses below the tolerable upper intake level (UL), which is 40 mg daily for adults. Topically, zinc is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, diarrhea, metallic taste, nausea and vomiting (dose-related).
Topically: Burning, discoloration, itching, stinging, and tingling when applied to irritated tissue.
Intranasally: Bad taste, dry mouth, headache, irritation, reduced sense of smell.
Serious Adverse Effects (Rare):
Orally: There have been cases of acute renal tubular necrosis, interstitial nephritis, neurological complications, severe vomiting, and sideroblastic anemia after zinc overdose.
Intranasally: There have been cases where intranasal zinc caused permanent loss of smell (anosmia).

Dermatologic ...Topically, zinc can cause burning, stinging, itching, and tingling when applied to inflamed tissue (6911,8623,87297). Zinc oxide can be deposited in the submucosal tissue and cause dark discoloration of the skin. This can occur with prolonged topical application to intact skin, application to eroded or ulcerated skin, or penetrating traumatic exposure, and also parenteral administration (8618).
In rare cases, oral zinc has resulted in worsened acne (104056), skin sensitivity (6592), a leishmanial reaction with a macular rash that occurred on exposed parts of the body (86935), eczema (104055), systemic contact dermatitis (109457), and the development of severe seborrheic dermatitis (86946).

Gastrointestinal ...Orally, zinc can cause nausea (338,2663,2681,6592,6700,18216,106230,106233,106227,113661), vomiting (2663,2681,6519,6592,96069,96074), a metallic or objectionable taste in the mouth (336,338,6700,11350,18216,106902,113661), abdominal cramping (6592,96069), indigestion (87227), heartburn (96069), dry mouth (87533), and mouth irritation (336,2619). When used orally in amounts above the tolerable upper intake level, zinc may cause irritation and corrosion of the gastrointestinal tract (331,86982,87315,106902), watery diarrhea (1352), epigastric pain (2663,2681), and severe vomiting (2663,2681).
Intranasally, zinc can cause bad taste, dry mouth, and burning and irritation of the throat (8628,8629).
When used topically as a mouth rinse, zinc may cause tooth staining (90206).

Hematologic ...There is concern that high daily doses of zinc, above the tolerable upper intake level (UL) of 40 mg per day, might increase the risk of copper deficiency, potentially leading to anemia and leukopenia (7135,112473). To prevent copper deficiency, some clinicians give a small dose of copper when zinc is used in high doses, long-term (7303).

Hepatic ...There are two cases of liver deterioration in patients with Wilson disease following initiation of treatment with zinc 50-200 mg three times daily. The mechanism of action is not understood, and the event is extremely uncommon (86927,87470).

Immunologic ...Daily doses of 300 mg of supplemental zinc for 6 weeks appear to impair immune response (7135). A case of erythematosus-like syndrome, including symptoms such as fever, leg ulcers, and rash, has been reported following intake of effervescent tablets (Solvezink) containing zinc 45 mg (87506). In another case, severe neutropenia was reported after taking supplemental zinc 900 mg daily for an unknown duration (112473).

Musculoskeletal ...Orally, zinc may cause body aches in children (113661).

Neurologic/CNS ...Zinc-containing denture adhesives can cause toxicity if used more frequently than recommended for several years. Case reports describe hyperzincemia, low copper levels, blood dyscrasias, and neurological problems, including sensory disturbances, numbness, tingling, limb weakness, and difficulty walking in patients applying denture adhesive multiple times daily for several years (17092,17093,90205,90233). Due to reports of zinc toxicity associated with use of excessive amounts of zinc-containing denture adhesives for several years, GlaxoSmithKline has reformulated Polygrip products to remove their zinc content (17092,17093).
Intranasally (8628) and orally (87534), zinc can cause headache. When used orally in amounts above the tolerable upper intake level (UL), zinc may cause central nervous system (CNS) symptoms including lethargy, fatigue, neuropathy, dizziness, and paresthesia (2663,2681,87369,87470,87533,87534,112473).

Oncologic ...There is concern that zinc might worsen prostate disease. For example, some preliminary evidence suggests that higher dietary zinc intake increases the risk for benign prostatic hyperplasia (6908). Epidemiological evidence suggests that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study also suggests that men who take a multivitamin more than 7 times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). However, a large analysis of population research suggests that there is no association between zinc intake and the risk of prostate cancer (96075).

Pulmonary/Respiratory ...There are several hundred reports of complete loss of sense of smell (anosmia) that may be permanent with use of zinc gluconate nasal gel, such as Zicam (11306,11155,11707,16800,16801,17083,86999,87535). Loss of sense of smell is thought to be dose related but has also been reported following a single application (11306,11155,11707,16800). Patients often report having sniffed deeply when applying the gel, then experiencing an immediate burning sensation, and noticing anosmia within 48 hours (17083). On June 16, 2009, the US Food and Drug Administration (FDA) advised patients not to use a specific line of commercial zinc nasal products (Zicam) after receiving 130 reports of loss of smell (16800). The manufacturer of these products had also received several hundred reports of loss of smell related to its intranasal zinc products (16801). Zinc sulfate nasal spray was used unsuccessfully for polio prophylaxis before the polio vaccine was developed. It caused loss of smell and/or taste, which was sometimes permanent (11713). Animal studies suggest that zinc sulfate negatively affects smell, possibly by damaging the olfactory epithelium and neurons (11156,11703,11704,11705,11706). Zinc gluconate nasal spray has not been tested for safety in animals or humans. The clinical studies of intranasal zinc have not described anosmia as an adverse effect, but testing was not done to see if zinc use adversely affected sense of smell (6471,8628,8629,10247). Also, these clinical studies reported tingling or burning sensation in the nostril, dry nose, nose pain, and nosebleeds.
When used in amounts above the tolerable upper intake level (UL), zinc may cause flu-like symptoms including coughing (2663).

Renal ...In overdose, zinc can cause acute renal tubular necrosis and interstitial nephritis (331,1352,87338).

Other ...Occupational inhalation of zinc oxide fumes can cause metal fume fever with symptoms including fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste, and salivation (331).

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