Sport [Discontinued] by GNC TriFlex

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)

POSSIBLY EFFECTIVE

• Cataracts. Chondroitin sulfate in combination with sodium hyaluronate is approved as a medical device to be ophthalmically injected during cataract surgery. It is unknown if other routes of administration are beneficial. Details: Injecting ophthalmic viscosurgical devices (OVDs) containing a combination of chondroitin sulfate and sodium hyaluronate into the eye protects the corneal endothelium during small-incision cataract surgery. Various medical devices containing chondroitin sulfate and sodium hyaluronate (Viscoat, Alcon Laboratories) have been granted approval by US Food and Drug Administration (FDA) for use as an adjunct to cataract surgery (89436,89437). However, OVDs that cannot be easily removed after surgery can cause intraocular pressure (IOP) spikes and reduced visual acuity. A meta-analysis of small clinical studies shows that using a specific chondroitin sulfate 4% and sodium hyaluronate 3% solution (Viscoat, Alcon Laboratories) after small-incision cataract surgery increases IOP at postoperative days 1 and 2, but not at any later postoperative days for up to 1 month (104452).
• Osteoarthritis. Chondroitin sulfate seems to modestly reduce osteoarthritis pain and improve function. Pharmaceutical-grade chondroitin sulfate products have shown the most benefit. Details: Meta-analyses of randomized controlled trials in patients with mostly knee osteoarthritis show that taking chondroitin sulfate 800-2000 mg in single or divided doses daily for at least 3 months modestly reduces pain and disability when compared with placebo. However, included studies were heterogeneous and most had high attrition bias. A sub-group analysis of high-quality studies shows that 16 patients need to take chondroitin sulfate for 6 months for one patient to experience at least a 20% reduction in pain (94381,95792,99685,104446). When compared with conventional treatments like diclofenac 50 mg three times daily, chondroitin sulfate improves symptoms more slowly; however, the improvement seems to persist for up to 3 months after treatment cessation (322). Chondroitin also seems to have disease-modifying benefits. Clinical research in patients with osteoarthritis of the knee or hip shows that taking chondroitin sulfate 800 mg daily or more for 2 years might modestly reduce joint degeneration and narrowing when compared with placebo or celecoxib (42348,42398,94381,95516). Overall, most of the positive research involved pharmaceutical-grade chondroitin sulfate products, which are available as prescription products in some countries, such as Chondrosulf (IBSA Institut Biochimique SA) (17732,42348,42398,42536,89596,94360,104446), Chondrosan (Bioibérica, S.A.) (42463,42513), and Structum (Laboratoires Pierre Fabre) (22212,42520,89593). One clinical study shows that taking a pharmaceutical-grade chondroitin product (Chondrosulf) 800 mg daily seems to be comparable to taking celecoxib 200 mg daily for reducing pain and improving knee function (94360). Pharmaceutical-grade chondroitin products might demonstrate greater benefit due to higher quality (94360,102116). It is also important to note that most clinical studies using pharmaceutical-grade products are manufacturer-funded (94381). Furthermore, they may not be readily available for purchase in the US. Experts have conflicting stances on the use of chondroitin for osteoarthritis. The American College of Rheumatology (ACR) strongly recommends against the use of chondroitin for any form of osteoarthritis (102114). Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade chondroitin products. Additionally, the ESCEO provides a weak recommendation against the use of chondroitin in combination with glucosamine (102141). These differing recommendations seem to be related to interpretation of the evidence for pharmaceutical-grade products. The ACR has determined that the inconsistent evidence may indicate the presence of industry bias; the ESCEO has determined that the inconsistent evidence is due to inconsistent product quality. Chondroitin is often used in combination with glucosamine and/or other products. Long-term studies in patients with osteoarthritis show that taking non-branded chondroitin sulfate with glucosamine sulfate modestly reduces joint-space narrowing when compared with control (89558,94380,95792). However, meta-analyses and individual clinical studies assessing non-branded preparations of chondroitin sulfate with glucosamine hydrochloride or glucosamine sulfate do not show reduced pain in patients with knee osteoarthritis when compared with control (13579,89558,95788,99683,99685). In contrast, pain reduction was reported for branded formulations such as chondroitin sulfate with glucosamine hydrochloride and manganese ascorbate (Cosamin DS, Nutramax Laboratories) (4237,7169); chondroitin sulfate with glucosamine hydrochloride (Droglican, Bioiberica, S.A.) (89516); or chondroitin sulfate with collagen peptides and hyaluronic acid (BioCell Collagen, BioCell Technology, LLC) (28678,28680). A large, prospective observational study in adults with knee or hip osteoarthritis suggests that taking glucosamine hydrochloride 500 mg and chondroitin sulfate 400 mg (Theraflex, Bayer) three times daily for the first 3 weeks, then twice daily thereafter for up to 64 weeks, is associated with reductions in pain, stiffness, and the need for concomitant analgesic therapy, and improvements in daily function and knee- or hip-related quality of life, when compared to baseline. The most pronounced improvements are from 16-24 weeks (111647). It is unclear if the benefit seen with these specific products is due to bias introduced by industry funding or due to higher quality. Limited research has also evaluated INTRAMUSCULAR and TOPICAL chondroitin. Some clinical research shows that receiving daily intramuscular injections of chondroitin sulfate for 6 months improves pain and function in patients with osteoarthritis (42396,42397). A topical preparation of chondroitin sulfate in combination with glucosamine sulfate, shark cartilage, and camphor also seems to reduce arthritis symptoms. However, any symptom relief is most likely due to the counterirritant effect of camphor and not the other ingredients (10327). There is no research showing that chondroitin is absorbed topically.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with aging skin shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing chondroitin sulfate 200 mg, collagen peptides 600 mg, and hyaluronic acid 100 mg daily for 12 weeks reduces lines and wrinkles by about 13% when compared with baseline (28681). The validity of these findings is limited by the lack of a comparator group. It is also unclear if these improvements are due to chondroitin sulfate, other ingredients, or the combination. Furthermore, it should be noted that this study was funded by the product manufacturer.
• Aromatase inhibitor-induced arthralgia. Oral chondroitin sulfate has only been evaluated in combination with glucosamine sulfate; its effect when used alone is unclear. Details: A small open-label clinical study in postmenopausal females with early stage breast cancer shows that taking a combination of glucosamine sulfate 1500 mg and chondroitin sulfate 1200 mg in 2-3 divided doses daily for 24 weeks improves pain and symptoms associated with aromatase inhibitor-induced arthralgias when compared to baseline (89561). The validity of this finding is limited by the lack of a control group.
• Cancer. Some low-quality observational studies suggest that oral chondroitin use is not associated with a lower risk of cancer. Details: A meta-analysis of observational research has found that use of chondroitin with or without glucosamine is not associated with a lower risk of cancer when compared with no use (110625).
• Colorectal adenoma. Oral chondroitin has only been evaluated in combination with glucosamine; its effect when used alone is unclear. Details: An observational study in older adults has found that taking oral chondroitin and glucosamine is associated with a 26% reduced chance of high-risk adenoma and 10% reduced chance of conventional adenoma when compared with not using these supplements. This benefit was not seen in a subgroup of younger females (104444).
• Dry eye. It is unclear if ophthalmic chondroitin sulfate improves dry eye symptoms. Details: A small clinical study in patients with dry eye suggests that administering an ophthalmic preparation of chondroitin sulfate every two hours while awake for 2 weeks seems to improve symptoms when compared to baseline (1974). Chondroitin has also been used in combination with other ingredients. A large clinical trial in patients with mild to moderate dry eye disease shows that applying preservative-free eye drops containing chondroitin sulfate with sodium hyaluronate (Humylub Ofteno PF, Laboratorios Sophia), one drop into each eye four times daily for 90 days, seems to be no different for improving dry eye severity when compared with using polyethylene/propylene glycol eye drops (Systane Ultra, Alcon Laboratories) (104443). Another small clinical trial in patients with mild to moderate dry eye shows that using specific eye drops containing chondroitin sulfate and xanthan gum (PRO-148, Laboratorios Sophia) four times daily for 60 days does not improve tear stability, but might improve dry eye severity, when compared with using polyethylene/propylene glycol eye drops (Systane, Alcon Laboratories) (89591).
• Exercise-induced muscle soreness. It is unclear if oral chondroitin sulfate improves muscle soreness from exercise. Details: Preliminary clinical research in untrained males shows that taking chondroitin sulfate 1800 mg twice daily for 14 days before exercise does not reduce post-exercise muscle soreness when compared with placebo (42352). However, another small clinical study in healthy, recreationally active adults shows that a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing chondroitin sulfate 300 mg, collagen peptides 900 mg, and hyaluronic acid 150 mg, taken twice daily for 6 weeks prior to two bouts of resistance exercise, attenuates muscle damage and decreases delayed-onset muscle soreness when compared with placebo (96301). It is unclear if these effects are due to chondroitin sulfate, the other ingredients, or the combination.
• Gastroesophageal reflux disease (GERD). Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Patients with non-erosive GERD are thought to be less responsive to conventional acid suppression with proton pump inhibiters (PPIs) and H-2 blockers. A small preliminary clinical study shows that taking a syrup containing hyaluronic acid and chondroitin sulfate along with PPIs, H2-receptor antagonists, and/or antacids, reduces the intensity of symptoms associated with non-erosive GERD by about 3.5-fold when compared with placebo (89592). A larger clinical study in patients with non-erosive GERD shows that taking the same combination agent (Esoxx by Alfa Wassermann) in addition to acid suppression with PPIs improves GERD symptom severity by 21%, heartburn by 15%, and regurgitation by 10% when compared with PPIs with a placebo (101271). This product is available in Canada as EsopH (Exzell Pharma). It is unclear if the benefit of this combination product is due to chondroitin sulfate, hyaluronic acid, or the combination. Chondroitin sulfate has also been evaluated in patients with GERD who experience extraesophageal symptoms. A small clinical study in patients reporting symptoms of cough, hoarseness, postnasal drip, sore throat, and/or throat clearing shows that taking a specific combination product (Gerdoff, SOFAR S.p.A.) containing chondroitin sulfate, hyaluronic acid, and aluminum hydroxide three times daily with omeprazole 40 mg once daily for 6 weeks does not reduce overall symptom scores, based on the Reflux Symptoms Index (RSI) score, when compared with omeprazole alone. However, it does increase the probability of treatment response, defined as a 50% or greater improvement in RSI score, by nearly 40% (109648). This product is available in Italy. It is unclear if these findings are due to chondroitin sulfate, other ingredients, or the combination.
• Gastritis. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with gastritis shows that taking a specific liquid product (Esoxx, Alfa Wasserman Spa) containing chondroitin sulfate and hyaluronic acid four times daily for 4 weeks modestly reduces upper abdominal pain when compared with placebo (99687). It is not clear if this effect is due to chondroitin sulfate, hyaluronic acid, or the combination.
• Hyperlipidemia. Although there is interest in using oral chondroitin for hyperlipidemia, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Interstitial cystitis. Small clinical studies suggest that intravesical chondroitin sulfate may not improve interstitial cystitis symptoms. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Several uncontrolled, open-label studies suggest that intravesical chondroitin sulfate, with or without hyaluronic acid, improves clinical symptoms of interstitial cystitis and reduces the problems caused by symptoms in these patients (42338,42371,42373,42385,42387). However, in controlled clinical trials, intravesical chondroitin sulfate 2%, instilled weekly for 6-7 weeks, does not significantly improve symptoms when compared with a placebo solution (42473,42517). Furthermore, a meta-analysis of clinical research shows that intravesical chondroitin sulfate with hyaluronic acid does not improve pain due to interstitial cystitis better than using hyaluronic acid solution alone (97054). Oral chondroitin has been evaluated in combination with other ingredients. Preliminary clinical research shows that taking a specific product (CystoProtek, Tischon Corporation) containing glucosamine sulfate 120 mg, sodium hyaluronate 10 mg, chondroitin sulfate 150 mg, quercetin 150 mg, and rutin 20 mg, as two capsules twice daily for 12 months, reduces symptoms of interstitial cystitis by 44% to 52% (42391). It is not clear if this effect is due to chondroitin, other ingredients, or the combination.
• Kashin-Beck disease. It is unclear if oral chondroitin sulfate improves Kashin-Beck disease symptoms such as pain. Details: A small clinical study in Chinese adults with Kashin-Beck disease shows that taking chondroitin sulfate 600 mg twice daily with or without glucosamine hydrochloride 480 mg three times daily for 6 months decreases pain and stiffness when compared with placebo (42516).
• Osteoporosis. Although there is interest in using oral chondroitin for osteoporosis, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Overall mortality. Oral chondroitin has only been evaluated in combination with glucosamine; its effect when used alone is unclear. Details: A cross-sectional observational study suggests that using oral chondroitin and glucosamine for at least one year is associated with a 27% lower incidence of overall mortality and 58% lower incidence of cardiovascular mortality when compared with not using these supplements (104445). However, this study did not clarify the forms of chondroitin and glucosamine used, or the doses, frequencies, or durations of use. Furthermore, the adults that reported glucosamine and chondroitin use also reported overall healthier lifestyle habits than those that were not taking glucosamine and chondroitin. Another observational study suggests that regular use of chondroitin with glucosamine for an average of 8 years is associated with a 30% lower risk of mortality when compared with no use. However, when these findings are adjusted for differences in age, body mass index, and comorbidities, overall mortality risk does not seem to be reduced with chondroitin and glucosamine supplementation (110626). Higher quality, prospective research is needed to clarify the relationship, if any, with overall mortality. Additionally, it is unclear if the effects on mortality are due to chondroitin, glucosamine, or the combination.
• Psoriasis. It is unclear if oral chondroitin sulfate is beneficial for reducing psoriasis disease severity. Details: A clinical study in patients with plaque psoriasis and knee osteoarthritis shows that taking chondroitin sulfate (Condrosan, CS Bio-Active, Bioibérica S.A.) 800 mg daily for 3 months does not appear to reduce the extent or severity of plaque psoriasis when compared with placebo (42463).
• Stroke. It is unclear if oral chondroitin sulfate is beneficial for reducing stroke risk. Details: An observational study in Spanish patients found that chondroitin sulfate use is associated with 23% lower odds of ischemic stroke when compared with non-use; however, the benefit was only observed in patients taking at least 800 mg for no more than one year (109643).
• Temporomandibular disorders (TMD). Oral and topical chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of two small clinical studies in patients with TMD shows that taking chondroitin sulfate 1200 mg and glucosamine sulfate 1500 mg daily for 2 months does not reduce pain or increase maximum mouth opening when compared with tramadol 50-100 mg daily (109647). Another small clinical trial in children aged 10-13 years with class II malocclusion shows that application of a specific combination gel product containing glucosamine, chondroitin, and essential oils (Jointace Gel, Vitabiotics) with an expander device twice daily for 3 months does not improve pain, tension, or temporomandibular space measures when compared with placebo (110629).
• Urinary incontinence. Although there is interest in using intravesical chondroitin for urinary incontinence, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Urinary tract infections (UTIs). It is unclear if intravesical administration of chondroitin sulfate alone is beneficial in patients with recurrent UTIs. Most research has evaluated the effects of chondroitin sulfate in combination with hyaluronic acid, with promising results. Details: One small observational study in patients with recurrent UTIs has found that intravesical administration of 40 mL of chondroitin sulfate 0.2% weekly for 6 weeks, then every 2 weeks for 2 months, then every 3 weeks for 2 months, and finally every 6 weeks for a total treatment duration of 1 year is associated with a lower number of UTIs and urologist visits when compared with low-dose long-term antibiotic therapy (109649). Most research on the use of chondroitin sulfate for UTIs has evaluated its effects when used in combination with hyaluronic acid. Several small clinical studies and a pooled analysis of the available clinical research show that intravesical administration of 50 mL of specific solutions containing chondroitin sulfate 2% and hyaluronic acid 1.6% (iAluRil, IBSA Farmaceutici; Cystistat, Bioniche) for up to 6 months reduces the rate of UTI recurrence by about 2-3 incidents per year and delays the time to the first UTI recurrence when compared with placebo or prophylaxis with sulfamethoxazole-trimethoprim (42511,42519,89590,89594,99688). However, the validity of these findings is limited by the low quality and high heterogeneity of the included studies, as well as concerns for publication bias (99688). More evidence is needed to rate chondroitin sulfate for these uses.

(Read more about CHONDROITIN SULFATE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral hops-derived bitter acids are beneficial for memory and attention in patients with age-related cognitive decline. Details: A small exploratory clinical study in older adults aged 45-64 years, with self-awareness of cognitive decline, shows that taking matured hops bitter acids (Kirin Holdings Co. Ltd) 35 mg daily for 12 weeks does not improve memory, attention, or performance on most cognitive tests when compared with placebo (102899). A follow-up clinical study in patients aged 45-69 years with subjective cognitive decline shows that taking the same dose of the same product for 12 weeks also does not improve memory, learning, or selective attention, but might improve divided attention as measured on the Symbol Digit Modalities Test (SDMT), when compared with placebo (105953). Both studies were funded by the supplement manufacturer and conducted in Japan; it is unclear if these findings are generalizable to other geographic locations.
• Anxiety. Although there is interest in using oral hops for anxiety, there is insufficient reliable information about the clinical effects of hops for this condition.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral hops for ADHD, there is insufficient reliable information about the clinical effects of hops for this condition.
• Body odor. Although there is interest in using topical hops to reduce body odor, there is insufficient reliable information about the clinical effects of hops for this purpose.
• Insomnia. Taking oral hops extract in combination with valerian root extract seems to be modestly beneficial in patients with insomnia. However, the effect of hops extract when used alone is unclear. Details: In patients with diagnosed sleep disorders, taking hops extract in combination with valerian root for at least 28 days seems to be beneficial. One clinical study in adults with mild insomnia shows that taking two tablets of a combination product containing a total of 83.8 mg hops extract and 374 mg valerian root extract nightly seems to modestly improve subjective sleep measures, including sleep latency, when compared with placebo, after 28 days. However, there was no difference in efficacy between treatment groups after only 14 days (15018). Additionally, a small clinical study in patients with non-organic sleep disorders shows that taking a specific fixed combination product (Ze91019) containing hops extract 120 mg and valerian root extract 500 mg daily for 28 days improves sleep latency when compared with placebo (19413). It is unclear if taking hops and valerian root as a single dose is beneficial in healthy patients. One small clinical study in healthy volunteers with poor sleep shows that taking a specific preparation (Dormeasan, Bioforce AG) containing hops extract 460 mg and valerian root extract 460 mg dissolved in 50 mL of honey water once at night increases total sleep time and time spent in deep sleep when compared with placebo (19418). However, another preliminary clinical study in healthy adults shows that taking a single dose of a specific product (Hova, Zyma S.A.) containing hops extract 200 mg and valerian root extract 400 mg does not improve sleep latency when compared with placebo (6248). Research also shows that taking certain combination products containing hops and at least two other ingredients can improve sleep quality. These combination products have combined hops with lemon balm and valerian (Valerina Natt) (19417); or passionflower and valerian (NSF-3, M/s Tablets India) (88193,89406). However, other combination products have not been beneficial. These have combined hops with soya oil, soya lecithin, and cannabis (Cyclamax, Persee Medica) (55382); or with vitamin B6, zizyphus extract, hydrolyzed milk protein (Lactium), and magnesium oxide (LZ Complex3, Sanofi) (95971).
• Dyspepsia. Although there is interest in using oral hops-derived bitter acids for dyspepsia, there is insufficient reliable information about the clinical effects of hops for this condition.
• Lactation. Although there is interest in using oral hops for increasing lactation, there is insufficient reliable information about the clinical effects of hops for this purpose.
• Menopausal symptoms. It is unclear if oral hops extract is beneficial in patients with menopausal symptoms. Details: Small clinical studies in menopausal patients show that taking a specific hops extract (MenoHop, Biodynamics) 75.1-300 mg standardized to contain 100-200 mcg of 8-prenylnaringenin daily does not improve menopausal symptoms, including hot flashes, after 8-12 weeks of treatment when compared with placebo (55338,55370).
• Overactive bladder. Oral hops extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in females with overactive bladder has found that taking a specific combination product (Granu Fink femina, Omega Pharma) containing hops extract 18 mg, sweet sumac bark extract 56 mg, and pumpkin seed oil 227 mg three times daily for 12 weeks decreases the frequency of urination from an average of 0.9 to 0.4 episodes daily and the frequency of leakage when compared with baseline. The study also shows this specific combination product (Granu Fink femina, Omega Pharma) improves quality of life when compared with baseline (103253). The validity of these findings is limited by the lack of a control group. Also, it is unclear if these findings are due to hops extract, other ingredients, or the combination.
• Psychological well-being. It is unclear if drinking non-alcoholic beer containing matured hops bitter acids is beneficial in healthy adults. Details: A clinical study in healthy adults shows that consuming 350 mL of non-alcoholic beer containing matured hops bitter acids 35 mg (Kirin Holdings Co. Ltd) daily for 3 weeks improves mood scores on the Profile of Mood States 2 (POMS2) and Two-dimensional Mood Scale (TDMS) when compared with baseline (107813). The validity of these findings is limited by the lack of a control group.
• Shift work disorder. It is unclear if drinking non-alcoholic beer containing hops is beneficial in patients with shift work disorder. Details: A small open-label clinical study in healthy female nurses working rotating or night shifts shows that drinking 333 mL of non-alcoholic beer containing hops (San Miguel 0% alcohol) at dinner for 2 weeks diminishes sleep latency by about 8 minutes, decreases total activity during the night, and decreases anxiety when compared with baseline. However, it does not appear to increase duration of sleep (55403). The validity of these findings is limited by the lack of a control group and unconfirmed hops content in the beer.
• Vaginal atrophy. Topical hops extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An open-label, multicenter clinical study in postmenopausal patients with vaginal atrophy shows that inserting 2.5 grams of a vaginal gel containing hops extract 1%, hyaluronic acid, liposomes, and vitamin E (Gynomunal Vaginal gel or Esvegyne, Polichem SA) into the vagina daily for one week followed by twice weekly for 11 weeks reduces vaginal dryness, burning, itching, and rash when compared with baseline (55339). The validity of these findings is limited by the lack of a control group. Also, it is unclear if these effects are due to hops, other ingredients, or the combination.
• Venous leg ulcers. Although there is interest in using topical hops for venous leg ulcers, there is insufficient reliable information about the clinical effects of hops for this condition. More evidence is needed to rate hops for these uses.

(Read more about HOPS)

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))

LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

(Read more about SODIUM)

POSSIBLY EFFECTIVE

• Back pain. Oral willow bark extract has been evaluated for the treatment of back pain, with promising results. Details: Clinical research in patients with chronic low back pain shows that taking a standardized willow bark extract providing salicin 120 mg or 240 mg daily for 4 weeks reduces lower back pain and decreases the need for rescue analgesia when compared with placebo. Salicin 240 mg appears to be more effective than salicin 120 mg, and significant pain relief may be observed after 1 week of high-dose use (6456). Additional research suggests that taking willow bark extract providing salicin 240 mg daily for 4 weeks is as effective as rofecoxib (Vioxx) for lower back pain (12804).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Ankylosing spondylitis. Although there has been interest in using oral willow bark for pain associated with ankylosing spondylitis, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Common cold. Although there has been interest in using oral willow bark for common cold symptoms, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Dysmenorrhea. Although there has been interest in using oral willow bark for dysmenorrhea, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Gout. Although there has been interest in using oral willow bark for gout, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Headache. Although there has been interest in using oral willow bark for headache, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Influenza. Although there has been interest in using oral willow bark for pain and fever associated with influenza, including swine flu, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Joint pain. Oral willow bark has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with joint pain shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 500 mg, methylsufonlylmethane 167 mg, white willow bark extract 83 mg, ginger root concentrate 17 mg, boswellia extract 42 mg, turmeric root extract 17 mg, cayenne 40 m H.U. 17 mg, and hyaluronic acid 1.3 mg three times daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, the specific combination product does not appear to significantly improve joint stiffness or function when compared with placebo (89560). It is unclear if these findings are due to willow bark, other ingredients, or the combination.
• Myalgia. Although there has been interest in using oral willow bark for myalgia, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Obesity. Oral willow bark has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests that willow bark in combination with ephedra and cola nut might cause modest weight loss in overweight and obese people. Willow bark 600 mg daily (containing 90 mg salicin) in divided doses given for 3 months in combination with these central nervous system stimulants might cause a 2 kg reduction in weight (12811). However, this combination may not be appropriate due to safety concerns associated with ephedra. Ephedra is banned in the US due to severe adverse effects (10055).
• Osteoarthritis. Small clinical studies suggest that oral willow bark extract may improve symptoms of osteoarthritis, although some conflicting evidence exists. Details: Some preliminary clinical research in patients with osteoarthritis shows that taking willow bark extract standardized to contain 240 mg of salicin daily for 2 weeks produces moderate analgesic activity when compared with placebo (12474,86490). Additional research shows that taking a specific willow bark extract (Optovit actiFLEX, Hermes Arzneimittel GmbH) standardized to contain salicin 120-240 mg daily for 6 weeks improves swelling, tenderness, and physical function similarly to conventional non-steroidal anti-inflammatory drugs (NSAIDs) (91406). However, other research shows that taking willow bark extract standardized to 240 mg of salicin daily for 6 weeks does not improve pain, stiffness, or physical function when compared with placebo (12475).
• Rheumatoid arthritis (RA). It is unclear if oral willow bark is beneficial in patients with RA. Details: Clinical research in a small number of patients with RA shows that willow bark extract standardized to 240 mg of salicin daily for 6 weeks does not improve pain when compared with placebo (12475). However, it is possible this study was underpowered to detect a significant difference in pain in these patients. More evidence is needed to rate willow bark for these uses.

(Read more about WILLOW BARK)

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

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

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

(Read more about CHONDROITIN SULFATE)

LIKELY SAFE ...when consumed in amounts commonly found in foods. Hops extract and hops oil have Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when hops extract and hops-derived bitter acids are used orally and appropriately for medicinal purposes, short-term. Hops extract has been used with apparent safety in doses of up to 300 mg daily for 2-3 months. Hops-derived bitter acids have been used with apparent safety at a dose of 35 mg daily for 3 months (12,55338,55370,102899,105953,107813).

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

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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.

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LIKELY SAFE ...when used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Willow bark has been used safely for up to 12 weeks (6456,12474,12475,12804,12811,86473,91406).

CHILDREN: POSSIBLY UNSAFE
when used orally for viral infections. Salicylic acid and aspirin are contraindicated in children with viral infections (12801). Although Reye's syndrome has not been reported, the salicin constituent in willow bark is similar to aspirin and might pose the same risk.

PREGNANCY:
Insufficient reliable information available; avoid using.

LACTATION: POSSIBLY UNSAFE
when used orally. Willow bark contains salicylates which are excreted in breast milk and have been linked to adverse effects in breast-fed infants (12802,12803).

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

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

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

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

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

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

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

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CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of hops with sedative drugs might cause additive sedation.  Details Some animal research shows that hops has sedative effects (55415,55340,105930).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Hops extract does not seem to affect the metabolism of CYP1A2 substrates.  Details In vitro research suggests that flavonoid constituents of hops inhibit CYP1A2 enzyme activity (10686). However, a pharmacokinetic study in healthy postmenopausal patients shows that taking a standardized extract of spent hops containing prenylated phenols, as 59.5 mg twice daily for 2 weeks, does not affect levels of caffeine, a CYP1A2 probe substrate (105954).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, hops extract might alter metabolism of CYP3A4 substrates; however, this effect may not be clinically significant.  Details Animal research suggests that specific constituents of hops, called lupulones, can induce hepatic CYP3A4 enzyme activity (55325). However, a pharmacokinetic study in healthy postmenopausal patients with normal metabolism shows that taking a standardized extract of spent hops containing prenylated phenols, as 59.5 mg twice daily for 2 weeks, decreases the concentration of alprazolam, a CYP3A4 probe substrate, by 7.6%. This reduction is unlikely to be clinically relevant (105954).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of large amounts of hops might interfere with hormone replacement therapy due to competition for estrogen receptors.  Details In vitro research suggests that certain hops constituents can competitively bind to estrogen receptors (3701,10684,10685). However, most hops extracts contain very small amounts of these constituents (105930).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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ACETAZOLAMIDE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, willow bark might result in additive adverse effects associated with acetazolamide.  Details Willow bark contains salicin, a plant salicylate. Human case reports suggests that a combination of acetazolamide and salicylate increases unbound plasma levels of acetazolamide, as well as adverse effects related to acetazolamide (86481).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the risk of bleeding when taken with anticoagulant/antiplatelet drugs.  Details Willow bark has antiplatelet effects, but less so than aspirin (12810).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of aspirin.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as aspirin (12808).

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of choline magnesium trisalicylate.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as choline magnesium trisalicylate (12808).

SALSALATE (Disalcid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of salsalate.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as salsalate (12808).

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

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

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

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

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

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

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

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

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

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

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

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

Hepatic ...Although relatively uncommon, combinations of glucosamine and chondroitin sulfate have been associated with acute liver injury that mimics autoimmune hepatitis. Two cases of elevated aminotransferase levels have been reported for patients taking glucosamine (form unspecified) and chondroitin sulfate at recommended doses. Aminotransferase levels, which were increased by four- to seven-fold, returned to normal following discontinuation of treatment (89515). Another case of abdominal pain, jaundice, fatigue, and elevated liver enzymes has been reported for a patient who used chondroitin sulfate (Condrosulf) for 2 years followed by a combination of glucosamine sulfate and chondroitin sulfate (Vita Mobility Complex) for 8 weeks. The patient required maintenance treatment with azathioprine to remain in remission (89518). A case of acute cholestatic hepatitis due to Glucosamine Forte, which contains glucosamine hydrochloride, chondroitin sulfate, Devil's claw, and shark cartilage, has been reported (89522). It is unclear whether these adverse events were related to chondroitin sulfate, other ingredients, or the combination.

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

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

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

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

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General ...Orally, hops extract and oil are generally well tolerated when used in food amounts. Hops extract also seems to be well tolerated when used in supplemental amounts.
Most Common Adverse Effects:
Orally: Drowsiness, sedation.

Dermatologic ...Topically, allergic reactions have been reported after contact with the fresh hops plant and plant dust. Contact dermatitis is attributed to the pollen (4,12,105930).

Genitourinary ...Orally, supplements containing hops and soy have been associated with 4 cases of postmenopausal bleeding (55404). It is unclear if this effect is due to hops, soy, or the combination. Also, menstrual disturbances have been reported in female workers harvesting hops (10684,55405).

Neurologic/CNS ...Orally, hops might cause drowsiness and sedation. Historically, hops are thought to have sedative effects, since workers harvesting hops were observed to tire easily after oral contact with hop resin. The European Medicines Agency states that hops may have sedative effects; however, there is a lack of clinical research confirming that hops extract causes drowsiness and sedation (105930).

Pulmonary/Respiratory ...Occupational exposure to dust from hops, usually in combination with dust from other products, is associated with chronic respiratory symptoms such as dry cough, dyspnea, chronic bronchitis, and other occupational respiratory diseases (55333,55414).

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

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

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

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

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

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

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General ...Orally, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

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General ...Orally, willow bark seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, dyspepsia, heartburn, and vomiting. May cause itching and rash in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal bleeding and renal impairment. May cause serious allergic reactions, including anaphylaxis, in people who are allergic to aspirin.

Cardiovascular ...In one clinical trial, a single patient withdrew from the study investigating oral willow bark due to blood pressure instability that the authors determined was 'possibly' related to treatment (12804).

Dermatologic ...Orally, willow bark may cause itching and rash in some people due to allergy (6456,12474,12475,12804,86459).

Gastrointestinal ...Orally, willow bark extract can cause gastrointestinal adverse effects, but these appear to be less frequent than those caused by NSAIDs. Examples include diarrhea, heartburn, vomiting, and dyspepsia (12474,12475,12804,86459). In a case report of a child, severe gastrointestinal bleeding occurred following use of a specific syrup (FreddoBaby), which contained ribwort plantain, licorice, willow bark, black elder, meadowsweet, and propolis. The adverse effect was attributed to salicylate content of the syrup. This product has since been withdrawn from the market (86477).

Immunologic ...Orally, willow bark may cause serious allergic reactions, including anaphylaxis, in people who are allergic to aspirin (10392)

Neurologic/CNS ...Orally, willow bark may cause headache and dizziness (12804). In a clinical trial evaluating a combination product containing willow bark, black cohosh, sarsaparilla, poplar bark, and guaiac wood (Reumalex), severe headaches occurred (35946).

Ocular/Otic ...Orally, symptoms of allergy to willow bark have included swollen eyes (6456).

Renal ...Salicylates can inhibit prostaglandins, which can reduce renal blood flow (12805). Salicin can cause renal papillary necrosis (12806). The risk for toxicity is greater with high acute doses or chronic use (12805).

(Read more about WILLOW BARK)