Ultra Joint Builder [Discontinued] by Jarrow Formulas

LIKELY EFFECTIVE

• Boron deficiency. Oral boron treats and prevents boron deficiency. Details: Taking boron orally is effective for preventing and treating boron deficiency (7135).

POSSIBLY EFFECTIVE

• Radiation dermatitis. Topical application of sodium pentaborate pentahydrate gel to radiation sites may reduce the risk of dermatitis in patients with breast cancer who are receiving radiotherapy. Details: A small clinical study in patients with breast cancer shows that applying a hydrogel containing sodium pentaborate pentahydrate 3% four times daily during radiotherapy for 5 weeks reduces the risk of moderate to severe dermatitis by 50% when compared with petroleum jelly (Vaseline). However, there is no difference in patient satisfaction (95660). Additionally, a larger clinical trial in patients with breast cancer shows that applying a sodium pentaborate pentahydrate 3% gel to radiation sites 15 minutes before each session for 25 sessions reduces the risk of dermatitis by 90%, erythema by 87%, dry desquamation by 92%, and moist desquamation by 97% when compared with a placebo gel (109557).
• Vaginal candidiasis. Boric acid applied intravaginally seems to reduce vaginal candidiasis. Details: Some limited clinical research shows that applying boric acid powder intravaginally 600 mg once or twice daily for up to 3 weeks can treat candidiasis and other vaginal fungal infections, including resistant and chronic infections (15443,15444,15446,15449,15450,15451,15453); however, this research is limited by low study quality. For Candida glabrata yeast infections, which are less prevalent than Candida albicans infections, some evidence shows that intravaginal boric acid capsules are effective in about 65% to 70% of azole-resistant infections; however, boric acid capsules appear to be less effective than intravaginal flucytosine (Ancobon) (15445,15454). For Candida krusei infections, which are rare and resistant to azole antifungal treatment, boric acid capsules also appear to be effective in some cases (15448).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral boron does not seem to improve athletic performance. Details: A small clinical study in male bodybuilders shows that taking boron 2.5 mg daily for 7 weeks does not increase lean body mass, muscle mass, or testosterone levels when compared with placebo (944). Furthermore, the International Society of Sports Nutrition (ISSN) does not recommend boron supplementation as a nutritional ergogenic aid due to a lack of supportive evidence (101009).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral boron is beneficial for age-related cognitive decline. Details: Two very small clinical studies in healthy older adults show that taking boron 3.25 mg daily for up to 49 days orally might improve cognitive function and fine motor skills when compared with lower amounts of boron (943).
• Diabetic foot ulcers. It is unclear if topical boron is beneficial for use in diabetic foot ulcers. Details: A large clinical study in adults with diabetic foot ulcers shows that applying boron (sodium pentaborate 3%) gel twice daily for 1 month marginally reduces ulcer severity, measured by the Wagner Classification system at 25 days and 2 months, when compared with control; recurrence and infection rate were also modestly reduced at 2 months (112423). However, it is unclear whether the analysis controlled for systemic antibiotic use among the two groups, which effects the validity of these findings.
• Dysmenorrhea. It is unclear if oral boron is beneficial for reducing pain during menstruation. Details: A small clinical study in young females with moderate to severe dysmenorrhea suggests that taking boron tetraborate 10 mg daily, starting two days before and continuing until three days after the start of menstruation for two menstrual cycles, reduces pain levels by 24% and pain duration by 1.5 hours, or 34%. Both pain and pain duration were decreased by only 9% in patients receiving placebo (95428).
• Kidney stones (nephrolithiasis). It is unclear if boron is beneficial for medical expulsive therapy after extracorporeal shockwave lithotripsy. Details: A large clinical study in adults undergoing extracorporeal shockwave lithotripsy for kidney stones conducted in Iran shows that taking boron 10 mg twice daily for 2 weeks does not statistically improve the rate of stone expulsion when compared with tamsulosin; however, boron may have fewer side effects (i.e., orthostatic hypotension, headache, nausea, erectile dysfunction) (112414).
• Kidney transplant. It is unclear if oral boron is beneficial in patients receiving a kidney transplant. Details: Observational research in kidney transplant recipients has found that higher boron intake, as measured by urinary boron levels, is associated with a lower risk of mortality when compared with lower intake. Patients with 24-hour urinary boron levels in the top tertile had a 49% lower risk of all-cause mortality when compared with those in the lowest tertile; however, there was no association with graft failure (109556). It is unclear if these findings can be generalized to boron supplements.
• Obesity. Although there has been interest in using oral boron for obesity, there is insufficient reliable information about the clinical effects of boron for this purpose.
• Osteoarthritis. It is unclear if oral boron is beneficial for osteoarthritis symptoms. Details: Small low quality studies in patients with osteoarthritis suggest that taking boron tetraborate 3-6 mg daily for up to 8 weeks might improve pain and other symptoms when compared with a lower intake of boron (941,36870).
• Osteoporosis. It is unclear if oral boron is beneficial for osteoporosis. Details: Preliminary clinical research in postmenopausal adults shows that taking boron 3 mg daily does not improve bone density when compared with placebo (36872).
• Periodontitis. Small clinical studies suggest that adding topical boric acid to scaling and root planing treatment may be beneficial in periodontitis. Details: A meta-analysis of four small clinical studies in 117 patients with periodontitis shows that using boric acid 0.75% gel or solution in addition to scaling and root planing seems to slightly improve probing pocket depth (PPD) and clinical attachment level (CAL) when compared with placebo or saline control (105690). Another small clinical study in patients with periodontitis shows that using boric acid 0.5% for irrigation in addition to scaling and root planing seems to improve CAL and PPD to a similar degree as using povidone-iodine 0.1% (105691). The available research was conducted in Turkey, Vietnam, and India; it is unknown if these findings are generalizable to other geographic locations.
• Tooth extraction. It is unclear if boron is beneficial for use in periodontal healing after impacted third molar surgery. Details: A moderate-sized clinical study in adults 18 to 40 years old shows that using boron 0.1% to 2.5% and chlorhexidine 0.12% mouthwash for 7 days after impacted third molar surgery marginally improves swelling and self-reported pain on day 7, and the higher boron concentrations also improve pain at day 4 when compared with chlorhexidine alone, but does not improve the number of analgesics used or periodontal scores (112379). However, the validity of these results is limited by a lack of statistical adjustment for multiple comparisons which can lead studies to show differences between treatment groups in error (i.e., false positive findings). Additionally, the study period coincides with the expected recovery time (i.e., 2-7 days), making it unclear if any effects are due to the intervention or control. More evidence is needed to rate boron for these uses.

(Read more about BORON)

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.

(Read more about BOSWELLIA SERRATA)

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 and function when compared with placebo (14305,89521,94382,95785,99684). 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. 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). 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 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). This study 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).
• 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). 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

• Dry eye. Applying eye drops containing hyaluronic acid alone or in combination with other ingredients, seems to improve symptoms of dry eye. Details: A large meta-analysis of clinical studies in patients with dry eye disease shows that using eye drops containing hyaluronic acid 0.1% to 0.4% for at least 14 days modestly improves tear production when compared with artificial tears or saline control, with a more significant improvement when compared with saline control. Tear stability is also modestly improved when compared with saline control (108622). Several individual clinical studies using specific hyaluronic acid eye drops have also demonstrated improvement. One clinical study in patients with dry eye disease shows that applying eye drops containing hyaluronic acid 0.1% to 0.3% 5-6 times daily for 12 weeks might improve symptoms to a similar degree as cyclosporine 0.05% eye drops. The products used in this study included Hyalein ophthalmic solution 0.1%, New Hyaluni ophthalmic solution 0.15%, and Hyaluni ophthalmic solution 0.3% (97885). Another clinical study shows similar efficacy between hyaluronic acid 0.15% eye drops (New Hyaluni), applied 6 times daily for 12 weeks, and eye drops containing cyclosporine 0.05% and carboxymethylcellulose 0.5%, applied twice daily (110555). A smaller clinical study in patients with dry eye disease shows that applying specific eye drops containing hyaluronic acid 0.2% (Hyalistil) seems to have similar efficacy as using tamarind seed polysaccharide eye drops (16301). Furthermore, adding hyaluronic acid to conventional treatment seems to offer additional benefit. A large multicenter clinical trial in patients with dry eye disease shows that applying 1-2 drops of artificial tears containing carboxymethylcellulose 0.5% and hyaluronic acid 0.1% (Optive Fusion, Allergan) at least 2 times daily for 3 months seems to further improve pain and discomfort when compared with using artificial tears containing carboxymethylcellulose alone (104384). One small clinical study also shows that hyaluronic acid 0.3% ocular gel and hyaluronic acid 0.18% eye drops, applied 4-6 times daily for 12 weeks, are equally effective for improving dry eye symptoms (110556). Hyaluronic acid has also been studied in combination with other ingredients. Several small clinical studies in patients with dry eye syndrome ranging from mild to severe shows that applying eye drops containing hyaluronic acid 0.2% or 0.3%, polyvinylpyrrolidone, and glycerin (Visaid 0.2% or 0.3%, Avizor S.A.), administered as one drop 3-8 times daily for one month, improves some signs and symptoms of dry eye when compared with sodium chloride 0.9% (97894,97895). Conversely, a large clinical study in patients with mild to moderate dry eye disease shows that applying preservative-free eye drops containing sodium hyaluronate with chondroitin sulfate (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 (104443).
• Venous leg ulcers. Topical application of hyaluronic acid-impregnated gauze reduces wound size and promotes wound healing. Details: Clinical studies in patients with at least one leg ulcer of venous or mixed arterial/venous origin show that once daily application of a specific hyaluronic acid-impregnated gauze (Ialuset, Laboratoires Genévrier) reduces wound size at 45 days by 73% and produces complete wound healing at or before 20 weeks in 40% of patients. In those receiving a neutral vehicle gauze, these improvements occurred in 46% and 19% of patients, respectively (108627,108640).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral hyaluronic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is also unclear if topical hyaluronic acid is beneficial for aging skin. Details: A very small study shows that taking a specific combination product (GliSODin Skin Nutrients Advanced Anti-Aging Formula, Isocell North America Inc.) containing hyaluronic acid, krill oil, sea buckthorn berry oil, and cacao bean extract orally three times daily for 90 days, along with applying tazarotene 0.1% cream, moderately decreases wrinkling and photodamage and improves skin moisture and elasticity when compared with tazarotene cream alone (91778). Another small clinical study in females with aging skin shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing hyaluronic acid 100 mg, chondroitin sulfate 200 mg, and collagen peptides 600 mg daily for 12 weeks reduces lines and wrinkles by about 13% when compared with baseline (28681). The validity of this finding is limited by the lack of a comparator group. Furthermore, it should be noted that both studies were funded by the product manufacturer. A small open-label clinical study in females with mild to moderate lip dryness and mild to severe lip condition shows that three daily applications of a two-step lip treatment containing hyaluronic acid for 4 weeks improves the overall condition of lips, as well as texture/visual roughness, plumpness, color/rosiness, definition/contour, and lines/wrinkles when compared with baseline (108634). The validity of these findings is limited by the lack of a comparator group.
• Allergic rhinitis (hay fever). It is unclear if nasal irrigation with sodium hyaluronate is beneficial in patients with mild, persistent seasonal allergic rhinitis. Details: A small clinical study in patients with mild, persistent seasonal allergic rhinitis receiving an oral antihistamine and an intranasal corticosteroid shows that nasal irrigation with sodium hyaluronate twice daily for 1 month improves mucociliary clearance time by 3 minutes, compared with 1 minute with the use of isotonic saline and 5 minutes with the use of surfactant (108630). It is unclear if this change is associated with clinically relevant symptom improvement.
• Burns. It is unclear if topical hyaluronic acid is beneficial in patients with burns. Details: A meta-analysis of small clinical trials suggests that topical hyaluronic acid and hyaluronic acid derivatives might improve the healing of wounds, including burns, when compared with control (104389). A small nonrandomized clinical study in patients with partial- to full-thickness burns shows that hyaluronic acid 0.2% gel daily for 12 weeks during the re-epithelialization phase reduces erythema, tension, pruritus, burning, and neoangiogenesis when compared with baseline (108636). The lack of statistical comparison to the ozonated oil group and the single-blinded nature of the study limit the validity of these findings.
• Canker sores. It is unclear if topical hyaluronic acid is beneficial for canker sores. Details: A clinical study in adults with recurrent canker sores shows that applying a gel containing hyaluronic acid 0.2% two to three times daily for 7 days reduces soreness immediately and for up to 30 minutes after application when compared with baseline. However, these improvements are numerically similar to those seen with placebo (108637). The lack of statistical comparison to placebo limits the validity of this finding. A small observational study in children with recurrent canker sores has found that applying a gel containing hyaluronic acid 0.2% twice daily for 7 days is similarly effective to dexamethasone topical ointment applied three times daily for 5 days for reducing pain and ulcer size (104388).
• Corneal abrasion. It is unclear if eye drops containing hyaluronic acid are beneficial in preventing recurrence in patients with a history of traumatic corneal abrasion. Details: A small clinical study in patients with fully healed traumatic corneal abrasion at risk for recurrence shows that administration of eye drops containing hyaluronic acid 0.3% five times daily for 3 months does not reduce the incidence rate of major symptomatic episodes at 12 months when compared with observation alone (108623).
• Diabetic foot ulcers. Oral hyaluronic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of results from 4 clinical studies shows that applying hyaluronic acid combination gels or hyaluronic acid-based biomaterials to diabetic foot ulcers increases the odds of complete healing at 12 weeks by about 1.7-fold when compared to control treatment. Forms of hyaluronic acid assessed in the evaluated studies included zinc hyaluronate, hyaluronic acid-based biomaterial (Hyalograft 3D autograft), and a gel containing hyaluronic acid and amino acids (Vulnamin Gel, Errekappa) (91776). It is not clear if the beneficial effects were due to hyaluronic acid or other components of the treatments.
• Exercise-induced muscle soreness. Oral hyaluronic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in healthy, recreationally active adults shows that a specific product (BioCell Collagen, BioCell Technology, LLC) containing hyaluronic acid 150 mg, chondroitin sulfate 300 mg, and collagen peptides 900 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 hyaluronic acid, the other ingredients, or the combination. Furthermore, it should be noted that both studies were funded by the product manufacturer.
• Gastroesophageal reflux disease (GERD). Oral hyaluronic acid 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 a different formulation of the same combination of chondroitin sulfate and hyaluronic acid (Esoxx, Alfa Wassermann) 4 times daily for 14 days, in conjunction with a PPI, improves GERD symptom severity by 21%, heartburn by 15%, and regurgitation by 10% when compared with using a PPI and placebo (101271). Hyaluronic acid has also been evaluated in combination with chondroitin sulfate in patients with extraesophageal symptoms of GERD. A small, open-label study shows that taking a specific combination product (Gerdoff, SOFAR S.p.A.) containing hyaluronic acid and chondroitin sulfate three times daily with omeprazole 40 mg daily for 6 weeks increases the rate of treatment response, defined as a 50% or greater improvement in reflux symptoms index scores, by around 40% when compared with omeprazole alone. While average symptom scores were not significantly improved with the combination product over omeprazole, the need for omeprazole as rescue therapy for breakthrough symptoms was reduced in the treatment group (109648). It is unclear if the findings described above are due to hyaluronic acid, chondroitin sulfate, or the combination.
• Gingivitis. It is unclear if hyaluronic acid used in a mouthwash reduces gingivitis severity. Details: A small clinical study in patients with biofilm-induced gingivitis shows that rinsing with 10 mL of hyaluronic acid 0.025% mouth wash (Gengigel, RICERFARMA SRL) for 1 minute twice daily reduces probing index and bleeding when compared with rinsing with a placebo solution, but is less effective when compared with chlorhexidine 0.12% solution (104383). Another small clinical study in patients with plaque-induced gingivitis shows that rinsing with 10 mL of a mouthwash containing hyaluronic acid 0.1% and hydrogen peroxide 1.8% for 30 seconds twice daily for 21 days reduces gingival index scores but not plaque index scores when compared with placebo (110554). It is unclear if these findings are due to hyaluronic acid, hydrogen peroxide, or the combination.
• Intranasal surgery. It is unclear if topical hyaluronic acid irrigation improves recovery in patients after nasal surgery. Details: A small clinical study in patients that underwent nasal surgery for chronic rhinosinusitis shows that performing nasal irrigation with high molecular weight sodium hyaluronate 9 mg twice daily for 6 weeks improves sinus scarring, crusting, and headache when compared with nasal irrigation with saline. However, the sodium hyaluronate irrigation did not improve sinus inflammation or secretions, nasal obstruction, or facial pain (101288).
• Intrauterine adhesions. Several small studies suggest that intrauterine administration of hyaluronic acid gel seems to prevent intrauterine adhesions after uterine surgery. Details: Meta-analyses of 11-12 small clinical studies in patients undergoing uterine surgery shows that intrauterine application of 1-10 mL of hyaluronic acid gel after surgery reduces the risk of intrauterine adhesions by around 50% and increases pregnancy rates when compared with no treatment (110551,110552). One analysis suggests that hyaluronic acid is most effective for prevention of intrauterine adhesions when at least 5 mL of gel is applied (110551).
• Lichen planus. It is unclear if topical hyaluronic acid is beneficial in patients with oral lichen planus. Details: A clinical study in patients with oral lichen planus shows that application of a gel containing hyaluronic acid 0.2% four to five times daily for 28 days reduces soreness in as little as 5 minutes for up to 4 hours when compared with baseline. These findings are numerically similar to those seen with placebo; however, the lack of statistical comparison to placebo limits the validity of this finding (108635). A small clinical study in patients with symptomatic oral lichen planus (including mixed forms) shows that application of a gel containing hyaluronic acid 0.2% three times daily for 4 weeks is similarly effective to triamcinolone for improving pain, erythema, and lesion size (108633). It is unclear if the improvement from baseline differed between groups.
• Melasma. It is unclear if topical hyaluronic acid is beneficial in patients with moderate to severe facial melasma. Details: A small clinical study in patients with mostly mixed-type, moderate to severe facial melasma shows that twice daily application of hyaluronic acid along with isobutylamido thiazolyl resorcinol reduces melasma severity similarly to isobutylamido thiazolyl resorcinol alone (108628). The single-blinded nature of the study limits the validity of these findings.
• Oral mucositis. Topical hyaluronic acid has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: A small clinical study in children aged 5 years or older with chemotherapy-induced oral mucositis shows that using a solution containing sodium hyaluronate, verbascoside, and polyvinylpyrrolidone (Mucosyte; Biopharm) three times daily is more effective than placebo for improving pain and other symptoms (97890). Another small clinical study in adults in recovery from hematopoietic stem cell transplantation shows that using a spray product containing sodium hyaluronate with synthetic amino acid precursors of collagen (Mucosamin) attenuates the development of severe oral mucositis when compared with chlorhexidine 0.2% (97889).
• Osteoarthritis. It is unclear if oral hyaluronic acid is beneficial in patients with osteoarthritis of the knee. Details: A small study in patients with knee osteoarthritis shows that taking chicken comb extract (Hyal-Joint, Bioibérica) 80 mg, standardized to contain hyaluronic acid 60% to 70%, once daily for 8 weeks does not reduce pain when compared with placebo (55742). This study was limited by small size and a significant placebo effect. Another small study in patients with knee osteoarthritis shows that taking a different supplement (Oralvisc, Bioibérica) 80 mg standardized to contain hyaluronic acid 70% and glycosaminoglycans once daily for 3 months modestly reduces pain when compared with placebo (91779). Reasons for these differing findings may relate to hyaluronic acid formulation, study funding sources, or the magnitude of placebo effect. Hyaluronic acid has also been studied in combination with chondroitin and collagen peptides (BioCell Collagen, BioCell Technology, LLC) with some evidence of benefit (28680).
• Otitis media. It is unclear if using intranasal hyaluronic acid solution is beneficial for otitis media in children. Details: Preliminary clinical research in children 3-12 years of age who have recurrent or chronic middle ear inflammation and adenoiditis shows that using a compound (Yabro, IBSA Farmaceutici Italia S.r.l.) containing hyaluronic acid in saline intranasally 15 days per month for 3 months modestly reduces the number of patients with impaired otoscopy or middle ear function when compared to baseline (97888). It is unclear if this effect is due to the hyaluronic acid product or to the natural resolution of inflammation over time.
• Radiation dermatitis. It is unclear if topical hyaluronic acid is beneficial for the prevention of radiation dermatitis. Details: A small clinical study in patients with breast cancer undergoing adjuvant radiation therapy following lumpectomy shows that three daily applications of a specific hyaluronic acid gel (RadiaPlex, MPM Medical) to one side of the breast results in a grade 2 or greater dermatitis occurrence rate of 62%, compared with a rate of 48% on the side receiving petrolatum-based gel. A review of a planned interim analysis led to early trial discontinuation (108638).
• Rhinosinusitis. It is unclear if hyaluronic acid solution is beneficial for acute or chronic rhinosinusitis when used in an intranasal saline rinse. Details: A small clinical study in adults with acute rhinosinusitis who are being treated with levofloxacin and prednisone shows that using a 3% hyaluronic acid in saline nasal douche twice daily improves smell, obstruction, and discharge within 14 days when compared with saline alone (97886). A very small clinical study in patients with chronic rhinosinusitis without nasal polyps shows that receiving micronized nasal hyaluronic acid douches twice daily for 30 days improves nasal symptoms, nasal obstruction, and ability to smell to a similar degree as normal saline (104387).
• Sexual dysfunction. It is unclear if vaginal hyaluronic acid is beneficial for improving sexual function in adults with dyspareunia. Details: A small nonrandomized clinical study in females with dyspareunia while taking oral hormonal contraceptives shows that once daily vaginal application of a hyaluronic acid gel for 12 weeks reduces pain and improves sexual function at 12 weeks when compared baseline. Though patients treated with twice weekly vaginal estrogen therapy had better 12-week scores than patients treated with hyaluronic acid, it is unclear if the improvements from baseline differed between groups (108639).
• Tooth extraction. It is unclear if topical hyaluronic acid is beneficial for wound healing after tooth extraction. Details: A small clinical study in patients undergoing tooth extraction shows that application of hyaluronic acid 0.2% gel or hyaluronic acid 0.1% spray to the extraction socket twice daily for 7 days increases the rate of wound closure when compared with no treatment (110553). The validity of these findings is limited by a lack of placebo control group.
• Urinary tract infections (UTIs). Oral and intravesical hyaluronic acid have been evaluated for the prevention of UTI in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of prospective and retrospective studies shows that intravesical administration of 50 mL of specific solutions containing chondroitin sulfate 2% and hyaluronic acid 1.6% (iAluRil, IBSA Farmaceutici; Cystistat, Bioniche), once weekly to once monthly 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 (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. Also, the effect of hyaluronic acid alone is unclear. Oral hyaluronic acid has also been evaluated in combination with other ingredients for the prevention of recurrent UTI. A small prospective observational study shows that taking 1-2 capsules of a combination of hyaluronic acid, chondroitin sulfate, curcumin, and quercetin daily for 15 days each month, in conjunction with the use of local topical estrogen therapy for up to 12 months, reduces the number of women with recurrent UTIs when compared with taking the oral combination product or the vaginal estrogen product alone (96781). It is unclear if this effect is due to hyaluronic acid, other ingredients, or the combination.
• Vaginal atrophy. It is unclear if topical hyaluronic acid is beneficial for improving symptoms of vaginal atrophy. Details: A small, open-label clinical trial in patients going through menopause with symptoms of vaginal atrophy shows that applying 3 grams of a topical vaginal preparation of hyaluronic acid (Hyalo Gyn, Fidia Farmaceutici) every 3 days for 30 days improves vaginal health scores and reduces vaginal itching, vaginal burning, and pain during intercourse when compared to baseline. However, it does not appear to be any more effective than a polycarbophil vaginal gel (110549). Also, a small observational study in postmenopausal patients with vulvovaginal atrophy has found that applying a topical vaginal preparation containing hyaluronic acid (Justgin, JustPharma) three times weekly for 8 weeks is associated with improved symptoms of vaginal dryness, burning, and itching, as well as pain during intercourse, when compared to baseline (97887). The validity of these findings is limited by the lack of a comparator group and retrospective nature of the study. Some research has evaluated combination products containing hyaluronic acid for vaginal atrophy. A clinical trial in patients with cervical cancer shows that intravaginal administration of a specific suppository (Santes, Lo.Li. Pharma) containing hyaluronic acid, vitamin E, and vitamin A, once daily for the 5 week duration of radiotherapy reduces vaginal dryness, inflammation, and dyspareunia when compared with no additional treatment (101283). Also, a small, open-label clinical study in patients with vaginal atrophy after treatment for breast cancer shows that intravaginal application of a suppository containing hyaluronic acid and extract of aloe, marigold, tiger grass, and tea tree daily for 10 days then every 3 days for 80 days improves vaginal health scores and reduces vaginal dryness and pain during intercourse when compared to baseline, with no difference between the hyaluronic acid-containing suppository and vaginal laser therapy (110550). It is unclear if these findings are due to hyaluronic acid, other ingredients, or the combination.
• Wound healing. Small clinical studies show that topical hyaluronic acid and hyaluronic acid derivatives may improve the healing of various types of wounds. Details: A meta-analysis of small clinical trials suggest that topical hyaluronic acid and hyaluronic acid derivatives might improve the healing of burns, wounds, and skin ulcers when compared with control (104389). More evidence is needed to rate hyaluronic acid for these uses.

(Read more about HYALURONIC ACID)

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.
• 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

• Bleeding. Although there has been interest in using topical yucca for bleeding, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Dandruff. Although there has been interest in using topical yucca for dandruff, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Diabetes. Although there has been interest in using oral yucca for diabetes, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Hypercholesterolemia. Oral yucca has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with hypercholesterolemia shows that taking purified yucca extract in combination with quillaia extract orally three times daily for 4 weeks decreases total and low-density lipoprotein (LDL) cholesterol levels by more than 10% and 15%, respectively, when compared with baseline (86899). The validity of this finding is limited by the lack of statistical comparison to the placebo group.
• Hypertension. Although there has been interest in using oral yucca for hypertension, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Joint pain. Although there has been interest in using topical yucca for joint pain, there is insufficient reliable information about the clinical effects of yucca for this purpose.
• Migraine headache. Although there has been interest in using oral yucca for migraine headache, there is insufficient reliable information about the clinical effects of yucca for this purpose. More evidence is needed to rate yucca for these uses.

(Read more about YUCCA)

LIKELY SAFE ...when used orally and appropriately. Boron is safe in amounts that do not exceed the tolerable upper intake level (UL) 20 mg daily (7135). ...when used vaginally. Boric acid, the most common form of boron, has been safely used for up to six months (15443,15444,15445,15446,15458,15449,15451,15453,15454). ...when used topically. Boron, in the form of sodium pentaborate pentahydrate 3% gel, has been applied to the skin with apparent safety up to four times daily for up to 5 weeks (95660,109557).

POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 20 mg daily. Higher doses might adversely affect the testes and male fertility (7135). Poisoning has occurred after ingestion of boron 2.12 grams daily for 3-4 weeks (17). Death has occurred after ingesting a single dose of 30 grams (36848,36863).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Boron is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL by age is 3 mg daily at 1-3 years, 6 mg daily at 4-8 years, 11 mg daily at 9-13 years, and 17 mg daily at 14 years or older (7135). The UL for infants has not been determined (7135).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the age-based UL (7135). ...when applied topically in large quantities. Infant deaths have occurred after the use of topical boric acid powder to prevent diaper rash (36873,36874).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Boron is safe in amounts that do not exceed the UL during pregnancy or lactation, which is 20 mg daily in those 19-50 years of age or 17 mg daily for those 14-18 years of age (7135).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher doses might impair growth and cause adverse effects in the developing fetus (7135,102058). ...when used vaginally. Intravaginal boric acid has been associated with a 2.7- to 2.8-fold increased risk of birth defects when used during the first 4 months of pregnancy (15443,15645).

(Read more about BORON)

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.

(Read more about BOSWELLIA SERRATA)

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)

LIKELY SAFE ...when used orally and appropriately. Supplements standardized to contain hyaluronic acid 70%, in an 80 mg daily dose, have been used daily for up to 3 months with no reports of adverse effects (55742,91779). ...when used topically and appropriately. Hyaluronic acid, in a gel or impregnated gauze, has been safely applied to the skin in clinical trials (7889,7892,104389,108627,108640). ...when eye drop preparations containing up to 0.3% hyaluronic acid are used multiple times per day for up to 3 months (97885,97894,97895,110555).

PREGNANCY:
There is insufficient reliable information available about the safety of hyaluronic acid; avoid using.

LACTATION:
There is insufficient reliable information available about the safety of hyaluronic acid. It is not known if hyaluronic acid is excreted in breast milk (7890); avoid using.

(Read more about HYALURONIC ACID)

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))

LIKELY SAFE ...when used orally in amounts commonly found in foods. Specific species of yucca, including Mojave yucca (Yucca shidigera) and Joshua tree (Yucca brevifolia), have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of yucca when used orally as medicine or when applied topically.

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

(Read more about YUCCA)

(Read more about BORON)

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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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).

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General ...Orally, boron is generally well tolerated when used in doses below the tolerable upper intake level (UL) of 20 mg. Vaginally, boron is well tolerated.
Most Common Adverse Effects:
Orally: Anorexia, dermatitis, erythema, indigestion.
Vaginally: Burning and pain.

Dermatologic ...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause dermatitis and alopecia (7135).
Larger doses can result in acute poisoning. Symptoms of poisoning in adults and children may include skin erythema, desquamation, and exfoliation (17).

Gastrointestinal ...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause anorexia and indigestion (7135).
Larger doses can result in acute poisoning. Children who have ingested 5 grams or more of borates can have persistent nausea, vomiting, and diarrhea leading to acute dehydration, shock, and coma. Adults who have ingested 15-20 grams of borate can exhibit nausea, vomiting, diarrhea, epigastric pain, hematemesis, and a blue-green discoloration of feces and vomit (17).

Genitourinary ...Vaginally, boric acid can cause vulvovaginal burning and dyspareunia in males if intercourse occurs shortly after vaginal treatment (15447).

Neurologic/CNS ...Orally, large doses can result in acute poisoning. Poisoning with boron can cause hyperexcitability, irritability, tremors, convulsions, weakness, lethargy, and headaches (17).

Ocular/Otic ...Exposure to boric acid or boron oxide dust has been reported to cause eye irritation (36852).

Pulmonary/Respiratory ...Exposure to boric acid and boron oxide dust has been reported to cause mouth and nasal passage irritation, sore throat, and productive cough (36852).

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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, 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). 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). 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). 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).

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General ...Orally and topically, hyaluronic acid appears to be well tolerated.
Most Common Adverse Effects:
Topically: Eczema, erythema, itching, wound hemorrhage, wound infection (e.g., erysipelas).

Dermatologic ...The use of needle-free devices to inject hyaluronic acid for cosmetic purposes has been reported to cause serious injury, and in some cases permanent harm, to the skin, lips, and eyes (108613).
Topically, hyaluronic acid application has been reported to cause eczema, erythema, itching, wound hemorrhage, and wound infection (e.g., erysipelas) (108628,108640).

Ocular/Otic ...Ocular pain has been reported rarely in patients using eye drops containing up to 0. 3% hyaluronic acid (97885).

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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 ...There is currently a limited amount of information on the adverse effects of yucca. A thorough evaluation of safety outcomes has not been conducted.

Dermatologic ...Topically, yucca has been reported to cause phytodermatitis (68294). In one case report, an atopic gardener developed contact urticaria after occupational exposure to weeping fig, spathe flower, and yucca. Allergen skin tests were positive for all three plants (49961).

Gastrointestinal ...Orally, the saponins in yucca can be irritating to mucous membranes and might cause gastrointestinal irritation (7,4077).

Pulmonary/Respiratory ...Environmental exposure to yucca has been associated with allergic rhinitis in 59 patients who exhibited sensitization to yucca after allergen skin testing (86902).

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