Ligaflex by Biomed International Product Corp.

POSSIBLY EFFECTIVE

• Acne. Topical black seed extract hydrogel seems to improve acne. Details: In patients with mild to moderate acne, clinical research shows that topical application with a hydrogel containing black seed extract 0.1% twice daily for 60 days reduces the number of comedones, papules, and pupules by a large amount when compared with placebo. The overall improvement, as rated by a physician, was 78% for the black seed extract hydrogel, compared with 3% for the placebo gel (101551).
• Allergic rhinitis (hay fever). Oral black seed oil seems to reduce symptoms of allergic rhinitis over 4-8 weeks. It is unclear if black seed is beneficial long-term. Details: Clinical research shows that taking capsules containing black seed oil 0.5 mL daily for 1 month can reduce symptoms such as itching, nasal congestion, sneezing, and runny nose when compared with placebo in adults with allergic rhinitis (95989). Other preliminary clinical research shows that taking a specific product containing black seed oil 500 mg (Immerfit, Phyt-Immun) for a total dose of 40-80 mg/kg orally daily for 4-8 weeks improves patient-scored symptoms of allergic rhinitis in 81% of patients, compared to 45% of patients taking placebo (36071). More research is needed to determine if black seed is beneficial long-term and how it compares to conventional allergy medications.
• Asthma. Oral black seed seems to be beneficial for symptoms like wheezing and coughing and might improve lung function measures in patients with poor pulmonary function. Details: Some clinical research shows that taking black seed extract for 3 months can improve symptoms such as wheezing and coughing when compared with placebo in patients with moderate to severe asthma who already take conventional asthma medication (36175). Other research shows that taking black seed oil (Cuminmar, Marnys) 500 mg twice daily for 4 weeks can improve self-reported asthma control and daily functioning when compared with placebo in adults with inadequately controlled asthma despite using maintenance inhalers (95987). The effects of black seed on pulmonary function are conflicting. Some research shows that taking black seed can improve lung function measures such as forced expiratory flow (36175,36280,94490,101556), while other research shows no significant benefit (95987,101556). Doses used in studies showing benefit include ground black seed 2 grams daily for 12 weeks, black seed extract 15 mL/kg daily for 3 months, or a single dose of 50-100 mg/kg (36175,36280,94490). Differing findings may relate to pulmonary function at baseline. Taking black seed extract or black seed oil seems to improve pulmonary function in patients with abnormally low pulmonary function at baseline, but not those with predicted forced expiratory volume in 1 second (FEV1) of at least 80% (36175,95987). Also, single doses of black seed extract do not appear to improve pulmonary function as effectively as bronchodilators such as theophylline or salbutamol (36280).
• Chronic obstructive pulmonary disease (COPD). Oral black seed seems to improve lung function measures in patients with COPD using inhaled corticosteroids. Details: In middle-aged adults undergoing routine treatment with inhaled corticosteroids for COPD, clinical research shows that taking black seed oil (Amazing Herbs) 1 gram twice daily for 3 months improves pulmonary function tests by a small to moderate amount when compared with placebo (104663).
• Diabetes. Oral black seed powder in doses of at least 2 grams daily or black seed oil 1 gram daily seem to improve glucose control in patients with type 2 diabetes. Details: A meta-analysis of 4 clinical studies shows that black seed reduces glycated hemoglobin (HbA1c) by 0.4%. However, analysis of 7 clinical studies suggests that black seed does not reduce fasting blood glucose (111503). One clinical study shows that taking black seed powder 1 gram twice daily for 3-12 months improves HbA1c and decreases fasting blood glucose by 17% to 26% when compared to baseline in patients with diabetes who are already using antidiabetes medications (94479,94485). These improvements were significant when compared with placebo at 3 months and 9 months, but not at 12 months (94485). Clinical research also shows that taking black seed powder 1 gram twice daily also improves levels of total cholesterol by 10% to 12% when compared with placebo in patients with diabetes (94478); a lower dose of 1 gram daily does not seem to be beneficial (94479). The effect of black seed oil has also been investigated. Clinical research shows that taking black seed oil 450 mg three times daily for 12 weeks decreases fasting blood glucose by around 14 mg/dL and HbA1c by 0.3% in patients with newly diagnosed diabetes when compared with baseline. However, these improvements were inferior to those reported in patients taking metformin 2000 mg daily (102062). Other clinical research shows that taking black seed oil 1 gram daily for 8 weeks decreases fasting blood glucose by 23.0 mg/dL and HbA1c by 0.69% from baseline. These changes, as well as reductions in low-density lipoprotein (LDL) cholesterol, triglycerides, and systolic and diastolic blood pressure were significant when compared with placebo (110269). Other clinical research also shows that taking black seed oil 1 gram daily for 8 weeks reduces fasting blood glucose, triglyceride, and low-density lipoprotein (LDL) cholesterol levels when compared with placebo. However, baseline levels for each of these parameters were higher in the treatment group when compared with the placebo group, raising concerns about the validity of these findings (101552). The black seed constituent thymoquinone has also been investigated in clinical research. Clinical research in patients with type 2 diabetes shows that taking thymoquinone 50 mg or 100 mg daily in addition to metformin 1 gram daily for 90 days increases the number of patients with HbA1c levels of less than 7.0% when compared with metformin alone. However, it is unclear if fasting blood glucose levels are further reduced (110270). Black seed has also been evaluated in combination with other ingredients. A moderate-sized clinical study in treatment-naïve adults newly diagnosed with type 2 diabetes shows that taking a combination product containing extracts of black seed 250 mg, cassia cinnamon, and ficin (NW Low-Glu) 4-5 times daily for 12 weeks reduces HbA1c by 0.6-0.8% and 2-hour postprandial glucose by 25-35 mg/dL when compared to baseline and is similarly effective to metformin. However, there were no notable improvements in fasting blood glucose, insulin resistance, or beta cell function (111710). It is unclear if these effects are due to black seed, other ingredients, or the combination.
• Helicobacter pylori. Oral black seed 2 grams daily seems to improve H. pylori eradication when used in combination with standard therapies. Details: Clinical research shows that in patients receiving quadruple therapy with metronidazole, amoxicillin, bismuth subcitrate, and omeprazole, the eradication of H. pylori occurred in 88% of patients receiving quadruple therapy plus black seed powder 1 gram twice daily for 8 weeks, compared with 55% of patients taking quadruple therapy alone. Quality of life was also improved (101555). Clinical research also shows that taking black seed powder (BioExtract Ltd) 2 grams daily along with omeprazole 40 mg daily for 4 weeks produces H. pylori eradication in 67% of patients, compared to 83% of patients taking standard triple therapy with clarithromycin, amoxicillin, and omeprazole taken for 1 week. However, this study also found that taking black seed powder 1 gram or 3 grams daily along with omeprazole was less effective than standard triple therapy (95980). The reasons for this discrepancy are unclear.
• Hyperlipidemia. Oral black seed seems to modestly improve serum lipids in patients with or without hyperlipidemia. Details: A meta-analysis of 24 moderate-quality, clinical studies in healthy adults and patients with various cardiometabolic conditions shows that taking black seed modestly reduces total cholesterol, LDL cholesterol, and triglycerides, and increases HDL cholesterol when compared with placebo or control (114813). Interpretation of findings is limited by significant heterogeneity in results which may be due to the inclusion of different patient populations, doses or types of black seed preparations, and treatment durations. Similarly, a meta-analysis of 5 clinical studies in adults with type 2 diabetes with or without hyperlipidemia shows that taking black seed reduces total cholesterol by 17 mg/dL, low-density lipoprotein (LDL) cholesterol by 11 mg/dL, and triglycerides by 12 mg/dL, but does not improve high-density (HDL) lipoprotein cholesterol, when compared with a control (111503). Additionally, some preliminary clinical research shows that taking whole crushed black seed 1 gram twice daily or black seed powder 1 gram daily for 4-8 weeks reduces total cholesterol by 5% to 16%, LDL cholesterol by 8% to 27%, and triglycerides by 17% to 22% when compared to baseline in these patients; these improvements are significantly greater than changes in the placebo group (18221,94484). The effect of black seed when used in combination with statins shows conflicting results. One clinical study shows that taking black seed powder 1 gram twice daily for 6 weeks does not decrease cholesterol levels when compared with statins alone in normocholesterolemic, borderline hypercholesterolemic, or hypercholesterolemic patients (36244). Other clinical research in adults with hypercholesterolemia shows that taking whole crushed black seed 500 mg, garlic oil 250 mg, and simvastatin 10 mg daily for 8 weeks produces a larger increase in HDL cholesterol and a greater reduction in total cholesterol, LDL cholesterol, and triglycerides when compared with simvastatin 10 mg daily alone (95985). Reasons for these conflicting results may relate to the black seed dose or formulation and the cholesterol levels of the included patients at baseline. Taking whole crushed black seed 1 gram twice daily for 8 weeks in conjunction with aerobic training does not appear to improve LDL cholesterol, total cholesterol, or triglyceride levels when compared with aerobic training alone in females with hypercholesterolemia; however, it appears to modestly increase HDL cholesterol levels (95983).
• Hypertension. Oral black seed powder and black seed oil seem to reduce blood pressure by a small amount. However, if it is unclear if taking black seed is beneficial in patients with hypertension. Details: Meta-analyses of results from 33 small clinical studies in patients with or without hypertension show that taking black seed powder 0.5-3 grams daily or black seed oil 0.1-4.2 grams daily for 4-16 weeks reduces both systolic and diastolic blood pressure by about 2-3 mmHg when compared with placebo (16437,94489,112242). Subgroup analysis suggests that black seed supplementation is most beneficial for durations of 8 weeks or less and in patients over 50 years old with a BMI of 25-30 kg/m2 (112242). Another study in the analysis that included patients with or without hypertension found that taking black seed oil 2.5 mL twice daily after meals for 8 weeks reduces systolic and diastolic blood pressure by about 11 mmHg and 10 mmHg, respectively, when compared to baseline (96929).
• Mastalgia. Topical black seed oil seems to reduce breast pain. Details: Clinical research shows that applying 2 grams of gel containing 30% black seed oil at the site of pain twice daily for two menstrual cycles reduces breast pain by about 82% when compared to baseline. This improvement is similar to diclofenac gel and significantly greater than placebo gel, which reduces pain by only 18% (94483).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anthracycline cardiotoxicity. It is unclear if oral black seed oil reduces cardiac toxicity associated with doxorubicin treatment. Details: Preliminary clinical research in children aged 2-16 years with acute lymphoblastic leukemia shows that taking black seed oil 80 mg/kg in three divided doses daily for one week, starting with each doxorubicin infusion therapy, is protective against some, but not most, measures of cardiac toxicity associated with doxorubicin. However, it is unclear if any of these changes are associated with clinically meaningful improvements in outcome (101554).
• Atopic dermatitis (eczema). It is unclear if oral or topical black seed oil is beneficial for reducing symptoms of atopic dermatitis. Details: One small study reports that using 15% black seed oil ointment topically for 4 weeks does not improve disease severity, pruritus, or hydration in patients with atopic dermatitis (36316). Other preliminary clinical research shows that taking a specific product containing black seed oil 500 mg (Immerfit, Phyt-Immun) for a total dose of 40-80 mg/kg daily for 4-8 weeks improves subjective patient-scored symptoms of atopic dermatitis in 50% of patients when compared to baseline (36071).
• Autoimmune thyroiditis. It is unclear if oral black seed is beneficial for patients with autoimmune thyroiditis. Details: Clinical research in patients with Hashimoto's thyroiditis shows that taking black seed powder 2 grams daily for 8 weeks increases thyroid stimulating hormone levels by 36% and anti-thyroid peroxidase (anti-TPO) antibody levels by 50% when compared to baseline; these improvements are significant when compared with placebo. However, black seed powder does not improve thyroxine or triiodothyronine levels when compared with placebo (94481).
• Cancer. Although there is interest in using oral black seed for cancer, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Cardiovascular disease (CVD). It is unclear if oral black seed is beneficial for patients with coronary artery disease. Details: A small clinical trial shows that taking black seed oil 2 grams daily for 8 weeks reduces systolic and diastolic blood pressure by 9.52 mm Hg and 8.26 mm Hg, respectively, when compared with placebo. Fasting blood glucose, body mass index, and waist and hip circumferences were also modestly reduced. There was no effect on other glycemic indices. There was also no effect on blood lipids; however, most patients were taking statins (110276).
• Chemotherapy-induced lymphocytopenia. It is unclear if oral black seed is beneficial for preventing febrile neutropenia. Details: Preliminary clinical research in children undergoing chemotherapy for brain tumors shows that taking whole or ground black seed 5 grams daily as part of the diet for 3-9 months of chemotherapy reduces the incidence of febrile neutropenia episodes by 88% when compared with placebo. To prevent one case of febrile neutropenia, six patients would need to be treated with black seed. The duration of hospital stay was also reduced by 2.5 days when compared with placebo (96931).
• Chemotherapy-induced phlebitis. It is unclear if oral black seed is beneficial for reducing the severity of phlebitis in patients receiving intravenous chemotherapy. Details: Preliminary clinical research in cancer patients receiving intravenous chemotherapy shows that applying 5 drops of black seed oil around the peripheral vein catheter twice daily for 3 days decreases phlebitis severity and reduces the relative risk of phlebitis at 72 hours by 35% when compared with no treatment. These results suggest that for every 3 patients treated with black seed oil for 3 days, one additional case of phlebitis will be prevented (102060).
• Chronic kidney disease (CKD). It is unclear if oral black seed oil is beneficial for patients with CKD. Details: Preliminary clinical research in patients with stages 3 and 4 CKD shows that taking black seed oil (Kalonji oil, Mohammedia products) 2.5 mL once daily for 12 weeks as add-on therapy with alpha-keto analogues of essential amino acids improves measures of kidney function by a small amount when compared with taking the alpha-keto analogues alone (101550).
• Cognitive function. Oral black seed might improve some measures of memory or cognitive function. Details: Clinical research in a small group of adolescent males shows that taking crushed black seed 500 mg daily for 4 weeks improves some measures of short-term or long-term recall when compared with placebo (96915). Other clinical research in a small group of middle-aged men shows that taking black seed 500 mg twice daily for 9 weeks improves some measures of memory, attention, and cognitive function when compared with placebo (96928). The improvements in both studies appear to be modest, so the clinical significance is unclear.
• Constipation. Although there is interest in using oral black seed for constipation, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Contraception. Although there is interest in using oral black seed for contraception, there is insufficient reliable information about the clinical effects of black seed for this purpose.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral black seed is beneficial for patients with COVID-19. Details: Preliminary clinical research in patients with mild COVID-19 shows that taking black seed oil (Marnys Cuminmar) 500 mg twice daily for 10 days results in recovery by day 14, defined as freedom of symptoms lasting three days, in 62% of patients, compared with 36% of those patients not given black seed oil. Also, the duration to recovery was reduced by 1.6 days (110267). Preliminary clinical research in patients with mild to moderate COVID-19 shows that taking black seed (Baraka, Pharco Pharmaceuticals, Cairo, Egypt) 900 mg twice daily for 14 days modestly reduces the severity of some symptoms, including cough, diarrhea, fatigue, and pharyngitis, as well as the percentage of patients with viral positivity at day 7, when compared with standard care alone. Similar findings occurred when black seed was taken with vitamin D3 (Davalindi, Medical Union Pharma, Cairo, Egypt) 2,000 IU daily (110265). These studies are limited by a lack of placebo and blinding. A meta-analysis of 3 studies in patients with COVID-19 shows that taking black seed 40-80 mg/kg for 13-14 days or 500 mg twice daily for 7 days reduces the odds of mortality by 78% relative to patients with COVID-19 who did not use black seed (112243). In contrast to these findings, clinical research in patients with mild or asymptomatic COVID-19 does not show that taking black seed for 10 days has beneficial effects on symptoms or inflammatory markers when compared with charcoal as control. The black seed form in this study varied between whole seeds and powder, as well as the number (two to nine) of capsules taken in divided doses daily (110271). Black seed oil has also been investigated in combination with other compounds. Preliminary clinical research in patients with moderate to severe COVID-19 given standard care shows that taking black seed powder 80 mg/kg daily in combination with raw honey 1 gram/kg daily for 13 days reduces the time to alleviate symptoms by approximately 50%, and the time to clear virus by about 35%, when compared with placebo capsules and no honey. In patients with moderate symptoms, 63.6% had resumed normal activity within 6 days when compared with 10.9% of those taking placebo. In patients with severe symptoms, 50% were discharged from hospital by day 6 compared with 2.8% of those taking placebo, and the mortality rate was reduced by approximately 79% (110261). It is not clear if any beneficial effects are due to black seed, honey, or the combination.
• Diarrhea. Although there is interest in using oral black seed for diarrhea, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Dysmenorrhea. It is unclear if topical black seed oil reduces menstrual pain. Details: Clinical research shows that topical application of black seed oil (Barij Essence Company) 1-2 drops to the fontanel lobe of the head each night for up to 8 days, starting three days before menstruation, for three menstrual cycles modestly reduces menstrual pain when compared with olive oil (104662). It is unclear if any benefits are clinically significant.
• Dyspepsia. Oral black seed oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a 1:1:1 mixture of a black seed oil, honey, and water orally for 2 months improves overall symptoms of dyspepsia by approximately 43%, compared to only 10% in the placebo group (94487).
• Epilepsy. It is unclear if oral black seed is beneficial for patients with epilepsy. Details: Some preliminary clinical research in children aged 13 months to 13 years with epilepsy shows that taking black seed extract 40 mg/kg every 8 hours for 4 weeks reduces the frequency of seizures in 65% of, compared to only 20% of patients taking placebo (36180). Other preliminary clinical research in children 2-16 years of age with epilepsy shows that taking black seed oil 40-80 mg/kg daily does not reduce seizure frequency or severity when compared with placebo (94491). It is possible that there is a constituent found in the extract, and absent in the oil, that is responsible for any anti-seizure effects of black seed.
• Gingivitis. It is unclear if topical black seed is beneficial for patients with gingivitis. Details: In patients with moderate to severe gingivitis, preliminary clinical research shows that topical application of black seed extract for three days reduces gingival swelling and redness by a moderate amount, and plaque by a small amount, when compared to baseline. However, it is less effective than scaling and root planing (104664).
• Hemorrhoids. Although there is interest in using oral black seed for hemorrhoids, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Hepatitis C. It is unclear if oral black seed is beneficial for patients with hepatitis C. Details: Preliminary clinical research shows that taking black seed oil (Baraka, Pharco Pharmaceuticals) 450 mg three times daily for 3 months reduces hepatitis C viral load in 67% of patients, improves lower limb edema, and modestly increases total protein and albumin levels when compared to baseline; however, no improvement is seen in Child-Pugh score or other measures of liver function, including bilirubin, liver enzymes, or INR (95986). The validity of these findings is limited by the lack of a control group.
• HIV/AIDS. Although there is interest in using oral black seed for HIV/AIDS, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Impaired glucose tolerance (prediabetes). It is unclear if oral black seed oil is beneficial for patients with prediabetes. Details: Preliminary clinical research in obese patients with prediabetes shows that taking black seed oil (Baraka450; Pharco Pharmaceutical Company) 450 mg twice daily for 6 months improves most anthropometric, lipid, and glycemic parameters when compared with baseline. Also, most improvements are similar to changes following the use of metformin 500 mg twice daily or following a controlled diet and exercise regimen (110275).
• Influenza. Although there is interest in using oral black seed for influenza, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Insomnia. It is unclear if oral black seed oil is beneficial for patients with insomnia. Details: A small clinical study in healthy adults with self-reported sleep problems shows that taking a specific black seed oil extract product containing 5% thymoquinone (BlaQmax, Akay Natural Ingredients) 200 mg daily before bedtime for 90 days increases sleep quality, latency, duration, and efficiency and reduces sleep disturbances and daytime dysfunction when compared with placebo. Black seed oil also improves biomarkers of sleep as shown by increased salivary melatonin and decreased orexin A (112244).
• Lichen planus. It is unclear if topical black seed oil is beneficial for patients with oral lichen planus. Details: Clinical research in patients with oral lichen planus shows that topical application with cream containing black seed oil (Greenish Baraka black seed oil, Greenish India Pvt. Ltd., Chennai) 75% twice daily after meals for 45 days is as effective as gel containing clobetasol propionate 0.05% for reducing lesion size and burning severity (110263). Similarly, a very small, open-label, non-randomized intervention in patients with oral lichen planus shows that topical application of a mucoadhesive patch containing black seed extract 10% three times daily for 4 weeks is as effective as a triamcinolone acetonide 0.1% patch for reducing pain and burning intensity and lesion severity (114815). Both studies are limited by the lack of inclusion of a placebo-controlled group.
• Male infertility. It is unclear if oral black seed oil is beneficial for male infertility. Details: Clinical research shows that taking black seed oil 2.5 mL twice daily for 2 months improves sperm count by 40%, sperm morphology by 32%, and sperm motility by 13% when compared with placebo in infertile males (94486).
• Meniere disease. It is unclear if oral black seed is beneficial for patients with Meniere disease. Details: A very small clinical study in adults with Meniere disease shows that taking black seed oil 1 gram daily for 3 months does not improve hearing threshold, tinnitus severity, or vertigo when compared with placebo (112245).
• Menopausal symptoms. Oral black seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is unclear if topical black seed oil is beneficial for menopausal symptoms. Details: Preliminary clinical research in postmenopausal females shows that taking a combination of black seed and vitex agnus-castus daily for 8 weeks, in combination with citalopram 20 mg, improves vasomotor, psychosocial, and physical symptoms of menopause when compared with placebo and citalopram (100325). It is not clear if these effects are due to black seed, vitex agnus-castus, or the combination. Clinical research in postmenopausal females shows that topical application with 2-3 drops of black seed oil (Barij Essence Pharmaceutical Company, Kashan, Iran) on the lower abdomen twice daily for 8 weeks does not improve sexual function or quality of life related to menopause when compared with placebo (110262).
• Metabolic syndrome. It is unclear if oral black seed is beneficial for patients with metabolic syndrome. Details: Clinical research in patients with metabolic syndrome after menopause shows that taking black seed extract 500 mg daily for 8 weeks improves levels of fasting blood sugar by 23%, low-density lipoprotein (LDL) cholesterol by 12%, and triglycerides by 8% over baseline. These changes were significant when compared with placebo. However, taking black seed extract did not improve anthropometric measures when compared with placebo (101549). In addition, preliminary clinical research in patients with metabolic syndrome shows that taking a specific black seed oil product (Mohammedia Products, Hyderabad) 2.5 mL twice daily for 6 weeks decreases total cholesterol by 59%, LDL cholesterol by 50%, and fasting blood glucose by 58% over placebo (36262). The effects of this black seed oil product on other important parameters of metabolic syndrome, such as weight and blood pressure, were not reported in this study. In contrast, other clinical research shows that taking bread providing black seed powder 3 grams daily for 2 months does not have a significant effect on lipid profiles in patients with metabolic syndrome. Weight and waist circumference were not reported (104667).
• Methotrexate toxicity. It is unclear if oral black seed oil is beneficial for reducing toxicity associated with methotrexate treatment. Details: Preliminary clinical research shows that taking black seed oil (Baraka, Pharco Pharmaceuticals) 80 mg/kg orally in three divided doses daily for 1 week after each methotrexate dose prevents elevations in bilirubin and liver function enzymes when compared with placebo in children aged 4-13 years with acute lymphoblastic leukemia (95984).
• Nonalcoholic fatty liver disease (NAFLD). Research suggests that oral black seed or black seed oil modestly improves some metabolic and liver health parameters in patients with NAFLD. However, some studies are small, and research related to measures of steatosis, including liver biopsy and magnetic resonance imaging (MRI), is needed. Details: Clinical research in adults with NAFLD shows that taking black seed oil 2.5 mL twice daily for 3 months, or 1000 mg (Barij Essence Co., Iran) daily for 8 weeks, modestly increases high-density lipoprotein (HDL) cholesterol levels and reduces levels of liver function enzymes, low-density lipoprotein (LDL) cholesterol, and triglycerides when compared with placebo (100322,110282). These studies also show that taking black seed oil also modestly improves levels of fasting blood glucose (110282) and steatosis grade as measured by ultrasound (100322). In one study, both black seed oil capsule and placebo capsule also contained honey and water (100322). However, taking black seed oil does not seem to improve insulin levels (110282). The effect of black seed oil on blood pressure has also been investigated. Clinical research shows that taking black seed oil (Barij Black Seed Oil, Barij Essence Pharmaceutical Company, Kashan, Iran) 1000 mg daily for 8 weeks does not reduce systolic or diastolic blood pressure when compared with placebo (110274,110282). Black seed has also been investigated in small clinical trials in adults with NAFLD. One trial shows that taking black seed 2 grams daily for 12 weeks reduces glucose and insulin levels, improves measures of insulin sensitivity and resistance, and reduces hepatic steatosis percentage when compared with placebo. However, there was no improvement in fibrosis scores, steatosis grades, and levels of lipids and liver function enzymes (102061). Another trial shows that using the same dose of black seed powder results in large reductions in body weight and body mass index (BMI), as well as liver enzymes, when compared with placebo. Also, 57.1% of patients taking black seed had normal fatty liver grading on abdominal ultrasound, compared with 6% of those taking placebo (110268). The reasons for these disparate results are unclear. However, it is possible the studies were underpowered to detect differences in secondary outcomes. More research is needed using gold standard measures of steatosis, including liver biopsy and magnetic resonance imaging (MRI).
• Obesity. It is unclear if oral black seed is beneficial for increasing weight loss. Details: Meta-analyses of preliminary clinical research show that taking black seed oil 3-5 grams daily, black seed powder 0.1-3 grams daily, or black seed extract 100-200 mg daily for up to 13 weeks reduces body weight by about 2-4 kg and body mass index (BMI) by 0.85-1.2 kg/m2 when compared with placebo. It is unclear if these reductions are clinically significant. In addition, most studies in these meta-analyses do not involve patients with a BMI over 25 kg/m2 (96926,98815,111503). Although some individual research shows that taking black seed powder 2 grams or black seed oil 3 grams daily for 8 weeks does not reduce BMI in overweight females who are also exercising or following a low-calorie diet (95983,96927), most individual studies show that black seed or black seed oil reduces body weight and waist circumference (95730,96927,104661,110269). One study shows that black seed has a moderate effect on weight loss, BMI, and waist circumference, and a small effect on total and visceral fat mass (104661). These studies have used black seed powder 1.5 grams twice daily for 3 months or black seed oil 2 or 3 grams daily for 8 weeks (95730,96927,104661). Reasons for the discrepancies may relate to concomitant use with dieting or exercise. It is unclear if taking black seed oil improves the lipid profile of individuals with a BMI of at least 25 kg/m2. One small clinical study shows that taking black seed oil 2 grams daily for 8 weeks has a small to moderate effect on levels of high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol when compared with placebo (104666). However, another study shows that although taking black seed oil 3 grams daily for 8 weeks reduces triglyceride levels more than placebo, there is no effect on HDL or LDL cholesterol levels (96927).
• Opioid withdrawal. It is unclear if oral black seed is beneficial for reducing symptoms of opioid withdrawal. Details: Preliminary clinical research shows that taking black seed powder 500 mg by mouth three times daily for 12 days decreases symptoms of opioid withdrawal by 70% to 77% when compared to baseline (36239). The validity of this finding is limited by the lack of a comparator group.
• Oral submucous fibrosis. It is unclear if oral black seed is beneficial for oral submucous fibrosis. Details: A small clinical study in patients with oral submucous fibrosis shows that taking black seed 1000 mg 3 times daily for 3 months increases mouth opening by 14%, cheek flexibility by 44%, tongue protrusion by 9%, and reduces burning sensations by 79% when compared to baseline, but not when compared with a combination product containing turmeric and black pepper (114880). The validity of this study is limited by the lack of a placebo group.
• Osteoarthritis. It is unclear if topical black seed oil is beneficial for knee osteoarthritis. Details: Preliminary clinical research shows that applying black seed oil 1 mL to the knee by massaging into the skin for 5 minutes three times daily for 3 weeks reduces pain when compared to baseline and produces a larger reduction in pain than acetaminophen 325 mg three times daily for 3 weeks (95981). Other clinical research shows that applying approximately 10 mL of black seed oil to the knees three times weekly for 1 month reduces pain severity when compared to baseline (98814). The validity of this finding is limited by the lack of a control group.
• Polycystic ovary syndrome (PCOS). It is unclear if oral black seed is beneficial for PCOS. Details: A moderate-sized clinical study in adolescents with PCOS shows that taking black seed 1000 mg daily for 16 weeks reduces ovarian volume, testosterone and luteinizing hormone levels, hirsutism, and menstrual irregularities when compared with oral medroxyprogesterone 10 mg daily on menstrual cycle days 14 to 23 (114814). The validity of this study is limited by poor methodology, including results presented only using a per-protocol analysis.
• Psoriasis. Although there is interest in using topical black seed for psoriasis, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Radiation dermatitis. It is unclear if topical black seed is beneficial for preventing dermatitis caused by radiotherapy. Details: Clinical research in breast cancer patients undergoing radiation treatment shows that applying a gel containing black seed extract providing thymoquinone 0.01% twice daily delays the incidence of radiation dermatitis and the onset of moist desquamation by 2-6 days when compared with placebo gel. However, there was no effect on the quality of life related to skin condition (101557).
• Rheumatoid arthritis (RA). It is unclear if topical black seed is beneficial for RA. Details: Preliminary clinical research shows that taking a specific brand of black seed oil (Nigellar, Kahira Pharmaceutical and Chemical Industries Company) 500 mg twice daily for one month improves symptoms of RA, such as pain, morning stiffness, and disease severity, when compared with placebo in patients who are already taking methotrexate (94482).
• Senile rhinitis. It is unclear if topical black seed is beneficial for patients with senile rhinitis. Details: The elderly population is particularly susceptible to symptoms of nasal dryness and irritation due to a reduction in mucus production. Preliminary clinical research shows that black seed oil given as 3 sprays into each nostril three times daily for 2 weeks can modestly improve symptoms of nasal dryness, obstruction, and crusting in this population when compared with sodium chloride nasal spray; however, there is no improvement in burning, itching, or nasal mucociliary clearance (95988).
• Stress. It is unclear if oral black seed is beneficial for patients with stress. Details: A small clinical study in healthy adults with self-reported stress shows that taking a specific black seed oil extract product containing 5% thymoquinone (BlaQmax, Akay Natural Ingredients) 200 mg daily before bedtime for 90 days reduces measures of perceived stress and salivary cortisol levels when compared with placebo (112244).
• Tonsillopharyngitis. Oral black seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that the combination of chanca piedra 50 mg and black seed 360 mg, taken orally three times daily for 7 days, may relieve pain in patients with tonsillopharyngitis when compared with placebo (36199).
• Ulcerative colitis. It is unclear if oral black seed is beneficial for patients with ulcerative colitis. Details: Preliminary clinical research in adults with mild to moderate ulcerative colitis shows that taking black seed powder 2000 mg daily for 6 weeks does not improve disease activity scores or symptoms of ulcerative colitis when compared with placebo (100323).
• Urinary incontinence. It is unclear if topical black seed oil is beneficial for patients with urinary incontinence. Details: Clinical research in postmenopausal females with urinary incontinence shows that topical application with 2-3 drops of black seed oil (Barij Essence Pharmaceutical Company, Kashan, Iran) on the lower abdomen twice daily for 8 weeks modestly improves symptoms of mixed urinary incontinence, as well as related quality of life, when compared to placebo. However, there was no beneficial effect of topical black seed oil on stress incontinence, urge incontinence, or severity of symptoms (110262).
• Vaginal candidiasis. Although there is interest in using intravaginal black seed for vaginal fungal infections, there is insufficient reliable information about the clinical effects of black seed for this condition.
• Vitiligo. It is unclear if topical black seed oil is beneficial for patients with vitiligo. Details: Preliminary clinical research in adults with vitiligo shows that applying a cream containing black seed oil to the skin twice daily for 6 months improves skin pigmentation. This cream induced repigmentation of 50% or more in around 44% of patients with facial or hand involvement and 88% of patients with genital region involvement (102064). The validity of these findings is limited by the lack of a comparator group. More evidence is needed to rate black seed for these uses.

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POSSIBLY EFFECTIVE

• Aging skin. Oral collagen peptides seem to improve skin hydration and elasticity in older adults. However, it is unclear if any improvements related to wrinkles are cosmetically important. Details: Meta-analyses of the available research, as well as multiple individual clinical studies, show that collagen peptide products, taken in doses of 372 mg to 12 grams daily for 4-12 weeks, improve skin hydration and elasticity in older adults. Studied products include Peptan-F or Peptan-P (Rousselot), Wellnex (Nitta Gelatin), Gold Collagen Active (Minerva Research Labs), VERISOL (Gelita AG), and Nippi peptide FCP-EX (Nippi/Shizuoka) (97632,100703,101597,104647,107460,112457). Pooled study results also suggest that hydrolyzed collagen sourced from fish improves skin hydration and elasticity, while collagen peptides originating from chickens seems to modestly improve skin elasticity but not hydration. Collagen peptides derived from bovine do not seem to improve skin hydration or elasticity (112457). Despite research showing improvement in skin hydration and elasticity, it is unclear if collagen peptides reduce skin wrinkles to a cosmetically significant degree, as most studies have not evaluated this outcome. In one clinical study, taking a freshwater fish-derived collagen peptide (Vinh Wellness Collagen, Vinh Hoan Corporation) 10 grams every morning reduced wrinkle count in the nasolabial region of the right side, but not the left side, of the face by 24% when compared with placebo. Collagen peptides did not improve participant-reported measures of wrinkles, elasticity, hydration, and others, when compared with placebo (104639). Another clinical study shows that taking a specific fish scale-derived collagen peptide (Wellnex, Nitta Gelatin) with either a high or low ratio of prolyl-hydroxyproline and hydroxylpropyl-glycine as 5 grams orally daily for 8 weeks modestly improves wrinkle depth and roughness, but not wrinkle volume, when compared with placebo. The product with a high ratio of dipeptides had a larger effect (97632). Also, one clinical study shows that taking a specific product containing porcine collagen type I peptides (VERISOL, Gelita AG) 2.5 grams daily for 8 weeks reduces eye wrinkle volume by 20% when compared with placebo (101648). Two similar moderate-size clinical studies in middle-aged adults with crow's feet wrinkles and dry skin show that taking specific low-molecular-weight fish-derived collagen peptide products (Geltech Co.; CPNS) at doses of 2000 mg or 1650 mg, respectively, daily for 12 weeks improves eye wrinkles, skin hydration, and elasticity when compared with placebo (110729,110730). While investigator satisfaction scores regarding wrinkle reduction were modestly improved, participant satisfaction was not improved (110729). Small clinical studies have shown contradictory findings when collagen peptides are taken in combination with other ingredients. In one clinical trial, a specific drink (Diva Luxe) providing fish collagen peptides 5.5 grams plus Chenopodium formosanum extract 1 gram daily for 8 weeks improved some measures of skin brightness and hydration, but not wrinkles and crow's feet, when compared with placebo (104646). Another small clinical study shows that taking collagen peptides 4 grams daily in combination with coenzyme Q10 50 mg, vitamin C, vitamin A, and biotin for 12 weeks reduces wrinkles and improves skin smoothness by a small amount when compared with placebo. However, there was no difference in skin elasticity or hydration (104638). A clinical study in older females shows that taking collagen peptides 9 grams in combination with zinc and vitamins A, C, and E daily for 90 days increases stratum corneum water content and skin viscoelasticity when compared with placebo. However, it is unclear if the improvement from baseline differed between groups. Small improvements in dermal echogenicity, wrinkles, or skin pores were noted in some facial regions, but the lack of statistical comparison to placebo limits the validity of these findings (107464). Some small clinical studies have shown mixed effects with low doses of collagen peptides from preliminary clinical research using BioCell Collagen (BioCell Technology, LLC) or Celergen (Laboratories-Dom) (28681,97930). It is unclear if any improvements from these studies are due to collagen peptides, other ingredients, or the combinations. Topical application of collagen peptides has been minimally evaluated. A very small observational study in older adults has found that application of a carbopol gel containing collagen peptides 1% to the periorbital area twice daily for 8 weeks is associated with increased skin hydration and elasticity and reduced transepidermal water loss, skin roughness, and wrinkles when compared with baseline (107459). The validity of these findings is limited by poor study methodology, lack of statistical comparison to baseline, and lack of a comparator group.
• Dry skin. Oral collagen peptides seem to improve skin hydration and elasticity in adults with dry skin. However, their effect on other measures of dry skin is unclear. Details: A meta-analysis of 19 clinical studies, along with several small and moderate-sized individual studies, some of which are included in the meta-analysis, show that taking collagen peptides 372 mg to 12 grams daily for 4-12 weeks improves skin hydration and elasticity when compared with placebo in healthy adults (107461,110729,110730,112457,112458). Some studies show that collagen peptides improve skin roughness (107461), decrease peeling (110729,110730), and increase stratum corneum and epidermis water content (107462) but not skin gloss (107461) or elasticity (107462). Some research shows that collagen peptides reduce transepidermal water loss (107462), while another study shows no change (107461). Subgroup analysis of the meta-analysis suggests that hydrolyzed collagen sourced from fish improves skin hydration and elasticity the most, while collagen peptides originating from chicken seem to modestly improve skin elasticity but not hydration. Collagen peptides from bovine do not seem to improve skin hydration or elasticity (112457). Studied products include FCP-Z (Nippi Co., Ltd), Geltech Co., CPNS, and GPVGPS Collagen (Daehan Chemtech) (107462,110729,110730,112458). Collagen peptides have also been evaluated in combination with other ingredients. A small clinical study in healthy adults with low skin moisture shows that drinking 30 mL of a beverage containing fish scale-derived collagen peptides 10 grams and ornithine 400 mg (FUJIFILM) daily for 8 weeks does not improve skin moisture but seems to improve skin elasticity and reduce water loss when compared with placebo (101607). Another very small clinical study in a mixed population of patients with dry skin and mild atopic dermatitis shows that twice daily application of an emollient containing collagen peptides, soluble proteoglycan, and hyaluronic acid for 4 weeks reduces itching severity from moderate at baseline to mild or almost none. Transepidermal water loss and skin hydration also improved when compared to baseline (107465). The validity of these findings is limited by the lack of a comparator group. Both of these studies are limited by their small size, and it is unclear if any improvements are due to collagen peptides, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Muscle strength. Most research suggests that oral collagen peptides do not improve leg strength. However, they may improve hand-grip strength and fat-free mass. Details: Small clinical studies in healthy male and female athletes or non-athletes undergoing resistance or other training show that taking collagen peptides 15-30 grams daily or after training sessions for up to 15 weeks, with or without vitamin C, does not improve leg strength (i.e. squat strength, knee extension, or flexor strength) when compared with placebo (101608,104641,107457,110668,110669). Similarly, 2 very small clinical studies in healthy adults show that taking a specific oral collagen peptide product (Bodybalance, Gelita AG) 5-15 grams daily while completing a resistance training program for 14-15 weeks increases patellar tendon cross-sectional area but does not improve most measures of tendinous tissue remodeling including patellar tendon size, vastus lateralis aponeurosis size, patellar tendon mechanical properties, tendon stiffness, maximal knee extension strength, or rectus femoris muscle cross-sectional area when compared with placebo (112452,112454). However, a small clinical study with the same product in untrained females aged 18-50 years shows that taking 15 grams daily in addition to resistance training three times weekly for 12 weeks improves hand-grip strength when compared with resistance training and placebo (101608). In untrained males aged 30-60 years, taking the same dose of this collagen peptide product along with resistance training for 12 weeks improves fat-free mass by 3 kg, compared with 2 kg with resistance training and placebo. A post-hoc exploratory analysis suggests that the effects seen in males are similar to those seen with whey protein (107457).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using oral collagen peptides for acne, there is insufficient reliable information about the clinical effects of collagen peptides for this condition.
• Androgenic alopecia. Oral collagen peptides have only been evaluated in combination with other ingredients, their 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 hydrolyzed collagen 300 mg, taurine, cysteine, methionine, iron, and selenium (GFM Oral, Cantabria Labs) daily along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to collagen peptides, other ingredients, or the combination.
• Athletic performance. It is unclear if oral collagen peptides improve performance in most athletes. Details: In recreationally active female runners undergoing resistance and endurance training 3 times weekly, clinical research shows that taking collagen peptides 7.5 grams twice daily for 12 weeks increases running distance by approximately 1,034 meters, compared with an increase of 703 meters in those taking placebo, although there was no effect on speed (104641). A clinical study in healthy young male athletes undergoing heavy strength and power training shows that taking collagen peptides 20 grams and vitamin C 50 mg daily for 3 weeks improves squat performance and countermovement jump performance when compared with placebo. However, removal of a single outlier negated the statistical significance of most of these findings (107456). Also, it is unclear if any improvements from this study are due to collagen peptides, vitamin C, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral or topical collagen peptides are beneficial for improving the severity of eczema. Details: A small clinical study in patients with atopic dermatitis shows that taking a porcine skin-derived collagen peptide with a high ratio of tripeptides with glycine-X-Y sequences, 3.9 grams daily for 12 weeks, improves symptoms and severity of eczema when compared to baseline. There was no improvement in the group taking the same dose of porcine skin-derived collagen peptide without the high ratio of tripeptides (101605). Another very small clinical study in a mixed population of patients with atopic dermatitis and dry skin shows that twice daily application of an emollient containing collagen peptides, soluble proteoglycan, and hyaluronic acid for 4 weeks reduces itching severity from moderate at baseline to mild or almost none. Transepidermal water loss and skin hydration also improved when compared to baseline (107465). It is unclear if any improvements are due to collagen peptides, the other ingredients, or the combination. Both of these studies are limited by their small size and lack of comparator groups.
• Burns. Some preliminary clinical research suggests that oral collagen peptides might reduce the time needed for burn healing. Details: In male patients with 20% to 30% body surface area burns, a small clinical trial shows that taking a collagen-based supplement providing collagen peptides (Amutiya, Qom) 36 grams daily for 4 weeks improves wound healing when compared with taking an isocaloric supplement containing the same amount of soy protein. Complete wound healing occurred in 50% and 100% of patients taking collagen for 2 and 4 weeks, respectively, compared with 7% and 40% of those taking the isocaloric product. The duration of hospital stay was not significantly different between the two groups (104642). A small clinical study in hospitalized adults with 20-45% body surface area 2nd or 3rd degree burns shows that consuming a beverage containing collagen peptides 40 grams daily for 4 weeks shortens the time to wound healing, improves scar scores, and reduces the duration of hospital stays but does not limit wound infections when compared with placebo. Adding fish oil 3 grams daily did not further improve outcomes (110667).
• Brittle nails. One small clinical study suggests that oral collagen peptides may improve nail health in people with brittle nails. Details: A small clinical study shows that taking a specific porcine type I collagen peptide product (VERISOL, Gelita AG) 2.5 grams daily for 6 months improves overall symptoms of brittle nail syndrome, increases nail growth rate by 12%, and reduces broken nail frequency by 42% when compared with baseline (101606). This study was limited by its small size and lack of a comparator group.
• Cellulite. One small clinical study suggests that oral collagen peptides may reduce cellulite. Details: In people with cellulite, a small clinical study shows that taking specific collagen peptides (VERISOL by Gelita AG) 2.5 grams daily for 6 months seems to reduce cellulite, skin waviness, and dermal density by a small amount when compared with placebo (101619).
• Cognitive function. It is unclear if oral collagen peptides are beneficial for improving memory. Details: In healthy adults, preliminary clinical research shows that taking collagen peptides 5 grams daily for 4 weeks improves some measures of memory and verbal learning when compared to baseline (104643). This study was limited by its small size and lack of a comparator group.
• Dermatoporosis. One small clinical study suggests that using oral or topical collagen peptides does not improve this condition. Details: A small clinical study in post-menopausal patients aged 70 years on average with mild dermatoporosis shows that taking collagen peptides 5 grams daily, applying a collagen peptides 2.5% serum 3 pumps nightly to each forearm, or using these in combination for 6 months does not improve skin lesions, epidermal thickness, collagen or elastin density, or patient perception of skin improvement when compared with placebo (110731). However, it is unclear if these results apply to patients with more severe dermatoporosis.
• Diabetes. Some preliminary clinical research suggests that oral collagen peptides might have a small effect on glycemic indices. Details: Preliminary clinical research in patients with type 2 diabetes shows that taking fish-derived collagen peptides 6.5 grams orally twice daily for 3 months, in addition to treatment with antidiabetes drugs, may modestly reduce levels of fasting blood glucose, glycated hemoglobin, and fasting blood insulin and may increase levels of insulin sensitivity when compared with antidiabetes drugs and placebo (101626,101627).
• Erythema. It is unclear if oral collagen peptides are beneficial for erythema. Details: A moderate-sized clinical study in adults with dry and wrinkled eye skin shows that taking low-molecular weight collagen peptides (GPVGPS Collagen, Daehan Chemtech) 2000 mg daily for 12 weeks reduces erythema index when compared with placebo (112458).
• Exercise-induced gastrointestinal (GI) symptoms. It is unclear if oral collagen peptides prevent GI symptoms due to exercise. Details: A small crossover study in moderately well-trained young adults shows that taking collagen peptides 10 grams daily for 7 days prior to rigorous treadmill exercise does not limit GI symptoms but may attenuate some markers of GI distress when compared with placebo (110665).
• Exercise-induced muscle soreness. It is unclear if oral collagen peptides prevent muscle soreness after exercise. Details: Preliminary clinical research in a small number of healthy, recreationally active adults shows that taking collagen peptides (Peptan, Rousselot BVBA, Collagen Peptides, Vital Proteins) 10-15 grams twice daily, starting 7 days prior to strenuous exercise and continuing for 2-5 days after, does not reduce muscle soreness when compared with placebo (100700,104648). However, there was a small benefit on the recovery of countermovement jump ability within 24 hours (104648). Furthermore, another small clinical study in adults unaccustomed to exercise shows that taking collagen peptides 10 grams daily for 33 days modestly reduces muscle soreness and fatigue immediately after the exercise load, but not 2 hours after exercise or the next morning, when compared with placebo (111639). Also, a small clinical study in active middle-aged adults shows that taking specific collagen peptides (SOLUGEL Collagen Peptides, PB Leiner) 10 grams daily for 6 months improves pain in those who exercise frequently (>188 minutes weekly) when compared with placebo. However, collagen peptides do not seem to improve pain in low frequency exercisers (<188 minutes weekly) (112455). Collagen peptides have also been evaluated in combination with other ingredients. One preliminary clinical study in healthy, recreationally active adults shows that taking a specific product (BioCell Collagen, BioCell Technology, LLC) containing collagen peptides from chicken collagen type II, hyaluronic acid, and chondroitin sulfate 1.5 grams twice daily for 6 weeks prior to two bouts of intense resistance exercise attenuates increases in biomarkers of muscle damage and decreases delayed onset muscle soreness when compared with placebo (96301). It is unclear if these benefits are due to collagen peptides, other ingredients or the combination.
• Gingivitis. It is unclear if oral collagen peptides are beneficial for patients with gingivitis. Details: A small clinical study in patients with mild-to-moderate chronic gingivitis shows that taking a specific collagen peptide product (Verisol B, Gelita AG) 5 grams daily for 90 days following mechanical plaque removal reduces bleeding and inflammation but does not improve plaque scores when compared with placebo (110666).
• Hypertension. Limited research suggests that oral collagen peptides may lower systolic or diastolic blood pressure. However, results are inconsistent. Details: One preliminary clinical study in patients with hypertension and type 2 diabetes shows that taking fish-derived collagen peptides 6.5 grams twice daily for 3 months modestly reduces diastolic, but not systolic, blood pressure when compared with placebo (101626). Another small clinical study in patients with mildly elevated blood pressure shows that taking a test food containing chicken leg-derived collagen peptides 2.9 grams daily for 12 weeks lowers systolic, but not diastolic, blood pressure when compared with placebo (101610). An additional small clinical study in patients with mild hypertension shows that taking chicken leg-derived collagen peptides 5.2 grams daily 4 weeks reduces systolic blood pressure by 12 mmHg when compared with baseline (101618). This study was limited by its small size and lack of a comparator group. The reasons for conflicting data are unclear.
• Insomnia. It is unclear if oral collagen peptides are beneficial for insomnia. Details: A very small clinical study in physically active males with difficulty sleeping shows that taking collagen peptides 15 grams before bedtime for 7 nights reduces the frequency of nocturnal awakenings and improves cognitive accuracy but does not improve objective measures of total sleep time, latency, efficiency, stage changes, waking after sleep onset, other cognitive function measures, or subjective measures of sleepiness, fatigue, and sleep quality when compared with placebo (112459).
• Joint pain. Most research shows that oral collagen peptides might moderately reduce joint pain in young athletes. However, evidence in elderly patients is conflicting. Details: Preliminary clinical research in student athletes with joint pain shows that taking a specific collagen peptide product (FORTIGEL, Gelita AG) 10 grams in 25 mL of liquid daily for 24 weeks modestly improves pain during movement and at rest when compared with placebo (101601). Other clinical research in young adults exercising or participating in sports at least 3 hours weekly with activity-related knee pain shows that taking this same product 5 grams daily for 12 weeks reduces pain intensity during activity by 38% to 41%, compared with a 26% to 28% reduction in those taking placebo. However, there was no improvement in pain at rest or after the activity when compared with placebo (97623,107454). Furthermore, it is not clear if these effects are clinically significant. Research on the use of collagen peptides in older patients is conflicting. A small clinical study in otherwise healthy patients aged 40-65 years with joint discomfort shows that taking a specific collagen peptides product (AVC-H2, Avicenna) 1.25 grams twice daily for 8 weeks improves overall Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores by 37% at 4 weeks, compared with 14% in those receiving placebo. However, this difference in improvement was no longer significant at 8 weeks. Collagen peptides also improved the physical activity and stiffness subdomains, but not the pain subdomain, at 4 and 8 weeks when compared with placebo (107455). A larger clinical study in patients 50 years or older with general joint pain shows that taking a specific collagen peptides product (Genacol) 1200 mg daily for 6 months does not reduce pain or improve function when compared with placebo (97657). However, collagen peptides used in combination with other ingredients have shown benefit. Preliminary clinical research in patients 51-70 years of age shows that taking a specific combination product (Gold Collagen Active, Minerva Research Labs) containing fish collagen peptides 4 grams, glucosamine hydrochloride 1000 mg, chondroitin sulfate 500 mg, L-carnitine 200 mg, and other ingredients daily for 90 days reduces joint pain by 43% when compared with baseline, while patients taking placebo saw negligible improvement in pain. A greater percentage of patients taking this product also perceived improvements in joint discomfort, flexibility, mobility, and rigidity when compared with placebo (100703). It is unclear if these effects are due to collagen peptides, other ingredients, or the combination.
• Obesity. It is unclear if oral collagen peptides are beneficial for weight loss. Details: A preliminary clinical study in adults with overweight shows that taking skate skin-derived collagen peptides 2 grams daily for 12 weeks modestly reduces body fat mass by 1.2 kg, compared with an increase of 0.3 kg in the placebo group (101621). It is unclear if collagen peptides improve weight loss or reduce body fat mass in the long-term.
• Osteoarthritis. Most research suggests that oral collagen peptides improve pain in patients with knee osteoarthritis; however, any improvement is modest and may not be considered clinically significant. Details: A meta-analysis of 3 clinical studies, all of which are included below, in adults with knee osteoarthritis shows that taking collagen peptides or hydrolyzed collagen reduces pain when compared with placebo (112456). Clinical research shows that taking specific collagen peptides (Colnatur, Protein SA) 10 grams daily for 5 months increases the number of patients who experience at least a 30% improvement in pain by approximately 42% when compared with placebo. However, there is no difference between groups when the Western Ontario and McMaster Universities (WOMAC) scale is used. Patients with the greatest joint deterioration at baseline, as well as those with the lowest dietary meat intake, seemed most likely to experience benefit from collagen peptides (97635). Another small clinical study shows that taking collagen peptides isolated from pork skin and bovine bone (Nitta Gelatin Inc.) 5 grams dissolved in 250 mL water or milk twice daily after food for 13 weeks modestly improves pain when compared with placebo (101611). Another small clinical study in patients over 40 years old shows that taking collagen peptides (Colatech) 10 grams daily for 90 days reduces pain by about 2 points on a 100-point scale, compared with a 0.9-point reduction with glucosamine sulfate 1.5 grams. Ibuprofen use was not affected (101622). One multicenter clinical study shows that taking collagen peptides 10 grams daily for 6 months does not relieve pain or improve joint function when compared with placebo, although a trend towards reduced pain and improved joint function was observed in patients with severe symptoms at baseline (7704). Collagen peptides have also been evaluated in combination with other ingredients. Clinical research in patients with osteoarthritis of the knee, hip, or hand shows that taking a specific product (BioCell Collagen, BioCell Technology, LLC) containing collagen peptides from chicken collagen type II, hyaluronic acid, and chondroitin sulfate 1 gram twice daily for up to 10 weeks reduces pain and the need for rescue analgesics and increases physical activity when compared with placebo (28678,28680). Similarly, a moderate-size clinical study in patients aged 45-75 years with mild to moderate knee osteoarthritis undergoing resistance exercise twice weekly shows that taking a specific product (Suntory Beverage and Food Asia) containing collagen peptides from chicken collagen type II, hyaluronic acid, and chondroitin sulfate 2 grams daily for 24 weeks does not improve WOMAC scores when compared with glucosamine 1.5 grams daily or placebo, but may modestly improve pain scores when compared with placebo. However, the use of rescue analgesics was not assessed. Adding essence of chicken 5.81 grams daily to collagen peptides did not improve WOMAC or pain scores (110670). Also, preliminary clinical research in patients with knee osteoarthrosis shows that taking a specific product (Ialoral 1500, PharmaSuisse Laboratories Srl) containing collagen peptides, chondroitin sulfate, hyaluronic acid, and keratin peptides for 4 weeks improves pain and function by a moderate amount when compared with baseline (104645). However, the validity of these findings is limited by the lack of statistical comparison to the control group. It is unclear if these effects are due to collagen peptides, other ingredients, or the combination.
• Osteopenia. It is unclear if oral collagen peptides prevent loss of bone mineral density (BMD) in postmenopausal adults. Details: A large clinical study in patients with reduced BMD after menopause shows that taking specific collagen peptides (Fortibone, Gelita AG) 5 grams daily for 12 months increases BMD of the spine and the femoral neck by 3% and 7%, respectively, compared with losses of 1% with placebo (101609). In a very small observational extension of this study, BMD continued to increase over an additional 4 years when compared with baseline. However, the validity of these findings is limited by the lack of a comparator group (107340). Collagen peptides have also been evaluated in combination with calcium and vitamin D. In patients with osteopenia after menopause, a small clinical study shows that taking collagen peptides calcium chelate 5 grams, containing elemental calcium 500 mg and vitamin D3 200 IU, daily for 12 months does not affect total hip, total body, or vertebral BMD when compared with calcium 500 mg and vitamin D 200 IU (101604). The validity of these results is limited by a high dropout rate and insufficient power to detect smaller effects. Conversely, another small study in this population shows that taking specific collagen peptides (Fortibone, Gelita AG) in combination with elemental calcium (as calcium lactate) 500 mg and vitamin D3 400 IU daily for 12 months improves trabecular bone mineral content, trabecular volumetric BMD, and cortical volumetric BMD, but not cortical bone mineral content, when compared with a combination tablet containing equivalent doses of elemental calcium (as calcium carbonate) and vitamin D (107453). It is unclear if these effects are due to collagen peptides, other ingredients, or the combination.
• Osteoporosis. It is unclear if oral collagen peptides improve bone mineral density (BMD) in adults with osteoporosis after menopause. Details: In patients with osteoporosis after menopause, clinical research shows that taking collagen peptides 10 grams daily in addition to twice weekly intramuscular calcitonin for 6 months does not improve BMD in the forearm when compared with calcitonin alone (104649). It is unclear if supplementation with collagen peptides improves BMD in the femoral neck or lumbar spine.
• Pressure ulcers. Oral collagen peptides might help to improve ulcer size and healing. Details: A small clinical study in patients with Stage II, III, or IV pressure ulcers shows that taking collagen peptides 5 grams orally three times daily for 8 weeks in addition to standard care improves ulcer size and exudate when compared with placebo and standard care (101612). This study was limited because it only used one scale to assess healing of the pressure ulcer. Another small clinical study in patients with stage II or III pressure ulcers shows that receiving standard care and collagen peptides with high levels of prolyl-hydroxyproline 5 grams twice daily for 16 weeks improves ulcer exudate, healing, and wound size when compared with standard care plus placebo (101620).
• Sarcopenia. Oral collagen peptides might help to increase fat-free mass. However, it is unclear if collagen peptides are more beneficial than other types of protein. Details: A small clinical study in elderly males with sarcopenia shows that taking collagen peptides from type I collagen 15 grams daily for 12 weeks along with three resistance training sessions weekly modestly increases fat-free mass and power when compared with resistance training and placebo (101624). It is unclear if supplementation with collagen peptides is more beneficial than supplementation with protein.
• Sprains. It is unclear if oral collagen peptides improve ankle instability after a previous sprain. Details: A small clinical study in athletes with chronic ankle instability from an ankle sprain shows that taking collagen peptides 5 grams daily for 6 months improves subjective ankle instability when compared with placebo. However, ankle stiffness, which is a more objective measure of ankle instability, is not improved when compared with placebo (101603).
• Tendinopathy. It is unclear if oral collagen peptides improve tendon pain. Details: A small clinical study in patients with Achilles tendinopathy shows that taking a specific collagen peptides supplement (TENDOFORTE, Gelita AG) 2.5 grams daily for 3 months in addition to a calf-strengthening program improves pain when compared with baseline (101615). The validity of this finding is limited by the lack of a comparator group.
• Wound healing. It is unclear if oral collagen peptides improve wound healing. Details: A small clinical study in healthy volunteers with wounds after photothermolysis shows that taking collagen peptides 3 grams daily for 4 weeks improves erythema, skin hydration, and skin elasticity when compared with placebo (101599). This study was limited by small size, short duration, and no direct measurement of wound healing or scar formation.
• Wrinkled skin. Some small clinical studies suggest that oral collagen peptides might help to reduce lines and wrinkles from sun damage. Details: Preliminary clinical research in females with photodamaged skin shows that taking a specific low molecular weight collagen peptide product (Evercollagen, Newtree Co.) 1000 mg daily for 12 weeks modestly improves most measures of skin wrinkling, hydration, and elasticity when compared with placebo. This specific collagen peptide product is standardized to contain more than 15% glycine-containing tripeptides, including 3% glycyl-prolyl-hydroxyproline (100702). Another moderate-sized clinical study in adults with dry and wrinkled eye skin shows that taking low-molecular weight collagen peptides (GPVGPS Collagen, Daehan Chemtech) 2000 mg daily for 12 weeks reduces skin wrinkling parameters including facial skin roughness, peak-to-valley values, maximum wrinkle height, and eye wrinkle volume and improves skin hydration and skin elasticity when compared with placebo. However, there was no improvement in maximum wrinkle depth (112458). Another preliminary clinical study shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing collagen peptides from chicken collagen type II 600 mg, low molecular weight hyaluronic acid 100 mg, and chondroitin sulfate 200 mg daily for 12 weeks reduces lines and wrinkles associated with both natural aging and photoaging by about 13% when compared to baseline (28681). This study was limited by the lack of a comparator group. Additionally, it is unclear if these effects are due to collagen peptides, other ingredients, or the combination. More evidence is needed to rate collagen peptides for these uses.

(Read more about COLLAGEN PEPTIDES)

LIKELY EFFECTIVE

• Osteoarthritis. Oral glucosamine sulfate taken for at least 4 weeks is modestly beneficial for improving pain and function in knee osteoarthritis. However, oral glucosamine hydrochloride seems to only be beneficial when used in combination with chondroitin and other ingredients. It is unclear if glucosamine can slow disease progression or improve symptoms in other forms of osteoarthritis. Details: Meta-analyses of the available research in adults with KNEE osteoarthritis show that taking glucosamine SULFATE 1500 mg daily for up to 3 years modestly improves pain, function, and joint space narrowing when compared with placebo (14305,89521,94382,95785,99684,113636). Individual studies show 28% to 41% pain reduction and 21% to 46% improvement in function when compared with placebo (7026,8942,12461,20084,94382). Some research suggests that glucosamine sulfate reduces pain similarly to various non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen 400 mg three times daily and piroxicam 20 mg daily. However, NSAIDs appear to relieve symptoms within 2 weeks, while glucosamine sulfate takes 4-8 weeks. Notably, glucosamine sulfate appears to sustain benefit for longer after treatment withdrawal when compared with piroxicam (2604,20094,20096). Other clinical research shows that glucosamine sulfate 1500 mg once daily for 6 months might be more effective for reducing symptoms than acetaminophen 1 gram three times daily or 650 mg once daily in patients with moderate knee osteoarthritis (13578,20098). However, not all research shows benefit. One meta-analysis of clinical studies in adults with knee osteoarthritis shows that taking glucosamine sulfate 1500 mg daily for 4 weeks to 3 years reduces some, but not all, measures of pain intensity and does not reduce pain when moving or improve function when compared with placebo (113636). Furthermore, small clinical studies suggest that glucosamine sulfate 1500 mg daily for 2-6 months may NOT work for severe, long-standing osteoarthritis (1330,11459). It is unclear if glucosamine sulfate can slow disease progression. A specific crystalline glucosamine sulfate product (Dona, Rotta Pharmaceuticals) taken as 1500 mg daily for up to 3 years seems to prevent joint space narrowing of greater than 0.5 mm by up to 54% when compared with placebo (7026,8942,13719,42420). In contrast, other glucosamine sulfate formulations have not consistently been shown to improve symptoms or prevent joint space narrowing when compared with placebo (14305,89558,94382,95788). It is unclear if the benefit seen with this specific product (Dona) is due to bias introduced by industry funding or due to a higher quality product (42492). Glucosamine products associated with quality concerns have demonstrated inconsistent benefits in research (8128,102116). Limited research on the use of a different salt, glucosamine HYDROCHLORIDE, has found no benefit for knee osteoarthritis. A meta-analysis of clinical research and two other clinical trials show that taking glucosamine hydrochloride 1500 mg daily for up to 18 months does not seem to reduce pain when compared with placebo (18344,89519,89521). However, one small, unblinded clinical study in patients with mild to moderate osteoarthritis shows that taking a combination of glucosamine hydrochloride 480 mg every 12 hours and celecoxib 200 mg daily reduces pain scores, osteoarthritis severity, and inflammatory markers to a greater extent than celecoxib alone (106883). There is mixed evidence of benefit when glucosamine hydrochloride is used with chondroitin. Clinical research in patients over 40 years of age shows that taking a noncommercial preparation of glucosamine hydrochloride 1500 mg daily in combination with chondroitin sulfate 1200 mg daily for 6-24 months does not reduce pain when compared with placebo. The placebo response in these studies was sometimes as high as 60% (13579,14809,42477). However, a large, prospective observational study in adults with knee or hip osteoarthritis suggests that taking glucosamine hydrochloride 500 mg and chondroitin sulfate 400 mg (Theraflex, Bayer) three times daily for the first 3 weeks then twice daily thereafter for up to 64 weeks is associated with reductions in pain, stiffness, and the need for concomitant analgesic therapy and improvements in daily function and knee- or hip-related quality of life when compared to baseline. The most pronounced improvements were from 16-24 weeks (111647). The validity of these effects is limited by subjective outcomes, a lack of control group, and the observational design of the study. Furthermore, another clinical trial shows that taking a prescription product available in Spain (Droglican, Bioibérica S.A.), providing a similar daily dose of glucosamine hydrochloride with chondroitin sulfate for 6 months is non-inferior to celecoxib 200 mg daily for relieving pain, but not stiffness or function (89516). Small clinical studies show that taking a specific combination product (Cosamin or Cosamin DS, Nutramax Laboratories) containing glucosamine hydrochloride 1500-2000 mg, low molecular weight chondroitin sulfate 1200-1600 mg, and manganese ascorbate 228-304 mg, in 2-3 divided doses daily for 2-6 months improves pain in patients with mild or moderate, but not severe, osteoarthritis when compared with placebo (4237,7169). A different combination product (Gurukosamin & Kondoroichin, Suntory Wellness Ltd.) containing glucosamine hydrochloride 1200 mg, chondroitin sulfate 60 mg, and quercetin glycosides 45 mg, taken daily for 16 weeks, also seems to improve symptoms of knee osteoarthritis when compared with placebo (42514). It is unclear if the findings of any of these studies are due to glucosamine, chondroitin, other ingredients, or the combination. Despite evidence suggesting differing benefit (89521,94382), head-to-head comparisons of glucosamine sulfate and glucosamine hydrochloride are limited, and it is not universally acknowledged that these salts have different effectiveness profiles. One large clinical study in patients with knee osteoarthritis shows that taking a specific product (Artrolive, Aché Laboratórios Farmacêuticos S.A.) containing glucosamine sulfate 500 mg and chondroitin sulfate 400 mg three times daily for 4 months seems to be no different for reducing pain when compared with taking glucosamine hydrochloride 500 mg and chondroitin sulfate 400 mg (Cosamin DS, Nutramax Laboratories, Inc.) three times daily (89520). This study was funded by the supplement manufacturer. Many meta-analyses have pooled studies of both glucosamine salts together, producing largely inconsistent results (94381,99683,99685,112444). Experts have conflicting stances on the use of glucosamine. The American College of Rheumatology (ACR) strongly recommends against the use of any glucosamine products for any form of osteoarthritis (102114). Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends the use of pharmaceutical-grade glucosamine sulfate products, such as Dona (Rotta Pharmaceuticals), in patients with osteoarthritis. Additionally, the ESCEO provides a weak recommendation against the use of glucosamine in combination with chondroitin (102141). These differing recommendations seem to be related to interpretation of the evidence for pharmaceutical-grade products. The ACR has determined that the inconsistent evidence may indicate the presence of industry bias; the ESCEO has determined that the inconsistent evidence is due to inconsistent product quality. Limited research has found mixed benefit of using glucosamine on osteoarthritis of the SPINE, HIP, or HAND. In one study of patients with osteoarthritis of the lumbar spine, taking glucosamine sulfate (Dona, Rotta Pharmaceuticals) 1500 mg daily for 6 weeks reduced pain in more patients when compared with placebo (1316). However, in another study, using a different glucosamine sulfate product (Glucosamine Sulfate, PharmaNord) 1500 mg daily for 6 months did not reduce pain when compared with placebo (89562). In patients with hip osteoarthritis, taking glucosamine sulfate 1500 mg once daily for 2 years did not reduce symptoms or slow disease progression when compared with placebo (16717,20100); however, there was a high rate of hip replacement, which may have confounded results (16717,16718). In patients with erosive osteoarthritis of the hand, observational research has found that taking glucosamine sulfate (Dona, Rotta Pharmaceuticals) 1500 mg daily along with conventional therapy for 6 months is associated with reduced hand pain, a shorter duration of morning stiffness, and improved hand function when compared with conventional therapy alone (108897). Limited research has also evaluated INTRAMUSCULAR and TOPICAL glucosamine sulfate. A clinical study in patients with mild to moderate knee osteoarthritis (radiological stage I-III) shows that giving intramuscular glucosamine sulfate 400 mg twice per week for 6 weeks reduces the severity of symptoms when compared with placebo (2605). There is also a small study showing that a topical preparation of glucosamine sulfate in combination with chondroitin sulfate, shark cartilage, and camphor reduces osteoarthritis symptoms when compared with placebo. However, any symptom relief is most likely due to the counterirritant effect of camphor and not the other ingredients (10327,12467). There is no evidence that glucosamine is absorbed topically. Glucosamine sulfate does not seem to PREVENT osteoarthritis. Clinical studies in overweight healthy females aged 50-60 years shows that taking crystalline glucosamine sulfate 1500 mg orally daily for 2.5 years does not reduce the incidence of osteoarthritis after a 6-7 year follow-up; however, it may reduce the percentage of patients who experience knee joint space narrowing (95789,97053).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Topical N-acetyl glucosamine has only been evaluated in combination with niacinamide for reducing hyperpigmentation and liver skin spots on aging skin; its effect when used alone is unclear. Details: A clinical study in females ages 40-60 years with skin hyperpigmentation and solar lentigines (liver spots) primarily due to aging and sun exposure shows that applying a cream containing 2% N-acetyl glucosamine and 4% niacinamide to the face twice daily with sunscreen for 10 weeks decreases facial hyperpigmentation when compared with sunscreen alone (92721). The effect of N-acetyl glucosamine alone is unclear.
• Aromatase inhibitor-induced arthralgia. Oral glucosamine sulfate has only been evaluated in combination with chondroitin; its effect when used alone is unclear. Details: A small open-label clinical study in patients with aromatase inhibitor-induced arthralgia shows that taking a combination of glucosamine sulfate 1500 mg and chondroitin sulfate 1200 mg in 2-3 divided doses daily for 24 weeks improves pain when compared to baseline in postmenopausal adults with early stage breast cancer (89561). The validity of this finding is limited by a lack of control group.
• Back pain. Although there is interest in using oral glucosamine for back pain, there is insufficient reliable information about the clinical effects of glucosamine for this condition.
• Cancer. Some low-quality observational studies have inconsistently found that glucosamine may be associated with a lower risk of different cancers; however, better quality evidence is needed. Details: A meta-analysis of observational research has found that use of glucosamine with or without chondroitin is associated with a 7% to 12% lower risk of cancer when compared with no use of glucosamine. A subgroup analysis showed a reduction in the risk of colorectal cancer, but not other types of cancer (110625). Observational research report conflicting relationships between glucosamine and cancer. Some observational research in adults in the United Kingdom has found that taking glucosamine is associated with 4% higher risk of cancer over a median follow up for 13 years. However, a subgroup analysis showed a reduction in the risk of lung cancer (110627). Other observational research in adults in the United Kingdom has found that taking glucosamine is associated with a 5% reduced risk of cancer mortality over a median follow-up of around 12 years, with reductions specifically occurring in those with kidney, lung, and rectal cancers. However, glucosamine use was not linked to a reduced risk of mortality due to bladder, brain, breast, colon, ovarian, prostate, skin, stomach, thyroid, or uterine cancer (109645). Other large, propensity-score-adjusted, observational research in adults with osteoarthritis in the United Kingdom suggests that treatment with glucosamine, with an average of 8 years of follow-up, is not associated with a reduction in cancer, including lung, colorectal, breast, or prostate cancer, when compared with patients not prescribed glucosamine (114571). These studies are limited by observational designs, which also did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Although some studies attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and the risk for cancer and/or cancer-related mortality. Of note, some researchers have called into question the results from observational research linking glucosamine use to a lower rate of cancer, claiming that these studies suffer from a high risk of selection bias (109646).
• Cardiovascular disease (CVD). It is unclear if oral glucosamine prevents fatal or non-fatal CVD events. Details: Some observational research of adults in the United Kingdom has found that taking glucosamine is associated with an overall 15% reduced risk for fatal and non-fatal CVD events, including coronary heart disease (CHD) and stroke (99682). However, this study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Conversely, an observational study in Chinese patients with osteoarthritis has found that glucosamine use is associated with a 10% increase in the risk of CVD events and a 12% increase in the risk of CHD, with no increase in the risk of stroke. The risk for these outcomes was greatest in patients with higher adherence to glucosamine and in those taking larger doses (109642). However, this study also did not clarify the form of glucosamine used or provide specifics related to the frequency or duration of use. Furthermore, glucosamine users were generally older, more likely to be on antihyperlipidemic or antiplatelet therapy, and more likely to have multiple comorbidities compared with non-users. Both studies attempted to control for the differences in characteristics between glucosamine users and non-users; despite this, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and CVD risk.
• Colorectal adenoma. Oral glucosamine has only been evaluated in combination with chondroitin; its effect when used alone is unclear. Details: An observational study in older adults has found that taking glucosamine and chondroitin is associated with a 26% reduced risk of high-risk adenoma and 10% reduced risk of conventional adenoma when compared with not using these supplements. This benefit was not seen in a subgroup of younger females (104444). This study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use.
• Colorectal cancer. It is unclear if oral glucosamine reduces the risk of colorectal cancer. Details: A meta-analysis of observational research has found that use of glucosamine with or without chondroitin is associated with a 7% to 12% lower risk of cancer when compared with no use of glucosamine. A subgroup analysis showed a reduction in the risk of colorectal cancer, but not other types of cancer (110625). However, not all research agrees. A large, observational study in adults has found that regular use of oral glucosamine is not associated with a reduced risk of colorectal cancer over a median of 7 years of follow-up, regardless of sex, age, body mass index, smoking status, or non-steroidal anti-inflammatory drug use (108018). Other large, propensity-score-adjusted, observational research in adults with osteoarthritis in the United Kingdom suggests that treatment with glucosamine, with an average of 8 years of follow-up, is not associated with a reduction in cancer, including colorectal cancer, when compared with patients not prescribed glucosamine (114571).These studies did not clarify the form or dose of glucosamine used or the frequency or duration of use.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral glucosamine is beneficial for COVID-19. Details: A large observational study in adults suggests that regular glucosamine use over a median of 1.7 years is not linked to a lower odds of COVID-19 infection but is associated with a 20% lower risk of hospital admission and a 19% lower risk of mortality due to COVID-19 when compared with adults not using glucosamine (111649). This study did not clarify the form or dose of glucosamine used or the frequency or duration of use.
• Dementia. Observational studies suggest that long-term, regular glucosamine intake might reduce the risk of developing certain types of dementia. Details: An observational study has found that regularly taking glucosamine for an average of 8.9 years is associated with a 19% lower risk of developing dementia, including Alzheimer disease and vascular dementia (110630). Another large observational study in older adults without dementia suggests that regularly taking glucosamine for a median of 12 years is associated with an 18% lower risk of vascular dementia. However, habitual glucosamine consumption is not associated with a reduced risk of Alzheimer disease or frontotemporal dementia (112461).
• Depression. It is unclear if oral glucosamine hydrochloride reduces depression symptoms. Details: A small, open-label clinical trial in patients with unipolar depression shows that taking glucosamine hydrochloride 1 gram daily for 1 week, followed by 2 grams daily for 3 weeks, reduces scores on the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) by 31% or 33% when compared to baseline. However, only 20% of patients experienced a 50% or greater reduction in HAM-D scores, and there were no improvements in Clinical Global Impression scores (103281). The lack of a control group limits the validity of these findings.
• Diabetes. It is unclear if oral glucosamine reduces the risk of developing type 2 diabetes in adults. Details: Observational research in adults in the United Kingdom has found that glucosamine use is associated with a 17% lower risk of type 2 diabetes. The relationship between glucosamine use and diabetes appears to be even more pronounced in patients with high baseline levels of C-reactive protein, a marker of inflammation (103234). However, this study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Although this study attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and the risk for diabetes.
• Gout. It is unclear if oral glucosamine reduces the risk of developing gout. Details: Observational research in adults in the United Kingdom has found that glucosamine use is associated with a 19% lower risk of gout in females, but not males (109644). However, this study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Although this study attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and the risk for gout.
• Heart failure. It is unclear if oral glucosamine prevents heart failure. Details: A large, prospective observational study in adults without heart failure suggests that taking glucosamine regularly over a median of 9 years is associated with a 13% lower risk of developing heart failure when compared with adults not taking glucosamine (111646). This study did not clarify the form or dose of glucosamine used or the frequency or duration of use.
• Hyperlipidemia. It is unclear if oral glucosamine hydrochloride improves hyperlipidemia when used with conventional medicine. Details: Preliminary clinical research shows that glucosamine hydrochloride does not reduce cholesterol or triglyceride levels in patients with hyperlipidemia. A small crossover study in older adults taking simvastatin or atorvastatin shows that adding a specific glucosamine hydrochloride product (Artrox, Pfizer) 750 mg twice daily for 4 weeks does not seem to affect lipid levels when compared with placebo (18341).
• Inflammatory bowel disease (IBD). It is unclear if oral or rectal N-acetyl glucosamine improves symptoms of IBD in children. Details: A very small clinical study in children ages 8-17 years with Crohn disease or ulcerative colitis that were unresponsive to conventional treatment suggests that oral or rectal N-acetyl glucosamine 1.5-2 grams in 10 mL water twice daily for 6 weeks might decrease symptoms of IBD when compared with baseline (10234). The validity of this finding is limited by a lack of control group.
• Interstitial cystitis. Oral glucosamine sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An open-label clinical study in patients with interstitial cystitis shows that taking a specific product (CystoProtek, Tischon Corporation) containing glucosamine sulfate 120 mg, sodium hyaluronate 10 mg, chondroitin sulfate 150 mg, quercetin 150 mg, and rutin 20 mg per capsule, as two capsules twice daily for 12 months, reduces symptom severity by up to 52% when compared with baseline (42391). The validity of this finding is limited by a lack of control group.
• Joint pain. Oral glucosamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with joint pain shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 1500 mg, methylsulfonylmethane 500 mg, white willow bark extract 250 mg, ginger root concentrate 50 mg, Boswellia serrata extract 125 mg, turmeric root extract 50 mg, cayenne 40 m H.U. 50 mg, and hyaluronic acid 4 mg, daily in three divided doses for 8 weeks, reduces joint pain severity by 37% compared to only 16% with placebo. However, the specific combination product does not appear to improve joint stiffness or function compared with placebo (89560).
• Kashin-Beck Disease. It is unclear if oral glucosamine hydrochloride improves Kashin-Beck Disease symptoms such as pain. Details: A small clinical study in Chinese adults with Kashin-Beck Disease shows that taking glucosamine hydrochloride 480 mg three times daily along with chondroitin sulfate 600 mg twice daily for 6 months decreases pain scores by at least 20% to 50% in more patients when compared with placebo. Taking glucosamine alone had a non-significant trend toward pain reduction in these patients (42516). An open-label study in Chinese adults with Kashin-Beck Disease shows that taking glucosamine hydrochloride 750 mg twice daily for 6 weeks seems to be no different for improving pain and physical function when compared with taking to diclofenac 50 mg twice daily or naproxen 300 mg twice daily (18339). The validity of this finding is limited by a lack of blinding.
• Kidney stones (nephrolithiasis). Oral glucosamine might reduce the risk of developing kidney stones. Details: A large observational study in adults without kidney stones suggests that regularly taking glucosamine is associated with a 28% lower risk of new-onset kidney stones in people with a total sedentary time under 3.5 hours daily. This association follows a dose-dependent relationship. However, regular glucosamine use does not seem to reduce the risk of new-onset kidney stones in people with total sedentary time exceeding 3.5 hours daily (112451).
• Knee pain. Small clinical studies suggest that oral glucosamine hydrochloride might improve exercise-induced knee pain and chronic knee pain. However, it is unclear if glucosamine sulfate, N-acetyl glucosamine, or lower doses of glucosamine hydrochloride are beneficial in these patients. Details: A small clinical study in athletes following an acute knee injury shows that taking glucosamine sulfate 500 mg three times daily for 28 days does not improve pain but might modestly improve mobility when compared with placebo (20103). Glucosamine has also been evaluated for chronic knee pain. A small clinical study in patients with chronic knee pain of unclear origin shows that taking glucosamine hydrochloride 2000 mg daily for 12 weeks might modestly improve pain when compared with placebo (10312). However, lower doses of glucosamine hydrochloride and N-acetyl glucosamine used in combination with other ingredients have not demonstrated benefit for chronic knee pain. A small clinical trial in Japanese adults over 40 with knee pain shows that taking a combination supplement with glucosamine hydrochloride and other ingredients for 16 weeks does not improve pain, function, or walking speed when compared with placebo. The combination supplement provided glucosamine hydrochloride 1200 mg, chondroitin sulfate 60 mg, type II collagen peptides 45 mg, quercetin glycosides 90 mg, imidazole peptides 10 mg, and vitamin D 200 IU daily (95784). Another small clinical study in Japanese patients over 50 years of age with chronic knee pain shows that taking a specific supplement (Walker's Glucosamine, Kyowa) containing N-acetyl glucosamine 100 mg and chondroitin sulfate 180 mg daily for 24 weeks does not reduce pain or improve knee function when compared with placebo (95795).
• Metabolic dysfunction-associated steatotic liver disease (MASLD). It is unclear if oral glucosamine is beneficial in patients with MASLD. Details: Observational research in adults with MASLD and type 2 diabetes suggests that regular use of glucosamine orally for an average follow up of 11 years is associated with a lower risk of adverse liver outcomes when compared with those not regularly using glucosamine. Non-users of glucosamine had 35% to 44% higher risk of cirrhosis, encephalopathy, and esophageal varices. This study did not report the glucosamine dose or frequency (114573).
• Multiple sclerosis (MS). It is unclear if oral glucosamine sulfate is beneficial in patients with MS. Details: A small clinical study in patients with MS shows that taking glucosamine sulfate 1000 mg once daily for 6 months modestly reduces relapse when compared to baseline, but not when compared with placebo (20104).
• Overall mortality. It is unclear if oral glucosamine reduces overall mortality. Details: An observational study in the United States has found that regular use of oral glucosamine, with or without chondroitin, for an average of 8 years is associated with a 30% lower risk of mortality when compared with no glucosamine use. However, when adjusted for covariates such as age, body-mass index, and comorbidities, there was no difference in overall mortality (110626). In contrast, a cross-sectional observational study has found that using oral glucosamine and chondroitin for at least one year is associated with 27% reduced incidence of overall mortality and 58% reduced incidence of cardiovascular mortality when compared with not using these supplements (104445). This study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine and chondroitin use also reported overall healthier lifestyle habits than those that were not taking glucosamine and chondroitin. Although this study attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, with overall mortality. Of note, some researchers have called into question the results from observational research linking glucosamine use to a lower rate of overall mortality, claiming that these studies suffer from a high risk of selection bias (109646).
• Postoperative recovery. It is unclear if oral glucosamine sulfate improves recovery after surgery. Details: A small clinical study in male athletes who have undergone anterior cruciate ligament (ACL) reconstruction shows that taking glucosamine sulfate (Solgar Inc.) 1000 mg daily for 8 weeks does not improve rehabilitation outcomes such as functional ability, pain, and muscular performance when compared with placebo (95584).
• Rheumatoid arthritis (RA). It is unclear if oral glucosamine hydrochloride is beneficial in patients with RA. Details: A small clinical study in patients with RA shows that taking glucosamine hydrochloride tablets (Rohto Pharmaceutical Co.) 500 mg three times daily by mouth for 12 weeks reduces pain, but not the number of painful or swollen joints, when compared with placebo (17407).
• Stroke. It is unclear if oral glucosamine is beneficial for reducing stroke risk. Details: An observational cohort study of adults in the United Kingdom found that taking glucosamine is associated with a modest 9% reduced risk for overall stroke; however, sub-analyses show that glucosamine use is not associated with a reduced risk for fatal or non-fatal stroke, hemorrhagic stroke, or ischemic stroke (99682). This study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. A case-control study in Spanish patients found that glucosamine use is associated with 45% lower odds of ischemic stroke when compared with non-use; however, the benefit was only observed in patients taking glucosamine for 1 year or less (109643). This study did not clarify the form of glucosamine used or the dose or frequency of use. Furthermore, patients in the control group were generally healthier and less likely to have a history of cardiovascular disease, diabetes, or hyperlipidemia. Although both studies attempted to control for differences between patient populations, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and stroke risk.
• Temporomandibular disorders (TMD). It is unclear if oral glucosamine sulfate is beneficial in patients with temporomandibular joint osteoarthritis. Details: A small and low-quality clinical study in patients with temporomandibular joint osteoarthritis shows that taking glucosamine sulfate 500 mg three times daily for 90 days seems to be no different than taking ibuprofen 400 mg three times daily for relieving pain and improving functional abilities such as chewing, yawning, talking, and laughing (3714). However, another small clinical study in patients with the same condition shows that taking glucosamine sulfate 1200 mg daily for 6 weeks does not improve pain or jaw opening capacity when compared with placebo (20105). Glucosamine sulfate has also been evaluated in combination with chondroitin for this condition. A meta-analysis of two small clinical studies in patients with TMD shows that taking glucosamine sulfate 1500 mg and chondroitin sulfate 1200 mg daily for 2 months does not reduce pain or increase maximum mouth opening when compared with tramadol 50-100 mg daily (109647). Other meta-analyses have reported similar results, however, these analyses may have been inadequately powered to detect a difference between groups (114572). Another small clinical trial in children aged 10-13 years with class II malocclusion shows that application of a specific combination gel product containing glucosamine, chondroitin, and essential oils (Jointace Gel, Vitabiotics) with an expander device, twice daily for 3 months does not improve temporomandibular space measures or pain or tension scores, when compared with placebo (110629).
• Wound healing. Although there is interest in using topical glucosamine for wound healing, there is insufficient reliable information about the clinical effects of glucosamine for this condition. More evidence is needed to rate glucosamine for these uses.

(Read more about GLUCOSAMINE)

POSSIBLY EFFECTIVE

• Burns. Topical gotu kola seems to improve the rate of burn healing. Details: Clinical research shows that applying a cream containing gotu kola 3% once daily to second degree burns increases the rate of re-epithelialization and complete healing by about 7 days when compared with silver sulfadiazine (SSD) 1% cream. Gotu kola cream also seems to reduce dryness, itching, irritation, and scar severity when compared with SSD (97027). Other research in adults with second degree burns shows that applying a gauze dressing containing gotu kola 5% and aloe 2.5%, covered with absorbent cotton wool and changed every 3 days, reduces time to healing by 1.5 days and length of hospital stay by 1.7 days when compared with the use of a gauze dressing containing chlorhexidine acetate 0.5% (97028).
• Venous insufficiency. Oral gotu kola seems to improve symptoms of venous insufficiency. Details: Clinical research shows that taking gotu kola or a specific extract of gotu kola (Centellase) 60-180 mg daily orally for 4-8 weeks seems to improve measures of circulation and decrease symptoms such as edema in patients with venous insufficiency (6887,9786,11063,11064,11066,11070,52894,52909).

POSSIBLY INEFFECTIVE

• Cognitive function. Oral gotu kola does not seem to be beneficial for cognitive function. Details: A meta-analysis of a small number of generally moderate quality clinical trials shows that taking a single dose of gotu kola, alone or in combination with other ingredients, does not improve cognitive function when compared with placebo (105334). In one study, gotu kola was taken in combination with ginkgo and docosahexaenoic acid (DHA) for 4 months by healthy, cognitively intact older adults (52880).
• Radiation dermatitis. Topical gotu kola does not seem to reduce symptoms of radiation dermatitis. Details: Clinical research in females undergoing radiotherapy for breast cancer shows that applying a cream containing gotu kola extract 7% once daily during and up to 4 weeks following radiotherapy does not reduce the severity of dermatitis when compared with no treatment or applying a moisturizing cream (102792).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy, middle-aged females shows that applying a topical emulsion containing extracts of gotu kola 3% and Indian gooseberry 3% twice daily for 60 days improves skin hydration, some measures of skin wrinkles, and elasticity of the cheek (but not the eye) when compared with placebo (111571). It is unclear if these effects are due to gotu kola, Indian gooseberry, or the combination.
• Alzheimer disease. Although there is interest in using oral gotu kola for Alzheimer disease, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Anal fissures. It is unclear if topical gotu kola is beneficial for anal fissures. Details: In patients with chronic anal fissures who are using standard dietary and hygiene treatments, preliminary clinical research shows that taking gotu kola extract 60 mg twice daily for 8 weeks and locally applying an ointment containing gotu kola does not reduce the mean time to bleeding cessation when compared with standard treatments alone. However, pain may be modestly improved. Also, gotu kola was less effective than an unspecified flavonoid mixture used both orally and topically (105332).
• Atherosclerosis. It is unclear if oral gotu kola is beneficial for slowing the progression of atherosclerotic plaques. Details: Some preliminary clinical research shows that taking gotu kola extract 60 mg orally three times daily for 12 months helps stabilize low-density atherosclerotic plaques when compared with placebo (11062,11069). Gotu kola has also been evaluated in combination with a specific maritime pine bark product (Pycnogenol, Horphag Research). A non-randomized clinical trial shows that taking gotu kola 225 mg and Pycnogenol 150 mg in two divided doses daily for 3 months reduces plaque height and length and increases plaque echogenicity and stability when compared to control (97030). Another non-randomized clinical study in adults with atherosclerotic plaques and no other cardiovascular risk factors shows that taking gotu kola extract 100 mg and Pycnogenol 100 mg daily for up to 4 years reduces plaque progression and increases plaque echogenicity when compared with Pycnogenol alone or no treatment at all. Taking gotu kola and Pycnogenol is also associated with a reduced rate of clinical vascular events, including angina, myocardial infarction, minor transient ischemic attacks (TIAs), and minor strokes when compared with taking Pycnogenol alone or receiving no treatment at all (97029). It is unclear how these outcomes would compare to the use of gotu kola alone.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral gotu kola for ADHD, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Atopic dermatitis (eczema). Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying an ointment containing 5% each of the extracts of heart's ease, gotu kola, and Oregon grape twice daily for 4 weeks does not improve eczema when compared with a base cream. However, patients with eczema on skin exposed to cold weather might experience some improvement (67372).
• Depression. Although there is interest in using oral gotu kola for depression, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Diabetic foot ulcers. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with deep diabetic foot ulcers, preliminary clinical research shows that applying a cream (WH-1 cream) containing 1.25% of gotu kola and Plectranthus amboinicus extracts in a 4:1 ratio twice daily for 2 weeks after surgical debridement is as effective as the use of a standard hydrocolloid fiber wound dressing for improving wound size. However, when compared with baseline, changes in wound size were not statistically significant (105335).
• Diabetic microangiopathy. It is unclear if oral gotu kola is beneficial for diabetic microangiopathy. Details: Preliminary clinical research shows that taking gotu kola extract 60 mg orally twice daily for 6-12 months helps increase measures of circulation and decrease edema in patients with diabetic microangiopathy (11065,11068,52917).
• Dry skin. It is unclear if topical gotu kola is beneficial for dry skin. Details: In patients with dry skin associated with type 2 diabetes, clinical research shows that topical application with 0.25 grams of a gotu kola 1% ointment twice daily, either alone or with oral gotu kola 1100 mg twice daily, for 28 days does not improve dry skin when compared with placebo. However, in a sub-group of patients with well-controlled diabetes, the combination of oral and topical gotu kola modestly improved dry skin (105329). Additionally, a small clinical study in individuals with dry skin due to working with synthetic and natural dyes shows that application of a gotu kola 2% ceramide-based cream to the hands and arms twice daily for 4 weeks improves skin barrier hydration, as measured by hydration of the stratum corneum and skin acidity, when compared to baseline. These improvements were similar to those seen with a ceramide 5% cream (109554). As the gotu kola cream was formulated with ceramide, it is unclear if these findings are due to gotu kola, ceramide, or the combination.
• Epilepsy. Although there is interest in using oral gotu kola for epilepsy, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Generalized anxiety disorder (GAD). It is unclear if oral gotu kola is beneficial for GAD. Details: In patients with GAD, preliminary clinical research shows that taking gotu kola extract 500 mg twice daily for 60 days reduces symptoms of anxiety, depression, and stress by 22% to 26% when compared with baseline (105333). The validity of these findings is limited by the lack of a comparator group.
• Hemorrhoids. It is unclear if topical gotu kola is beneficial for hemorrhoids. Details: Preliminary clinical research in patients with chronic hemorrhoids, as well as patients with acute symptoms following a hemorrhoidectomy or surgical treatment for hemorrhoidal thrombosis, shows that taking gotu kola extract (Centella complex) 60 mg twice daily for 15 weeks and locally applying an ointment (Proctocella) containing gotu kola, arnica, and aloe, in conjunction with standard treatments, does not reduce the mean time to bleeding cessation when compared with standard treatments alone. Anal irritation was modestly improved in the patients with chronic hemorrhoids and in those undergoing treatment for hemorrhoidal thrombosis, but not in those that had undergone a hemorrhoidectomy (105336).
• Herpes zoster (shingles). Although there is interest in using oral gotu kola for shingles, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Hypertension. It is unclear if oral gotu kola is beneficial for hypertension. Details: Preliminary clinical research in patients with hypertension shows that drinking a tea made by boiling gotu kola 4 grams in 250 mL water three times daily for 3 days modestly reduces systolic and diastolic blood pressure when compared with baseline. After consuming the tea, about 40% of patients had normal or high-normal systolic blood pressure and 77% had optimal or normal diastolic blood pressure, compared with 0% and 45%, respectively, prior to consumption (105330). The validity of these findings is limited by the lack of a comparator group.
• Hypertrophic scars. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that topical use of a specific silicone gel (Bangkok Botanica) containing 15% extracts of gotu kola, onion, aloe, and paper mulberry, starting 2 weeks after surgery and continuing for 6 months, moderately improves the height and pliability of the post-surgical hypertrophic scar when compared with a silicone placebo gel. There was no effect on pigmentation or vascularity (102793). It is unknown whether any benefit is related to gotu kola, other ingredients, or their combination.
• Idiopathic interstitial pneumonia. Oral gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational registry study in males less than 65 years old with idiopathic interstitial pneumonia has found that taking a specific gotu kola extract (Centellicum; Horphag Research) 225 mg three times daily in combination with a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 8 months is associated with a modest improvement in Karnofsky Performance Scale scores and a reduction in fatigue when compared with pirfenidone (108862). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Keloids. It is unclear if oral or topical gotu kola are beneficial for keloids. Details: There is some early evidence that applying a specific extract of gotu kola (Madecassol) topically might help reduce keloids and hypertrophic scarring (13558). Gotu kola has also been taken orally for keloids. Preliminary clinical research in patients at high risk for keloids shows that taking a specific extract of gotu kola (Centellicum, Horphag Research Ltd) 450 mg daily for 4 weeks starting on the second week after surgery seems to improve scar homogeneity and regularity (99756). However, the reliability of these results is limited because patients in this study were not randomized or blinded to different interventions.
• Laser skin resurfacing. It is unclear if topical gotu kola is beneficial for recovery from laser skin resurfacing. Details: A small clinical trial shows that applying a gel containing gotu kola extract (ECa 233) 0.05% four times daily for 7 days, then twice daily for 3 months, improves wound healing following laser resurfacing for facial acne. Redness returned to baseline levels by day 7, in contrast to day 28 on the side treated with a placebo gel. The general wound appearance and crusting were also improved on the side on which the gotu kola extract gel was applied (102794).
• Osteoarthritis. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large, single-blind clinical study in adults with knee osteoarthritis causing moderate pain shows that applying a specific cream (TMP-4) containing extracts of gotu kola leaf, sesame seed, soybean, and mangosteen peel four times daily for 4 weeks provides similar improvement in pain scores when compared with diclofenac 1% gel. Topical TMP-4 cream also seems to improve knee stiffness, stair climbing, and mobility similarly to diclofenac gel. However, patient impression of overall improvement was higher with diclofenac (110128). The validity of this study is limited by inadequate blinding.
• Scarring. It is unclear if topical gotu kola is beneficial for scarring or tenderness from scarring. Details: Preliminary clinical research in patients without a history of keloid formation suggests that applying a specific cream (Alpha Centella, not available in the US) containing gotu kola and Bulbine frutescens extracts twice daily for 6-8 weeks following suture removal might help to reduce scarring (11072). Also, a large clinical study in adults who underwent carpal tunnel release surgery shows that applying gotu kola cream 1% three times daily for 6 months after suture removal marginally improves self-reported scar tenderness pain when compared with control, and modestly improves scarring scores when compared to baseline (112425). However, the interpretation of these findings is limited by patient-reported outcomes and insufficient validity of the scar scoring tool in this population.
• Skin grafts. Although there is interest in using topical gotu kola for skin graft recovery, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Stretch marks (striae gravidarum). It is unclear if oral gotu kola is beneficial for stretch marks; topical gotu kola has only been evaluated in combination with other ingredients. Details: Preliminary clinical research in females with stretch marks shows that taking a specific extract of gotu kola (Centellicum, Horphag Research Ltd) 225 mg three times daily for 6 weeks increases skin thickness, elasticity, and perfusion when compared with a stretch mark minimizer cream (Clarins) and regular control cream (99757). The validity of these results is limited by the fact that patients were not randomized or blinded to the different interventions. Gotu kola has also been evaluated topically in combination with other ingredients. Preliminary clinical research shows that applying a specific mixture of gotu kola, vitamin E, and collagen-elastin hydrolysates in a cream (Trofolastin, not available in the US) daily during the second and third trimesters reduces stretch marks when compared with a placebo cream (13559). Another small clinical study shows that applying a specific mixture of gotu kola, vitamin E, essential fatty acids, hyaluronic acid, elastin, and menthol in an ointment (Verum, not available in the US) helps decrease the formation of stretch marks during pregnancy when compared with placebo (11073). Other preliminary clinical research in patients without previous striae shows that applying a specific formula containing hydroxyprolisilane C, rosehip oil, gotu kola triterpenes, and vitamin E (Velastisa Antiestrías, ISDIN) twice daily, beginning at week 10-14 and continuing throughout pregnancy, decreases the severity of both new and old stretch marks and the incidence of stretch marks when compared with placebo (92507). It is unclear if the effects seen in these studies are due to gotu kola, other ingredients, or the combinations.
• Systemic lupus erythematosus (SLE). Although there is interest in using oral gotu kola for SLE, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Tonsillitis. Although there is interest in using oral gotu kola for tonsillitis, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Venous thromboembolism (VTE). It is unclear if oral gotu kola is beneficial for VTE prevention. Details: Preliminary clinical research shows that gotu kola decreases edema and improves measures of circulation in patients traveling on airplanes for more than 3 hours when compared to a control group receiving no treatment (11067). However, it is unknown if these changes reduce the incidence of clots.
• Wound healing. Although there is interest in using topical gotu kola for wound healing, there is insufficient reliable information about the clinical effects of gotu kola for this purpose.
• Wrinkled skin. It is unclear if topical gotu kola is beneficial for wrinkled skin. Details: Small, low-quality studies in healthy adults suggest that topical formulations of gotu kola extract or the constituent asiaticoside 0.1% or 0.2% applied 1-3 times daily have shown modest benefit for wrinkled skin. Cream or gel formulations were used for 12 weeks for periorbital wrinkles and a lipstick was used for 8 weeks for lip wrinkles. However, the extent of benefit is not clear and meta-analyses are limited to a very small number of studies with varied comparator groups, including placebo, vehicle, tretinoin 0.02%, and Pueraria mirifica extract (106639). More evidence is needed to rate gotu kola for these uses.

(Read more about GOTU KOLA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Although there is interest in using oral horsetail for alopecia, there is insufficient reliable information about the clinical effects of horsetail for this condition.
• Hypertension. Oral horsetail seems to reduce blood pressure in patients with hypertension. Details: A clinical trial in patients with stage 1 systemic arterial hypertension shows that taking horsetail extract 900 mg daily for 3 months decreases systolic and diastolic blood pressure by 13 mmHg and 8 mmHg, respectively, and is similarly effective to hydrochlorothiazide 25 mg daily (108849). The validity of this finding is limited due to high withdrawal rates and low adherence to treatment protocols.
• Kidney stones (nephrolithiasis). Although there is interest in using oral horsetail for kidney stones, there is insufficient reliable information about the clinical effects of horsetail for this condition.
• Obesity. Although there is interest in using oral horsetail for weight loss, there is insufficient reliable information about the clinical effects of horsetail for this purpose.
• Osteoporosis. It is unclear if oral horsetail is beneficial for osteoporosis. Details: Preliminary clinical research shows that taking two tablets of either dried horsetail extract or a specific combination of horsetail extract with calcium (Osteosil Calcium) daily for 2-month intervals separated by 2 weeks of no treatment for up to one year can increase bone density when compared with no treatment in postmenopausal patients with osteoporosis. The effect of horsetail extract plus calcium (Osteosil Calcium) seems to be greater than the effect of dried horsetail extract alone (55578).
• Tonsillitis. Oral horsetail has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with acute non-bacterial tonsillitis shows that taking a specific combination product (Imupret) for 10 days in addition to standard symptomatic therapy accelerates recovery by a small amount when compared with symptomatic therapy alone. Overall treatment response after 10 days occurred in 82% of patients taking the combination product compared with 65% of patients receiving symptomatic therapy alone. Withdrawal from antipyretic drugs occurred approximately one day earlier in children using the horsetail product. Per 100 grams, Imupret provides 29 grams of an alcoholic extract produced from horsetail 0.5 grams, marshmallow root 0.4 grams, chamomile flowers 0.3 grams, walnut leaves 0.4 grams, English walnut leaves 0.4 grams, yarrow 0.4 grams, oak bark 0.2 grams, and dandelion 0.4 grams. In children aged 6-11 years, 15 drops 6 times daily for 5 days and then 15 drops 3 times daily for 5 days was used. In children aged 12-18 years, 25 drops 6 times daily for 10 days was used. (100347). Due to the small difference between the two groups and the open-label design, the clinical relevance of this study is unclear. Also, it is unclear if these benefits are due to horsetail, the other ingredients, or the combination.
• Urinary incontinence. Oral horsetail has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific supplement (Urox, Seipel Group) 840 mg, containing a combination of horsetail stem, three-leaf caper, and lindera root daily with food for 8 weeks modestly decreases urinary frequency, stress incontinence, and urgency incontinence when compared with placebo in patients with urinary incontinence and/or overactive bladder (97575). It is unclear if these effects are due to horsetail, the other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there is interest in using oral horsetail for UTIs, there is insufficient reliable information about the clinical effects of horsetail for this condition. More evidence is needed to rate horsetail for these uses.

(Read more about HORSETAIL)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there is interest in using oral L-cysteine for prevention of cancers of the upper gastrointestinal tract, there is insufficient reliable information about the clinical effects of L-cysteine for this purpose.
• Diabetes. Although there is interest in using oral L-cysteine for diabetes, there is insufficient reliable information about the clinical effects of L-cysteine for this condition.
• Erythropoietic protoporphyria (EPP). Although there is interest in using oral L-cysteine for EPP, there is insufficient reliable information about the clinical effects of L-cysteine for this condition.
• Hangover. Oral L-cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that an immediate release product (Catapult Cat L-cysteine vitamin tablet) providing L-cysteine 1200 mg in combination with other ingredients, taken six times between 7 pm and midnight in conjunction with alcohol 1.5 grams/kg over 3 hours, modestly reduces symptoms of hangover, including nausea, headache, stress, and anxiety, when compared with placebo. Each L-cysteine tablet also contained thiamine 50 mg, riboflavin 1.4 mg, niacin 16 mg, vitamin B6 1.4 mg, biotin 50 mcg, folic acid 200 mcg, vitamin B12 2.5 mcg, and vitamin C 80 mg (109709). Other researchers have questioned the validity of the statistical methods used in this study and suggest that not all of the noted outcomes were statistically significant (109716).
• Photoreactive keratectomy. It is unclear if oral L-cysteine is beneficial for promoting wound healing after photoreactive keratectomy. Details: Preliminary clinical research shows that taking L-cysteine 100 mg twice daily for 14 days starting one week before photoreactive keratectomy reduces complete corneal healing time by about 2 days when compared with taking placebo (109727).
• Venous leg ulcers. Topical L-cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that topical application of a cream containing L-cysteine 2 mg/gram, glycine 10 mg/gram, and D,L-threonine 1 mg/gram for 12 weeks modestly increases healing and decreases pain when compared with placebo. However, there was no difference in exudate, offensive smell, or granulation. The cream was used as part of a treatment regimen involving cleaning and bandaging, two to five days each week (10255).
• Smoking cessation. It is unclear if oral L-cysteine is beneficial for promoting smoking cessation. Details: Preliminary clinical research shows that use of a slow-release lozenge containing L-cysteine 3 mg (Acetiumlozenge; Biohit Oyj) with each cigarette for 6 months does not increase the odds of smoking cessation when compared with placebo (109714). However, this study may have been inadequately powered to detect a difference between groups. An adequately powered study by the same research group shows that using this lozenge increases the odds of smoking cessation by about 51% when compared with placebo (109710).
• Stroke. Although there is interest in using oral L-cysteine for stroke prevention, there is insufficient reliable information about the clinical effects of L-cysteine for this purpose. More evidence is needed to rate L-cysteine for these uses.

(Read more about L-CYSTEINE)

POSSIBLY EFFECTIVE

• Osteoarthritis. Most clinical research shows that MSM is modestly beneficial when used alone or in combination with other ingredients. Details: Clinical research shows that taking MSM 1.5-6 grams orally in two to three divided doses daily, either alone or in combination with glucosamine, can modestly improve joint function and some symptoms of osteoarthritis such as pain and swelling (12469,14335,17127,19312). However, MSM does not seem to reduce stiffness or total symptom score (14335). Also, some patients may not consider the modest benefit to be clinically significant (17127). Some clinical research has evaluated MSM in combination with other ingredients. One clinical study in adults with knee osteoarthritis shows that taking MSM 500 mg, glucosamine sulfate 1500 mg, and chondroitin sulfate 1200 mg daily for 12 weeks is associated with greater reductions in pain and osteoarthritis scores when compared with glucosamine sulfate and chondroitin sulfate alone (96447). Clinical studies using combination products containing MSM 5 grams daily and boswellic acid 7.2 mg daily with or without vitamin C (Lignisul, Triterpenol; Artosulfur C, Laborest Italia S.p.A), orally for 60 days show reductions in anti-inflammatory drug use, but conflicting results for pain reduction (19313,96446). Also, one small study suggests that taking a combination of MSM with collagen type II, cetyl myristoleate, lipase, vitamin C, turmeric, and bromelain (AR7 Joint Complex, Robinson Pharma) orally for 12 weeks improves scores for joint pain and tenderness, but does not improve X-rays of affected joints (19314).

POSSIBLY INEFFECTIVE

• Chronic venous insufficiency (CVI). Clinical research suggests that topical MSM is not beneficial in CVI. Details: Clinical research shows that topical application of MSM plus EDTA can reduce the circumference of the calf, ankle, and foot in patients with CVI. However, application of MSM alone appears to increase swelling in these patients (19315).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if oral MSM improves the appearance of aging skin to a clinically meaningful extent. Details: Preliminary clinical research shows that taking MSM (OptiMSM, Bergstrom Nutrition) 3 grams daily for 16 weeks improves facial wrinkles associated with aging by a moderate amount when compared with placebo. When compared with baseline, taking MSM 1 gram daily for 16 weeks is as effective as taking 3 grams for reducing fine lines and wrinkles and improving smoothness, radiance, firmness, and elasticity (102000).
• Allergic rhinitis (hay fever). It is unclear if oral MSM is beneficial in patients with allergic rhinitis. Details: Preliminary clinical research shows that taking MSM (OptiMSM 650 mg) 2600 mg orally for 30 days might relieve some symptoms of seasonal allergic rhinitis when compared with baseline (8574). However, this study lacked blinding and a control group, and also did not provide information on severity of symptoms (12000).
• Alzheimer disease. Although there is interest in using oral MSM for Alzheimer disease, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Androgenic alopecia. Although there is interest in using oral and topical MSM for androgenic alopecia, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Aromatase inhibitor-induced arthralgia. Oral MSM has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with estrogen receptor positive (ER+) breast cancer and aromatase inhibitor-induced arthralgia shows that taking a specific combination product (Opera, GAMFARMA s.r.l) containing MSM 200 mg, boswellia 40 mg, alpha-lipoic acid 240 mg, and bromelain 20 mg once daily for 6 months reduces arthralgia intensity when compared to baseline, with around 22% of patients having complete symptom resolution at the end of the study (109570). The validity of these findings is limited by a lack of control group.
• Asthma. Although there is interest in using oral MSM for asthma, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Athletic performance. It is unclear if topical MSM is beneficial for improving athletic performance. Details: A small clinical study in healthy, physically active adults shows that applying a specific cream containing magnesium and MSM (MagPro, Custom Prescription Shoppe) prior to stretching and pedaling on a stationary bicycle does not appear to improve flexibility or endurance when compared with a placebo cream (19317).
• Chemotherapy-induced peripheral neuropathy. Oral MSM has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with chemotherapy-induced peripheral neuropathy shows that taking a specific product (OPERA, GAMFARMA s.r.l.) containing MSM 200 mg, alpha-lipoic acid 240 mg, boswellia 40 mg, and bromelain 20 mg daily for 12 weeks reduces overall pain when compared with baseline (96449). The validity of these findings is limited by the lack of a placebo group. Additionally, it is not clear if benefit is associated with MSM, other ingredients, or the combination.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral MSM for CFS, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Chronic obstructive pulmonary disease (COPD). Although there is interest in using oral MSM for COPD, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Constipation. Although there is interest in using oral MSM for constipation, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Diabetes. Although there is interest in using oral MSM for diabetes, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Dyslipidemia. It is unclear if oral MSM is beneficial for dyslipidemia. Details: A very small clinical study in adults with overweight or obesity shows that taking a specific MSM product (OptiMSM, Bergstrom Nutrition) 3 grams daily for 16 weeks modestly increases high-density lipoprotein (HDL) cholesterol when compared with baseline, but not when compared with placebo. Taking MSM also did not improve total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, or triglycerides (110572). However, this study may have been underpowered to detect differences between groups.
• Dyspepsia. Although there is interest in using oral MSM for dyspepsia, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Exercise-induced muscle damage. It is unclear if oral MSM is beneficial for preventing exercise-induced muscle damage. Details: Clinical research shows that taking MSM 50 mg/kg in 200 mL water orally daily beginning 10 days prior to a 14-km run can attenuate the increase in creatine kinase (CK) and bilirubin levels caused by exercise-induced muscle damage (19320). However, other clinical research shows that taking MSM (OptiMSM, Bergstrom Nutrition) 3 grams daily beginning 3 weeks prior to a 13.1-mile run and continuing for 2 days after does not reduce muscle or joint pain or alter serum markers of oxidative stress or muscle damage when compared with placebo (96448).
• Hangover. Although there is interest in using oral MSM for hangover, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Hemorrhoids. Topical MSM has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying a specific gel containing MSM in combination with hyaluronic acid and tea tree oil (Proctoial, BSD Pharma) for 14 days improves symptoms of hemorrhoids, including pain during defecation, visible bleeding, and inflammation/irritation, when compared with placebo (19318). It is not clear if these effects are due to MSM, the other ingredients, or the combination.
• Insect bite. Although there is interest in using oral MSM for preventing insect bites, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Interstitial cystitis. Although there is interest in using oral MSM for interstitial cystitis, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Knee pain. It is unclear if oral MSM is beneficial for knee pain. Details: A moderate-sized clinical study in healthy adults with mild knee pain shows that taking MSM (OptiMSM, Bergstrom Nutrition) 1000 mg twice daily for 12 weeks modestly improves morning pain and pain while standing but does not benefit nocturnal or movement-associated pain, stiffness, or activities of daily living when compared with placebo (114751).
• Muscle cramps. Although there is interest in using oral MSM for muscle cramps, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Obesity. It is unclear if oral MSM is beneficial for obesity. Details: A very small clinical study in adults with overweight or obesity shows that taking a specific MSM product (OptiMSM, Bergstrom Nutrition) 3 grams daily for 16 weeks does not improve body weight, body mass index, waist circumference, or body composition when compared with placebo. (110572). However, this study may have been underpowered to detect differences between groups.
• Osteoporosis. Although there is interest in using oral MSM for osteoporosis, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Periodontitis. Although there is interest in using topical MSM for periodontitis, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Pneumonia. Although there is interest in using oral MSM for pneumonia, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Postoperative pain. Oral MSM has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients who have undergone arthroscopic rotator cuff repair shows that taking a specific combination product (Tenosan, Agave s.r.l.) containing MSM 550 mg, arginine alpha-ketoglutarate 500 mg, collagen peptides 300 mg, apple and grape polyphenols 125 mg, bromelain 40 mg, and vitamin C 60 mg for 3 months can reduce postoperative pain and slightly improve repair integrity (19322). However, improvement in overall functional outcomes was not observed.
• Rheumatoid arthritis (RA). Although there is interest in using oral and topical MSM for RA, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Rosacea. Oral MSM has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with rosacea shows that topical application of a cream containing silymarin and MSM twice daily for one month improves skin redness, papules, itching, hydration, and skin color when compared to baseline (19319). The validity of these findings is limited by the lack of a comparator group.
• Scleroderma. Although there is interest in using oral and topical MSM for scleroderma, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Stretch marks (striae gravidarum). Although there is interest in using topical MSM for stretch marks, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Systemic lupus erythematosus (SLE). Although there is interest in using oral MSM for SLE, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Temporomandibular disorders (TMD). Although there is interest in using oral MSM for TMD, there is insufficient reliable information about the clinical effects of MSM for this condition.
• Tendinopathy. Oral MSM has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with Achilles tendinopathy shows that taking two sachets orally daily of a specific combination product (Tenosan, Agave s.r.l.) each containing MSM 550 mg, arginine alpha-ketoglutarate 500 mg, collagen peptides 300 mg, apple and grape polyphenols (Vinitrox) 125 mg, bromelain 50 mg, and vitamin C 60 mg for 60 days might improve the outcomes of extracorporeal shock wave therapy (ESWT) (19321). However, it is unclear if any benefit is due to MSM, other ingredients, or the combination.
• Wound healing. Although there is interest in using topical MSM for wound healing, there is insufficient reliable information about the clinical effects of MSM for this condition. More evidence is needed to rate MSM for these uses.

(Read more about METHYLSULFONYLMETHANE (MSM))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). Although there has been interest in using oral Monterey pine for preventing CVD, there is insufficient reliable information about the clinical effects of Monterey pine for this condition.
• Cognitive function. It is unclear if oral Monterey pine bark extract improves cognition. Details: Preliminary clinical research shows that taking vitamin C 120 mg daily along with a specific product containing Monterey pine bark extract (Enzogenol, ENZO Nutraceuticals) 960 mg daily for 5 weeks improves response speed related to working memory tasks and immediate recognition tasks in middle-aged and elderly males when compared with baseline. Improvements in memory do not appear to occur with vitamin C alone (63620).
• Migraine headache. Although there has been interest in using oral Monterey pine for preventing migraine headache, there is insufficient reliable information about the clinical effects of Monterey pine for this condition.
• Neurological trauma. It is unclear if oral Monterey pine bark extract is beneficial in patients with neurological trauma. Details: A small clinical study in patients 3-12 months post-traumatic brain injury shows that taking a specific Monterey pine bark extract (Enzogenol, ENZO Nutraceuticals) 1000 mg daily for 12 weeks improves cognitive function scores when compared with placebo. However, measures of working memory, episodic memory, anxiety, and depression were not improved (105777). Another small clinical study in college students suffering from chronic concussion symptoms shows that taking a specific Monterey pine bark extract (Enzogenol, ENZO Nutraceuticals) 1000 mg daily for 6 weeks improves mental fatigue when compared with placebo (105779). More evidence is needed to rate Monterey pine for these uses.

(Read more about MONTEREY PINE)

LIKELY SAFE ...when used orally in amounts found in foods (6).

POSSIBLY SAFE ...when black seed oil is used orally at doses of up to 5 mL or 5 grams daily for up to 12 weeks (36071,94486,96927,96929,98815,101550,102062,110269,110276). ...when a specific black seed oil formulation containing 5% thymoquinone (BlaQmax) is used in doses of 200 mg daily for 90 days (110264). ...when black seed powder is used orally at doses of up to 2 grams daily for up to 12 months (36239,36244,94478,94479,94485,96928,102061,110268,110271) or 3 grams daily for 3 months (114880). ...when used topically and appropriately, short-term. There is some clinical evidence that black seed oil can be safely applied as an oil 2 times daily for up to 6 months or 3 times daily for up to 1 month (95981,98814,102064,110262), as a 30% gel twice daily for approximately 2 months (94483), or as a 10% solution in a patch to oral lesions 3 times daily for 4 weeks (114815).

CHILDREN: POSSIBLY SAFE
when black seed oil is used orally at doses of 40-80 mg/kg daily for 2-19 months in children ages 4-17 years old (36071,95984). However, the higher dose of 80 mg/kg daily has been associated with increased adverse effects such as gastrointestinal complaints when taken on an empty stomach (36071).

PREGNANCY: LIKELY UNSAFE
when used orally in amounts exceeding those found in food. Black seed may decrease or inhibit uterine contractions (241) and may have contraceptive activity (242).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about BLACK SEED)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Collagen peptides have been used with apparent safety at doses up to 10 grams daily for up to 6 months and in doses up to 40 grams daily for up to 4 weeks (97632,97635,101615,101621,104638,104643,104644,104647,101622,110667). PREGNANCY &

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about COLLAGEN PEPTIDES)

LIKELY SAFE ...when glucosamine sulfate is used orally and appropriately. Glucosamine sulfate has been used safely in multiple clinical trials at a dose of 1000-1500 mg daily for 4 weeks to 3 years (2604,7026,8942,11340,12461)(14305,16717,89558,89567,94380,94382,95785).

POSSIBLY SAFE ...when glucosamine hydrochloride is used orally and appropriately. Glucosamine hydrochloride has been used with apparent safety at a dose of 1400-1600 mg daily for up to 2 years (4237,13579,14809,18344,42477,89516,89519,95784). Glucosamine hydrochloride 2 grams daily has also been used with apparent safety for up to 3 weeks (103281). ...when N-acetyl glucosamine is used orally and appropriately. N-acetyl glucosamine 100 mg daily has been used with apparent safety for up to 24 weeks (95795). ...when N-acetyl glucosamine is applied topically and appropriately. A 2% N-acetyl glucosamine cream has been safely used for up to 10 weeks (92721). ...when N-acetyl glucosamine is used rectally and appropriately. N-acetyl glucosamine 3-4 grams daily in 2 divided doses has been safely used (10234). ...when glucosamine sulfate is used intramuscularly and appropriately, short-term. Intramuscular glucosamine sulfate seems to be well tolerated when given twice weekly for up to 6 weeks (2605).

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

(Read more about GLUCOSAMINE)

POSSIBLY SAFE ...when used topically and appropriately. Gotu kola has been used safely in a cream or ointment for up to 10 weeks (11072,11073,67372,102792,105329,105335). An emulsion containing gotu kola extract 3% and other ingredients has been applied safely to the skin twice daily for up to 60 days (111571). ...when used orally and appropriately. Gotu kola extract has been used with apparent safety in doses of up to 180 mg daily for up to 12 months or 1000 mg daily for 60 days. Dried gotu kola has been used with apparent safety in doses of up to 2200 mg daily for 4 weeks (6887,11062,11063,11064,11065,11066,11067,11068,11069,11070)(11071,99756,99757,99758,105329,105332,105333). A specific gotu kola extract (Centellicum, Horphag Research Ltd) 450-675 mg daily has been used with apparent safety for up to 6 weeks (99756,99757).

PREGNANCY: POSSIBLY SAFE
when used topically and appropriately (11073,13559). There is insufficient reliable information available about the safety gotu kola when used orally during pregnancy; avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about GOTU KOLA)

POSSIBLY UNSAFE ...when horsetail products containing thiaminase are used orally, long-term. Thiaminase is an enzyme that destroys thiamine, which could theoretically lead to thiamine deficiency. In Canada, horsetail products are required to be thiaminase-free (105301).

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

(Read more about HORSETAIL)

LIKELY SAFE ...when used orally in amounts found in foods. There is insufficient reliable information available about the safety of L-cysteine when used orally in amounts greater than those found in foods or when used topically.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods. There is insufficient reliable information available about the safety of amounts greater than those found in foods; avoid use. Some research suggests that taking L-cysteine during lactation increases levels of free L-cysteine in breastmilk. However, these levels are lower than those found in some commercial hydrolyzed protein infant formulas (109718).

(Read more about L-CYSTEINE)

POSSIBLY SAFE ...when used orally and appropriately, short term. MSM in doses of 1.5-6 grams daily or 50 mg/kg daily has been used safely in studies lasting up to 6 months (8574,12469,14335,17127,19312,96446,96448,102555). One specific product (OptiMSM, Bergstrom Nutrition) is Generally Recognized As Safe (GRAS) by the United States Food and Drug Administration (FDA) (102555). ...when used topically. Topical cream containing MSM and silymarin, as well as topical gel containing MSM, hyaluronic acid, and tea tree oil, have been used with apparent safety for up to 20 days (19318,19319).

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

(Read more about METHYLSULFONYLMETHANE (MSM))

POSSIBLY SAFE ...when used orally and appropriately, short-term. A specific product containing Monterey pine bark extract (Enzogenol, ENZO Nutraceuticals) has been used with apparent safety at a dose of 1000 mg daily for up to 12 weeks (63614,63618,63620,105777) or 480 mg daily for up to 6 months (105778). There is insufficient reliable information available about the safety of Monterey pine when used topically.

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

(Read more about MONTEREY PINE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research suggests that black seed extract can inhibit platelet aggregation and clotting, and increase bleeding time (36029,36049,36100,108701). In addition, decreased platelet counts have occurred in a human case report and in animal research (104665).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking black seed with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some clinical research (36262,94479,94485,101552,102062,110269,110276) and numerous animal studies (36037,36086,36150,36155,36214,110270) suggest that black seed, especially its constituent thymoquinone, can have hypoglycemic effects.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking black seed with antihypertensive drugs might increase the risk of hypotension.  Details Clinical research suggests that black seed powder and oil might reduce blood pressure by 2-3 mmHg (16437,94489). In animal research, black seed modestly reduces blood pressure and concomitant use of black seed and amlodipine (Norvasc) or metoprolol (Lopressor) increased the blood pressure lowering effects of these drugs (101559,108703).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed may increase the risk of bleeding if used with clopidogrel.  Details Animal research shows that taking black seed extract daily for 2 weeks prior to a single dose of clopidogrel increases maximum concentrations of clopidogrel by approximately 31% and modestly decreases oral clearance. Furthermore, bleeding time was increased by 12% (108701). This has not been shown in humans.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with drugs that have sedative properties may cause additive effects.  Details Animal research suggests that black seed may have CNS depressant effects (36064).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically taking black seed might reduce the levels and clinical effects of cyclosporine.  Details In animal research, black seed extract decreased the maximal levels of cyclosporine in the blood by 35.5% (94474). This has not been shown in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed might increase levels of drugs metabolized by CYP2C9.  Details In vitro research suggests that thymoquinone, a constituent of black seed, can decrease the metabolism of phenytoin by a mechanism possibly related to the inhibition of CYP2C9 (110281). The effect of black seed on CYP2C9 is unclear. This has not been shown in humans.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking black seed with diuretic drugs might increase potassium loss and the risk of hypokalemia.  Details Black seed extract has shown diuretic effects in animals, which could theoretically increase potassium loss (36026). This has not been shown in humans.

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed might interfere with immunosuppressive therapy.  Details Animal and in vitro studies suggest that black seed might stimulate immune function (36086,36137,36161). However, other animal studies suggest that black seed may suppress immune function (36085,36142).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed might increase or decrease levels and effects of phenytoin.  Details In vitro research suggests that thymoquinone, a constituent of black seed, can decrease the metabolism of phenytoin (110281). This effect may be due to inhibition of cytochrome P450 2C9 (CYP2C9). However, animal research shows that black seed decreases the maximum concentration of and total systemic exposure to phenytoin by 57% and 87%, respectively. This seems to be related to increased clearance and steady state volume of distribution (110905). This interaction has not been shown in humans.

PREDNISOLONE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically black seed might reduce plasma levels and therapeutic effects of prednisolone.  Details In animal research, oral administration of a single dose of black seed oil 15 minutes prior to oral prednisolone decreases the prednisolone maximum plasma concentration by 65% and area under the curve by 25%(114811). This has not been shown in humans.

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining serotonergic drugs with black seed might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders.  Details Animal research suggests that black seed can increase brain serotonin levels (36180,94488). In one case report, a 35-year-old man undergoing endoscopic surgery experienced immediate postoperative serotonin syndrome that was likely associated with the use of black seed oil 600 mg daily starting 4 days before surgery, and precipitated by the use of serotonergic pain medications, including fentanyl and oxycodone (101558). Monitor patients for signs of serotonin syndrome and other serotonergic side effects if using black seed with serotonergic drugs.

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed might reduce plasma levels and the therapeutic effects of sildenafil.  Details Animal research shows that black seed reduces the total systemic exposure to sildenafil by 43% (110898). So far, this interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black seed might increase levels of warfarin and increase the risk of bleeding.  Details In vitro research suggests that thymoquinone, a constituent of black seed, can decrease the metabolism of warfarin (110280). This effect may be due to inhibition of cytochrome P450 2C9 (CYP2C9). The effect of black seed on warfarin metabolism is unclear. This has not been shown in humans.

(Read more about BLACK SEED)

(Read more about COLLAGEN PEPTIDES)

ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acetaminophen might interfere with the activity of glucosamine sulfate by interacting with the sulfate portion.  Details Anecdotal reports suggest that adding glucosamine to an acetaminophen regimen might decrease pain control in patients with osteoarthritis (14806). Some research suggests that the sulfate portion of glucosamine sulfate might contribute to its effect in osteoarthritis. Since acetaminophen metabolism requires sulfur and reduces serum sulfate concentrations, acetaminophen could theoretically interfere with the action of glucosamine sulfate. Conversely, the administration of sulfate could theoretically decrease the effectiveness of acetaminophen in sulfate-deficient people by increasing its clearance (10313).

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Despite initial concerns, it is unlikely that glucosamine will interfere with the effects of antidiabetes drugs.  Details In vitro and animal research has suggested that glucosamine might increase insulin resistance or decrease insulin production (371,372,3406,18342,18343). This has raised concerns that taking glucosamine might worsen diabetes and decrease the effectiveness of diabetes drugs. However, clinical research suggests that glucosamine does not have adverse effects on blood glucose or glycated hemoglobin (HbA1C) in healthy, obese, or type 2 diabetes patients (7026,7075,8942,10311,10317,15111).

TOPOISOMERASE II INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically glucosamine may induce resistance to topoisomerase II inhibitors.  Details In vitro research suggests that glucosamine might induce resistance to etoposide (VP16, VePesid) and doxorubicin (Adriamycin) by reducing inhibition of topoisomerase II, an enzyme required for DNA replication in tumor cells (7639). This effect has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Glucosamine might increase the anticoagulant effects of warfarin and increase the risk of bruising and bleeding.  Details In two individual case reports, glucosamine/chondroitin combinations were associated with a significant increase in international normalized ratio (INR) in patients previously stabilized on warfarin (11389,16130). In one case, the increase in INR occurred only after tripling the dose of a glucosamine/chondroitin supplement from 500 mg/400 mg daily to 1500/1200 mg daily (16130). Additionally, 20 voluntary case reports to the U.S. Food & Drug Administration (FDA) have linked glucosamine plus chondroitin with increased INR, bruising, and bleeding in patients who were also taking warfarin (16130). There have also been 20 additional case reports to the World Health Organization (WHO) that link glucosamine alone to increased INR in patients taking warfarin (16131). The mechanism of this interaction is unclear. Glucosamine is a small component of heparin, but is not thought to have anticoagulant activity; however, animal research suggests that it might have antiplatelet activity (16131).

(Read more about GLUCOSAMINE)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gotu kola might increase the sedative effects of CNS depressants.  Details In vitro research suggests that gotu kola may have sedative effects via binding of GABA receptors (6887,11071).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gotu kola with hepatotoxic drugs might have additive adverse effects.  Details There are at least four case reports of hepatotoxicity associated with the use of gotu kola. However, more information is needed to determine if gotu kola was the causative factor in these cases (13182,92506).

(Read more about GOTU KOLA)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking horsetail with antidiabetes drugs might increase the risk of hypoglycemia.  Details Equisetum myriochaetum has demonstrated hypoglycemic activity in clinical research (13576). In an animal diabetic model, Equisetum giganteum had hypoglycemic effects (105300). It is unclear whether other horsetail species have hypoglycemic effects.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking horsetail with diuretic drugs might increase potassium loss and the risk of hypokalemia.  Details Laboratory research shows that various species of horsetail have diuretic properties (13574,13575). Due to its diuretic effects, there has been concern that taking horsetail along with potassium-depleting diuretics might increase the risk for hypokalemia. However, pharmacokinetic research in humans shows that taking horsetail 900 mg daily for 4 days does not affect urinary excretion of electrolytes, including potassium and sodium, despite having a diuretic effect similar to taking hydrochlorothiazide 25 mg daily (92288). It is unclear if taking horsetail for a longer duration would affect electrolyte levels. Until more is known, use with caution.

EFAVIRENZ (SUSTIVA) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, horsetail might decrease the levels and clinical effects of efavirenz.  Details In two case reports, patients were found to have detectable viral loads when taking horsetail-containing supplements along with an antiretroviral regimen that included efavirenz. In one case, the antiretroviral regimen included zidovudine, lamivudine, and efavirenz; in the other case, the regimen consisted of emtricitabine, tenofovir disoproxil fumarate, and efavirenz. One month after discontinuing horsetail, the viral loads became undetectable in both cases. The exact mechanism of this interaction is unknown (97573). It is also unclear if this interaction is specific to efavirenz or if it is related to various components of antiretroviral therapy.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, horsetail might increase the levels and adverse effects of lithium.  Details Animal research suggests that horsetail has diuretic properties (13574). Theoretically, due to these potential diuretic effects, horsetail might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, horsetail might decrease the levels and clinical effects of NRTIs.  Details In two case reports, patients were found to have detectable viral loads when taking horsetail-containing supplements along with an antiretroviral therapy. In one case, the antiretroviral regimen included zidovudine, lamivudine, and efavirenz; in the other case, the regimen consisted of emtricitabine, tenofovir disoproxil fumarate, and efavirenz. One month after discontinuing the supplement, the viral loads became undetectable in both cases. The exact mechanism of these interactions is unknown (97573). It is also unclear if these interactions are specific to NRTIs or if they are related to various components of antiretroviral therapy.

(Read more about HORSETAIL)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking L-cysteine supplements with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research suggests that L-cysteine can have hypoglycemic effects (109722).

(Read more about L-CYSTEINE)

(Read more about METHYLSULFONYLMETHANE (MSM))

(Read more about MONTEREY PINE)

General ...Orally and topically, black seed seems to be well tolerated.
Most Common Adverse Effects:
Orally: Constipation, gastric burning or discomfort, nausea, and vomiting.

Dermatologic ...Orally, black seed can cause itching, but this adverse effect is rare (94481). It has also been reported to cause bullous drug eruption and maculopapular eruption (94480,100324). Topically, black seed and its oil have been reported to cause allergic contact dermatitis (36053,36296,36297,100324). Rarely, topical use of the oil has been reported to cause a rash related to drug reaction with eosinophilia and systemic symptoms (DRESS) (110277).

Gastrointestinal ...In a clinical trial, unspecified gastrointestinal complaints occurred in 20% of patients taking black seed oil orally (36071). Gastrointestinal complaints occurred rarely in another clinical trial; however, one patient in this study was hospitalized for nausea and vomiting thought to be associated with black seed oil (110267). Gastrointestinal adverse effects to black seed have included constipation (36180), burning sensation (94487), epigastric discomfort (94479), vomiting (94491), or mild nausea (94481,94489,94491,96927,96929). Gastrointestinal adverse effects to a specific black seed oil formulation containing 5% thymoquinone (BlaQmax) have included mild cases of bloating, burping and mild diarrhea (110264).

Genitourinary ...Orally, relatively severe menstrual bleeding has occurred in one clinical trial (104661).

Hepatic ...While intake of black seed has been associated with hepatotoxicity in some animal research, other animal research has not confirmed this finding (245,95982). One case report describes hepatotoxicity, kidney injury, and rhabdomyolysis occurring in an otherwise healthy 26-year-old male after taking black seed oil 1000 mg twice daily for 1 month. The patient was hospitalized for critical care management, including hemodialysis. After 52 days in the hospital, the patient had recovered and was discharged (114812).

Immunologic ...Orally, black seed has been reported to cause bullous drug eruption and maculopapular eruption (94480,100324). Topically, black seed and its oil can cause allergic contact dermatitis (6,36053,36296,36297,100324,110266). One case of bullous drug eruption with skin detachment has been reported for a 54-year-old woman who used black seed oil orally. The eruptions resolved following treatment with clobetasol propionate 0.05%. Although this patient showed a positive skin prick test for undiluted black seed oil, the tests were negative when the oil was diluted to 10% and 1% (94480). A 28-year-old woman developed a rash following topical use of black seed oil. She was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), including enlarged lymph nodes, and required systemic corticosteroid treatment. This diagnosis was confirmed six months later following confirmation with a patch test (110277). In another case report, a 58-year-old woman developed eczematous lesions on the lower and upper eyelids after topical application of an oil containing black seed. This reaction was followed by the development of a diffuse maculopapular eruption after taking two oral capsules containing black seed oil. It is theorized that the topical application of black seed oil led to systemic sensitization prior to the use of oral black seed in this patient (100324).

Renal ...Orally, black seed might cause renal dysfunction. A case of acute renal failure thought to be related to use of black seed tablets 2-2.5 grams daily has been reported for a 62 year-old patient with diabetes (94477). Additionally, a case of acute kidney injury, rhabdomyolysis, and hepatotoxicity has been reported in an otherwise healthy 26-year-old male after taking black seed oil 1000 mg twice daily for 1 month. The patient was hospitalized for critical care management, including hemodialysis. . After 52 days in the hospital, the patient had recovered and was discharged (114812).

(Read more about BLACK SEED)

General ...Orally, collagen peptides seem to be well tolerated.

Dermatologic ...Orally, a case of a mild skin rash has been reported for a patient who used a specific collagen peptide-containing product (BioCell Collagen) (28680).

Gastrointestinal ...Orally, collagen peptides may cause nausea, dyspepsia, diarrhea, and flatulence, but these adverse effects are rare (101622,104639).

(Read more about COLLAGEN PEPTIDES)

General ...Orally, all forms of glucosamine seem to be well tolerated. Topically and rectally, N-acetyl glucosamine also seems to be well tolerated. Intramuscularly, glucosamine sulfate seems to be well tolerated. However, a thorough evaluation of safety outcomes has not been conducted for non-oral routes of administration.
Most Common Adverse Effects:
Orally: Bloating, constipation, cramps, diarrhea, heartburn, nausea.
Serious Adverse Effects (Rare):
Orally: There have been rare reports of severe allergic reactions and hepatotoxicity.

Cardiovascular ...One case of mesenteric occlusion in a clinical trial was considered possibly related to use of oral glucosamine hydrochloride and chondroitin sulfate (89520).
Some observational research has found that glucosamine use in patients with osteoarthritis is associated with a higher risk of cardiovascular disease (CVD) events when compared with non-use (109642). However, glucosamine users tended to be older, have multiple comorbidities, and be on antihyperlipidemic or antiplatelet therapy. Furthermore, other observational research in healthy adults has found that glucosamine use is associated with a reduced risk of fatal and non-fatal CVD events (99682). Higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and CVD risk.

Dermatologic ...Orally, glucosamine might cause skin reactions, including itching, rash, and erythema (2608,20084,89567,110628,113636). Also, fingernail and toenail toughening, with an increased rate of growth, has been reported (89572). Topically, N-acetyl glucosamine 2% with niacinamide 4% cream might cause rare skin reactions (92721). Photosensitization that was reproducible with re-challenge was reported in a case report of an individual using glucosamine (form unknown) and chondroitin (10408).

Endocrine ...Orally, glucosamine does not seem to impact blood glucose. Preliminary research and anecdotal reports have found that various forms of glucosamine might increase insulin resistance or decrease insulin production, increasing fasting plasma glucose levels (22,371,372,1203,3406,5059,7637,14810). This has raised concerns that taking glucosamine sulfate might worsen diabetes and decrease the effectiveness of diabetes drugs. However, clinical research suggests that various forms of glucosamine do not have adverse effects on blood glucose or glycated hemoglobin (HbA1C) in healthy, obese, patients with type 2 diabetes or impaired glucose tolerance (7026,7075,7638,8942,10311,10317,12107,14808,15111,89563).

Gastrointestinal ...Orally, glucosamine has been associated with gastrointestinal problems, including epigastric and abdominal pain, cramps, heartburn, diarrhea, nausea, dyspepsia, vomiting, constipation, and flatulence (1520,2608,16717,20084,20104,20105,89561,89562,89567,89568)(108897,110628,111647,113636). In older persons, use of glucosamine sulfate is associated with oral dryness (89564). In a clinical trial, a case of Helicobacter pylori gastritis was considered probably related to the use of glucosamine hydrochloride (89516).

Hepatic ...Although relatively uncommon, combinations of glucosamine and chondroitin sulfate have been associated with acute liver injury that mimics autoimmune hepatitis. Of 151 patients at an outpatient clinic for liver diseases, 23 acknowledged use of products containing glucosamine (form unspecified) and/or chondroitin. However, only 2 cases had an apparent relationship between transaminase elevation and the use of recommended doses of glucosamine and chondroitin sulfate. Aminotransferase levels, which were increased by four- to seven-fold, returned to normal following discontinuation of treatment (89515). In another case, a 65-year-old male presented to the hospital with signs and symptoms of drug-induced autoimmune hepatitis. The patient had used Condrosulf, containing chondroitin sulfate, for two years, followed by Vita Mobility Complex, containing chondroitin sulfate and glucosamine sulfate, for 8 weeks. The patient required maintenance treatment with azathioprine to remain in remission (89518). A case of acute cholestatic hepatitis due to Glucosamine Forte, which contains glucosamine hydrochloride, chondroitin sulfate, Devil's claw, and shark cartilage, has been reported (89522). It is unclear whether these adverse events were related to glucosamine, other ingredients, or the combination.

Immunologic ...There is some concern that glucosamine products might cause allergic reactions in sensitive individuals. One review of glucosamine-related adverse events in Australia found that 72% of all reports involved hypersensitivity reactions. Of these reactions, 35% were mild, including pruritis, urticaria, and lip edema, 49% were moderate, including dyspnea, and 16% were severe, including gait disturbance, somnolence, and hypotension. Anaphylaxis was reported in 1.5% of cases (102115). Also, in one clinical trial, a single patient developed allergic dermatitis considered to be likely due to glucosamine hydrochloride (89516). Glucosamine is derived from the exoskeletons of shrimp, lobster, and crabs. However, it is unclear if these adverse reactions were due to a shellfish sensitivity or general atopy. Additionally, shellfish allergies are caused by IgE antibodies to antigens in the meat of shellfish, not to antigens in the exoskeleton. Regardless, it is possible that some glucosamine products might be contaminated by this allergen during production (102115).

Neurologic/CNS ...Orally, glucosamine has been reported to cause drowsiness and headache (2608,89561,113636). Glucosamine plus chondroitin combination products that also contain manganese (e.g., CosaminDS) should always be taken according to product directions. When taken at doses slightly higher than the recommended dose, these products can sometimes supply greater than the tolerable upper limit (UL) for manganese which is 11 mg/day. Ingestion of more than 11 mg/day of manganese might cause significant central nervous system toxicity (7135).

Ocular/Otic ...In older persons, use of glucosamine sulfate has been associated with ocular dryness (89564). Increased intraocular pressure has occurred with glucosamine sulfate supplementation (89573,112460). Data from the FDA MedWatch adverse event reporting system shows that 0.21% of subjects taking glucosamine reported glaucoma, which is significantly greater than the 0.08% of subjects who reported glaucoma while using any other drug (112460).

Pulmonary/Respiratory ...Cases of asthma exacerbations associated with the use of glucosamine (form unknown)-chondroitin products have been reported (10002).

Renal ...Anecdotal reports have associated glucosamine with nephrotoxicity signals such as modestly elevated creatine phosphokinase and 1+ to 2+ proteinuria, but changes in kidney function have not been reported in long-term studies (7026,8942,10408,10409). It was also noted that effects may have been due to other concurrent medications or impurities in glucosamine-chondroitin products. Cases of acute interstitial nephritis induced by glucosamine (form unknown) have also been reported (89523).

Other ...There has been concern that glucosamine might increase the risk of metabolic disturbances resulting in increased cholesterol levels and blood pressure. However, glucosamine does not appear to increase the risk of these adverse effects. Taking glucosamine sulfate for up to 3 years does not significantly increase blood glucose or lipid levels, or cause any other disturbances in metabolism (7026,7075,8942,10311,10317).

(Read more about GLUCOSAMINE)

General ...Orally and topically, gotu kola seems to be well tolerated.
Most Common Adverse Effects:
Orally: Gastric irritation and nausea.
Topically: Eczema.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity.

Dermatologic ...Topically, gotu kola may cause eczema (10277,10278). Also, gotu kola can cause allergic contact dermatitis, characterized by erythema, itching, papules, and a burning sensation (4,6887,9789,52875,52887,52896,52902). One specific gotu kola product (Blasteostimulina,Almirall, S. A.) has been reported to cause allergic contact dermatitis. However, not all patients with reactions to this product are sensitive to gotu kola; some patients are sensitive to neomycin, another ingredient in the product (52875). Madecassol ointment (Rona Laboratories Limited) is another gotu kola product that has resulted in allergic contact dermatitis. Controlled testing suggests that this product can cause this adverse effect in about 8% of patients (9789). Centellase cream has also caused allergic contact dermatitis in at least two cases (52887,52888).

Gastrointestinal ...In some patients, gotu kola can extract cause gastrointestinal upset and nausea (780,6887,52894).

Hepatic ...There is concern that gotu kola may cause liver toxicity in some patients. There are at least four case reports of hepatotoxicity associated with gotu kola; however, hepatotoxic contaminants cannot be ruled out, as laboratory analysis was not conducted on the products used. Additionally, the doses of gotu kola used in these cases were not reported (13182,92506). In a clinical trial where liver function was monitored, taking gotu kola 120 mg daily for 6 months was not associated with changes in liver function (11065).
In one case of hepatotoxicity, a 61-year-old female developed elevated liver transaminase and total bilirubin levels after taking gotu kola tablets for 30 days. Liver biopsy showed granulomatous acute hepatitis. Months later, the patient took gotu kola again and developed elevated liver transaminases after 2 weeks. In another case, a 52-year-old female developed symptoms of hepatitis and increased liver transaminases after taking gotu kola for 3 weeks. Biopsy indicated chronic hepatitis and granulomas, areas of necrosis, and cirrhotic transformation. Liver function normalized after discontinuation of gotu kola. In a third case, a 49-year-old female developed symptoms of hepatitis after taking gotu kola for 2 months. Biopsy revealed granulomatous hepatitis. Liver function normalized after discontinuation of gotu kola (13182). In a fourth case, a 15-year-old female taking an unknown dose of gotu kola and lymecycline for 6 weeks for acne experienced acute liver failure with abdominal pain and vomiting, as well as elevated liver transaminases, bilirubin, international normalized ratio (INR), and prothrombin. Liver function returned to normal after both products were discontinued (92506).

Immunologic ...Topically, gotu kola can cause allergic contact dermatitis, characterized by erythema, itching, papules, and a burning sensation (4,6887,9789,52875,52887,52896,52902). One specific gotu kola product (Blasteostimulina, Almirall, S. A.) has been reported to cause allergic contact dermatitis in some patients. However, not all patients who react to this product are sensitive to gotu kola; some are sensitive to neomycin, another ingredient in the product (52875). Madecassol ointment (Rona Laboratories Limited) is another gotu kola product that has resulted in allergic contact dermatitis. Controlled testing suggests that this product can cause this adverse effect in about 8% of patients (9789). Centellase cream has also caused allergic contact dermatitis in at least two cases (52887,52888).

Psychiatric ...A case of night eating syndrome has been reported for a 41-year-old female who had been taking a gotu kola tincture (dose not specified) for 2 years. Symptoms resolved after gotu kola use was discontinued (52878).

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General ...There is limited clinical research evaluating the safety of horsetail.
Most Common Adverse Effects:
Orally: Abdominal distension, increased bowel movements, and nausea.

Dermatologic ...In one case report, a patient developed seborrheic dermatitis after topical application of horsetail, requiring treatment with local epinephrine and oral antihistamines. The nicotine component of horsetail was determined to be the likely cause of this reaction (13563).

Gastrointestinal ...Orally, horsetail has been associated with mild gastrointestinal side effects including abdominal distension, increased frequency of bowel movements, and nausea (55576). Orally, chronic consumption of horsetail infusion has been associated with acute pancreatitis. In a case report, a 56-year-old female presenting with recurrent mild acute pancreatitis every 6-7 months, previously thought to be drug-induced, discontinued ingesting horsetail infusions. The patient had a history of bilateral adrenal gland removal and was being treated for hypertension, dyslipidemia, and hormone replacement, and then self-medicated with horsetail infusions. After discontinuing horsetail infusions, there were no further recurrences of pancreatitis during a 14-month follow-up (97574).

Hepatic ...In one case report, a patient with asymptomatic hepatitis B developed symptomatic liver failure following consumption of boiled horsetail juice 500 mL daily for 2 weeks. Liver enzymes returned to normal following discontinuation of the juice (92291). It is not known if the horsetail juice was contaminated or mixed with other ingredients.

Immunologic ...Horsetail has been associated with cross-allergenicity with carrots (13577).

Renal ...There are at least 4 case reports of hyponatremia thought to be at least partially associated with horsetail consumption. In one case report, an elderly patient who had taken oral horsetail 15 mg daily for 10 years presented with hyponatremia and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to reduced oral intake and nausea for the previous 2 days. Horsetail was thought to be a contributing factor. The patient's symptoms resolved after 5 days of treatment with oral sodium chloride and fluid restriction (108851).

Other ...Crude horsetail contains thiaminase, which can cause thiamine deficiency with prolonged consumption. Canadian Equisetum arvense products are required to be certified as free from thiaminase-like activity (55579,105301). In one case report, the development of autism in a child exposed to both horsetail and alcohol during pregnancy was thought to be caused by thiamine deficiency attributed to this combination (92292). However, it is not known if other genetic or environmental factors were involved in the development of this condition in utero.

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General ...Orally, L-cysteine is well tolerated in amounts found in foods. When used in higher doses or when applied topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

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General ...Orally, MSM is generally well tolerated.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, gastrointestinal discomfort, nausea.

Dermatologic ...In rare cases, MSM has caused pruritus when taken orally (8574).

Gastrointestinal ...Orally, MSM may cause mild gastrointestinal discomfort, nausea, bloating, and diarrhea (8574,12469).

Immunologic ...Orally, MSM may increase allergy symptoms (8574).

Neurologic/CNS ...Orally, MSM may cause headache, fatigue, insomnia, and difficulty concentrating (8574,14335).

Ocular/Otic ...In a case report, a 35-year-old female presented with bilateral acute angle closure glaucoma, which resolved 4 days after discontinuing a multi-ingredient product. Although the product contained over 35 vitamins, minerals, and other ingredients, only MSM contained sulfur, which the authors suggest acted like a sulfa-drug to cause acute angle closure glaucoma (90613).

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General ...Orally, Monterey pine seems to be well tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

Dermatologic ...Contact dermatitis from Monterey pine sawdust has been reported (63615).

Immunologic ...Monterey pine pollen may cause seasonal rhinoconjunctivitis (63612).

(Read more about MONTEREY PINE)