Flex by New Earth

POSSIBLY EFFECTIVE

• Hypertension. Oral blue-green algae seem to modestly reduce blood pressure in patients with hypertension. Details: Some small clinical studies show that blue-green algae can decrease blood pressure in patients with hypertension (97206,99654). A meta-analysis of five small clinical trials in patients with hypertension, type 2 diabetes, or chronic pain shows that taking spirulina blue-green algae 1-8 grams daily for up to 12 weeks reduces systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure (DBP) by 7 mmHg when compared with placebo. The effect size was larger in patients with hypertension and in those treated for at least 12 weeks (109964). Another small clinical study shows that taking spirulina blue-green algae (A. maxima) 4.5 grams daily for 6 weeks decreases blood pressure in adults with hypertension, with the number of subjects fulfilling the criteria for hypertension decreasing from 45% to 14% when compared to baseline (18297). A more recent clinical study in patients with hypertension shows that consuming a salad dressing containing 2 grams spirulina blue-green algae daily for 8 weeks reduces SBP by around 6 mmHg and DBP by around 4 mmHg when compared to baseline. While overall reduction in blood pressure with spirulina dressing was larger when compared with patients consuming a control dressing, the study groups were heterogenous at baseline, limiting the validity of any statistical comparisons between groups (109965).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if oral blue-green algae are beneficial in allergic rhinitis. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. platensis) 2 grams daily for 6 months, improves self-rated scores for sneezing, nasal discharge, nasal congestion, and itching when compared with placebo in adults with allergic rhinitis (18300).
• Antiretroviral-induced insulin resistance. It is unclear if oral blue-green algae are beneficial for insulin resistance due to antiretrovirals. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. platensis) 19 grams daily for 2 months increases insulin sensitivity by about 225% when compared to baseline in patients with antiretroviral-induced insulin resistance (75944). The validity of this finding is limited by the lack of a comparator group.
• Anxiety. Although there has been interest in using oral blue-green algae for anxiety, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Arsenic poisoning. It is unclear if oral blue-green algae are beneficial for chronic arsenic toxicity. Details: Preliminary clinical research in people living in areas of Bangladesh with high arsenic levels in drinking water shows that taking a combination of an alcoholic extract of spirulina blue-green algae 250 mg and zinc 2 mg orally twice daily for 16 weeks, in addition to use of filtered drinking water, increases urinary arsenic excretion, reduces hair arsenic levels, and improves skin manifestations of chronic arsenic toxicity when compared with placebo plus filtered water (18301).
• Athletic performance. Most research suggests that oral blue-green algae are not beneficial for improving athletic performance; however, the available studies are small. Details: AAlthough some research disagrees, most small or preliminary clinical trials show that taking spirulina blue-green algae does not improve athletic performance in trained or untrained adults. One study shows that, when compared with placebo, taking spirulina blue-green algae (Hawaiian Spirulina, Cyanotech Corporation) 3 grams daily for up to 8 weeks has no effect on exercise output during a 30-minute elliptical trainer workout in active males (97203). In elite rugby players, taking spirulina blue-green algae (Algae Green Value) 5.7 grams daily for 7 weeks does not improve jump or sprint performance or body composition when compared to placebo (104567). In healthy untrained males, a small study shows that taking spirulina blue green algae 6 grams daily for 7 days does not increase the time to fatigue related to arm cycling following a 30-minute submaximal exercise bout (104566). In male recreational runners, spirulina blue-green algae (A. platensis) 2 grams three times daily for 4 weeks was not associated with any change in exercise intensity during a 2-hour treadmill jogging period. However, sprinting time to exhaustion following the 2-hour jog increased from 2.05 minutes to 2.7 minutes (18306). Also, a study of athletes and non-athletes shows that taking spirulina blue-green algae (Parry Nutraceuticals) 2 grams daily for 8 weeks has a small effect on isometric muscle strength, but not muscle endurance, when compared with placebo (104568).
• Attention deficit-hyperactivity disorder (ADHD). Oral blue-green algae have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking 3 mL of a specific combination of spirulina blue-green algae, peony, ashwagandha, gotu kola, bacopa, and lemon balm (Nurture and Clarity, Tree of Healing-LD) diluted in 50-60 mL of water three times daily for 4 months improves ADHD scores when compared with placebo in previously untreated children aged 6-12 years (19272). It is unclear if this effect is due to blue-green algae, other ingredients, or the combination.
• Beta-thalassemia. It is unclear if oral blue-green algae are beneficial in beta-thalassemia. Details: In children with beta-thalassemia, preliminary clinical research shows that taking spirulina blue-green algae (GNC Natural Brand Spirulina, General Nutrition Corporation) 250 mg/kg daily, up to a maximum dose of 4 grams daily, for 3 months reduces the percentage of children requiring blood transfusion during an interval of less than 2 weeks from 66% to 40%. There were also improvements in red blood cell count and levels of hemoglobin, ferritin, and liver function enzymes (104569). However, the validity of these findings is limited by the lack of a comparator group.
• Blepharospasm. It is unclear if oral blue-green algae are beneficial when used in conjunction with botulinum toxin injections. Details: Preliminary clinical research shows that taking a specific product containing the blue-green algae species Aphanizomenon flos-aquae (Super Blue-Green Algae, Cell Tech) 1500 mg per day orally for 6 months in addition to botulinum toxin-A injections does not reduce eyelid spasms when compared with botulinum toxin-A alone in people with essential blepharospasm or Meige syndrome (14842).
• Cancer. Although there has been interest in using oral blue-green algae for cancer, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral blue-green algae for CVD, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Cognitive Impairment. It is unclear if oral blue-green algae are effective for improving cognitive impairment. Details: A small clinical study in patients aged 60 or older with mild cognitive impairment shows that taking blue-green algae extract 1 gram 3 times daily for 12 weeks slightly improves some components of cognitive function testing related to visual learning, memory, and vocabulary when compared with placebo (112001). However, the validity of these findings is limited by lack of adjustment for multiple comparisons, which may explain the discrepant results with the other components of the cognitive function tests.
• Depression. Although there has been interest in using oral blue-green algae for depression, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Diabetes. It is unclear if oral blue-green algae are beneficial in diabetes. Details: A meta-analysis of seven small clinical studies in patients with type 2 diabetes shows that taking spirulina blue-green algae 0.8-14 grams daily for 6-12 weeks reduces fasting blood glucose and improves total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, but does not affect low-density lipoprotein (LDL) cholesterol, when compared with placebo. There was no reduction in glycated hemoglobin (HbA1c); however, all but two of the studies lasted less than 12 weeks, limiting the validity of the findings related to HbA1c (109970).
• Dyslipidemia. It is unclear if oral blue-green algae are beneficial in dyslipidemia. Details: Several clinical studies in patients with normal or elevated cholesterol levels show that doses of spirulina blue-green algae (A. platensis, A. maxima, A. fusiformis) ranging from 1-10 grams daily for 1-6 months may reduce total cholesterol by 8% to 27%, low-density lipoprotein (LDL) cholesterol by 10% to 65%, and triglycerides by 0% to 23%; and increase high-density lipoprotein (HDL) cholesterol by 0% to 66% (18297,18298,18299,91705,91708,91710,91717,102689). However, the validity of these studies is limited by methodological weaknesses and heterogeneous population characteristics. A meta-analysis of 23 small studies, several of which were in patients with type 2 diabetes or obesity, shows that taking blue-green algae 0.8-10 grams for 4 to 24 weeks modestly improves levels of LDL, HDL, triglycerides, and total cholesterol when compared with placebo or no treatment (112004). The interpretation of these findings is limited by the high heterogeneity of the included studies which enrolled patients of varying health status and employed various study designs.
• Dyspepsia. Although there has been interest in using oral blue-green algae for dyspepsia, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Exercise-induced muscle soreness. It is unclear if oral blue-green algae are effective for the prevention of exercise-induced muscle soreness. Details: A small clinical study in recreationally trained males shows that taking spirulina blue-green algae 2 grams three times daily does not reduce delayed onset muscle soreness after eccentric exercise when compared with placebo (109967).
• Hepatitis C. Evidence for the use of oral blue-green algae in hepatitis C is conflicting. Details: One clinical study in adults with chronic hepatitis C who are unresponsive to interferon treatment shows that taking spirulina blue-green algae (A. platensis) 500 mg orally three times daily for 6 months is associated with greater improvements in alanine aminotransferase (ALT) levels than taking silymarin 140 mg three times daily. Complete virological response rates were 13% with blue-green algae and 3% with silymarin, although this difference was not statistically significant (63247). However, in another study in people with chronic hepatitis B or C, liver function enzyme levels worsened after one month of treatment with oral spirulina blue-green algae (18304).
• HIV/AIDS. It is unclear if oral blue-green algae are beneficial for people with HIV/AIDS who do not have access to antiretrovirals. Details: One clinical study in adults with untreated HIV shows that taking spirulina blue-green algae (A. platensis) powder 5-10 grams daily for 3-6 months does not affect CD4 counts, viral load, or weight gain in patients with HIV (75927,91707). However, in one study, the incidence of opportunistic infections, respiratory disease, gastrointestinal symptoms, and fatigue was 43% for patients taking spirulina blue-green algae, compared to 70% for patients taking placebo (91707).
• Iron deficiency anemia. Although there has been interest in using oral blue-green algae for iron deficiency anemia, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Lichen planus. It is unclear if oral blue-green algae are beneficial in patients with oral lichen planus. Details: A small clinical study in patients with oral lichen planus shows that taking spirulina blue-green algae 500 mg twice daily for 8 weeks along with application of triamcinolone acetonide 0.1% oral paste three times daily for 1 week reduces pain and lesion size when compared with only triamcinolone acetonide three times daily for 8 weeks (109963).
• Malnutrition. Evidence for the use of oral blue-green algae in malnutrition is conflicting. Details: Some clinical research in severely undernourished children shows that adding spirulina blue-green algae (A. platensis) 5 grams orally twice daily for 8 weeks to a traditional diet results in an average daily weight gain of 25 grams, compared with only 15 grams for those given the traditional diet alone. Similarly, giving blue-green algae 10 grams twice daily for 8 weeks in addition to a misola diet (millet, soy, peanut kernel, sugar, and salt) results in an average daily weight gain of 34 grams, compared with only 20 grams for children given the misola diet alone (18308). However, a small clinical study in malnourished children aged 3 months to 3 years shows that giving spirulina blue-green algae 5 grams daily for 3 months in addition to a traditional diet fails to increase weight gain more than the traditional diet alone (18309). Similarly, a moderate-size crossover study in preschool-aged children in Cambodia shows that taking blue-green algae 2 grams 5 times a week during the first hour of school for 8 weeks does not improve weight gain or height but may reduce the proportion of children with anemia when compared with placebo (112002). The interpretation of these findings is limited by the high rate of patients lost to follow-up and the lack of statistical adjustment for confounding factors, such as parasitism and home diet.
• Memory. Although there has been interest in using oral blue-green algae for memory, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Menopausal symptoms. It is unclear if oral blue-green algae are beneficial for improving symptoms of menopause. Details: A preliminary clinical study shows that taking a product containing the blue-green algae species Aphanizomenon flos-aquae (Klamin, Nutrigea) 1.6 grams daily for 8 weeks reduces anxiety and depression when compared with placebo in menopausal adults aged 50-60 years. The treatment has no effect on vasomotor symptoms or hormone levels (18310).
• Mental alertness. It is unclear if oral blue-green algae are beneficial for reducing mental fatigue. Details: A preliminary clinical study shows that taking spirulina blue-green algae (Hawaiian Spirulina, Cyanotech Corporation) 3 grams daily for up to 8 weeks improves performance on a mathematical based mental fatigue test in healthy men when compared with placebo. Subjective improvement in mental alertness over placebo was also reported (97203).
• Metabolic syndrome. It is unclear if oral blue-green algae are beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking spirulina blue-green algae (Spirulysat, AlgoSource), providing phycocyanin 20 mg, daily for 12 weeks improves triglyceride levels, but does not reduce body mass index, waist circumference, blood pressure, glycemic indices, or other lipid levels, when compared with placebo (109971).
• Nonalcoholic fatty liver disease (NAFLD). Although there has been interest in using oral blue-green algae for NAFLD, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Obesity. Evidence for the use of blue-green algae in obesity is conflicting. Details: Small, low-quality clinical trials have shown mixed results in people with obesity (18295,91717,97205,99655,99703,102688). When results are analyzed together, there is evidence of a very small benefit for both body weight and plasma lipid levels. Two meta-analyses show that taking spirulina blue-green algae may increase weight loss by up to 1.85 kg when compared with placebo (102690,104565). A greater effect is seen in patients with obesity when compared with overweight patients. In addition, there is a small effect on fat loss (102690). However, there is evidence from two studies lasting longer than 12 weeks that taking blue-green algae may slightly increase BMI (104565). A meta-analysis of small clinical trials also shows that taking spirulina blue-green algae reduces fasting blood sugar and total cholesterol levels by a small amount when compared with placebo, but has no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels, in patients with obesity (102689). When combined with an exercise program, taking spirulina blue-green algae increases weight loss by 1.4 kg and improves exercise tolerance and total, LDL, and high-density lipoprotein (HDL) cholesterol levels when compared with exercise alone (99655,102688). Doses have included a specific product containing the spirulina blue-green algae species A. fusiformis (Multinal, New Ambadi Estate Pvt. Ltd.) 1 gram twice daily or four times daily for 3 months (91717) or spirulina blue-green algae 2 grams daily for 3 months, or 4.5 grams daily for 6 weeks, alone or in combination with exercise (97205,99655,102688).
• Oral leukoplakia. It is unclear if oral blue-green algae are beneficial for oral leukoplakia in tobacco chewers. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. fusiformis) orally 1 gram daily for 12 months produces regression of precancerous oral leukoplakia lesions in 45% of tobacco chewers, compared to only 7% of those receiving placebo. Regression rates appear to be highest in those with homogeneous lesions and lowest in those with ulcerated or nodular lesions (15782).
• Periodontitis. It is unclear if injecting blue-green algae into periodontal pockets is beneficial in periodontitis. Details: Preliminary clinical research shows that injecting a 4% w/v gel prepared from spirulina blue-green algae into periodontal pockets of adults with chronic periodontitis, after scaling and root planing, is associated with a decrease in probing pocket depth of 1.57 mm after 120 days, compared with only 0.84 mm in patients receiving scaling and root planing alone (91709).
• Premenstrual syndrome (PMS). Although there has been interest in using oral blue-green algae for PMS, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Stress. Although there has been interest in using oral blue-green algae for stress, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
• Ulcerative colitis. It is unclear if oral blue-green algae are beneficial in patients with ulcerative colitis. Details: A small clinical study in patients with ulcerative colitis shows that taking spirulina blue-green algae 500 mg twice daily for 8 weeks improves quality of life scores and reduces stress and sleep disturbances when compared with placebo. However, there was no effect on most measures of sleep quality, mood, and fatigue (109969).
• Wound healing. Although there has been interest in using oral blue-green algae for wound healing, there is insufficient reliable information about the clinical effects of blue-green algae for this condition. More evidence is needed to rate blue-green algae for these uses.

(Read more about BLUE-GREEN ALGAE)

POSSIBLY EFFECTIVE

• Osteoarthritis. Oral Boswellia serrata extracts, taken alone or in combination with other ingredients, appear to reduce pain and improve function in knee osteoarthritis. However, most clinical studies have been small and methodologically flawed. Details: A meta-analysis of small, randomized, controlled trials in patients with knee osteoarthritis shows that taking Boswellia serrata extract 100-250 mg daily for 1-3 months moderately reduces pain and improves function when compared with placebo (103785). However, the validity of the included studies is limited by incomplete reporting, inadequate blinding, and other methodological issues. Studies included in the meta-analysis tested a specific Boswellia serrata extract (5-Loxin), as well as a specific Boswellia serrata gum resin extract (ApresFLEX, also known as Aflapin). Pain reduction was first noted within 7 days of treatment (17948,17949,21145). More recent evidence on the use of a Boswellia serrata gum resin extract (Aflapin) 100 mg daily for 30 days is consistent with the findings in this meta-analysis (109564). Lower quality studies, not included in the meta-analysis, tested another specific Boswellia serrata gum resin extract (Wokvel, Pharmanza). When taken in a dose of 333 mg three times daily for 2-6 months, this product improves pain and knee function when compared with control. Wokvel seems to have comparable benefit to a solid lipid Boswellia serrata particle product (Wokvida) (12432,21146,103784). Finally, another clinical trial not included in the meta-analysis shows that taking a different Boswellia serrata extract (Boswellin, Sabinsa Corp.) 169 mg twice daily for 4 months also moderately improves pain, stiffness, functional ability, and quality of life when compared with placebo (100699). Several studies also show that taking specific combination products containing Boswellia serrata and other ingredients can improve pain and functionality in patients with osteoarthritis. These products have combined Boswellia serrata 100 mg with ashwagandha 450 mg, turmeric 50 mg, and zinc complex 50 mg (Articulin-F) three times daily for 3 months (19276); Boswellia serrata 100 mg with ginger 33.33 mg, Tinospora cordifolia 73.33 mg, and Indian gooseberry 166.66 mg three times daily for 6 months (89557); a specific Boswellia serrata extract (BosPure, Arjuna Natural Extracts Ltd) 300 mg with turmeric extract (BCM 95, Arjuna Natural Extracts Ltd) 700 mg daily for 12 weeks (89719); boswellic acid 7.2 mg (from Boswellia serrata) with methylsulfonylmethane 5 grams and vitamin C daily for 2 months (96446); and a specific combination product (Tregocel, Max Biocare) providing Boswellia serrata extract 1 gram, curcumin 100 mg, devil's claw tuber 1 gram, celery seed 1 gram, and ginger rhizome 330 mg daily for 36 weeks (106078). However, research in patients with osteoarthritis of the hand suggests that taking a combination of Boswellia serrata extract 250 mg, pine bark extract 100 mg, methylsulfonylmethane 1500 mg, and curcumin 168 mg daily for 12 weeks does not improve pain or functionality (109563).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there is interest in using oral Boswellia serrata for hay fever, there is insufficient reliable information about the clinical effects of Boswellia serrata for this condition.
• Alzheimer disease. It is unclear if oral Boswellia serrata improves cognitive function in patients with Alzheimer disease. Details: A small clinical study in adults with mild to moderate Alzheimer disease shows that taking a specific Boswellia serrata extract (K-Vie, Kondor Pharma) 1200 mg daily for 6 months improves neuropsychiatric symptoms, dementia severity, and some but not all measures of cognitive function when compared with placebo (112807).
• Aromatase inhibitor-induced arthralgia. Oral Boswellia serrata 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 Srl) containing Boswellia serrata 40 mg, alpha-lipoic acid 240 mg, methylsulfonylmethane 200 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. It is unclear if oral Boswellia serrata can improve symptoms of asthma. Details: One small preliminary clinical study in patients with asthma suggests that taking a specific Boswellia serrata gum resin (S-compound, Rahul Pharma) 300 mg three times daily for 6 weeks may improve symptoms of asthma, such as forced expiratory volume (FEV), the number of asthma attacks, and dyspnea and rhonchi, in 70% of patients, compared to only 27% of patients in a control group (1708).
• Brain tumor. It is unclear if oral Boswellia serrata improves outcomes in patients with brain tumors. Details: One small clinical study in adults with brain tumors undergoing radiation therapy shows that taking an H15 Boswellia serrata extract 4200 mg in three divided doses daily throughout radiotherapy reduces cerebral edema and tumor volume, but not dexamethasone dosage, when compared with placebo (21149).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Rectal Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Two small, open-label clinical studies in males with prostatitis-like symptoms or CP/CPPS types IIIa or IIIb shows that rectal administration of a specific suppository containing Boswellia serrata resin extract and propolis polyphenols (MICTALASE) once daily for 20 days or once daily for 15 days per month for 3 months improves pain, urinary symptoms, quality of life, and total symptom scores, as measured by the Chronic Prostatitis Symptom Index (CPSI), when compared to baseline. However, there were no improvements in scores on the International Index of Erectile Dysfunction (IIED), and studies showed mixed findings regarding improvements on the International Prostate Symptoms Score (IPSS) (102091,109566). The validity of these results is limited by the lack of a comparator group.
• Cluster headache. Although there is interest in using oral Boswellia serrata for cluster headache, there is insufficient reliable information about the clinical effects of Boswellia serrata for this condition.
• Coronavirus disease 2019 (COVID-19). Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults hospitalized with moderate COVID-19 infection in Egypt shows that taking Boswellia serrata extract 300 mg and licorice extract 300 mg twice daily for 14 days, along with conventional therapy, reduces the risk of death, shortens the time to hospital discharge by around 5.5 days, and reduces the rate of mechanical ventilation when compared with placebo. For every five patients treated with this combination product, one additional patient survived. The standard treatments administered in this study included azithromycin, vitamin C, and zinc (108579). Another large clinical study in adults hospitalized with moderate COVID-19 infection in India shows that taking a specific product containing Boswellia serrata, ashwagandha, ginger, and turmeric (Artovid-20, Bioved Pharmaceuticals, Inc) 1,776 mg twice daily after meals for 14 days, starting within 48-96 hours of symptom onset along with conventional therapy, decreases the duration of illness by about 1 day and reduces patient-assessed severity scores of various symptoms (e.g. nasal congestion, sore throat, cough, taste and smell disorders) when compared with placebo. Almost all patients in this study also received steroids, and over 50% received remdesivir. Study results were similar in the subgroup of patients who received remdesivir (109899). However, the validity of this study is limited by use of data only from patients who fully adhered to the study protocol per protocol analysis and exclusion of patients with risks for progression to severe COVID-19, including uncontrolled hypertension, asthma, chronic obstructive pulmonary disease, diabetes, obesity, or immunocompromise.
• Crohn disease. It is unclear if oral Boswellia serrata reduces relapse rates in patients with Crohn disease. Details: One small clinical study in patients with Crohn disease who are in remission shows that taking Boswellia serrata (Boswelan, Pharmasan) 800 mg orally three times daily for one year does not decrease relapse rates or improve quality of life when compared with placebo (17241).
• Diabetes. It is unclear if oral Boswellia serrata improves glycemic control in patients with diabetes. Details: A small clinical study in patients with diabetes who are taking metformin shows that taking powdered Boswellia serrata gum resin 400 mg twice daily after meals for 12 weeks modestly decreases fasting blood glucose, glycated hemoglobin (HbA1c), insulin, and lipid levels when compared with a toasted powder placebo (91378). In contrast, another small clinical study in patients with diabetes shows that taking capsules containing powdered Boswellia serrata gum 250 mg (standardized for 60% boswellic acids) twice daily after meals for 8 weeks does not improve fasting blood glucose, HbA1c, other glycemic parameters, or lipid levels when compared with placebo (105010). However, the interpretation of these findings, specifically the lack of improvement in HbA1c, may be limited by the short duration of the study. A meta-analysis pooling the results of the two trials described above shows that Boswellia serrata reduces HbA1c by about 0.5% and fasting blood glucose by about 24 mg/dL, with no improvement in lipid levels, when compared with placebo (111503).
• Diarrhea. It is unclear if oral Boswellia serrata is beneficial in patients with acute diarrhea. Details: A small clinical study in adults with acute diarrhea shows that taking a specific lecithin-based delivery form of Boswellia serrata extract (Casperome, Indena S.p.A.) 250 mg twice daily for 5 days decreases the time to diarrhea resolution by nearly 1.4 days, reduces stool frequency, and improves symptoms of abdominal pain and nausea when compared with placebo (109568).
• Dysmenorrhea. Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with moderately painful dysmenorrhea shows that taking a single dose of a combination product containing Boswellia serrata, turmeric, and sesame (Rhuleave-K, Arjuna Natural Private Ltd.) 1000 mg at the start of menstruation relieves menstrual cramp pain and reduces pain intensity for up to 6 hours when compared with placebo (112806). It is unclear if these effects are due to Boswellia serrata, other ingredients, or the combination.
• Exercise-induced muscle soreness. Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy active adults with moderate to severe exercise-induced muscle pain shows that taking a single, 1000-mg dose of Boswellia serrata and turmeric extracts in black sesame oil (Rhuleave-K; Arjuna Natural Private Ltd.) improves pain relief when compared with placebo, with maximal benefits within about 3 hours. The number of people needed to treat to obtain pain relief of at least 50% over a 6-hour period was 1.1 (109277).
• Irritable bowel syndrome (IBS). Small clinical studies suggest that an oral Boswellia serrata extract may improve symptoms of IBS. Details: A small clinical study in patients with mild IBS shows that taking a specific lecithin-based delivery form of Boswellia serrata extract (Casperome, Indena S.p.A.) 250 mg daily for 6 months reduces abdominal pain, cramps, and gas when compared with standard management with hyoscine butylbromide or papaverine hydrochloride plus belladonna extract 10 mg. Patients receiving Casperome required fewer rescue medications and had a 46% lower risk of needing additional medical care, including hospitalization (100713). In a short-term clinical trial of the same Boswellia serrata extract 250 mg daily for 4 weeks, the risk for requiring additional medical care was reduced by 67% when compared with the same standard treatment options above. While IBS symptoms improved over baseline, significant differences between Casperome and standard treatment options were lacking (102089). These studies were funded by the supplement manufacturer, which may limit the reliability of these findings.
• Knee pain. It is unclear if oral Boswellia serrata is beneficial for knee pain. Details: A small clinical study in otherwise healthy adults with knee pain shows that taking Boswellia serrata extract 12.5% tablets twice daily for 8 weeks improves physical function and pain but not stiffness, functional mobility, muscle function, or level of physical activity when compared to baseline (112808).
• Menorrhagia. It is unclear if oral Boswellia serrata is beneficial for menorrhagia. Details: A small clinical study in otherwise healthy adults with menorrhagia shows that taking Boswellia serrata oleoresin powder 300 mg three times daily for 7 days, repeated over 2 menstrual cycles, improves quality of life and modestly reduces the average duration of menstrual bleeding after the second cycle when compared with placebo. All patients were permitted to use ibuprofen 200 mg as needed (105401).
• Microscopic colitis. There is limited evidence on the oral use of Boswellia serrata in patients with collagenous colitis. Details: One small clinical trial shows that taking Boswellia serrata extract 400 mg three times daily for 6 weeks increases the clinical remission rate by 64% when compared with placebo in patients diagnosed with a type of microscopic colitis called collagenous colitis. Clinical remission was defined as having an average of three or fewer soft or solid stools daily during the last week of the study (21152).
• Pain (acute). Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with acute musculoskeletal pain shows that taking a specific combination product containing Boswellia serrata and turmeric extracts in black sesame oil (Rhuleave-K; Arjuna Natural Private Ltd.) 1000 mg daily for 7 days is as effective as acetaminophen 1000 mg daily for pain relief, onset of pain relief, and onset of maximal pain relief (109287). This study is limited by its lack of blinding and placebo control. Additionally, the dose of acetaminophen used in this study is below the standard recommended daily dose.
• Rheumatoid arthritis (RA). Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical trial in patients with RA shows that taking two capsules of a specific product containing Boswellia serrata 100 mg, ashwagandha 450 mg, turmeric 50 mg, and zinc complex 50 mg (Articulin-F) three times daily for 3 months improves pain, morning stiffness, grip strength, and disability scores when compared with placebo (21154). However, another clinical trial in patients with RA shows that taking two tablets of a standardized extract formulation (RA-1) containing Boswellia serrata, ashwagandha, ginger, and turmeric three times daily for 16 weeks does not improve most symptoms when compared with placebo (21155).It is unclear if these findings are due to Boswellia serrata, other ingredients, or the combination.
• Rhinosinusitis. Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking a combination product containing Boswellia serrata, black currant, bromelain, and vitamin D (Flogostop Forte, Humana Italia) with inhaled corticosteroids daily for 30 days reduces rhinorrhea, hyperemia of mucosa, and local inflammation when compared with inhaled corticosteroids alone (111501). It is unclear if these findings are due to Boswellia serrata, other ingredients, or the combination. Pharyngitis. Although there is interest in using oral Boswellia serrata for pharyngitis, there is insufficient reliable information about the clinical effects of Boswellia serrata for this condition.
• Stroke. It is unclear if oral boswellic acids improve neurological function after stroke. Details: One small clinical study in adults with recent ischemic stroke who are taking aspirin and clopidogrel shows that taking boswellic acids 800 mg three times daily for 30 days improves neurological function, as measured using the National Institutes of Health Stroke Scale, when compared with placebo (102092).
• Traumatic brain injury (TBI). It is unclear if oral Boswellia serrata is effective for reducing disability, or improving cognitive function or memory in adults recovering from TBIs. Details: A small clinical crossover study in adults admitted to the hospital for diffuse axonal injury shows that taking powdered Boswellia serrata oleogum resin 360 mg three times daily for 6 weeks does not improve disability when compared with placebo (91379). However, another small clinical study in patients suffering from a TBI 3 months to 3 years earlier shows that taking a specific Boswellia serrata extract (K-Vie, Kondor Pharma) 400 mg three times daily for 3 months improves performance on cognitive function tests, including those assessing processing speed, memory, and overall cognitive function, when compared with placebo (109567). A moderate-size clinical study in adults with memory dysfunction due to a recent mild traumatic brain injury in Iran shows that taking a specific product containing Boswellia serrata 360 mg and ginger 36 mg (Memoral, Goldarou) three times daily for 1 month modestly improves practitioner-assessed memory function scores when compared with placebo (110132). However, it is unclear if this effect is due to Boswellia serrata, ginger, or the combination.
• Ulcerative colitis. Small clinical studies suggest that oral Boswellia serrata extracts may improve symptoms of ulcerative colitis. Details: Two very small clinical trials in patients with active ulcerative colitis suggest that taking Boswellia serrata gum resin 300-350 mg three times daily for 6 weeks improves symptoms and disease markers comparably to taking sulfasalazine 1 gram three times daily (1709,12438). These findings are limited because the sample size may have been inadequate to assess differences between groups. In patients with ulcerative colitis in remission, one observational study has found that taking a specific lecithin-based delivery form of Boswellia serrata extract (Casperome, Indena S.p.A.) 250 mg daily for 4 weeks is associated with a reduction in abdominal pain, cramps, and malaise, a decrease in the need for additional medications, and a 58% lower risk for requiring additional medical care when compared with no treatment. Additionally, weekly episodes of bloody diarrhea, bowel movements, and watery stools were reduced when compared with baseline (102090).
• Urinary incontinence. Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in postmenopausal adults with urinary incontinence shows that taking a 3 tablets of a multi-ingredient herbal product containing Boswellia serrata 100 mg and five other herbs twice daily for 4 weeks reduces urinary incontinence frequency and leakage amount when compared with placebo, with improvements similar to those reported with solifenacin as standard therapy (111502). It is unclear if these effects are due to Boswellia serrata, other ingredients, or the combination.
• Urinary tract infections (UTIs). Oral Boswellia serrata has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with an uncomplicated UTI has found that taking two tablets of a specific combination product (Acidif plus) containing Boswellia serrata gummy dry extract 100 mg, L-methionine 400 mg, and hibiscus 100 mg daily for 7 days is associated with reduced UTI symptoms and reduced bacteriuria when compared with taking an unreported dose of fosfomycin for 2 days (103783). The validity of this study is limited by its observational nature and a lack of information on the severity of UTI at baseline. Also, it is unclear if these effects are due to Boswellia serrata, other ingredients, or the combination. More evidence is needed to rate Boswellia serrata for these uses.

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POSSIBLY EFFECTIVE

• Cataracts. Chondroitin sulfate in combination with sodium hyaluronate is approved as a medical device to be ophthalmically injected during cataract surgery. It is unknown if other routes of administration are beneficial. Details: Injecting ophthalmic viscosurgical devices (OVDs) containing a combination of chondroitin sulfate and sodium hyaluronate into the eye protects the corneal endothelium during small-incision cataract surgery. Various medical devices containing chondroitin sulfate and sodium hyaluronate (Viscoat, Alcon Laboratories) have been granted approval by US Food and Drug Administration (FDA) for use as an adjunct to cataract surgery (89436,89437). However, OVDs that cannot be easily removed after surgery can cause intraocular pressure (IOP) spikes and reduced visual acuity. A meta-analysis of small clinical studies shows that using a specific chondroitin sulfate 4% and sodium hyaluronate 3% solution (Viscoat, Alcon Laboratories) after small-incision cataract surgery increases IOP at postoperative days 1 and 2, but not at any later postoperative days for up to 1 month (104452).
• Osteoarthritis. Chondroitin sulfate seems to modestly reduce osteoarthritis pain and improve function. Pharmaceutical-grade chondroitin sulfate products have shown the most benefit. Details: Meta-analyses of randomized controlled trials in patients with mostly knee osteoarthritis show that taking chondroitin sulfate 800-2000 mg in single or divided doses daily for at least 3 months modestly reduces pain and disability when compared with placebo. However, included studies were heterogeneous and most had high attrition bias. A sub-group analysis of high-quality studies shows that 16 patients need to take chondroitin sulfate for 6 months for one patient to experience at least a 20% reduction in pain (94381,95792,99685,104446). When compared with conventional treatments like diclofenac 50 mg three times daily, chondroitin sulfate improves symptoms more slowly; however, the improvement seems to persist for up to 3 months after treatment cessation (322). Chondroitin also seems to have disease-modifying benefits. Clinical research in patients with osteoarthritis of the knee or hip shows that taking chondroitin sulfate 800 mg daily or more for 2 years might modestly reduce joint degeneration and narrowing when compared with placebo or celecoxib (42348,42398,94381,95516). Overall, most of the positive research involved pharmaceutical-grade chondroitin sulfate products, which are available as prescription products in some countries, such as Chondrosulf (IBSA Institut Biochimique SA) (17732,42348,42398,42536,89596,94360,104446), Chondrosan (Bioibérica, S.A.) (42463,42513), and Structum (Laboratoires Pierre Fabre) (22212,42520,89593). One clinical study shows that taking a pharmaceutical-grade chondroitin product (Chondrosulf) 800 mg daily seems to be comparable to taking celecoxib 200 mg daily for reducing pain and improving knee function (94360). Pharmaceutical-grade chondroitin products might demonstrate greater benefit due to higher quality (94360,102116). It is also important to note that most clinical studies using pharmaceutical-grade products are manufacturer-funded (94381). Furthermore, they may not be readily available for purchase in the US. Experts have conflicting stances on the use of chondroitin for osteoarthritis. The American College of Rheumatology (ACR) strongly recommends against the use of chondroitin for any form of osteoarthritis (102114). Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade chondroitin products. Additionally, the ESCEO provides a weak recommendation against the use of chondroitin in combination with glucosamine (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. Chondroitin is often used in combination with glucosamine and/or other products. Long-term studies in patients with osteoarthritis show that taking non-branded chondroitin sulfate with glucosamine sulfate modestly reduces joint-space narrowing when compared with control (89558,94380,95792). However, meta-analyses and individual clinical studies assessing non-branded preparations of chondroitin sulfate with glucosamine hydrochloride or glucosamine sulfate do not show reduced pain in patients with knee osteoarthritis when compared with control (13579,89558,95788,99683,99685). In contrast, pain reduction was reported for branded formulations such as chondroitin sulfate with glucosamine hydrochloride and manganese ascorbate (Cosamin DS, Nutramax Laboratories) (4237,7169); chondroitin sulfate with glucosamine hydrochloride (Droglican, Bioiberica, S.A.) (89516); or chondroitin sulfate with collagen peptides and hyaluronic acid (BioCell Collagen, BioCell Technology, LLC) (28678,28680). 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 are from 16-24 weeks (111647). It is unclear if the benefit seen with these specific products is due to bias introduced by industry funding or due to higher quality. Limited research has also evaluated INTRAMUSCULAR and TOPICAL chondroitin. Some clinical research shows that receiving daily intramuscular injections of chondroitin sulfate for 6 months improves pain and function in patients with osteoarthritis (42396,42397). A topical preparation of chondroitin sulfate in combination with glucosamine sulfate, shark cartilage, and camphor also seems to reduce arthritis symptoms. However, any symptom relief is most likely due to the counterirritant effect of camphor and not the other ingredients (10327). There is no research showing that chondroitin is absorbed topically.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with aging skin shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing chondroitin sulfate 200 mg, collagen peptides 600 mg, and hyaluronic acid 100 mg daily for 12 weeks reduces lines and wrinkles by about 13% when compared with baseline (28681). The validity of these findings is limited by the lack of a comparator group. It is also unclear if these improvements are due to chondroitin sulfate, other ingredients, or the combination. Furthermore, it should be noted that this study was funded by the product manufacturer.
• Aromatase inhibitor-induced arthralgia. Oral chondroitin sulfate has only been evaluated in combination with glucosamine sulfate; its effect when used alone is unclear. Details: A small open-label clinical study in postmenopausal females with early stage breast cancer 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 and symptoms associated with aromatase inhibitor-induced arthralgias when compared to baseline (89561). The validity of this finding is limited by the lack of a control group.
• Cancer. Some low-quality observational studies suggest that oral chondroitin use is not associated with a lower risk of cancer. Details: A meta-analysis of observational research has found that use of chondroitin with or without glucosamine is not associated with a lower risk of cancer when compared with no use (110625).
• Colorectal adenoma. Oral chondroitin has only been evaluated in combination with glucosamine; its effect when used alone is unclear. Details: An observational study in older adults has found that taking oral chondroitin and glucosamine is associated with a 26% reduced chance of high-risk adenoma and 10% reduced chance of conventional adenoma when compared with not using these supplements. This benefit was not seen in a subgroup of younger females (104444).
• Dry eye. It is unclear if ophthalmic chondroitin sulfate improves dry eye symptoms. Details: A small clinical study in patients with dry eye suggests that administering an ophthalmic preparation of chondroitin sulfate every two hours while awake for 2 weeks seems to improve symptoms when compared to baseline (1974). Chondroitin has also been used in combination with other ingredients. A large clinical trial in patients with mild to moderate dry eye disease shows that applying preservative-free eye drops containing chondroitin sulfate with sodium hyaluronate (Humylub Ofteno PF, Laboratorios Sophia), one drop into each eye four times daily for 90 days, seems to be no different for improving dry eye severity when compared with using polyethylene/propylene glycol eye drops (Systane Ultra, Alcon Laboratories) (104443). Another small clinical trial in patients with mild to moderate dry eye shows that using specific eye drops containing chondroitin sulfate and xanthan gum (PRO-148, Laboratorios Sophia) four times daily for 60 days does not improve tear stability, but might improve dry eye severity, when compared with using polyethylene/propylene glycol eye drops (Systane, Alcon Laboratories) (89591).
• Exercise-induced muscle soreness. It is unclear if oral chondroitin sulfate improves muscle soreness from exercise. Details: Preliminary clinical research in untrained males shows that taking chondroitin sulfate 1800 mg twice daily for 14 days before exercise does not reduce post-exercise muscle soreness when compared with placebo (42352). However, another small clinical study in healthy, recreationally active adults shows that a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing chondroitin sulfate 300 mg, collagen peptides 900 mg, and hyaluronic acid 150 mg, taken twice daily for 6 weeks prior to two bouts of resistance exercise, attenuates muscle damage and decreases delayed-onset muscle soreness when compared with placebo (96301). It is unclear if these effects are due to chondroitin sulfate, the other ingredients, or the combination.
• Gastroesophageal reflux disease (GERD). Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Patients with non-erosive GERD are thought to be less responsive to conventional acid suppression with proton pump inhibiters (PPIs) and H-2 blockers. A small preliminary clinical study shows that taking a syrup containing hyaluronic acid and chondroitin sulfate along with PPIs, H2-receptor antagonists, and/or antacids, reduces the intensity of symptoms associated with non-erosive GERD by about 3.5-fold when compared with placebo (89592). A larger clinical study in patients with non-erosive GERD shows that taking the same combination agent (Esoxx by Alfa Wassermann) in addition to acid suppression with PPIs improves GERD symptom severity by 21%, heartburn by 15%, and regurgitation by 10% when compared with PPIs with a placebo (101271). This product is available in Canada as EsopH (Exzell Pharma). It is unclear if the benefit of this combination product is due to chondroitin sulfate, hyaluronic acid, or the combination. Chondroitin sulfate has also been evaluated in patients with GERD who experience extraesophageal symptoms. A small clinical study in patients reporting symptoms of cough, hoarseness, postnasal drip, sore throat, and/or throat clearing shows that taking a specific combination product (Gerdoff, SOFAR S.p.A.) containing chondroitin sulfate, hyaluronic acid, and aluminum hydroxide three times daily with omeprazole 40 mg once daily for 6 weeks does not reduce overall symptom scores, based on the Reflux Symptoms Index (RSI) score, when compared with omeprazole alone. However, it does increase the probability of treatment response, defined as a 50% or greater improvement in RSI score, by nearly 40% (109648). This product is available in Italy. It is unclear if these findings are due to chondroitin sulfate, other ingredients, or the combination.
• Gastritis. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with gastritis shows that taking a specific liquid product (Esoxx, Alfa Wasserman Spa) containing chondroitin sulfate and hyaluronic acid four times daily for 4 weeks modestly reduces upper abdominal pain when compared with placebo (99687). It is not clear if this effect is due to chondroitin sulfate, hyaluronic acid, or the combination.
• Hyperlipidemia. Although there is interest in using oral chondroitin for hyperlipidemia, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Interstitial cystitis. Small clinical studies suggest that intravesical chondroitin sulfate may not improve interstitial cystitis symptoms. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Several uncontrolled, open-label studies suggest that intravesical chondroitin sulfate, with or without hyaluronic acid, improves clinical symptoms of interstitial cystitis and reduces the problems caused by symptoms in these patients (42338,42371,42373,42385,42387). However, in controlled clinical trials, intravesical chondroitin sulfate 2%, instilled weekly for 6-7 weeks, does not significantly improve symptoms when compared with a placebo solution (42473,42517). Furthermore, a meta-analysis of clinical research shows that intravesical chondroitin sulfate with hyaluronic acid does not improve pain due to interstitial cystitis better than using hyaluronic acid solution alone (97054). Oral chondroitin has been evaluated in combination with other ingredients. Preliminary clinical research 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, as two capsules twice daily for 12 months, reduces symptoms of interstitial cystitis by 44% to 52% (42391). It is not clear if this effect is due to chondroitin, other ingredients, or the combination.
• Kashin-Beck disease. It is unclear if oral chondroitin sulfate improves Kashin-Beck disease symptoms such as pain. Details: A small clinical study in Chinese adults with Kashin-Beck disease shows that taking chondroitin sulfate 600 mg twice daily with or without glucosamine hydrochloride 480 mg three times daily for 6 months decreases pain and stiffness when compared with placebo (42516).
• Osteoporosis. Although there is interest in using oral chondroitin for osteoporosis, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Overall mortality. Oral chondroitin has only been evaluated in combination with glucosamine; its effect when used alone is unclear. Details: A cross-sectional observational study suggests that using oral chondroitin and glucosamine for at least one year is associated with a 27% lower incidence of overall mortality and 58% lower incidence of cardiovascular mortality when compared with not using these supplements (104445). However, this study did not clarify the forms of chondroitin and glucosamine used, or the doses, frequencies, or durations 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. Another observational study suggests that regular use of chondroitin with glucosamine for an average of 8 years is associated with a 30% lower risk of mortality when compared with no use. However, when these findings are adjusted for differences in age, body mass index, and comorbidities, overall mortality risk does not seem to be reduced with chondroitin and glucosamine supplementation (110626). Higher quality, prospective research is needed to clarify the relationship, if any, with overall mortality. Additionally, it is unclear if the effects on mortality are due to chondroitin, glucosamine, or the combination.
• Psoriasis. It is unclear if oral chondroitin sulfate is beneficial for reducing psoriasis disease severity. Details: A clinical study in patients with plaque psoriasis and knee osteoarthritis shows that taking chondroitin sulfate (Condrosan, CS Bio-Active, Bioibérica S.A.) 800 mg daily for 3 months does not appear to reduce the extent or severity of plaque psoriasis when compared with placebo (42463).
• Stroke. It is unclear if oral chondroitin sulfate is beneficial for reducing stroke risk. Details: An observational study in Spanish patients found that chondroitin sulfate use is associated with 23% lower odds of ischemic stroke when compared with non-use; however, the benefit was only observed in patients taking at least 800 mg for no more than one year (109643).
• Temporomandibular disorders (TMD). Oral and topical chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of two small clinical studies in patients with TMD shows that taking chondroitin sulfate 1200 mg and glucosamine sulfate 1500 mg daily for 2 months does not reduce pain or increase maximum mouth opening when compared with tramadol 50-100 mg daily (109647). 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 pain, tension, or temporomandibular space measures when compared with placebo (110629).
• Urinary incontinence. Although there is interest in using intravesical chondroitin for urinary incontinence, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Urinary tract infections (UTIs). It is unclear if intravesical administration of chondroitin sulfate alone is beneficial in patients with recurrent UTIs. Most research has evaluated the effects of chondroitin sulfate in combination with hyaluronic acid, with promising results. Details: One small observational study in patients with recurrent UTIs has found that intravesical administration of 40 mL of chondroitin sulfate 0.2% weekly for 6 weeks, then every 2 weeks for 2 months, then every 3 weeks for 2 months, and finally every 6 weeks for a total treatment duration of 1 year is associated with a lower number of UTIs and urologist visits when compared with low-dose long-term antibiotic therapy (109649). Most research on the use of chondroitin sulfate for UTIs has evaluated its effects when used in combination with hyaluronic acid. Several small clinical studies and a pooled analysis of the available clinical research show that intravesical administration of 50 mL of specific solutions containing chondroitin sulfate 2% and hyaluronic acid 1.6% (iAluRil, IBSA Farmaceutici; Cystistat, Bioniche) for up to 6 months reduces the rate of UTI recurrence by about 2-3 incidents per year and delays the time to the first UTI recurrence when compared with placebo or prophylaxis with sulfamethoxazole-trimethoprim (42511,42519,89590,89594,99688). However, the validity of these findings is limited by the low quality and high heterogeneity of the included studies, as well as concerns for publication bias (99688). More evidence is needed to rate chondroitin sulfate for these uses.

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POSSIBLY SAFE ...when non-contaminated species of spirulina blue-green algae are used orally and appropriately (91713). The blue-green algae species Arthrospira platensis has been used with apparent safety in doses up to 19 grams daily for 2 months, or 10 grams daily for 6 months (18296,18300,18306,75944,91705,99703,104567,109965). The blue-green algae species Arthrospira fusiformis has been used with apparent safety in doses up to 4 grams daily for 3 months, or 1 gram daily for 12 months (15782,91717). Another blue-green algae species, Arthrospira maxima, has been used with apparent safety in a dose of 4.5 grams daily for up to 12 weeks (18297,99654,99655,102688). ...when non-contaminated, non-toxin producing strains of blue-green algae from the Aphanizomenon flos-aquae species are used orally and appropriately. Doses up to 1.6 grams daily have been used with apparent safety for up to 6 months (14842,18310). Some blue-green algae species can produce toxins called microcystins. According to the World Health Organization (WHO), the tolerable daily intake of microcystins in adults is 0.04 mcg/kg (96549).

POSSIBLY UNSAFE ...when contaminated blue-green algae are used orally. Blue-green algae can be contaminated with heavy metals (including mercury, cadmium, lead, or arsenic), neurotoxins, and toxic microcystin-producing cyanobacteria such as Microcystis aeruginosa (9171,75966,91704,91711,96550). Microcystins are most commonly reported in the blue-green algae species Aphanizomenon flos-aquae harvested from Upper Klamath Lake in Oregon. The Oregon Department of Health has set a limit of 1 mcg of microcystin-LR equivalents per gram dry weight of blue-green algae, assuming consumption of about 2 grams/day by adults (91704,91713). However, many samples of Aphanizomenon flos-aquae have been reported to contain higher levels than this (9171,91704). According to the World Health Organization (WHO), the tolerable daily intake of microcystins in adults is 0.04 mcg/kg (96549). When consumed orally, microcystins accumulate in the liver, binding to and inhibiting protein phosphatases, causing hepatocyte damage and possible tumor promotion (9171). Aphanizomenon flos-aquae can also produce neurotoxic compounds that may be present in supplements containing this organism (91704).

CHILDREN: POSSIBLY UNSAFE
when blue-green algae products are used orally. Blue-green algae can accumulate heavy metals such as lead and mercury (91704,91711). They can also contain toxic microcystins produced by contaminating species of cyanobacteria such a Microcystis aeruginosa (91704). Children are more sensitive to poisoning by microcystins (3536). The Oregon Department of Health has set a limit for microcystins of 1 mcg per gram dry weight of blue-green algae, but some countries have set very low exposure limits of 0.2 mcg per day and 0.8 mcg per day for infants and children, respectively (91704).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Some blue-green algae products, specifically those of the species Aphanizomenon flos-aquae, have been found to contain low amounts of beta-methylamino-L-alanine (BMAA). BMAA is associated with neurodegenerative diseases, and breast milk has been shown to be a potential source of BMAA exposure in infants (96550).

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LIKELY SAFE ...when used orally and appropriately. Boswellia serrata extract in doses up to 1000 mg daily has been safely used in several clinical trials lasting up to 6 months (1708,1709,12432,12434,12438,17948,17949,17950,91379)(100699,100713,102089,109568). Boswellia serrata extract has been used with apparent safety at a dose of 2400 mg for up to 1 month (102092).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of using Boswellia serrata in medicinal amounts; avoid using.

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LIKELY SAFE ...when used orally and appropriately. Chondroitin sulfate has been used safely in doses of up to 2000 mg daily for up to 6 years (1955,2533,13579,17732,22212,42339,42343,42348,42389,42396)(42398,42463,42477,42513,42520,42536,42541,89516,89558,89592)(89596,94360,94381,95788,95792). However, since chondroitin is often derived from bovine cartilage, historically, there was concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated chondroitin preparations. ...when used topically and appropriately as an ophthalmic viscosurgical device (OVD). Various products containing chondroitin sulfate and sodium hyaluronate have been granted approval by the US Food and Drug Administration (FDA) for use as an adjunct to cataract surgery (89436,89437).

POSSIBLY SAFE ...when used intramuscularly (10149,42397). ...when used topically as eye drops, short-term. Eye drops containing chondroitin sulfate with xanthan gum or glucosamine have been used with apparent safety four times daily for up to 3 months (89591,104443). ...when administered intravesically under the supervision of a physician (42338,42371,42373,42385,42387,42473,42511,42517,42519,109649).

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

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, spirulina blue-green algae might increase the risk of bleeding if used with other anticoagulant or antiplatelet drugs. However, this is unlikely.  Details Spirulina blue-green algae have shown antiplatelet and anticoagulant effects in vitro (18311,18312,75892,92162,92163). However, one preliminary study in 24 patients receiving spirulina blue-green algae 2.3 grams daily for 2 weeks showed no effect on platelet activation or measures of clotting time (97202).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking blue-green algae with antidiabetes drugs might increase the risk of hypoglycemia.  Details Human research shows that spirulina blue-green algae can have hypoglycemic effects in patients with diabetes, at least some of whom were using antidiabetes drugs (18299). However, blue-green algae does not seem to improve glycated hemoglobin (HbA1c) levels in patients with diabetes (102689,109970). A meta-analysis of animal studies also suggests that spirulina blue-green algae have hypoglycemic effects (109970).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of blue-green algae might interfere with immunosuppressive therapy.  Details Blue-green algae have been shown to stimulate the immune system (2534,10267).

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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Boswellia serrata might increase the levels of CYP1A2 substrates.  Details In vitro research shows that Boswellia serrata gum resin inhibits CYP1A2 enzymes (21178).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Boswellia serrata might increase the levels of CYP2C19 substrates.  Details In vitro research shows that Boswellia serrata gum resin inhibits CYP2C19 enzymes (21178).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Boswellia serrata might increase the levels of CYP2C9 substrates.  Details In vitro research shows that Boswellia serrata gum resin inhibits CYP2C9 enzymes (21178).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Boswellia serrata might increase the levels of CYP2D6 substrates.  Details In vitro research shows that Boswellia serrata gum resin inhibits CYP2D6 enzymes (21178).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Boswellia serrata might increase the levels of CYP3A4 substrates.  Details In vitro research shows that Boswellia serrata gum resin inhibits CYP3A4 enzymes (21178).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, Boswellia serrata might alter the effects of immunosuppressive drugs.  Details Some in vitro research suggests that Boswellia serrata extracts might inhibit mediators of autoimmune disorders such as leukotrienes and reduce production of antibodies and cell-mediated immunity (12432,12435,12437,12438). However, other in vitro research suggests that, when coupled with calcium ions, boswellic acids containing the keto group have immunostimulant properties within specific cell signaling pathways (21180).

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WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Taking chondroitin in combination with glucosamine might increase the anticoagulant effects of warfarin. However, the effect of chondroitin alone is unclear.  Details There have been multiple reports of increased international normalized ratio (INR) in patients taking warfarin with glucosamine, with or without chondroitin. The lack of reports with chondroitin alone seem to suggest that the interactions occurring in these reports may have been due to glucosamine. In two individual case reports, glucosamine/chondroitin combinations were associated with a significant increase in INR in patients previously stabilized on warfarin (11389,16130). Additionally, 20 voluntary case reports to the US 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, without chondroitin, to increased INR in patients taking warfarin (16131).

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General ...Orally, spirulina blue-green algae seem to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, bloating, diarrhea, dizziness, fatigue, flatulence, headache, nausea, and vomiting.

Dermatologic ...Orally, a severe rash has been reported in a 49-year-old woman after taking a spirulina blue-green algae supplement (species and dose unknown). After stopping the supplement, inflammatory myopathy with muscle weakness and elevated creatine kinase occurred. The condition resolved with corticosteroid and cyclophosphamide treatment (75936). In another case report, an 82 year-old woman developed a blistering skin condition over a 2-year period while taking spirulina blue-green algae (A. platensis, dose unknown). She had partly hemorrhagic bullae, secreting erosions and macerations. These symptoms resolved when the supplement was stopped and the patient was treated with oral prednisone, topical silver sulfadiazine, and topical triamcinolone / neomycin (75921).

Gastrointestinal ...Orally, gastrointestinal complaints are amongst the most common adverse effects associated with spirulina blue-green algae, including nausea, vomiting, diarrhea, and abdominal cramps (19272,75924,91713,109969). Similarly, common adverse effects associated with the blue-green algae species Aphanizomenon flos-aquae are stomach upset, flatulence, diarrhea, and bloating (14842).

Hematologic ...Orally, three cases of mild gum bleeding and one case of mild bruising have been reported in patients taking spirulina blue-green algae (Cyactiv, Cerule LLC) 2. 3 grams daily (containing approximately 1 gram of phycocanin) for 2 weeks (97202).

Hepatic ...Orally, significant elevations of liver function tests within 2 weeks of starting a spirulina blue-green algae supplement (species and dose unknown) have been reported in a 52-year-old man stabilized on amlodipine, simvastatin, and acarbose. A biopsy showed feathery degeneration and ballooning of hepatic cells. Cholestasis was present, and an ex-vivo lymphocyte stimulation test for spirulina blue-green algae was positive. All drugs and the spirulina blue-green algae supplement were stopped, with return of the LFTs to normal (9172).

Immunologic ...Orally, urticarial rashes and pruritus have occurred as part of generalized allergic reactions to blue-green algae (91706,91711,91712).
In one case report, a 14-year-old male experienced anaphylaxis with urticaria, lip edema, and asthma 6 hours after taking five tablets of spirulina blue-green algae (A. platensis, strength unknown). He had a positive skin prick test. Oral challenge to an extract of the tablets, and IgE from his serum, reacted with the beta chain of C-phycocyanin from A. platensis (91712).
In another case report, a 17-year-old male with a history of multiple allergies developed rash, pruritus, angioedema, wheezing, and dyspnea within 10 minutes of taking spirulina blue-green algae (A. platensis) 300 mg. He had a positive skin test to A. platensis but no other ingredients of the tablets (91706).

Musculoskeletal ...Orally, after a 49-year-old woman stopped taking a spirulina blue-green algae supplement (species and dose unknown), the patient experienced inflammatory myopathy with muscle weakness and elevated creatine kinase. The condition resolved with corticosteroid and cyclophosphamide treatment (75936). Another case report describes acute rhabdomyolysis that occurred after consumption of spirulina (Arthrospira platensis, Hawaiian spirulina, Solgar Inc., Leonia, NJ) 3 grams daily for 1 month. The 24-year old man presented with weakness, myalgias, elevated creatine kinase and liver function tests, and myoglobinuria (75922).

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General ...Orally, Boswellia serrata extract is generally well-tolerated. For information on the safety of Boswellia serrata when applied topically or used as aromatherapy, see the Frankincense monograph.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, headache, heartburn, itching, nausea.
Serious Adverse Effects (Rare):
Orally: Large amounts of Boswellia serrata gum resin can cause bezoar formation.

Dermatologic ...Orally, Boswellia serrata extract (5-Loxin) has been associated with itching at doses of 100-250 mg daily (17948).

Gastrointestinal ...Orally, Boswellia serrata extract may cause diarrhea, nausea, abdominal pain, and heartburn (1708,12432,12438,17948,17949,17950,21149,109567). A case of a large gastrointestinal bezoar has been reported in a 17-year-old female who chewed and swallowed large quantities of boswellia gum resin (Boswellia species not specified) for celiac disease (36914).

Musculoskeletal ...Orally, Boswellia serrata extract (5-Loxin) has been associated with one case of foot edema and four cases of generalized weakness in one clinical study (17948).

Neurologic/CNS ...Orally, Boswellia serrata extract may cause dizziness, headache, and vertigo. In one clinical study, nearly 11% of patients taking a specific Boswellia serrata extract (K-Vie) reported headache. Dizziness and vertigo were also reported, but at lower rates (109567). In another study, headache was reported in one patient taking a specific Boswellia serrata extract (5-Loxin) (17948).

Psychiatric ...Orally, one case of mania is reported in a 73-year-old male who took Boswellia powder mixed with honey for 3 days. The patient recovered after hospitalization and treatment with olanzapine (110526).

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General ...Orally and topically, chondroitin sulfate is generally well tolerated. Intramuscular and ophthalmic use also seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, constipation, diarrhea, heartburn, nausea.
Serious Adverse Effects (Rare):
Orally: There have been rare reports of hepatotoxicity.

Cardiovascular ...One case of congestive heart failure and another case of myocardial infarction has been possibly attributed to use of glucosamine hydrochloride and chondroitin sulfate (13579,42477). Also, a case of mesenteric occlusion in one patient was considered possibly related to treatment with chondroitin sulfate and glucosamine (89520).

Dermatologic ...Orally, chondroitin sulfate has been associated with skin symptoms, such as eyelid edema, lower limb edema, alopecia, and skin rash (42513). Combinations of chondroitin sulfate along with glucosamine hydrochloride may also be associated with rash, water retention around eyes and scars, and hives on face, chest, torso, and legs when taken orally (42436,110628). A case of photosensitization that was reproducible with rechallenge has been reported following treatment with oral glucosamine-chondroitin products. However, it is not clear if this effect was due to glucosamine, chondroitin sulfate, or contaminants in the product (10408). A case of rash following treatment with intravesical chondroitin sulfate has been reported to be possibly related to the product (42385).

Gastrointestinal ...Orally, chondroitin might cause nausea, bloating, abdominal pain, diarrhea, constipation, vomiting, dyspepsia, and epigastric burning (42396,42436,42541,89561,110628,111647).

Genitourinary ...Intravesical chondroitin sulfate has been associated with cases of vulvar burning, vaginitis, urinary tract infection (UTI), dysuria, pelvic pain, and other bladder symptoms, such as increased frequency, urgency, or incontinence. However, these effects might be due to catheterization rather than chondroitin sulfate (42385,42387,42473).

Hematologic ...Concern has been expressed about possible anticoagulant activity of oral chondroitin sulfate. However, hematological changes have not occurred in patients taking chondroitin sulfate in clinical trials (760).

Hepatic ...Although relatively uncommon, combinations of glucosamine and chondroitin sulfate have been associated with acute liver injury that mimics autoimmune hepatitis. Two cases of elevated aminotransferase levels have been reported for patients taking glucosamine (form unspecified) and chondroitin sulfate at recommended doses. Aminotransferase levels, which were increased by four- to seven-fold, returned to normal following discontinuation of treatment (89515). Another case of abdominal pain, jaundice, fatigue, and elevated liver enzymes has been reported for a patient who used chondroitin sulfate (Condrosulf) for 2 years followed by a combination of glucosamine sulfate and chondroitin sulfate (Vita Mobility Complex) 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 chondroitin sulfate, other ingredients, or the combination.

Musculoskeletal ...Orally, chondroitin has been associated with musculoskeletal and connective-tissue events and disorders (13579,42520,95516).

Neurologic/CNS ...Rare cases of headache have been reported following treatment with products containing a combination of oral chondroitin sulfate and glucosamine hydrochloride or glucosamine sulfate (42436,89561). It is unclear if this effect was due to chondroitin, glucosamine, or the combination.
Patients should adhere to product directions when using chondroitin sulfate products that contain manganese. When taken at doses slightly higher than the recommended dose, these products can sometimes supply greater than the tolerable upper limit (UL) for manganese of 11 mg per day. Ingestion of more than 11 mg per day of manganese might cause significant central nervous system toxicity (7135).

Ocular/Otic ...A case of bilateral pinna chondritis (inflammation of the cartilage of the external ear) has been reported for a patient who received supplements containing glucosamine and chondroitin sulfate (42503).

Pulmonary/Respiratory ...A case of asthma exacerbation has been reported occurred following use of an oral glucosamine and chondroitin sulfate combination product (10002).

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