GI Select Powder [Discontinued] by Moss Nutrition

POSSIBLY EFFECTIVE

• Acne. Topical aloe gel may reduce acne lesions when used with topical tretinoin in children and adults with acne. Details: One clinical trial in children and adults with acne shows that topical application of a gel containing aloe 50% in the morning and evening, in addition to topical application of tretinoin 0.025% cream and twice daily cleansing with a medical soap, improves acne lesions by approximately 35% more than using the same treatments without aloe (90124).
• Burns. Topical aloe gel or cream may reduce healing time in patients with superficial or partial thickness burns. Details: A meta-analysis of four small clinical trials in patients with second-degree burns shows that use of topical aloe vera reduces time to healing by about 4.4 days when compared to control groups treated with silvadene, silver sulfadiazine, or gauze containing 0.5% chlorhexidine acetate (110209). Most clinical research shows that applying aloe gel or cream topically up to twice daily reduces healing time when compared with silver sulfadiazine (19771,110210,110212), framycetin (19775), vaseline gauze (19773), or placebo (101,97320) in patients with superficial or partial thickness burns. Topical application of aloe cream up to twice daily might also decrease wound size when compared with silver sulfadiazine and framycetin (19771,19775). In addition, some clinical research in patients with burns caused by sulfur mustard shows that applying cream containing aloe and olive oil twice daily for 6 weeks improves pruritus similarly to betamethasone 0.1% cream and may lead to further reductions in excoriation and fissure (19768). However, some preliminary clinical research shows that applying fresh aloe mucilage or aloe extract daily is no more effective than silver sulfadiazine for reducing wound healing time in patients with superficial or partial thickness burns (19774,19776).
• Constipation. Oral aloe latex may improve symptoms in patients with constipation; however, the U.S. Food and Drug Administration (FDA) has banned the use of aloe latex as a laxative due to safety concerns. Details: Taking aloe latex 100-200 mg daily or aloe extract 50 mg as a stimulant laxative seems to relieve constipation due to the cathartic effects of the anthraquinones in the aloe (4,5,8). Taking 1-3 capsules of a formulation containing aloe 150 mg, celandine 300 mg, and psyllium 50 mg also seems to improve stool consistency and the mean number of stools in patients with chronic constipation when compared with placebo (19747). However, in 2002, the U.S. FDA banned the use of aloe latex for constipation due to safety concerns (8229,8443).
• Diabetes. Oral aloe may reduce blood glucose and glycated hemoglobin (HbA1c) in patients with diabetes. It may be most effective in patients with fasting blood glucose levels of 200 mg/dL or greater. Details: Most clinical research in adults with prediabetes and diabetes shows that taking aloe vera orally can reduce fasting blood glucose by 30-47 mg/dL and HbA1c by 0.41% to 1% (12164,17488,17489,19756,95943,95945,95946). One meta-analysis of 92 patients shows that aloe vera is associated with a larger overall reduction of fasting blood glucose in those with a baseline fasting blood glucose level greater than or equal to 200 mg/dL (95945). Another meta-analysis of 206 patients shows that aloe vera increases high-density lipoprotein (HDL) levels and reduces triglyceride, total cholesterol, and low-density lipoprotein (LDL) levels when compared with placebo in adults with prediabetes and untreated diabetes (95943). These analyses include studies that used multiple forms of aloe vera, including gel powder, extract, raw crushed leaves, and fresh extracted juice, as well as multiple doses ranging from 100-1000 mg of powder and 15-150 mL of juice taken for durations ranging from 4-14 weeks. Significant heterogeneity between studies, small sample sizes, and wide variability in the form and dose of aloe used limit the validity of these findings and the ability to identify an effective dose (95943,95945,95946). Additionally, some research has shown no benefit. This may be due to the different forms and doses of aloe used. One clinical study shows that taking aloe gel as 15 mL twice daily or taking aloe juice 15 mL twice daily does not decrease glucose levels in patients with type 2 diabetes (17420). Other clinical research shows that taking a specific aloe gel complex (Aloe QDM complex, Univera Inc.) containing processed aloe gel 147 mg twice daily for 8 weeks does not affect glycemic indices when compared with placebo in patients with diabetes or prediabetes (90121).
• Genital herpes. Topical aloe extract cream may improve healing of genital herpes lesions. Details: Clinical research in males with genital herpes shows that applying a cream containing aloe extract 0.5% three times daily, 5 days weekly, for up to 2 weeks increases healing rates when compared with aloe gel or placebo. The mean time to healing after application of the aloe extract was 5 days, compared with 12 days with placebo (12164,19745,19746).
• Lichen planus. Rinsing the mouth with aloe-containing mouthwash or applying aloe gel to the mouth or vulva may reduce pain and improve lesion healing in patients with lichen planus. Details: Clinical research in patients with oral lichen planus shows that using 0.4 mL of mouthwash containing aloe gel 70% three times daily for 12 weeks or applying a gel containing aloe mucilage 70% twice daily for 8 weeks is up to 6 times more likely to reduce pain when compared with placebo (19762,19763,19764). However, these findings are questionable due to poor study design. Other clinical research in patients with oral lichen planus shows that using 2 tablespoons of aloe-containing mouthwash four times daily for a month, or applying aloe gel three times daily for 8 weeks, reduces pain and improves lesion healing at least as much as triamcinolone acetonide paste (0.1% in one study) (19765,90130). However, aloe gel may not be as beneficial as laser therapy. A clinical study in patients with lichen planus show that applying a gel containing aloe powder 500 mg to the affected site three times daily for 2 months is less effective for improving pain and lesion healing than receiving low-level laser therapy twice weekly for 2 months. However, no between-group differences were maintained at 7 months after treatment completion (108722). A network meta-analysis of 2 small clinical trials shows that applying aloe trails only purslane of the herbal agents studied with regard to clinical improvement as measured by the Thongprasom scale. However, aloe does not seem to improve complete clinical resolution, clinical scores, or pain (111640). In patients with vulval lichen planus, clinical research shows that topical application with aloe gel twice daily for 8 weeks increases the number of patients who experience clinical improvement of at least 50% when compared with placebo (19766).
• Obesity. Oral aloe gel may modestly reduce body weight and fat mass in adults who are overweight or obese. Details: One clinical trial in overweight and obese adults with diabetes or prediabetes shows that taking a specific aloe gel complex (Aloe QDM complex, Univera Inc.) containing processed aloe gel 147 mg twice daily for 8 weeks reduces body weight by 0.6 kg and fat mass by 1 kg when compared with placebo (90121).
• Oral submucous fibrosis. Topical aloe may reduce burning sensations in patients with oral submucous fibrosis, but it may not improve mouth opening, tongue protrusion, or cheek flexibility in these patients. Details: A meta-analysis of five small clinical studies in patients with oral submucous fibrosis shows that topical application of aloe gel for 3 months reduces burning sensation, possibly for up to two months after treatment, when compared with placebo or active control. A network meta-analysis also found that aloe is most effective in reducing burning sensation, ranked only after treatment with corticosteroids, hyaluronidase, and antioxidants (113514). However, aloe does not seem to improve mouth opening, tongue protrusion, or cheek flexibility (100256). One of the studies included in the analysis used a specific aloe gel (Sheetal lab Surat) 5 mg applied topically on each side of the buccal mucosa three times daily for 3 months (90131). All of the studies included in the analysis were conducted in India, so it is unclear if the results are generalizable to other geographic locations. Limited research has also evaluated the use of topical and oral aloe vera in combination. A small clinical study shows that consuming pure aloe vera juice (Hamant Sai, Sun Vision Company) 30 mL twice daily and applying pure aloe vera gel (Hamant Sai, Sun Vision Company) three times daily for 3 months improves cheek flexibility and tongue protrusion when compared with a treatment regimen consisting of intralesional injections of hydrocortisone acetate 25 mg and hyaluronidase 1500 IU weekly for 6 weeks and supplementation with Cap SM Fibro (Indoco Remedies) twice daily for 3 months. Both treatment regimens show an improvement in mouth opening and burning sensation when compared to baseline, with the aloe vera treatment producing a more rapid improvement in burning sensation (95944). It is not clear how this combination of oral and topical aloe vera compares with topical aloe vera alone.
• Psoriasis. Topical aloe extract cream may reduce erythema and scaling and improve the resolution of psoriatic plaques in patients with psoriasis. Limited research suggests that topical aloe gel does not have the same effects. Details: Applying aloe extract 0.5% cream topically three times daily for 4 weeks significantly improves and increases the resolution of psoriatic plaques when compared with placebo (101,12096,12164). Aloe extract cream also seems to reduce desquamation, erythema, and infiltration (12096). Other preliminary clinical research shows that applying cream containing aloe mucilage 70% twice daily for 8 weeks improves psoriasis severity more effectively than triamcinolone 0.1% cream, although both treatments had similar effects on dermatology-specific quality of life (19741). Treatment with aloe gel does not seem to improve erythema, infiltration, and desquamation associated with psoriasis when compared with placebo (19748).
• Traumatic oral ulcers. Topical aloe gel may prevent oral ulcers after application of orthodontic appliances in adolescents and adults. Details: Clinical research in patients aged 12 years and older shows that applying a gel containing aloe 80% to the gums twice daily for one month after the cementation of orthodontic appliances prevents the development of mouth ulcers when compared with a chlorhexidine gel. Ulcers occurred in about 6% of patients using the aloe gel compared with 81% of those using the chlorhexidine gel. Bleeding and inflammation were also reduced (103305).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alveolar osteitis. It is unclear if topical aloe or the aloe constituent acemannan is beneficial in patients with alveolar osteitis. Details: One small clinical trial in patients with alveolar osteitis shows that applying a patch containing the aloe constituent acemannan (SaliCept patch) to the tooth socket, once after curettage and irrigation and again 3 days later, reduces pain intensity and improves clinical symptoms when compared with curettage and irrigation alone (19754).
• Amenorrhea. Although there has been interest in using oral aloe for amenorrhea, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Anal fissures. It is unclear if topical aloe is beneficial in patients with anal fissures. Details: One small clinical study in patients with chronic anal fissures shows that applying an aloe cream containing 0.5% powdered spray-dried inner aloe leaf juice (Zarban Phyto-Pharmaceutical Co) three times daily for at least 3 weeks, as an adjuvant to sitz baths three times daily, using a laxative, and eating a full fiber diet, improves pain, wound healing, and bleeding severity when compared with placebo (90129).
• Asthma. Although there has been interest in using oral aloe for asthma, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Atopic dermatitis (eczema). Topical aloe has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in patients with atopic dermatitis shows that application of a specific combination cream (Olivederma, Kimi Daru Pharmaceutical Co.) containing aloe gel and virgin olive oil twice daily for 6 weeks improves disease severity and quality of life when compared with betamethasone cream (105020). It is unclear if this effect is due to aloe, olive oil, or the combination.
• Breast engorgement. It is unclear if topical aloe improves lactation-associated breast pain. Details: Meta-analyses of 4-5 clinical trials in lactating patients show that use of topical aloe modestly reduces nipple/breast pain and irritation when compared with no treatment, routine care with topical breast milk or breast massage, or treatment with lanolin (110213). However, studies included in this analysis were not specific to breast engorgement.
• Burning mouth syndrome. It is unclear if topical aloe is beneficial in patients with burning mouth syndrome. Details: One small clinical trial in patients with chronic burning mouth syndrome shows that applying 0.5 mL of aloe 70% gel to sore areas on the tongue three times daily prior to wearing a tongue protector for 12 weeks does not improve pain or symptoms when compared with placebo gel or using the tongue protector alone in patients with chronic burning mouth syndrome (90127). However, differences in baseline pain ratings between study groups limit the validity of these findings.
• Cancer. Oral aloe has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with lung cancer shows that, when administered with standard chemotherapy, three daily doses of 10 mL of a mixture consisting of fresh aloe leaves 300 grams plus honey 500 grams dissolved in 40 mL of alcohol 40% increases the rate of complete response, partial response, or disease control when compared with chemotherapy alone (19752).
• Canker sores. Small clinical studies suggest that applying the aloe constituent acemannan to cancer sores may reduce ulcer size, but not pain. However, the effect of aloe is unclear. Details: Meta-analyses of clinical research show that topical aloe is no more effective than control interventions for reducing the size and pain of oral ulcers (110216). Control interventions have included carrier gel or triamcinolone acetonide 0.1% (19751,110216). However, a recent clinical trial shows that topical aloe gel (G.U.M Canker-X, Sunstar Americas, Schaumburg, USA) after meals and before bedtime for 5 days is more effective than amlexanox 5% paste and placebo for reducing pain and the size of canker sores in patients with recurrent symptoms (110215). Other small clinical trials have investigated the effects of fermented aloe or the aloe constituent acemannan. One small clinical trial in adults with recurrent canker sores shows that applying a fermented aloe gel to oral ulcers three times daily seems to accelerate healing time when compared with chitosan gel (104173). Another small clinical trial in patients with canker sores shows that using a wound dressing containing the aloe constituent acemannan (Carrisyn Gel Wound Dressing) shortens the average healing time of canker sores when compared with an oral analgesic (Orabase-Plain) (19750). Other clinical research shows that applying acemannan 0.5% in Carbopol 934P NF three times daily for 7 days reduces ulcer size, but not pain, when compared with Carbopol 934P NF alone in patients with canker sores (90123). However, applying triamcinolone acetonide 0.1% appears to be more effective in reducing pain and similarly effective in reducing ulcer size when compared with acemannan 0.5% (90123).
• Common cold. Although there has been interest in using oral aloe for the common cold, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Dental plaque. Using aloe-containing toothpaste may reduce dental plaque in adults; however, it is unclear if this is more effective than fluoride-containing toothpaste. Rinsing with an aloe-containing mouthwash may reduce dental plaque in children. Details: One small clinical trial in adults shows that brushing teeth with a dentifrice containing aloe gel (Forever Bright, Forever Living Products) three times daily for 30 days does not reduce the occurrence of plaque better than a fluoridated dentifrice (Sorriso Dentes Brancos, Kolynos do Brasil), although both treatments seem to show improvement when compared to baseline (19755). Another small clinical study in adults with gingivitis shows that using toothpaste containing aloe daily for 24 weeks reduces plaque more effectively than placebo or triclosan-containing toothpaste (19760). In children aged 8-14 years with mild plaque, using a mouth wash containing aloe vera 7% twice daily for 4 weeks reduced plaque by a large amount when compared with placebo. In addition, it was as effective as chlorhexidine 0.2% (103306).
• Depression. Although there has been interest in using oral aloe for depression, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Diabetic foot ulcers. It is unclear whether topical aloe is beneficial for patients with diabetic foot ulcers. Details: One small clinical trial in patients with a stage 1 or 2 diabetic foot ulcer who are receiving oral antibiotics shows that applying a topical product containing aloe and great plantain twice daily for 4 weeks reduces ulcer surface area and time to healing, but not ulcer depth, when compared with antibiotics alone (97323). The effect of applying aloe gel alone without concomitant oral antibiotic therapy is unknown.
• Diaper rash. Topical aloe has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial shows that applying a cream containing aloe gel and olive oil three times daily for 5-10 days reduces diaper rash severity in children less than 3 years of age when compared to baseline; however, it does not seem to be as effective as calendula ointment (19779). The validity of this finding is limited by the lack of a placebo group.
• Dry mouth. It is unclear if rinsing with an aloe-containing mouthwash is beneficial for dry mouth. Details: In patients with dry mouth related to type 2 diabetes, clinical research shows that an aloe vera 50% mouthwash, as 20 mL swished and spit three times daily for 14 days, modestly reduces symptoms of dry mouth when compared with rinsing with a saline control mouthwash (106068). The validity of this study is limited due to unclear reporting.
• Dry skin. Topical aloe or oral aloe sterols may improve some measures of dry skin. However, findings are mixed due to the use of varied formulations and doses. Details: One small clinical trial shows that applying a cream containing freeze-dried aloe extract 0.1% to 0.5% to the skin for 2 weeks increases the amount of water in the stratum corneum, but does not reduce transepidermal water loss, when compared with placebo (19758). Another small clinical study in females with occupational dry skin shows that wearing gloves coated in aloe 8 hours daily for 30 days improves symptoms of dry skin when compared with no treatment (19759). However, it is not clear if the benefits resulted from applying aloe or wearing gloves. One small clinical trial in healthy females shows that consumption of a yogurt containing 500 mg of aloe vera gel powder (0.4 mg of aloe sterol) daily for 12 weeks increases skin hydration, skin elasticity, and collagen content of the dermis while reducing markers of skin fatigue and transepidermal water loss when compared with placebo (95942). However, another study in healthy females shows that taking aloe sterol-enriched aloe extract 0.5 grams daily for 12 weeks does not improve skin hydration when compared with placebo, although redness, itching, collagen content, and transepidermal water loss were improved (101577).
• Epilepsy. Although there has been interest in using oral aloe for epilepsy, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Frostbite. Although there has been interest in using topical aloe for frostbite, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Gingivitis. Using aloe-containing toothpaste may reduce gingivitis in adults, but it does not seem to be more effective than fluoride-containing toothpaste. Rinsing with an aloe-containing mouthwash may reduce gingivitis in children. Details: One small clinical trial in adults shows that brushing teeth with a dentifrice containing aloe gel (Forever Bright, Forever Living Products) three times daily for 30 days does not reduce the occurrence of gingivitis more effectively than a fluoridated dentifrice (Sorriso Dentes Brancos, Kolynos do Brasil), although both treatments seem to show improvement when compared to baseline (19755). Another small clinical study in adults with gingivitis shows that using aloe-containing toothpaste daily for 24 weeks reduces gingivitis more effectively than placebo, but not more than triclosan-containing toothpaste (19760). In children aged 8-14 years with mild gingivitis, using a mouthwash containing aloe vera 7% twice daily for 4 weeks reduced gingivitis by a large amount when compared with placebo. In addition, it was as effective as chlorhexidine 0.2% (103306).
• Heart failure. It is unclear if oral aloe is beneficial in patients with systolic heart failure. Details: A very small clinical study in adults with moderate to moderately severe chronic systolic heart failure shows that taking aloe vera gel capsules 150 mg twice daily for 8 weeks in addition to standard treatment decreases New York Heart Association (NYHA) functional class, improves Minnesota Living with Heart Failure Questionnaire (MLHFQ) total, physical, emotional, and social scores, and enhances sleep quality but does not reduce the severity of obstructive sleep apnea scores or improve six-minute walk test distance when compared with placebo (111663). The study may have been inadequately powered to detect a difference between groups. Additionally, the validity of these effects may be limited by the small sample size.
• Hematopoietic stem cell transplant (HSCT). Oral and topical aloe have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing hematopoietic stem cell transplantation shows that treatment with colostrum and aloe orally (Remargin Colostrum Gastro-Gel, Solimè srl, Cavriago, Reggio Emilia, Italy) and as a mouthwash (Remargin Colostrum OS, Solimè srl, Cavriago, Reggio Emilia, Italy) modestly reduces the risk and duration of severe oral mucositis and febrile neutropenia when compared with historical values. There was no effect on the duration of neutropenia, the length of hospital stay, pain, or duration of medications. All patients were also given standard care. The mouthwash was used after each oral hygiene, and the oral treatment was 3 to 5 times daily depending on symptoms (110211).
• Hepatitis. It is unclear if oral aloe is beneficial in patients with hepatitis. Details: One small clinical trial in patients with liver fibrosis primarily caused by hepatitis B or hepatitis C shows that taking a high molecular weight fraction of aloe 0.05 grams three times daily for 12 weeks reduces fibrosis, attenuates liver enzyme activity, and decreases hepatic glutathione content when compared with placebo (19780).
• HIV/AIDS. Small clinical studies suggest that oral aloe or the aloe constituent acemannan may not improve CD4 counts or viral load in patients with HIV. Details: One small clinical trial in patients with HIV shows that taking the aloe constituent, acemannan, 400 mg four times daily does not significantly improve CD4 counts, ratio of CD4 to CD8, or viral load when compared with placebo (19851). Another small clinical study in patients with HIV shows that taking aloe gruel 30-40 mL daily does not improve CD4 counts when compared with those treated with antiretroviral therapy, although both groups show similar increases in weight compared to baseline (19852).
• Hyperlipidemia. Although there has been interest in using oral aloe for hyperlipidemia, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Hypertrophic scars. Topical aloe has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in patients undergoing median sternotomy shows that applying a silicone gel containing aloe extract and other herbal extracts (Bangkok Botanica) to postoperative hypertrophic scars for 6 months reduces the height of the scar and improves pliability by a moderate amount when compared with a silicone placebo gel. There was no effect on pigmentation or vascularity (102793). It is unknown whether any benefit is related to aloe, other ingredients, or their combination.
• Influenza. Oral aloe has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults shows that taking a combination supplement containing aloe vera gel, rosemary, and poria mushrooms twice daily 28 days before administering the influenza vaccine and 28 days after vaccination does not improve immunologic markers or reduce symptom severity, symptom duration, frequency of upper respiratory tract infection symptoms, or the use of cold and flu medications when compared with placebo (111921).
• Irritable bowel syndrome (IBS). Small clinical studies suggest that oral aloe extract or juice may not improve symptoms in patients with IBS. Details: Most research suggests that aloe is not effective for improving symptoms of IBS; however, the available evidence is of low-quality, with some studies having high dropout rates or inadequate power to detect significant differences. Two clinical trials show that taking a specific aloe extract (AVH200, Calmino Group AB) 250-500 mg twice daily for 4 weeks does not improve IBS-related symptoms or response rates when compared with placebo (101579,104169), although one of these studies did find a trend toward a higher response rate, defined as a 50% or greater improvement in symptom scores, with aloe over placebo (104169). Also, a pooled analysis of these two studies shows that taking this specific product improves IBS-related pain severity and frequency in patients with diarrhea-prominent IBS (IBS-D) when compared with placebo, but does not seem to improve stool consistency or frequency (108718). Clinical trials evaluating aloe juice 50 mL four times daily for 1 month or 60 mL twice daily for 5 months show no significant improvement in quality of life scores or IBS symptoms when compared with placebo (104170,104171), although one study did find a trend toward improved response in patients with IBS-D (104171). Despite a lack of significant findings in the individual studies, a pooled analysis of the two smallest studies above (104169,104171) shows that aloe extract or juice, taken for 4 weeks, may increase the rate of symptom response by almost 70% when compared with placebo (103307).
• Nipple Fissures. It is unclear if application of an aloe poultice improves nipple-related complications of breastfeeding, such as nipple fissures. Details: A clinical study in females who have just given birth and are breastfeeding for the first time shows that applying a poultice containing aloe gel to the nipples after breastfeeding six times daily for 5 days improves nipple eschar when compared with no treatment. Although there were modest improvements in other outcomes, such as redness, fissures, and epidermolysis, these differences were not significant (108721). Participants were instructed to clean with purified water before the next breastfeeding session.
• Multiple sclerosis (MS). Although there has been interest in using oral aloe for MS, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Oral mucositis. Small clinical studies suggest that oral aloe juice or application of aloe solution inside the mouth may prevent oral mucositis in patients receiving chemotherapy or radiation. Details: Some clinical research shows that drinking 15 mL of juice containing aloe 80% three times daily during radiation therapy decreases the risk of developing moderate or severe mucositis by approximately 39% when compared with placebo (19767,19964). In addition, in children aged 3-6 years undergoing chemotherapy for leukemia, application of a solution containing aloe 70% twice daily inside the mouth, starting three days before chemotherapy, reduces the severity of oral mucositis and delays its onset by 2 weeks when compared with sodium bicarbonate 5% (103304). Other clinical research in adults with head and neck cancer shows that rinsing and then swallowing 20 mL of a solution containing aloe juice 94.5% four times daily throughout the course of radiation therapy does not prevent mucositis when compared with placebo (19963). However, this study was not adequately powered to detect significant differences between study groups. Aloe has also been evaluated in combination with other ingredients for the treatment of oral mucositis. Preliminary clinical research in patients undergoing hematopoietic stem cell transplantation shows that treatment with colostrum and aloe orally (Remargin Colostrum Gastro-Gel, Solimè srl, Cavriago, Reggio Emilia, Italy) and as a mouthwash (Remargin Colostrum OS, Solimè srl, Cavriago, Reggio Emilia, Italy) modestly reduces the risk and duration of severe oral mucositis when compared with historical values. There was no effect on overall risk or time of onset of mucositis. All patients were also given standard care. The mouthwash was used after each oral hygiene, and the oral treatment was 3 to 5 times daily depending on symptoms (110211). Another small clinical study in adults with head and neck cancer receiving radiotherapy shows that rinsing with 5 mL of a mouthwash containing aloe, German chamomile, peppermint oil, and honey 3 times daily for 60 seconds for 6 weeks starting on the first day of radiotherapy reduces oral mucositis incidence, severity, and pain when compared with chlorhexidine and placebo (111291). It is unclear if these findings are due to aloe, other ingredients, or the combination.
• Osteoarthritis. Although there has been interest in using oral and topical aloe for osteoarthritis, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Peptic ulcers. Although there has been interest in using oral aloe for peptic ulcers, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Periodontitis. It is unclear if application of aloe inside the mouth is beneficial for chronic periodontitis. Details: A meta-analysis of small clinical studies in patients with chronic periodontitis shows that using various aloe-containing gels, mouthwashes, and toothpastes improves plaque index when compared with placebo or other treatments (i.e., chlorhexidine rinse, metformin, and tea tree oil). The effect of these aloe products on gingival index could not be determined (108719). The validity of this finding is limited by the variety of aloe formulations and comparators used in the included studies.
• Pressure ulcers. It is unclear if topical aloe is beneficial for the prevention or treatment of pressure ulcers. Details: One small clinical study shows that applying a gel containing the aloe constituent acemannan to pressure ulcers daily for 10 weeks does not reduce the time to healing when compared with management with moist saline gauze (12160,19853). Another small clinical study conducted in Iran in patients with category II pressure ulcers shows that applying topical aloe vera gel after cleaning with normal saline and prior to dressing daily for 15 days reduces pain during dressing changes when compared with normal saline dressing (113672). Other clinical research shows that cleansing wounds with a saline spray containing aloe, silver chloride, and decyl glucoside for 2 weeks improves pressure ulcer healing when compared with isotonic saline spray (19854). It is unclear if this improvement is due to aloe, other ingredients, or the combination in the spray. Aloe has also been evaluated for the prevention of pressure ulcers. A small clinical study in hospitalized patients in an orthopedic ward shows that applying aloe vera gel to the hips, sacrum, and heels twice daily for 10 days reduces pressure ulcer occurrence to 3 of 39 patients, compared to 12 of 38 patients of those receiving placebo (98816). However, methodological limitations with this study, including differences in how the gels were applied, limit the reliability of these results. A clinical study in hospitalized patients receiving intensive care has evaluated either aloe gel 94%, olive oil 100%, or a compounded product containing aloe vera and olive oil in a 3:2 ratio, applied to pressure areas as 10-15 mL every 8 hours. At the end of 30 days, pressure ulcers occurred in 17% of patients receiving the combination product, 20% receiving olive oil, 33% receiving aloe gel, and 37% receiving standard care, suggesting that any benefit may be due to olive oil (108723).
• Radiation dermatitis. There is conflicting evidence about the effectiveness of topical aloe gel for preventing or delaying dermatitis in patients undergoing radiation therapy. These conflicting findings may be due to differences in study designs, products used, and application practices. Details: Two meta-analyses of clinical trials, some of which overlap, in patients with various types of cancer shows that topical aloe does not reduce the incidence or severity of radiation dermatitis (110325,113674) and does not reduce the incidence of erythema, pruritis, moist desquamation, or dry desquamation when compared with control (110325). However, the included studies are limited by a lack of blinding, questionable methodological quality, and a high risk of bias. In contrast, another meta-analysis of generally poor quality randomized controlled trials shows that topical pre-treatment application with aloe as gel, cream, lotion, or fresh plant reduces the risk of radiation dermatitis by 23%, especially mild to moderate radiation dermatitis, when compared with a control group not treated with aloe (110214). One U.S. study included in the analysis shows that applying aloe 98% gel twice daily starting within three days of radiation initiation does not reduce radiation dermatitis when compared with a placebo gel or no treatment (12163). Other research has focused on specific side effects. One clinical trial shows that applying aloe 98% gel three times daily throughout radiation treatment and after treatment does not seem to reduce symptoms of radiation dermatitis in patients being treated for breast cancer (12098). Some research shows that applying aloe 100% gel 6-8 times daily might prolong the time before radiation-related side effects occur, but only when the cumulative dose of radiation is high (>2,700 cGy) (12159). In addition, applying aloe-based gel once daily after radiation treatment is less effective than applying anionic phospholipid-based cream for reducing dryness, erythema, and peeling in children being treated for Hodgkin disease (19855). Aloe has also been evaluated in combination with other ingredients. A small cohort study in patients with head and neck cancer receiving radiation therapy shows that applying aloe 2% and radish 4% gel twice daily until ten days after the last radiotherapy session prevents radiation dermatitis as shown by fewer cases of radiation dermatitis in the 10th, 30th, and 35th radiation sessions when compared with placebo. Furthermore, after the 35th session, the subjects prophylactically treated with the aloe and radish gel had milder grades of radiation dermatitis when compared with control (111662). A preliminary clinical study shows that applying a specific cream product (Radioskin 2, Herbalab di Perazza Massimiliano Company), which contains aloe, ginkgo extract, and metal esculetina, along with another specific cream product (Radioskin 1, Herbalab di Perazza Massimiliano Company), which contains alga atlantica and ethylbisiminomethylguaicolo manganese cloruro, may improve skin hydration and reduce skin toxicity associated with radiation therapy in patients with breast cancer (89727). These creams were applied topically 2-3 times daily at least 3 hours before and after radiation treatment, from 15 days prior to radiation until one month after completion.
• Radiation proctopathy. It is unclear if topical aloe is beneficial for the prevention or treatment of radiation proctopathy. Details: One very small clinical study in females with radiation proctopathy shows that applying 1 gram of an ointment containing aloe vera 3% rectally twice daily in conjunction with taking sulfasalazine 500 mg four times daily for 4 weeks modestly reduces diarrhea, fecal urgency, radiation toxicity, and clinical symptoms when compared with sulfasalazine alone (95941). This same product, applied twice daily for 6 weeks starting on the first day of radiotherapy, has also been evaluated for the prevention of radiation proctopathy. One small clinical study in patients with pelvic cancer shows that applying this ointment prevents proctopathy-related diarrhea, rectal bleeding, and fecal urgency when compared with placebo. Proctopathy-related symptoms occurred in 5% of patients using aloe, compared with 65% of those using placebo. However, there was no difference in rectal pain, constipation, or symptoms of cystitis between groups (101578). A very small clinical study in patients with colorectal cancer shows that applying this ointment prevents proctopathy-related diarrhea and reduces proctopathy severity, but does not improve rectal bleeding, rectal pain, fecal urgency, or symptoms of cystitis, when compared with placebo (108717). Reasons for discrepancies are unclear but might relate to differences in cancer diagnosis and radiation regimens.
• Scabies. It is unclear if topical aloe is beneficial in patients with scabies. Details: One small open-label clinical study in children and adults with scabies shows that application of crude aloe gel for 3 consecutive days, repeated again after one week, may reduce itching and lesions similar to benzyl benzoate lotion in patients with scabies when compared to baseline (19769). The validity of this finding is limited by the lack of a placebo group.
• Seborrheic dermatitis. It is unclear if topical aloe is beneficial in patients with seborrheic dermatitis. Details: One small clinical study in adults with seborrheic dermatitis shows that applying aloe 30% emulsion twice daily for 4-6 weeks reduces scaling, itching, and the number of sites involved, but not erythema, when compared with placebo (19749).
• Stretch marks (striae gravidarum). It is unclear if topical aloe is effective for the prevention or treatment of stretch marks. Details: One small clinical trial in nulliparous patients shows that topical application of a cream containing aloe twice daily, starting at gestational week 16-18, reduces erythema and itching related to abdominal stretch marks, but does not seem to decrease the number of stretch marks, when compared with a base cream (97322). Aloe gel has also been evaluated in combination with fractional carbon dioxide (CO2) laser treatments. A small clinical trial shows that applying a gel containing aloe 87.4% twice daily for up to one month after each of three CO2 laser treatments improves the texture of the skin for up to 6 months after the last laser treatment when compared to baseline. This was as effective as topical recombinant human epidermal growth factor (rhEGF) and CO2 laser treatments. However, when specific sites were examined, only the texture of stretch marks on the buttocks were improved, and these improvements were less than those seen with rhEGF (101580). The effect of aloe for the prevention of stretch marks is unknown.
• Sunburn. Although there has been interest in using topical aloe for sunburn, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Tungiasis. Topical aloe has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying a product containing coconut oil, jojoba oil, and aloe leaf extract (Zanzarin, Engelhard Arzneimittel GmbH & Co. KG) to the feet twice daily for one-week intervals seems to reduce the number of embedded sandfleas in individuals with tungiasis when compared with a control group (19778). It is not clear if this effect is due to aloe, the other ingredients, or the combination.
• Ulcerative colitis. It is unclear if oral aloe gel is beneficial in patients with ulcerative colitis. Details: One small clinical trial in patients with mild to moderate ulcerative colitis shows that taking aloe gel for 4 weeks, starting at 25-50 mL twice daily for the first 3 days and increasing to 100 mL twice daily thereafter, reduces symptoms when compared with placebo (11984).
• Vaginitis. It is unclear if topical aloe is beneficial for vaginitis. Details: One small clinical trial in postmenopausal patients with atrophic vaginitis shows that applying 5 mg of a vaginal cream containing aloe gel 2% nightly for 2 weeks, then 3 nights per week for 4 weeks, reduces vaginal dryness, burning, and pain during intercourse and improves measures of vaginal health and maturity when compared to baseline. These effects were similar to those seen with estrogen vaginal cream (104175).
• Varicose veins. Although there has been interest in using oral and topical aloe for varicose veins, there is insufficient reliable information about the clinical effects of aloe for this purpose.
• Wound healing. There is conflicting evidence about the effectiveness of topical aloe products for improving wound healing. These conflicting findings may be due to differences in study designs, products used, and application practices. Details: One small clinical study shows that applying aloe gel to a caesarean wound after surgery, followed by a dry gauze, improves wound healing over the first 24 hours when compared with the dry gauze alone (90128). However, other clinical research in a small number of patients undergoing gynecologic surgery or cesarean section shows that applying an aloe gel extract (Carrington Dermal Wound Gel) to surgical wounds may actually delay wound healing (11982). Another small clinical trial shows that applying a formulation of aloe gel 0.5% cream (Zarband, Phytopharmaceutical Co.) to hemorrhoidectomy wounds three times daily for 4 weeks improves healing rates and pain relief scores and decreases intake of narcotic analgesics when compared with placebo (17418). However, another clinical trial in patients with biopsy wounds shows that application of a hydrogel containing the aloe constituent, acemannan (Carrasyn, Carrington hydrogel), does not improve wound epithelialization, wound infections, or pain when compared with conventional therapy (19856). Additionally, there is contradictory evidence about the effectiveness of aloe for improving skin graft donor site healing. One small clinical study shows that applying aloe gel 87.4% daily to split-thickness skin graft donor sites reduces time to complete healing by about 2 days when compared with placebo (97320). However, another small clinical study shows that applying aloe cream three times daily to split-thickness skin graft donor sites does not improve healing time when compared with placebo (97321).
• Wrinkled skin. Although there has been interest in using topical aloe for wrinkled skin, there is insufficient reliable information about the clinical effects of aloe for this purpose. More evidence is needed to rate aloe for these uses.

(Read more about ALOE)

LIKELY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about GLUCOSAMINE)

EFFECTIVE

• Sickle cell disease. A specific oral glutamine powder (Endari, Emmaus Medical, Inc) is approved by the US Food and Drug Administration (FDA) to reduce acute complications of sickle cell disease. Details: Clinical research in adults and children 5 years of age and older shows that taking glutamine 5-15 grams (0.3 grams/kg body weight) orally twice daily for 48 weeks, either with or without hydroxyurea, delays the median time to first crisis by 30 days, and reduces the incidence of acute chest syndrome by 15%, number of hospitalizations by 33%, and the number of hospitalized days by 40%, when compared with placebo (96519,99414).

POSSIBLY EFFECTIVE

• Burns. Oral glutamine seems to improve healing in patients with severe burns and may also reduce the risk for burn wound infections; however, it is unclear if glutamine improves hospitalization length or mortality. Details: Some clinical research shows that administering enteral nutrition supplemented with glutamine 0.35-0.5 grams/kg daily for 12-14 days, beginning within 24-48 hours of hospitalization for severe burn injury (excluding inhalation injury), decreases the length of hospital stay by 6-9 days and may shorten wound healing when compared to control enteral nutrition (52307,52337). A clinical study in adults with moderate to severe burns (including inhalation injury) shows that administering enteral nutrition supplemented with intravenous alanyl glutamine 0.5 grams/kg daily, beginning within 24 hours of burn injury and continued for 14 days, may improve burn-induced organ damage, particularly intestinal mucosal injury, but does not improve mortality or length of hospitalization, when compared with standard nutritional support (108027). Another study in the same population shows that administering enteral nutrition supplemented with glutamine 4.3 grams every 4 hours, beginning within 24 hours of burn injury, decreases the risk of mortality by 83% and the risk of Pseudomonas wound infections; however, it does not decrease the duration of hospitalization (52311). A meta-analysis of these trials and one additional trial shows that administering glutamine enterally reduces the risk of Gram-negative bacterial wound infections by 73% and reduces the risk of mortality by 87% when compared to a control group. However, there was no difference in length of stay or overall wound infection rate (97363). Results were based on a small number of patients within each outcome evaluation. Intravenous glutamine has also been evaluated. One small clinical study shows that intravenous glutamine 0.57 grams/kg daily decreases the incidence of Gram-negative bacteremia by 35% when compared with control in patients with severe burns. However, it does not appear to decrease the incidence of Gram-positive bacteremia, the need to use antibiotics, or risk of mortality (52272).
• Critical illness (trauma). Oral and intravenous glutamine seem to reduce infectious complications in critically ill adults. However, glutamine does not seem to reduce mortality in this population. Details: Some studies show that glutamine reduces the risk of infectious complications in critically ill, multiple-trauma, or postoperative adult patients (5449,5450,7309,7731,8184,52288,52359). However, other studies show no benefit (52308,52360,97362). Meta-analyses of these and other clinical trials suggest that glutamine supplementation reduces the risk of nosocomial infections in critically ill patients by 15% to 18% and the risk of nosocomial infections in surgical patients by 30% to 41%. This benefit was seen only with parenteral glutamine; enteral glutamine does not appear to reduce the risk for nosocomial infection (91355,91358). The role of glutamine for reducing mortality in critically ill adults is conflicting. Some clinical trials suggest that glutamine-enriched enteral and parenteral nutrition reduces mortality in critically ill patients (52283,52289,52408). However, other studies show no benefit (52288,52308,52354,52359,97362). Meta-analyses of results from these and other clinical trials show that, overall, taking glutamine does not reduce the risk of mortality in critically ill patients (91355,91358). However, the dose and dosage form may affect outcomes. One meta-analysis shows that glutamine does not affect the risk of mortality when administered at doses up to 0.5 grams/kg daily, although doses greater than 0.5 grams/kg daily may INCREASE mortality by 18% (91355). Another meta-analysis shows that glutamine decreases short-term mortality in critically ill patients by 25% when administered parenterally, but not enterally (91358). Neither parenteral nor enteral glutamine appears to decrease the risk of long-term mortality in critically ill patients (91358). Research evaluating glutamine in critically ill children is limited. One clinical study in children ages 1-17 admitted to an intensive care unit (ICU) shows that enteral administration of glutamine along with zinc, selenium, and intravenous metoclopramide does not reduce nosocomial infections when compared with whey supplementation (86095).
• HIV/AIDS-related wasting. Oral glutamine seems to attenuate weight loss related to HIV/AIDS. Details: Very small clinical studies show that taking glutamine orally seems to enhance intestinal absorption of nutrients, decrease intestinal permeability, and increase weight gain in adults with HIV/AIDS when compared with placebo. Doses of 40 grams daily seem to produce the greatest effect (2337,2702). Lower doses of 14 grams daily might also be effective when used in combination with arginine and hydroxymethylbutyrate (a leucine metabolite) (7310).
• Postoperative recovery. Oral or intravenous glutamine seems to reduce the duration of hospitalization and improve postoperative nutritional status in adults. However, it does not seem to reduce postoperative mortality. Details: Although some conflicting evidence exists (52316), most clinical research shows that receiving free glutamine or glutamine-containing dipeptide intravenously decreases the duration of hospitalization after surgery, particularly after major abdominal surgery (2363,5448,7300,7732,52275,52341). A meta-analysis of this research and other studies shows that IV supplementation with glutamine-containing dipeptides reduces the length of hospital stay by 3 days when compared with no supplementation (96507). Other meta-analyses of clinical research also show that glutamine supplementation, as free glutamine or glutamine-containing dipeptides, reduces the risk of hospital-acquired infections by 30% in surgical intensive care unit (ICU) patients and by 41% in elective surgical patients (91355,91358). In cancer patients undergoing abdominal surgery, glutamine-supplemented parenteral nutrition seems to improve nutritional status and gastrointestinal function (100943). Glutamine-containing dipeptides also appear to help to preserve intestinal integrity (7299,7300,7732,52306). One small study has evaluated oral glutamine 10 grams, in combination with arginine 4.5 grams, in patients undergoing surgery for enterocutaneous fistulas. This study shows that taking this combination daily for 7 days prior to surgery reduces recurrence of fistulas by 35%, and also reduces postoperative infections (103837). Although glutamine seems to decrease length of stay and reduce infection rate, it does not appear to reduce the risk of mortality in either surgical ICU or elective surgical patients (91355,91358,96509,103834), including those receiving major abdominal surgery (5448,52316,91355,96507). Additionally, most research shows that glutamine supplementation does not reduce the incidence of infectious complications following abdominal surgery (52306,52316,52341,5448,7300,96507). The effects of glutamine on reducing infection rate might be related to patient population, modes of nutrition, or dose of glutamine. Taking a combination of glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.2 grams (Abound, Abbott) orally daily for 3 days before and 7 days after abdominal surgery does not reduce the incidence of wound infections or other complications (99413). Most of the research evaluating glutamine in surgical patients has been conducted in adults. Information in children is limited. Existing clinical research shows that glutamine-fortified parenteral nutrition does not improve intestinal permeability, nitrogen balance, duration of hospitalization, incidence of infectious complications, or risk of mortality in newborns and infants undergoing digestive-tract surgery (52338,96508).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral glutamine does not seem to improve athletic performance. Details: Small studies in trained athletes or healthy adults show that taking glutamine orally does not seem to enhance performance or immune response during intense acute or prolonged exercise when compared with placebo (2341,2342,5455,5456).
• Crohn disease. Oral glutamine does not seem to improve symptoms of this condition. Details: Small clinical studies in adults and children with Crohn disease show that taking glutamine 7 grams three times daily or following a glutamine-enriched diet for 4 weeks does not seem to improve intestinal permeability or disease activity, and might even worsen disease activity, when compared with placebo or a low-glutamine diet (2338,6256).
• Cystinuria. Oral glutamine does not seem to improve cystinuria. Details: According to case reports, taking glutamine orally does not seem to reduce the excretion of cysteine in the urine in patients with homozygous cystinuria (2339).
• Low birth weight. Oral glutamine does not seem to reduce adverse consequences of low birth weight in infants. Details: Most clinical studies show that glutamine supplementation does not improve the time to full enteral feeding, infant growth rate, or length of hospital stay in low birth weight infants (52305,52312,52325,52342,52362,52410). One follow-up study also shows that neonatal glutamine supplementation is not associated with improvements in cognitive function, motor skills, or behavior outcomes by school age when corrected for neonatal infection rate (52342,97365).
• Muscular dystrophy. Oral glutamine does not seem to improve symptoms of Duchenne muscular dystrophy. Details: Clinical studies show that taking glutamine 0.5-0.6 grams/kg orally does not significantly improve muscle strength or whole body protein degradation in children with Duchenne muscular dystrophy when compared with placebo or a nonspecific amino acid mixture (46657,52363).
• Prematurity. Oral glutamine does not seem to reduce morbidity or mortality associated with prematurity. Details: A meta-analysis of clinical trials in preterm infants, including infants with low to very low birth weight, shows that use of enteral or parenteral glutamine does not reduce the risk of mortality or morbidities, such as necrotizing enterocolitis, when compared with control. However, limited evidence from a sub-group analysis suggests that enteral glutamine might modestly reduce the risk of invasive infection when compared with control (105015). These findings are limited by the selection bias and heterogeneity of the included trials.
• Radiation-induced diarrhea. Oral glutamine does not seem to improve diarrhea due to radiation therapy. Details: One meta-analysis of five randomized, controlled trials shows that taking oral glutamine during radiotherapy for pelvic cancers does not prevent or reduce the severity of diarrhea when compared with placebo (97367).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antiretroviral-associated diarrhea. It is unclear if oral glutamine improves diarrhea caused by antiretroviral agents. Details: A small crossover clinical study in HIV patients shows that oral glutamine 30 grams daily for 10 days seems to reduce the severity of nelfinavir-associated diarrhea when compared with placebo (52313).
• Alcohol use disorder. Although there is interest in using oral glutamine for alcohol use disorder, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral glutamine for ADHD, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Chemotherapy-induced diarrhea. It is unclear if oral glutamine improves diarrhea caused by chemotherapy. Details: Although preliminary clinical studies show that glutamine might reduce the occurrence of chemotherapy-induced diarrhea (7235,7285), a meta-analysis of this research and others shows no difference in the severity of diarrhea (7233,7295,96516). Despite results showing a significant 1-day reduction in the duration of diarrhea, this might not be considered clinically significant (96516).
• Chemotherapy-induced lymphocytopenia. It is unclear if oral glutamine reduces lymphocytopenia caused by chemotherapy. Details: One small clinical study in patients with esophageal cancer receiving chemo-radiotherapy shows that taking glutamine 30 grams daily for 28 days seems to prevent a reduction in lymphocytes when compared with placebo (2705). However, another small clinical trial in patients with leukemia or lymphoma receiving intensive chemotherapy shows that adding glutamine 26 grams to total parenteral nutrition (TPN), in place of other amino acids, does not affect duration of neutropenia when compared with receiving an isonitrogenous standard TPN (7295).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral glutamine is beneficial in patients hospitalized with COVID-19 pneumonia. Details: A very small, nonblinded, non-randomized evaluation of otherwise healthy patients over 50 years of age who were hospitalized with mild COVID-19 pneumonia shows that taking glutamine 10 grams three times daily orally with meals is associated with a 1-day decrease in hospital stay (from 10 days to 9) when compared with patients not taking glutamine. In the latter group, 4 patients required transfer to the ICU, compared with no patients in the glutamine group (103839). A similar, non-randomized evaluation of adults hospitalized with COVID-19 pneumonia shows that adding the same dose of glutamine to other therapies for 5 days is associated with a 3-day decrease in hospital stay (from 14 days to 11) when compared with patients not taking glutamine. At the end of treatment, 0% of patients in the glutamine group required ICU services, compared with 54% of patients who did not receive glutamine. This study also shows that taking glutamine may increase appetite (108035). The validity of these findings is limited by short duration of treatment and use of non-standardized treatments.
• Cystic fibrosis. It is unclear if oral glutamine improves growth and development in children with cystic fibrosis. Details: A small clinical study in undernourished or stunted children with cystic fibrosis shows that taking glutamine 0.7 grams/kg daily orally for 4 weeks with or without recombinant human growth hormone (rhGH) does not promote protein gain when compared with rhGH alone (52321).
• Diabetic foot ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) twice daily for 16 weeks does not improve total wound closure or reduce the time to complete healing when compared with a control drink in patients with diabetic foot ulcers (96637). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
• Diarrhea. It is unclear if oral glutamine improves diarrhea in children and infants. Details: One preliminary clinical study in 6-24 month-old otherwise healthy children with acute diarrhea shows that taking capsules prepared with a specific glutamine powder (Power Glutamine, Champion Nutrition) 0.3 grams/kg daily for 7 days reduces the duration of diarrhea by about one day when compared with placebo (52323). However, other clinical research in male infants 1-12 months old with acute diarrhea and dehydration shows that adding glutamine 90 mmol/L along with the standard World Health Organization oral rehydration salts (ORS) does not decrease the duration of diarrhea, stool output, or the volume of oral rehydration solution required to achieve and maintain hydration when compared with standard ORS alone (7298).
• Hematopoietic stem cell transplant (HSCT). It is unclear whether oral glutamine or glutamine added to parenteral nutrition improves morbidity and mortality in patients undergoing HSCT. Some research has suggested that intravenous glutamine may actually worsen outcomes. Details: Some research suggests that patients receiving glutamine-supplemented parenteral nutrition (PN) after HSCT primarily to treat hematologic malignancies have a diminished incidence of clinical infections, lower rates of microbial colonization, and decreased length of hospital stay when compared to control (2366,52381). However, not all patients seem to benefit. Some research shows that oral glutamine or PN with glutamine does not reduce the risk of mortality or infections in patients with hematologic malignancies and/or solid tumors (5451,52385). Also, a small clinical study in patients undergoing HSCT shows that PN with glutamine dipeptide may increase the duration of hospital stay (52292). Furthermore, one small study has found that receiving PN with glutamine was associated with lower disease-free survival and event-free survival over 3 years when compared with standard PN in patients receiving HSCT for hematologic malignancies (52355).
• Irritable bowel syndrome (IBS). There is limited evidence on the oral use of glutamine in patients with IBS. Details: A clinical trial in adults with IBS (diarrhea-predominant, constipation-predominant, mixed, or alternating bowel habits) shows that following a low FODMAP diet supplemented with oral glutamine 15 grams three times daily for 6 weeks improves IBS-Severity Scoring System (IBS-SSS) scores, with 88% of patients in the glutamine group reporting a 45% improvement in severity scores, compared with 60% of patients following the low FODMAP diet alone (108037). The validity of this finding is limited by short duration of treatment and lack of follow-up. Preliminary clinical research in patients with postinfectious, diarrhea-predominant IBS shows that taking glutamine 5 grams three times daily for 8 weeks leads to a nearly 14-fold greater likelihood of symptom improvement, defined as a reduction of 50 points or more on the IBS-SSS, and decreases stool frequency by 2.45 stools daily when compared with placebo. Taking glutamine also seems to reduce abdominal pain ratings by 55% and improve quality of life scores by 53% when compared to baseline in these patients (100944). The validity of these findings is limited by the lack of a comparator group.
• Lung cancer. It is unclear if oral glutamine improves survival in patients with advanced lung cancer. Details: One small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with palliative chemoradiotherapy prevents weight loss, which is an important predictor of survival, but does not increase the likelihood of progression-free survival when compared with palliative chemoradiotherapy alone (100942). It is unclear if this study was adequately powered to detect a difference in survival between groups.
• Malnutrition. It is unclear if oral alanyl-glutamine improves height and weight in children at risk for malnutrition. Details: Preliminary clinical research in children aged 2 months to 5 years from a low-income area of Brazil and at risk for malnutrition, shows that taking 3-12 grams of alanyl-glutamine orally daily for 10 days improves gut integrity and is associated with a modest, short-term increase in weight when compared with a glycine placebo (103838).
• Exercise-induced muscle damage. It is unclear if oral glutamine is beneficial for exercise-induced muscle damage. Details: A very small clinical crossover trial in professional athletes undergoing rigorous training shows that taking oral glutamine 6 grams daily for 20 days reduces serum levels of creatine kinase and myoglobin when compared with placebo (108031). The validity of these findings is limited due to the small size and short duration of treatment.
• Obesity. It is unclear if oral glutamine is beneficial for weight loss. Details: A preliminary clinical study in 36 overweight or obese adults shows that taking glutamine 30 grams daily for 2 weeks reduces waist circumference by 1.8 cm, but does not improve body weight, body mass index, or glycemic indices, when compared to baseline. None of these outcomes were improved over baseline in an alanine control group (100941). Given the small study size and short duration of therapy, the long-term effects of glutamine on anthropometric measures is unclear.
• Opioid withdrawal. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in Chinese patients undergoing detoxification from heroin shows that taking a combination of tyrosine, lecithin, 5-HTP, and glutamine 50 mg/kg orally daily for 6 days might reduce mood-related withdrawal symptoms when compared with placebo (88178). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
• Oral mucositis. There is contradictory evidence about the effects of glutamine in patients with, or at risk of developing, oral mucositis from chemotherapy or radiotherapy. Details: Small clinical studies suggest that taking glutamine orally or swishing and swallowing a glutamine solution can decrease the incidence, severity, and duration of oral mucositis in some patients undergoing chemotherapy and/or radiation therapy for cancer or hematopoietic stem cell transplant (HSCT) (2336,2368,2704,5029). Additionally, three meta-analyses of highly heterogeneous clinical trials in patients with cancer receiving chemotherapy and/or radiation therapy suggests that glutamine reduces the incidence of severe (grade ≥3) oral mucositis when compared with control (105014,108028,108036). These analyses are limited for several reasons, including reporting bias, lack of sensitivity analysis, and population heterogeneity. Some small clinical studies included in these meta-analyses suggest that supplementation with glutamine may reduce the need for feeding tubes and opioid analgesics (108028,108036). However, not all research has been positive. Some small clinical studies in patients receiving chemotherapy with 5-fluorouracil for cancer or HSCT suggest that oral or intravenous glutamine does not reduce the incidence of oral mucositis when compared with control (2365,5451,5462,7296,52349,52350). Furthermore, a meta-analysis of 5 clinical trials in patients with head or neck cancers shows that oral glutamine does not reduce the overall incidence or the incidence of moderate to severe radiation-induced oral mucositis when compared with control (103836). The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO) cautiously recommends the use of oral glutamine to prevent oral mucositis in patients with head and neck cancer receiving chemoradiotherapy. However, due to some evidence suggesting that intravenous glutamine may actually worsen outcomes in HSCT patients, the MASCC/ISOO recommends against its use for the prevention of oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (105004).
• Paclitaxel-induced myalgia and arthralgia. It is unclear if oral glutamine reduces the risk for myalgias and arthralgias due to paclitaxel. Details: One small clinical study shows that taking glutamine 10 grams three times daily for 5 days, starting on the day of chemotherapy and repeated over 2 cycles of chemotherapy, does not reduce the rate or severity of paclitaxel-induced myalgias or arthralgias when compared with placebo (52331).
• Pancreatitis. It is unclear if oral glutamine improves outcomes in patients with acute pancreatitis. Details: Two meta-analyses of the available clinical research in patients with pancreatitis show that enteral or parenteral supplementation with glutamine increases albumin, decreases C-reactive protein, and might reduce mortality, multiple organ dysfunction syndrome, hospital length of stay, and infections. Results are difficult to interpret due to the significant heterogeneity of the included trials and limited generalizability of the results (96513,103835).
• Peptic ulcers. Although there is interest in using oral glutamine for peptic ulcers, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Postoperative infection. It is unclear if oral or intravenous glutamine is beneficial for the prevention of postoperative infection in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that daily supplementation with glutamine 0.3-1 grams/kg, administered either orally or parenterally, improves the rate of surgical site infections and anastomotic leakage when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
• Postoperative recovery. It is unclear if oral or intravenous glutamine is beneficial in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that taking either oral or parenteral glutamine 0.3-1 grams/kg daily may reduce the length of hospital stay when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
• Pressure ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with stages II-IV pressure ulcers shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams per packet (Abound, Abbott Nutrition) as two packets twice daily by mouth for 2 weeks has no effect on wound area or healing scores by the Pressure Ulcer Scale for Healing (PUSH) measurement when compared with standard nutritional care (96506).
• Radiation dermatitis. It is unclear if oral glutamine reduces the risk of developing dermatitis from radiation therapy. Details: One small clinical study in patients with head and neck cancers receiving cisplatin shows that taking a specific supplement containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) orally twice daily, starting on day 1 of radiation and continuing until 1 week after radiation therapy, does not reduce the incidence of severe radiation-induced dermatitis when compared with no supplementation (96639). However, another small clinical study in patients with breast cancer who have had both chemotherapy and surgery shows that taking oral glutamine 5 grams three times daily, starting 1 week before radiation and continuing until 1 week after radiation, is associated with a reduction in grade 1 and grade 2 radiation dermatitis when compared with placebo (97366).
• Radiation-induced esophagitis. It is unclear if oral glutamine reduces the risk of developing esophagitis from radiation therapy. Details: A small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with a palliative dose of chemoradiotherapy (total 30 Gy) results in a 7% incidence of symptomatic (grade 2 or higher) radiation-induced esophagitis, compared with a 53% incidence with palliative chemoradiotherapy alone. The glutamine group also had a 5.8-day delay in the onset of esophagitis (100942). However, a lower dose of glutamine in patients receiving higher doses of radiotherapy might not be beneficial. A small clinical study in patients with advanced thoracic malignancies shows that taking glutamine 4 grams mixed in water twice daily for 4 weeks along with radiotherapy (total dose of at least 45 Gy) to the esophagus, with or without chemotherapy, does not slow the onset of radiation-induced esophagitis or reduce its severity when compared with a glycine placebo (105011).
• Short bowel syndrome. It is unclear if oral glutamine improves symptoms of short bowel syndrome. Details: Although small clinical studies suggest that glutamine plus growth hormone can decrease dependence on parenteral nutrition in some patients (2334,2361,2362,2703), it has not shown benefit for improving intestinal absorption of energy in all studies (8185). Additionally, glutamine alone doesn't appear to be beneficial (7730).
• Traumatic Brain injury (TBI). It is unclear if intravenous glutamine is beneficial in patients hospitalized with severe TBI. Details: A clinical trial in patients hospitalized for a severe TBI shows that adherence to a hypocaloric, low-protein diet supplemented with daily intravenous glutamine 0.3 g/kg for 7 days does not improve 28-day mortality when compared with standard nutritional support alone. However, it may reduce the length of ventilator use, hospitalization, and duration of intensive care unit stay (108034).
• Vincristine-induced neuropathy. It is unclear if oral glutamine reduces the risk of developing neuropathy from treatment with vincristine in children. Details: Preliminary clinical research in children ages 1-21 years receiving vincristine for various cancer types shows that taking glutamine 6 grams/m2 twice daily orally for 21 days reduces sensory neuropathy when compared with placebo. There was a significant improvement in self-reported, but not parent-reported, quality of life scores as measured by the PedsQL scale. However, there was no effect on motor neuropathy with the use of glutamine (96517).
• Wound healing. It is unclear if oral glutamine improves wound healing. Details: Preliminary clinical research in trauma patients with wound healing disorders shows that taking glutamine 20 grams orally daily in combination with ascorbic acid 500 mg, vitamin E 166 mg, beta-carotene 3.2 mg, selenium 100 mcg, and zinc 6.6 mg (Glutamine Plus, Fresenius Kabi) for 14 days reduces the time to wound closure by 29 days when compared with placebo. However, there is no difference in length of stay (97364). More evidence is needed to rate glutamine for these uses.

(Read more about GLUTAMINE)

POSSIBLY EFFECTIVE

• Atopic dermatitis (eczema). Some clinical research suggests that topical licorice seems to improve symptoms of atopic dermatitis. Details: Applying gel formulations containing 1% or 2% licorice root extract three times daily for 2 weeks seems to reduce erythema by 35% to 61%, edema by 57% to 84%, and itching by 44% to 73%. The 2% gel seems to be more effective than the 1% gel (59732).
• Canker sores. Some clinical research suggests that topical licorice patches and mouth rinses seems to reduce ulcer size and pain in patients with recurrent aphthous stomatitis. Details: Clinical research shows that applying an oral patch containing licorice 0.015-0.229 mg/kg for 16 hours each day for 8 days does not affect ulcer healing time, but reduces ulcer size and post-stimulus pain, when compared with placebo (59769). A small clinical study also shows that applying bioadhesive hydrogel patches containing 1% licorice extract reduces the pain, as well as the diameter of necrosis and inflammatory halo of recurrent canker sores, when compared to baseline (59781). Mouth rinses containing licorice have also been used. One clinical study shows that swishing a diphenhydramine and 5% licorice extract solution around the mouth for about 3 minutes four times daily until the sores have healed reduces the average time to healing by 1.5 days when compared to a solution containing diphenhydramine alone. Pain was reduced by up to 69% more in those using licorice extract (104564). Another small clinical study shows that gargling with licorice extract four times daily for 2 days has a large beneficial effect on pain and ulcer size when compared with using a placebo gargle. The licorice extract was made by boiling licorice root 40 grams in one liter of water for 30 minutes and cooled (110319). In addition, preliminary clinical research shows that gargling with warm water containing deglycyrrhizinated licorice powder 200 mg four times daily for 7 days improves pain in 75% of patients by day one and results in complete healing in 75% of patients by day three (59857).
• Endotracheal intubation-related adverse effects. Some clinical research suggests that using licorice as a gargle or lozenge prior to endotracheal intubation can reduce adverse effects like sore throat and cough. Details: A meta-analysis of 5 clinical trials in patients undergoing elective surgical procedures shows that topical use of licorice, either as a gargle or lozenge, prior to endotracheal intubation reduces the risk for sore throat by 56% and reduces the risk for cough by 39% when compared with a control group at 24 hours post-extubation (100985). One clinical study included in this analysis shows that sucking on a single lozenge (Sualin, Hamdard Pharma) containing licorice extract 97 mg beginning 30 minutes prior to intubation reduces the risk for cough immediately after extubation by 56% when compared with a sugar candy lozenge. However, it doesn't seem to reduce cough at 30 minutes, 12 hours, or 24 hours post-extubation. This lozenge also appears to reduce the risk for sore throat by about 32% at 12 and 24 hours post-extubation, but not immediately or 30 minutes after extubation (25670). Additional clinical studies included in the meta-analysis show that gargling with fluid prepared with licorice 0.5 grams for at least one minute beginning 5 minutes prior to endotracheal intubation reduces the incidence and severity of post-extubation sore throat and coughing when compared with a water control (26464,59793).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with mild to moderate acne associated with mask wearing shows that topical application of a combination of licorice root extract 0.3%, calendula 4%, and snail secretion filtrate 40% (AI complex) to the face twice daily for 12 weeks modestly reduces inflammatory, but not non-inflammatory or total, acne lesions when compared with placebo. There was no difference in overall treatment success, defined as at least almost clear skin or a large improvement (110322). It is unclear if any benefits are due to licorice, other ingredients, or the combination.
• Addison disease. Although there has been interest in using oral licorice for Addison disease, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Adrenal insufficiency. Although there has been interest in using oral licorice for adrenal insufficiency, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Allergic rhinitis (hay fever). It is unclear if using a licorice-containing nasal irrigation suspension improves symptoms in patients with allergic rhinitis. Details: A clinical study in patients with allergic rhinitis shows that using a nasal irrigation suspension containing licorice extract 900 mg daily for 1 month improves symptoms such as nasal blockage, rhinorrhea, sneezing, postnasal discharge, and olfactory disturbance when compared with baseline (108569). Although the study also utilized mometasone 2 mg nasal spray and isotonic saline nasal irrigation as comparators, symptom improvement was observed in all three groups, and there was no statistical comparison of outcomes between groups.
• Antipsychotic-induced hyperprolactinemia. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with risperidone-induced hyperprolactinemia shows that taking a combination of licorice and peony (Peony-Glycyrrhiza Decoction; PGD) 45 grams daily for 4 weeks reduces prolactin levels to a similar extent as bromocriptine (59775). However, another study shows that taking the same product at the same dose for 16 weeks has no effect on prolactin levels in females with antipsychotic-induced hyperprolactinemia when compared with placebo. Although the prolactin-related adverse event questionnaire total score was moderately improved, there was no effect on clinically meaningful symptoms or menstrual resumption (97219). Both studies show no effect on psychotic symptoms (59775,97219). Preliminary clinical research in male patients with antipsychotic-induced hyperprolactinemia shows that taking an herbal extract containing licorice and peony (shakuyaku-kanzo-to) 2.5 grams three times daily reduces prolactin levels after 4 weeks, but does not have a significant effect on prolactin levels 4 weeks after treatment cessation (59907).
• Bleeding. Topical licorice might reduce bleeding when used in combination with other ingredients; its effect when used alone is unclear. Details: Some preliminary clinical research shows that topically applying 4 mL of a specific product (Ankaferd Blood Stopper, Mefar Ilaç Sanayi A.S.) containing licorice, Alpinia, thyme, stinging nettle, and common grape vine reduces bleeding, but does not improve the surgical time for episiotomy repair, when compared with saline (31010). Other preliminary clinical research shows that ampules of this same product placed in empty alveolus for up to 20 minutes reduces bleeding in postsurgical dental patients with increased bleeding tendency (31002).
• Cancer-related pain. It is unclear if oral licorice is beneficial for pain in patients with cancer. Details: Preliminary clinical research shows that taking a 1:1 combination of licorice root and peony root, along with a Taiwanese tonic vegetable soup comprised of lily bulb, lotus seed, and jujube fruit, reduces pain levels in terminal cancer patients when compared with patients consuming only the soup or the regular hospital diet (59770).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral licorice for CFS, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Colic. Although there has been interest in using oral licorice for colic, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Coronavirus disease 2019 (COVID-19). Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients hospitalized in Egypt with moderate COVID-19 shows that administering oral licorice extract 300 mg (standardized to contain glycyrrhizin 60 mg) once daily and Boswellia serrata extract 300 mg twice daily for 14 days, along with following an institution-based COVID-19 treatment protocol, may modestly improve mortality and time to recovery when compared with patients receiving the standard protocol alone. The standard treatment protocol included acetaminophen, azithromycin, vitamin C, zinc, and enoxaparin (108579). It is unclear if any effect is due to licorice, Boswellia serrata, or the combination.
• Dental caries. It is unclear if oral licorice is beneficial for the prevention of dental caries. Details: One clinical study in adults shows that swishing 15 mL of a solution containing licorice extract 1% once nightly before bed for 5 days may reduce the acid production of cavity-causing bacteria, which may modestly reduce cavity risk, when compared with using a saline solution (108567). The validity of this study is limited by the short duration of treatment and follow-up.
• Dental plaque. It is unclear if licorice toothpaste or mouthwash is beneficial for reducing plaque. Details: Preliminary clinical research shows that using 0.25% or 0.50% glycyrrhizin-containing toothpaste twice daily does not reduce the amount of plaque, gingivitis, or bleeding in patients with proper dental hygienic measures when compared with the same toothpaste without glycyrrhizin (59812). Also, other preliminary clinical research shows that using glycyrrhizin-containing mouthwash for 3 days does not significantly reduce plaque levels (59855).
• Depression. It is unclear if adding oral licorice to standard treatment is beneficial for improving depression. Details: A very small, nonblinded clinical study in hospitalized adults with major depressive disorder shows that adding licorice extract 1400 mg daily, standardized to glycyrrhizin 7% to 8%, to standard treatment for 2 weeks improves depression rating scores when compared with baseline, although these improvements were numerically similar to those seen with standard treatment alone. Patients in the treatment group also took oral magnesium citrate 300 mg daily to prevent magnesium depletion. The validity of this finding is limited due to the small size of the study, short duration of treatment, and unclear reporting (108575).
• Diabetes. Although there has been interest in using oral licorice for diabetes, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Dry mouth. It is unclear if rinsing the mouth with licorice is beneficial for dry mouth in people on hemodialysis. Details: Preliminary clinical research in hemodialysis patients with dry mouth shows that rinsing with a licorice mouthwash containing 8.34 grams of licorice concentrate per 500 mL of water with every meal for 10 days does not affect salivary flow rate, but reduces subjective feelings of dry mouth by about 28%, when compared with a water-based mouthwash and control group (97220).
• Dysmenorrhea. It is unclear if oral licorice is beneficial for reducing pain. Details: Preliminary clinical research shows that taking a syrup providing licorice extract 750 mg twice daily for the first 5 days of the menstrual cycle reduces pain as effectively as ibuprofen 400 mg every 8 hours in patients with moderate or severe dysmenorrhea (104558).
• Dyspepsia. Oral licorice might improve symptoms of dyspepsia when used in combination with other ingredients; its effect when used alone is unclear. Details: Various combination products manufactured by Steigerwald Arzneimittelwerk GmbH have been evaluated for dyspepsia. Two specific combination products containing licorice root (Iberogast; STW-5-S) seem to improve symptoms of dyspepsia. The combinations include licorice plus milk thistle, peppermint leaf, German chamomile, caraway, celandine, angelica, and lemon balm either with (Iberogast) or without clown's mustard plant (STW-5-S) 1 mL three times daily for 4 weeks (19532). A meta-analysis of studies using the Iberogast product shows that taking 1 mL orally three times daily over a period of 4 weeks reduces severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089). Also, using a preparation containing clown's mustard plant, German chamomile, peppermint, caraway, licorice, and lemon balm (STW 5-II) 1 mL three times daily for up to 12 weeks improves dyspepsia symptoms in 40% more patients when compared with placebo (12724).
• Familial Mediterranean fever. It is unclear if oral licorice is beneficial for familial Mediterranean fever. Details: Preliminary clinical research shows that taking a combination of licorice, andrographis, Siberian ginseng, and schisandra (ImmunoGuard, Inspired Nutritionals) four tablets three times daily for one month reduces the duration, frequency, and severity of attacks of familial Mediterranean fever in children when compared with placebo (12382). It is unclear if these effects are due to licorice, other ingredients, or the combination.
• Helicobacter pylori. It is unclear if oral licorice is beneficial for Helicobacter pylori eradication. Details: Some preliminary clinical research shows that adding licorice (D-Reglis, Iran Darouk Pharmaceutical Co.) 380 mg twice daily to conventional clarithromycin-based triple therapy for 14 days improves eradication rate by an additional 21% when compared with conventional treatment alone. However, any additional benefit might be limited to patients with peptic ulcer disease (97221). Other preliminary clinical research shows that taking a combination of licorice extract 100 mg and Lactobacillus paracasei HP7 in 150 mL of fermented milk daily for 8 weeks does not increase eradication rates when compared with fermented milk alone, although it may improve gastrointestinal symptom scores, decrease the gastric load of Helicobacter pylori, and improve some measures of inflammation when compared to baseline (100984).
• Hepatitis. Evidence for the use of intravenous licorice in the management of hepatitis B and C is mixed. Details: In some preliminary clinical research, a specific glycyrrhizin-containing intravenous preparation (Stronger Neominophagen C, Minophagen Pharmaceutical Co. Ltd.) appears to reduce mortality due to viral hepatitis by about 50% (3250). Other clinical research suggests that this same product reduces serum alanine aminotransferase (ALT) in hepatitis C patients but does not improve hepatitis C virus (HCV)-RNA levels (3247,59712,59721,59920). When used long-term, this preparation seems to reduce the risk of hepatocellular carcinoma in hepatitis C patients when compared to long-term use of other supplements, such as vitamin K (59905). This product has been used in various doses: 40 or 100 mL, containing 2 mg glycyrrhizin, 1 mg cysteine, and 20 mg of glycine per mL of solution, administered daily for 4-8 weeks, followed by 40 or 100 mL 2-7 times weekly for 2-16 weeks, has been used (3250,59905,59915); 40-120 mL diluted in 100 mL of 5% glucose solution and administered three times weekly for 4 weeks (59712,59721); 100 mL, which contained 200 mg glycyrrhizin, administered undiluted six times weekly for 4 weeks (59721); or 60 mL administered three times weekly for 16 weeks (59920). Other research shows that this preparation reduces ALT, aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) in patients with hepatitis B virus (59915). Oral licorice has not been evaluated for this purpose.
• Hypercholesterolemia. It is unclear if oral licorice is beneficial for improving cholesterol. Details: Preliminary clinical research shows that taking licorice root extract 0.1 grams daily for one month reduces plasma total cholesterol levels by 5%, plasma low-density lipoprotein (LDL) cholesterol levels by 9%, and plasma triglyceride levels by 14% when compared with baseline in patients with moderate hypercholesterolemia (59725). The validity of these findings is limited by the lack of a comparator group.
• Hyperkalemia. It is unclear if oral licorice is beneficial for reducing potassium levels. Details: Some clinical research in adults with diabetes and hypoaldosteronism suggests that taking glycyrrhizin 150 mg daily decreases potassium levels when compared with calcium polystyrene sulfonate (59897). Also, one very small clinical study in patients with anuria shows that taking glycyrrhetinic acid 1 gram daily for 2 weeks seems to decrease plasma potassium, but does not improve blood pressure, when compared with placebo (59723).
• IgA vasculitis. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small retrospective study in patients aged 5-36 years with newly diagnosed IgA vasculitis shows that taking compound glycyrrhizin (Eisai Pharmaceutical Co, Ltd) three times daily along with loratadine, calcium, vitamin C, rutin, and other unspecified conventional treatments is associated with an improvement in cutaneous purpura symptoms and time to symptom regression when compared with placebo. After 1 month, the rate of complete resolution and time to regression in the treatment group was 82% and 5 days, respectively, compared with 65% and 8 days, respectively, in the placebo group. Compound glycyrrhizin contained glycyrrhizin, glycine, and methionine and was dosed by age, with a dose of 25 mg daily in those 12 years or younger and 50 mg daily in those over 12 years (108580).
• Irritable bowel syndrome (IBS). Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a formulation containing licorice root, slippery elm bark, lactulose, and oat bran daily for 2 weeks improves stool consistency and increases bowel movement frequency by 20% in individuals with constipation-predominant IBS when compared to baseline. Symptoms of abdominal pain, bloating, straining, and global severity might also be reduced (35462). The validity of these findings is limited by the lack of a comparator group. Additionally, it is unclear if any benefits are due to licorice, other ingredients, or the combination.
• Lichen planus. It is unclear if intravenous licorice is beneficial for lichen planus. Details: A very small clinical study shows that intravenous administration of 0.2% glycyrrhizin solution, 40 mL daily for 4 weeks, improves clinical symptoms of oral lichen planus in a greater percentage of patients with chronic hepatitis C when compared with dental cleaning (59903). There is no evidence suggesting that oral licorice is beneficial.
• Liver cancer. Although there has been interest in using oral or intravenous licorice preparations for liver cancer, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Melasma. Topical licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a topical cream (Clariderm Clear, Stiefel Laboratories Inc.) containing 7% licorice, emblica, and belides twice daily for 60 days is as effective as a cream containing 2% hydroquinone for lightening the skin in patients with melasma (59824). It is unclear if this effect is due to licorice, other ingredients, or the combination.
• Menopausal symptoms. It is unclear if oral licorice is beneficial for reducing hot flash frequency or severity. Details: In one preliminary clinical study, taking licorice root extract 330 mg orally three times daily for 8 weeks modestly reduces the frequency of hot flashes by about 1.3 per day and the severity of hot flashes by about 40% when compared with placebo (94659). However, another preliminary clinical study shows that taking a specific licorice root extract (D-Reglis, Iran Darouk Pharmaceutical Co.) 650 mg orally daily for 90 days does not reduce the number or severity of hot flashes when compared to baseline (25694).
• Muscle cramps. It is unclear if oral licorice is beneficial for muscle cramps due to cirrhosis or hemodialysis. Details: Preliminary clinical research shows that taking a specific combination of licorice and peony (shakuyaku-kanzo-to) might reduce muscle cramps in patients with hepatic cirrhosis or in patients undergoing hemodialysis when compared to baseline (13550,13551,13552). This combination was taken as 6-7.5 grams daily in up to three divided doses for 2-4 weeks in two studies (13550,13552). In a third study, the combination was taken as 2.5 grams during hemodialysis with self-administration at the onset of muscle cramping (13551).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral licorice is beneficial for NAFLD. Details: A small clinical trial in females with NAFLD shows that taking licorice extract (Shirin Darou Company, Shiraz, Iran) 500 mg twice daily for 12 weeks improves some measures of liver health and glycemic control when compared with placebo. Modest improvements occurred in levels of alanine aminotransferase, as well as in measures of insulin resistance and severity of liver steatosis based on ultrasonographic evaluation. There were no effects on body mass index (BMI), plasma lipids, fasting blood glucose, or other liver enzymes. All patients were also given weight loss and healthy lifestyle advice (110320). Preliminary clinical research shows that taking licorice root extract 2 grams daily for 2 months reduces liver function enzyme levels in patients with NAFLD when compared to pre-treatment (59841). It is unclear if this reduction is clinically significant.
• Obesity. It is unclear if oral licorice is beneficial for weight loss. Details: Preliminary clinical research shows that taking a specific licorice flavonoid oil (Glavonoid) 300 mg daily for 8 weeks has no effect on weight or body fat when compared with placebo in obese patients (17727).
• Oral mucositis. It is unclear if oral or topical licorice is beneficial for the prevention or treatment of chemotherapy- or radiation-induced oral mucositis. Details: In patients with head and neck cancer undergoing chemoradiation, preliminary clinical research shows that using oral and topical licorice powder twice daily in addition to conventional treatments for 6 weeks reduces the overall incidence of mucositis and also reduces the risk of developing severe oral mucositis to 15.5%, compared with 20% in those using topical honey and 43% in those using conventional treatments alone. Licorice treatment consisted of yastimadhu powder 5 grams mixed in honey for topical application in the mouth, as well as yastimadhu capsule 500 mg twice daily orally (104562). A small clinical trial in patients with head and neck cancer and oral mucositis currently undergoing radiation therapy shows that applying a mucoadhesive film containing licorice to the upper lip mucosal surface four times daily for 4 weeks, in conjunction with standard oral care, improves pain scores, mucositis grading, and ulcer size when compared with placebo film (108572). The validity of this finding is limited due to the short duration of treatment and exclusion of patients with severe mucositis.
• Osteoarthritis. Although there has been interest in using oral licorice for osteoarthritis, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Osteoporosis. Although there has been interest in using oral licorice for osteoporosis, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Parkinson disease. It is unclear if oral licorice is beneficial for improving Parkinson disease symptoms. Details: A small clinical study in patients with Parkinson disease shows that taking licorice extract 136 mg (containing glycyrrhizin 12.14 mg, polyphenols 136 mcg, and flavonoids 2.6 mcg) in a 5 mL syrup twice daily for 6 months improves Parkinson symptoms, tremor, and overall daily activities when compared with placebo (102961).
• Peptic ulcers. Evidence for the use of oral licorice for peptic ulcers is mixed. Details: There is some evidence that taking 6-12 tablets each containing deglycyrrhizinated licorice 380 mg, bismuth subnitrate 100 mg, aluminum hydroxide gel 100 mg, magnesium carbonate 200 mg, sodium bicarbonate 100 mg, and powdered alder buckthorn bark 30 mg (Caved-S, Cedona) in up to three divided doses daily for 4-16 weeks might accelerate the healing of peptic ulcers (11312,11313). Some clinical research also shows that this product is as effective as carbenoxolone sodium (Biogastrone) when taken at doses of two tablets three times daily after meals for 4 weeks (59871). In contrast, taking deglycyrrhizinated licorice (Ulcedal, Cedona, and others) 450-1000 mg three to five times daily for 4-8 weeks or glycyrrhizinic acid-reduced licorice 760 mg three times daily for 6 weeks does not seem to reduce the need for medication, pain, burning, or other discomfort in patients with peptic ulcers when compared with placebo (59864,59865,59873,59874).
• Physical performance. It is unclear if oral licorice is beneficial for improving physical performance in older females. Details: A small clinical trial in healthy females 59 years and older shows that taking licorice flavonoid oil 300 mg orally daily for 16 weeks in addition to strength training does not improve walking speed or other measures of functional mobility when compared with strength training alone (102960).
• Polycystic ovary syndrome (PCOS). Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking licorice root extract 2250 mg daily along with Ceylon cinnamon, levant berry, St. John's Wort, peony, and tribulus for 3 months with lifestyle modification improves symptoms of PCOS, including a reduction in oligomenorrhea/amenorrhea by 33% and the number of days between menstrual cycles by 43 days when compared with lifestyle modification alone. Although conception rate increased 4-fold in the intervention group, live birth rate was similar between groups (97216). The effect of licorice alone for the treatment of PCOS is unknown.
• Prostate cancer. Although there has been interest in using oral licorice for prostate cancer, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Psoriasis. It is unclear if topical licorice is beneficial for improving psoriasis symptoms. Details: Preliminary clinical research shows that using a topical cream containing licorice extract and milk proteins twice daily for 4 weeks does not reduce the duration of corticosteroid cream therapy in patients with palmar and/or plantar psoriasis, but may improve skin peeling, the area of skin affected, and some subjective symptoms, when compared with corticosteroid cream alone (59823).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral licorice for SLE, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Tuberculosis. Although there has been interest in using oral licorice for tuberculosis, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Urticaria. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of clinical research in adults with chronic urticaria shows that taking compound glycyrrhizin, containing glycyrrhizin, N-acetyl cysteine, and glycine, as 50-75 mg three times daily along with desloratadine 5-8.8 mg daily for 4 weeks improves response rate, cure rate, and recurrence rate when compared with desloratadine alone (108571). However, most studies included in the meta-analysis were low quality, and all studies were conducted in China. Higher quality studies in other geographic locations are needed to confirm these findings.
• Vitiligo. It is unclear if the licorice constituent compound glycyrrhizin is beneficial for vitiligo. Details: A meta-analysis of 14 clinical studies in patients aged 3-68 years old with vitiligo shows that taking licorice constituent compound glycyrrhizin 25-75 mg 3 times daily for 2-6 months with standard treatment improves effectiveness, cure rate, and immune-mediated inflammatory markers when compared with standard treatment alone (112232). More evidence is needed to rate licorice for these uses.

(Read more about LICORICE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral marshmallow root is beneficial in patients with cough due to ACE inhibitors. Details: A small clinical study in patients with ACE inhibitor-induced cough shows that taking marshmallow root 40 mg (20 drops) three times daily for 4 weeks improves cough when compared to baseline (62027). The validity of this finding is limited by the lack of a control group.
• Atopic dermatitis (eczema). It is unclear if topical marshmallow is beneficial in children with eczema. Details: A very small clinical study in children ages 3 months to 12 years with a recent diagnosis of mild to moderate eczema shows that applying a marshmallow 1% ointment twice daily for 1 week and then three times weekly for 3 weeks seems to reduce symptoms, as measured on the SCORing Atopic Dermatitis (SCORAD) scale, when compared with applying hydrocortisone 1% ointment (105437). This finding is limited by the large number of drop-outs due to non-compliance, most of which were in the marshmallow group.
• Breast engorgement. It is unclear if topical marshmallow is beneficial in women with this condition. Details: A small clinical study in breastfeeding women with breast engorgement shows that applying a compress containing 40-50 mL of a solution made from marshmallow leaves and stems 3 times daily for 2 days in conjunction with standard treatment improves patient-reported breast engorgement scores when compared with standard treatment alone. Standard treatment consisted of massage and alternating warm and cold compresses before and after breastfeeding (92845).
• Constipation. Although there is interest in using oral marshmallow for constipation, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
• Cough. Although there is interest in using oral marshmallow for cough, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
• Diarrhea. Although there is interest in using oral marshmallow for diarrhea, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
• Fever. It is unclear if topical marshmallow is beneficial for pediatric fever. Details: A moderate-sized clinical study in children aged 6 months-10 years with fever receiving rectal acetaminophen shows that applying marshmallow extract body wash and lukewarm water reduces the time to defervescence by 8 minutes when compared with lukewarm water alone, but does not improve the change in body temperature, number of acetaminophen doses given, or incidence of fever recurrence (112375). However, the interpretation of these findings is limited to patients without fevers greater than 40 degrees Celsius or history of febrile seizures since these patients were not studied.
• Leishmania lesions. Topical marshmallow has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests that the topical application of an herbal extract containing a combination of marshmallow and Althaea rosa to affected areas for 5 days can help promote curing of Leishmania lesions (62020).
• Respiratory tract infections. Although there is interest in using oral marshmallow for respiratory tract infections, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
• Vaginal candidiasis. It is unclear if vaginal marshmallow is beneficial for vulvovaginal candidiasis. Details: A small clinical study in adults with vulvovaginal candidiasis shows that applying a vaginal cream comprised of marshmallow extract 4% and clotrimazole 1% daily for 7 days improves itching, dyspareunia, and dysuria at 7 days when compared with clotrimazole 1% alone. At 30 days, the marshmallow intervention also results in fewer positive yeast cultures and sustained reduction in itching (112371). However, the validity of these results is limited by significant differences between groups at baseline for dyspareunia and dysuria, and lack of adjustment for multiple comparisons which can increase false positive findings. Additionally, all primary outcomes were patient-reported.
• Venous leg ulcers. Although there is interest in using topical marshmallow for venous leg ulcers, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
• Wounds. Although there is interest in using topical marshmallow for wounds, there is insufficient reliable information about the clinical effects of marshmallow for this condition. More evidence is needed to rate marshmallow for these uses.

(Read more about MARSHMALLOW)

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about METHYLSULFONYLMETHANE (MSM))

POSSIBLY INEFFECTIVE

• Athletic performance. Oral quercetin does not seem to improve athletic performance. Details: A pooled analysis of data from seven clinical trials shows that intake of quercetin does not improve maximal oxygen consumption or capacity to perform prolonged exercise in trained or untrained athletes when compared with placebo (91577). Additionally, one small clinical study in male soldiers shows that taking quercetin 500 mg twice daily for 8.5 days before a loaded treadmill marching test and a cycling time trial test does not affect ratings of perceived exertion, cycling time, or peak oxygen consumption during treadmill testing when compared with placebo (91578). Quercetin has also been evaluated in combination with another ingredient. A small clinical study in trained athletes shows that taking a single dose of quercetin (Quercetin Powder from Sophora Japonica Flower, Aki Organics) 140 mg and mangiferin 84 mg, a mango constituent, one hour prior to an intermittent high-intensity exercise test improves performance as measured by circuit time and reduces perceived exertion, but does not improve heart rate, sprint time, or subjective muscle soreness when compared with placebo (113077). It is unclear whether these effects are due to quercetin, mangiferin, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral quercetin is beneficial in older adults with age-related cognitive decline. Details: Preliminary research in healthy adults aged 60 to 80 years with age-related forgetfulness shows that drinking 500 mL of a barley-based beverage containing 110 mg quercetin glycoside calculated as isoquercitrin, daily for 40 weeks seems to improve reaction times when compared with placebo. However, increase in score on the mini-mental state examination (MMSE), reduction in accumulation of amyloid beta in the brain, and prevention of reduction in cerebral blood flow occur to a similar extent with quercetin and placebo (110008).
• Allergic rhinitis (hay fever). It is unclear if oral quercetin is beneficial in patients with allergic rhinitis. Details: A small clinical study in Japanese adults with allergic rhinitis shows that taking a specific quercetin product (Quercetin Phytosome, Indena SpA) 100 mg twice daily for 4 weeks does not improve scores related to quality of life, activities of daily living, nasal symptoms, or ocular symptoms on the Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ). However, scores related to fatigue and sleep quality improved when compared with placebo. Additionally, sneezing, rhinorrhea, and activities of daily living scores improved when another scale was used to assess the severity of allergic rhinitis (109620). Quercetin has also been evaluated in combination with other ingredients. A small clinical study in children aged 6-12 years with allergic rhinitis who had gone through a treatment phase with antihistamines and a specific combination of quercetin, perilla, and vitamin D3 (Lertal) 1 tablet daily for 4 weeks shows that taking this specific combination for an additional 4-12 weeks reduces the chance of having symptom exacerbations by approximately 50% when compared with no further treatment past the first 4 weeks. The number of days requiring rescue medication was also reduced from 28.5 days to an average of 9.6 days (104676).
• Alzheimer disease. Although there has been interest in using oral quercetin for Alzheimer disease, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Asthma. It is unclear if oral quercetin is beneficial in patients with asthma. Details: Preliminary clinical research in patients with mild-to-moderate asthma shows that taking a specific quercetin product (QFit, Indena SpA) 250 mg or 500 mg daily for 30 days along with conventional therapy reduces daytime and nighttime asthma symptoms, improves spirometry measures, and decreases the use of rescue inhalers when compared to baseline. Significant improvements in these outcomes were lacking in patients receiving conventional therapy alone (102540).
• Atherosclerosis. Although there has been interest in using oral quercetin for atherosclerosis, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Autism spectrum disorder. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children aged 4-10 years with autism shows that taking a combination of luteolin 10 mg/kg, quercetin 7 mg/kg, and rutin 3 mg/kg in olive oil for 26 weeks improves hyperactivity, irritability, and lethargy by a moderate to large amount, and improves some indices of functioning, such as daily living and social behavior, by a small amount when compared with baseline. The validity of these findings is limited by the lack of a comparator group (96765).
• Benign prostatic hyperplasia (BPH). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking one tablet of a specific combination product (Difaprost) containing quercetin, beta-sitosterol, and saw palmetto daily for 3 months does not improve general symptoms of BPH when compared to baseline (96784). The validity of these findings is limited by the lack of a comparator group.
• Beta-thalassemia. It is unclear if oral quercetin is beneficial in patients with beta-thalassemia. Details: Preliminary clinical research in transfusion-dependent patients with beta-thalassemia shows that taking quercetin 500 mg daily for 12 weeks reduces iron and ferritin levels, increases transferrin levels, and decreases transferrin saturation when compared with placebo. However, total iron binding capacity was not improved. These results suggest that quercetin might reduce iron overload, which is a complication of frequent blood transfusions in these patients (102541).
• Cancer. Although there has been interest in using intravenous or intraperitoneal quercetin for cancer, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Canker sores. Topical quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a cream containing quercetin, glycol, zinc, and Myristica (Rootage skin cream, Elsi-Si) three times daily results in complete healing of minor canker sores and reduces pain in 100% of patients within 7-10 days, compared with only 60% of patients using a benzydamine hydrochloride mouthwash three times daily (104677).
• Cardiovascular disease (CVD). It is unclear if oral quercetin is beneficial for CVD prevention. Details: Population research has found that increasing dietary intake of quercetin from food sources such as tea, onions, and apples is associated with a significantly reduced risk of heart disease-related mortality in elderly males (7726). However, preliminary clinical research shows that quercetin 1 gram daily for 28 days does not significantly improve platelet aggregation, thromboxane B2 production, blood pressure, heart rate, or serum lipid levels when compared with placebo in healthy people (1998).
• Cataracts. Although there has been interest in using oral quercetin for cataracts, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Chemotherapy-induced cystitis. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with bladder cancer undergoing intravesical chemotherapy shows that taking a specific combination product (Ialuril, IBSA Farmaceutici) containing quercetin 400 mg, hyaluronic acid 40 mg, chondroitin sulfate 400 mg, and curcumin 400 mg every morning, starting 7 days before the first instillation and ending 30 days after the last instillation, improves lower urinary tract symptoms as measured using a visual analog scale and the International Prostate Symptom Score (IPSS) at 13 months when compared with placebo (109622).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral quercetin for CFS, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Chronic venous insufficiency (CVI). Although there has been interest in using oral quercetin for CVI, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Colorectal cancer. Although there has been interest in using oral quercetin for colorectal cancer prevention, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Contrast induced nephropathy. It is unclear if oral quercetin is beneficial for the prevention of contrast induced nephropathy. Details: Preliminary clinical research in patients undergoing coronary catheterization shows that taking quercetin 500 mg every 8 hours, starting two days prior to contrast imaging and continuing for two days after, does not appear to prevent contrast induced nephropathy when compared with a control group not receiving quercetin (102539). Given its small size, this study may have been inadequately powered to detect significant differences for this outcome.
• Coronavirus disease 2019 (COVID-19). Analysis of several small, open-label clinical studies suggest that oral quercetin may modestly reduce hospitalizations and intensive care unit (ICU) admissions in patients with COVID-19. Whether quercetin is beneficial in patients with severe COVID-19 is unclear. Details: A meta-analysis of 6 open-label clinical studies in patients with COVID-19 shows that taking quercetin 260-1000 mg daily for 7-30 days along with standard therapy with analgesics, antipyretics, antibiotics, remdesivir, or favipiravir reduces the odds of intensive care unit (ICU) admission by 69% and the odds of hospitalization by 75% but does not decrease the rate of all-cause mortality or the rate of recovery upon follow-up when compared with standard care (111412). However, the interpretation of these findings is limited by differences in the severity of COVID-19, doses and durations of quercetin therapy, and standard of care regimens used across the included studies. In outpatients in the early stages of COVID-19, two small, open-label clinical studies included in the meta-analysis above show that taking quercetin 200 mg two or three times daily for 14-30 days along with standard care reduces time to symptom resolution when compared with standard care alone. However, these studies show mixed results with respect to prevention of hospitalization, ICU admission, and death (106498,106499). More recent research in patients with early-stage, mild to moderate COVID-19 symptoms shows that taking quercetin 500 mg three times daily for 1 week, followed by 500 mg twice daily for 1 week, increases the rate of symptom resolution and achieving a negative COVID-19 test at 1 week by 116% and 183%, respectively, when compared with placebo (110009). Quercetin has also been evaluated in patients with severe COVID-19. A small, open-label clinical study of patients with severe COVID-19 who have not been admitted to the ICU shows that taking quercetin 500 mg twice daily for 7 days along with remdesivir or favipiravir shortens the time to discharge by around 1.5 days and improves symptoms of weakness and lethargy, but does not improve other symptoms of COVID-19 or reduce the risk of ICU admission or death, when compared with remdesivir or favipiravir alone (107450).
• Depression. It is unclear if oral quercetin is beneficial for depression in patients with a recent myocardial infarction (MI). Details: A moderate-sized clinical study in adults 6-8 weeks post-MI conducted in Iran shows that taking quercetin 500 mg daily for 8 weeks does not improve self-reported depression scores when compared with placebo (112228). However, the severity of patients' depression was minimal at baseline, which limits the power to detect a difference between groups.
• Diabetes. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with type 2 diabetes who are not using hypoglycemic agents shows that taking a specific combination of quercetin, myricetin, and chlorogenic acid (Emulin, Anderson Global Group LLC) 250 mg daily for 7 days reduces levels of fasting and postprandial glucose by about 5% when compared to baseline. These changes were significantly different than the slight increases seen in the placebo group. In patients taking metformin along with the combination supplement, fasting blood glucose levels decreased by about 20%, compared with a decrease of less than 1% with metformin alone (96779).
• Exercise-induced muscle damage. It is unclear if oral quercetin is beneficial for preventing muscle damage associated with exercise. Details: Some clinical research shows that taking quercetin 500 mg twice daily for 3 weeks prior to and during an endurance run or cycling event does not attenuate exercise-induced muscle damage, soreness, or inflammation (16429,16431). However, a series of two small clinical trials show that taking quercetin 1000 mg daily for 14 days prior to eccentric exercise modestly attenuates the decline in the maximal intensity of a contraction when compared with placebo (99236,104226). Additionally, this dosing regimen appears to modestly accelerate the recovery of muscle strength and neuromuscular function after exercise when compared with placebo (104226).
• Exercise-induced respiratory infections. It is unclear if oral quercetin is beneficial for prevention of respiratory infections induced by exercise. Details: Preliminary clinical research shows that taking quercetin 500 mg twice daily for 3 weeks before, and continuing during 3 days of prolonged, intense cycling, reduces the incidence of upper respiratory infections in the 14 days following the heavy exercise (16430).
• Gout. Although there has been interest in using oral quercetin for gout, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Herpes labialis (cold sores). Although there has been interest in using oral quercetin for herpes labialis, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Hypercholesterolemia. It is unclear if oral quercetin is beneficial for improving cholesterol levels. Details: Multiple meta-analyses show that taking quercetin does not affect total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (TG) when compared with placebo (96783,104229). However, a subgroup analysis shows that taking quercetin for at least 8 weeks seems to reduce TG levels by 13 mg/dL and increase HDL levels by 3 mg/dL, compared with no change in patients who took quercetin for less than 8 weeks (104229). It is unclear these patients had elevated cholesterol levels at baseline.
• Hypertension. It is unclear if oral quercetin is beneficial for reducing blood pressure. Details: Three meta-analyses show that taking quercetin 100-1000 mg daily for 4-12 weeks decreases systolic and diastolic blood pressure by 2-4 mmHg and 2-3 mmHg, respectively, when compared with placebo. However, only two of the studies included in these analyses evaluated patients with hypertension (16424,96775,104229,109617). Additional clinical research in patients with mild hypertension shows that taking a single dose of quercetin 1095 mg can lower systolic and diastolic blood pressure by 7 mmHg and 3 mmHg, respectively, when measured 10 hours later (96780). Overall, the benefit of quercetin on blood pressure seems modest; it is unclear whether the improvement is clinically significant for patients with hypertension.
• Kidney transplant. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific product containing a combination of quercetin 20 mg and curcumin 480 mg (Oxy-Q, Farr Labs) taken once or twice daily in combination with anti-rejection medications, starting within 24 hours of a kidney transplant and continuing for one month, improves early function of the graft and reduces serum creatinine when compared with taking placebo in combination with anti-rejection medications (16420).
• Lung cancer. It is unclear if oral quercetin is beneficial in lung cancer prevention. Details: Epidemiologic research has found that increasing dietary intake of quercetin is associated with a reduced risk of lung cancer in smokers (96778).
• Metabolic syndrome. It is unclear if oral quercetin is beneficial in patients with metabolic syndrome. Details: A meta-analysis of small clinical studies shows that taking quercetin 100-1000 mg daily for 4-12 weeks does not improve fasting blood glucose, glycated hemoglobin, or insulin levels when compared with placebo in patients with risk factors for metabolic syndrome, such as type 2 diabetes, prehypertension, polycystic ovary syndrome, and/or obesity (100967). Additional research is needed to determine if quercetin is beneficial in patients with existing metabolic syndrome.
• Niacin-induced flushing. Although there has been interest in using oral quercetin for niacin-induced flushing, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Obesity. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking quercetin 500 or 1000 mg daily for 12 weeks, in addition to niacin 5 mg or 10 mg and vitamin C 125 mg or 250 mg, does not reduce body weight or fat mass when compared with placebo in adults considered overweight or obese based on body mass index (BMI) (104678).
• Oral mucositis. It is unclear if oral quercetin is beneficial in patients with oral mucositis. Details: One small clinical study shows that taking quercetin 250 mg twice daily for 4 weeks does not prevent oral mucositis associated with chemotherapy when compared with placebo (96776).
• Ovarian cancer. It is unclear if oral quercetin is beneficial for ovarian cancer prevention. Details: One epidemiologic study found no association between dietary intake of quercetin and related flavonols and the risk of ovarian cancer (16428).
• Pancreatic cancer. It is unclear if oral quercetin is beneficial for pancreatic cancer prevention. Details: Epidemiologic studies have found that a high dietary intake of quercetin and related flavonols might reduce the risk of pancreatic cancer, especially in male smokers (16426,16427).
• Peptic ulcers. Although there has been interest in using oral quercetin for peptic ulcers, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Physical performance. It is unclear if oral quercetin is effective for improving physical performance in older adults. Details: A small clinical study in Japanese individuals 50-74 years of age shows that taking quercetin glycosides 200 mg or 500 mg daily along with low-intensity resistance training 3 days weekly for 24 weeks does not improve muscle size or lean body mass, but may reduce muscle stiffness, when compared with placebo (109621).
• Polycystic ovary syndrome (PCOS). It is unclear if oral quercetin is beneficial for improving hormone levels or pregnancy rates in patients with PCOS. Details: Clinical research in patients with PCOS shows that taking quercetin 1000 mg daily for 12 weeks reduces testosterone and luteinizing hormone (LH) levels by 9% and 3%, respectively, when compared to baseline; both of these improvements were significant when compared with placebo. Insulin resistance also improved by 18% when compared to baseline, which was significant when compared with placebo (96782). In a similar group of patients with higher levels of insulin resistance at baseline, taking the same dose of quercetin modestly reduced testosterone and LH levels when compared with placebo; however, there was no improvement in insulin resistance (99237). These disparate outcomes might be due to different baseline levels of insulin resistance. Also, it is unclear if these changes are associated with an improvement in the clinical symptoms of PCOS. Quercetin has also been evaluated for improving pregnancy rates in adults with PCOS and infertility. A small clinical study shows that taking quercetin 500 mg daily for 40 days increases pregnancy rates when compared with placebo. Quercetin supplementation also improves the grading of oocytes, but not the quality of embryos, in those undergoing in vitro fertilization (IVF). Nearly 84% of patients taking quercetin became pregnant spontaneously or via IVF in the 6 months following initiation of quercetin supplementation. Only 11% of patients taking placebo became pregnant during the study, all through IVF (109618). Due to a short duration of follow-up, it is unclear whether quercetin improves live birth rates.
• Prostatitis. It is unclear if oral quercetin is beneficial in patients with prostatitis. Details: Preliminary clinical research shows that taking quercetin 500 mg twice daily for one month reduces pain and improves quality of life, but does not seem to affect voiding dysfunction, in patients with chronic, nonbacterial prostatitis when compared with placebo (481).
• Rheumatoid arthritis (RA). It is unclear if oral quercetin is beneficial in patients with RA. Details: In patients with RA, clinical research shows that taking quercetin 500 mg daily for 8 weeks improves morning stiffness, morning pain, and after-activity pain when compared with placebo. However, taking quercetin does not seem to improve the number of swollen or tender joints or the disease activity score when compared with placebo (96774).
• Schizophrenia. Although there has been interest in using oral quercetin for schizophrenia, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Upper respiratory tract infection (URTI). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking quercetin 500 mg or 1000 mg daily for 12 weeks, in combination with vitamin C 500 mg or 1000 mg daily or niacin 20 mg or 40 mg daily, does not reduce the frequency or severity of URTIs. However, in a subgroup analysis of physically fit individuals 40 years and older, the severity of URTIs and the number of sick days related to URTIs were reduced by 36% and 31%, respectively, when quercetin 1000 mg was compared with placebo (104679).
• Urethral syndrome. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking one tablet daily of a specific formulation containing quercetin, bromelain, chondroitin sulfate, gotu kola, rhodiola, and barbed skullcap (Cistiquer, Deakos) for 7 weeks reduces urinary urgency by 91% when compared with baseline. Also, 55% of patients reported no discomfort associated with urination. This combination product was reported to be at least as effective as intravesical administration of betamethasone 8 mg plus gentamicin 80 mg twice weekly (96777).
• Urinary tract infections (UTIs). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking 1-2 capsules of a combination of hyaluronic acid, chondroitin sulfate, curcumin, and quercetin daily for 15 days each month, in combination with the use of local topical estrogen therapy (0.005% estriol vaginal gel) for up to 12 months, increases the number of women cured of recurrent UTIs to 66%, compared with only 34% of those taking the oral combination product or the vaginal estrogen product alone (96781). More evidence is needed to rate quercetin for these uses.

(Read more about QUERCETIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Oral slippery elm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Retrospective population research has found that taking a specific product containing burdock root, Indian rhubarb, sheep sorrel, and slippery elm bark (Essiac, Resperin Canada Limited) does not improve quality of life in breast cancer patients and may have a negative effect on physical well-being (37419).
• Constipation. Although there has been interest in using oral slippery elm for constipation, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Cough. Although there has been interest in using lozenges containing slippery elm for cough, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Diarrhea. Although there has been interest in using oral slippery elm for diarrhea, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Inflammatory bowel disease (IBD). Although there has been interest in using oral slippery elm for IBD, including Crohn disease and ulcerative colitis, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Irritable bowel syndrome (IBS). Oral slippery elm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific formulation containing slippery elm inner bark, lactulose, oat bran, and licorice root can improve stool frequency by 20% and reduce abdominal pain and bloating in people with constipation-predominant IBS when compared to baseline. Also, taking a different formulation containing slippery elm inner bark, bilberry fruit, cinnamon quilts, and agrimony aerial parts can reduce abdominal pain, bloating, and flatulence in people with diarrhea-predominant IBS when compared to baseline, although stool frequency is increased in these individuals as well (35462). It is unclear if these findings are due to slippery elm, other ingredients, or the combination.
• Peptic ulcers. Although there has been interest in using oral slippery elm for peptic ulcers, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Pharyngitis. It is unclear if lozenges containing slippery elm are beneficial in patients with sore throat. Details: Slippery elm has demulcent properties and, when added to lozenges, may soothe sore throats (272,512,1740). However, clinical research is lacking. More evidence is needed to rate slippery elm for these uses.

(Read more about SLIPPERY ELM)

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Oral turmeric seems to improve symptoms in people with allergic rhinitis. Details: A large clinical study in people with allergic rhinitis shows that taking a specific curcumin product (Organika Health Products) 500 mg daily for 2 months reduces nasal symptoms, including sneezing, itching, runny nose, and congestion, when compared with placebo (96138).
• Depression. Most research shows that oral curcumin, a constituent of turmeric, 1 gram daily improves symptoms of depression after 6 weeks when taken along with an antidepressant. However, it is unclear whether curcumin is beneficial when used for greater than 8 weeks. Details: Curcumin appears to be most beneficial for depression in middle aged patients compared to older patients, when taken for at least 6 weeks, and when used at a dose of at least 1 gram daily. In adults with major depressive disorder, a meta-analysis of data from six clinical studies, as well as individual studies not included in this analysis, show that taking curcumin 1 gram daily along with an antidepressant moderately improves depression symptoms when compared with placebo (96131,96139). Another meta-analysis of 10 studies shows symptom reductions in patients with major depression when combined with conventional antidepressants, but not when used alone in patients with milder depressive symptoms. However, the quality of the evidence is low (104971). When used alone, one clinical study shows that curcumin 1 gram daily for 6 weeks may be similarly effective to fluoxetine 20 mg daily. Taking both products together seems to be more effective than either product alone, increasing the response rate from 65% to 78% (89728). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that curcumin extract at doses of 500-1000 mg daily is provisionally recommended for monotherapy or adjunctive use in mild to moderate depression (110318).
• Dyspepsia. Oral turmeric may be modestly beneficial for some patients with dyspepsia. In patients with functional dyspepsia, small clinical studies show that oral curcumin, a constituent of turmeric, is similarly effective when compared with the proton-pump inhibitor omeprazole. Details: Clinical research shows that taking turmeric 500 mg four times daily for 7 days can relieve overall symptoms of dyspepsia in 64% more patients than taking placebo (11144). A small, unblinded clinical study in patients with a type of dyspepsia called postprandial distress syndrome shows that taking turmeric 250 mg or 500 mg orally three times daily after meals for 4 weeks is associated with reductions in symptom scores which are similar to those seen with simethicone 60 mg three times daily for 4 weeks. However, the recurrence rate upon stopping therapy was about 14% with simethicone, compared with 43% to 46% with turmeric (104963). In patients with functional dyspepsia, taking the constituent curcumin appears similarly effective when compared with omeprazole, but might not provide further symptom reduction in those also taking famotidine or omeprazole (106063,106801,111599). One small clinical study in Iran shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily in addition to famotidine 40 mg daily for 30 days is no more effective for reducing overall symptoms of dyspepsia, such as abdominal pain, heartburn, bloating, and nausea, when compared with famotidine alone (106063). Another small clinical study in Thailand shows that taking curcumin 500 mg four times daily for 4 weeks is similarly effective for reducing dyspepsia severity and improving satisfaction when compared with an unspecified dose of omeprazole and more effective when compared with placebo (106801). Similarly, a moderate-size clinical study in Thailand shows that taking curcumin 500 mg four times daily for 4 weeks is similarly effective for reducing dyspepsia severity when compared with omeprazole 20 mg daily. However, taking curcumin and omeprazole in combination did not provide further symptom reduction (111599). The validity of these results is limited by the high rate of study dropouts.
• Hyperlipidemia. Research is conflicting on whether oral turmeric, curcumin, or curcuminoids can reduce serum lipids. Any improvement in lipids is likely to be small. Reasons for the conflicting findings may relate to turmeric formulation, duration of treatment, and/or the baseline cholesterol status of the included patients. Details: Results from meta-analyses of clinical research show inconsistent and conflicting results. One large meta-analysis of over 50 clinical studies in healthy adults and those with a variety of conditions shows that supplementation with turmeric or curcumin 80-4000 mg daily for 4-24 weeks reduces total cholesterol by 4 mg/dL, low-density lipoprotein (LDL) cholesterol by 5 mg/dL, and triglycerides by 7 mg/dL and increases high-density lipoprotein (HDL) cholesterol by 2 mg/dL when compared with placebo (112119). Two other meta-analyses of 27 clinical studies agree that taking turmeric, curcumin, or curcuminoids moderately reduce triglyceride levels but suggest that turmeric does not improve total cholesterol when compared with placebo. However, the meta-analyses contradict one another on whether turmeric and its constituents reduce LDL cholesterol or increase HDL cholesterol. (96128,96135). Additionally, a third meta-analysis of 10 clinical trials shows that taking up to 2400 mg daily of curcumin or curcuminoids, from turmeric or isolated sources, for up to 12 weeks, does not significantly improve triglycerides, LDL cholesterol, HDL cholesterol, or total cholesterol (110220).
• Nonalcoholic fatty liver disease (NAFLD). Oral curcumin, a constituent of turmeric, seems to attenuate fat deposition and improve some metabolic parameters in adults with NAFLD. Details: Clinical research shows that taking curcumin daily reduces NAFLD severity in 30% to 79% of patients, compared to 5% to 27.5% of patients receiving placebo. Curcumin also reduces the quantity of additional fat deposition in the liver to 0% to 4.5%, compared to 17.5% to 26% in those taking placebo. Most research shows that taking curcumin also reduces liver enzyme levels, body mass index (BMI), blood glucose levels, glycated hemoglobin (HbA1c), and total cholesterol when compared with placebo. Although some clinical research shows that taking curcumin improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, a meta-analysis of clinical research shows that these lipid levels are not improved in patients with NAFLD, specifically (97430,97431,100258,102350,106062,107120,109279,111349). However, another meta-analysis of 14 small, heterogeneous clinical studies in adults with NAFLD, that included some of these studies, shows that taking various doses and forms of turmeric or curcumin modestly reduces liver enzyme levels, improves measures of insulin resistance, reduces waist circumference, and improves LDL, HDL, and triglyceride levels when compared with placebo (111348). A small clinical trial in patients with NAFLD given specific lifestyle recommendations shows that taking curcumin modestly reduces the frequency of metabolic syndrome and fatty liver but does not have beneficial effects on fatty liver-associated indices, adiposity, or the atherogenic index, when compared with placebo (109285). Findings for specific endpoints are mixed between individual studies and may depend on the formulation of curcumin used or the duration of treatment. These studies have used various doses and formulations. In one study, 500 mg of a dispersion formulation equivalent to 70 mg of curcumin daily for 8 weeks was used (97430). Also, 250 mg once daily or 500 mg twice daily of a specific phytosomal formulation (Meriva, Indena) containing curcumin and soy phosphatidylcholine in a 1:2 ratio and standardized to an overall curcuminoid content of 20% was taken for 8 weeks (97431,106062). Another study used 1 gram of powdered turmeric rhizome taken three times daily with meals for 12 weeks (102350). One study used a curcumin-piperine complex (Curcumin C3 complex 500 mg plus Bioperine 5 mg) daily for 8 weeks (107120). One study used curcumin (Arjuna Natural Extract) 500 mg three times daily for 12 weeks (109285). Despite positive results with curcumin in several small clinical studies of patients with NAFLD, there is some concern that curcumin might cause hepatotoxicity in rare cases, especially when highly bioavailable formulations are used in high doses (103633). There is also evidence that the risk for hepatotoxicity with curcumin may be increased in individuals with the HLAB*35:01 allele (109288). Curcumin-induced hepatotoxicity has not been reported in clinical trials of patients with NAFLD, and its potential mechanism is unclear. However, patients seeking to take curcumin for NAFLD should be advised to monitor for symptoms of hepatotoxicity, including abdominal pain, dark urine, fatigue, jaundice, nausea, and pruritus.
• Oral mucositis. Oral curcumin or curcumin-containing mouthwash seem to reduce the development of severe oral mucositis, as well as reduce the severity and pain of oral mucositis, associated with cancer treatment. Details: Clinical research in patients receiving radiotherapy following recent radical surgery for oral cancer shows that taking turmeric (BCM-95, Arjuna Natural Pvt. Ltd., India) during radiotherapy reduces the incidence of severe oral mucositis to 25% or 20% in those taking turmeric 500 mg two or three times daily, respectively, compared with 65% in those taking placebo. The incidences of severe oral pain, dysphagia, and dermatitis were also reduced by at least 50% (105398). A small clinical study in patients receiving chemotherapy with or without head and neck radiotherapy shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 7 weeks improves severity of oral mucositis at weeks 1, 4, and 7 and reduces pain at week 7 when compared with placebo. Effects were more pronounced in those with chemotherapy-induced oral mucositis than radiotherapy-induced oral mucositis (106800). In patients with head and neck cancer receiving radiotherapy, preliminary clinical research shows that swishing with 10 mL of turmeric solution (prepared by dissolving turmeric 400 mg in 80 mL of water) six times daily for 6 weeks delays mucositis and reduces the number of cases of intolerable mucositis by 49% when compared to swishing with 10 mL of povidone-iodine solution twice daily for 6 weeks (89726). Another small clinical study shows that swishing with 10 mL of nanoparticulate curcumin 0.1% mouthwash three times daily for 6 weeks is associated with a 50% lower risk of developing oral mucositis, and a delay of 2 weeks in the onset of mucositis, when compared with benzydamine 0.15% mouthwash (104969). A small clinical study in patients with mucositis due to head and neck radiotherapy shows that taking curcumin nanoparticles (SinaCurcumin, ExirNanoSina) 40 mg daily or using 10 mL of a curcumin 0.1% mouthwash three times daily for up to 21 days improves scores related to pain, burning, ulceration, and erythema when compared with placebo. Results with either oral or topical curcumin were similar (111350).
• Osteoarthritis. Some oral turmeric extracts and combination products containing turmeric seem to improve certain symptoms of knee osteoarthritis. However, it is unclear how turmeric compares to the use of non-steroidal anti-inflammatory drugs (NSAIDs). Details: Several meta-analyses of clinical studies show that turmeric extracts and/or curcuminoid products reduce knee pain and stiffness, improve physical function, and reduce the need for rescue medication when compared with placebo (104970,106792,109280,110222). However, a reduced effect was noted in patients with increasing age or body mass index (104790). The studies evaluated in these meta-analyses are heterogeneous, of low- to moderate-quality, and utilized a variety of products and/or dosing strategies (104970,106792,109280,110222). Small to moderate-sized clinical studies show that specific products (Meriva, Indena; Theracurmin, Theravalues Corp) containing curcumin 90-100 mg twice daily for up to 6 months, or specific turmeric extracts (Turmacin, Natural Remedies Pvt. Ltd.; Curcugen, DolCas Biotech, LLC) 500 mg twice daily for 6-12 weeks, reduce pain and analgesic use and improve functionality when compared with placebo (17953,80988,89721,97424,104148,107118). A specific turmeric extract (CuraMed, EuroPharma USA) 1500 mg daily for 12 weeks improves functionality, but not pain, when compared with placebo (96127). Also, a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina), 40 mg twice daily for 6 weeks, improves pain, stiffness, and physical activity scores and reduces intake of rescue acetaminophen by about 60% when compared with placebo (102349). However, not all turmeric products seem to be effective for improving symptoms of osteoarthritis. One small clinical study shows that taking a specific turmeric extract (B-Turmactive, PLAMECA S.A.) 500 mg daily for one week does not reduce knee pain when compared with placebo (104147). Also, a meta-analysis of clinical research shows that benefits are limited to bio-optimized forms of curcuminoids, and benefits related to pure extracts are lacking (110222). Turmeric has also been compared with conventional treatments for knee osteoarthritis in small meta-analyses, a network meta-analysis, and individual clinical studies. However, the evidence is mixed as to whether turmeric is as effective or more effective than NSAIDs, such as ibuprofen 400 mg taken 2-3 times daily, diclofenac 25-100 mg daily, or chondroprotective drugs (17952,89720,89722,106792,109280,110222,113607). A network meta-analysis comparing 6 interventions in adults with knee osteoarthritis suggests that curcumin monotherapy, curcumin with chondroprotective agents, or curcumin with NSAIDs improves scores related to pain, function, and stiffness while reducing the need for rescue medication and the incidence of adverse events (113607). Individual studies are heterogenous with respect to comparator medication and dosing schedule. Doses included a non-commercial turmeric extract 500 mg 3-4 times daily for 4-6 weeks (17952,89720) or turmeric extract 500 mg twice daily for 3 months (89722). Topical turmeric has also been evaluated. One clinical study shows that applying curcumin topically as a 5% ointment in Vaseline twice daily for 6 weeks reduces pain associated with knee osteoarthritis by a mean of about 11 on a 100-point visual analog scale when compared with placebo (104964). Another clinical study in patients with knee osteoarthritis shows that applying curcumin in a self-nano-emulsifying polyethylene glycol organogel 1.5 grams to the knee twice daily for 8 weeks reduces pain, stiffness, and difficulty with physical function scores by 72%, 62%, and 46%, respectively, when compared to baseline, with improvements superior to placebo for all outcomes (113357). Research also shows that taking specific combination products containing turmeric and other ingredients can improve pain and functionality in patients with osteoarthritis. These combination products have combined turmeric with chondroitin sulfate and glucosamine hydrochloride (CartiJoint Forte, Fidia Farmaceutici SpA); boswellic acid (Curamin, EuroPharma USA; Rhulief); Boswellia serrata (Rhulief); ashwagandha, Boswellia serrata, and zinc (Articulin-F, Eisen Pharmaceutical Co. Pvt. Ltd.); devil's claw and bromelain (AINAT, Laboratoire de Rhumatologie Appliquée); Boswellia serrata, guggul, and valerian (Phytoproflex, OPTM Healthcare); Boswellia serrata and terminalia (LI73014F2, Laila Nutraceuticals); ashwagandha, Boswellia serrata, and ginger (Artrex, Mendar); or extracts of ginger rhizome, devil's claw tuber, Boswellia serrata resin, and celery seed (Tregocel, Max Biocare) (19276,51950,81466,89717,89719,96127,97419,97421,97428,106078)(109280).
• Pruritus. Oral turmeric has been evaluated for the management of pruritus of various etiologies, with promising results. Details: Clinical research in patients with kidney failure shows that taking turmeric 500 mg orally three times daily for 8 weeks decreases symptoms of uremic pruritus by 1.9-fold when compared with placebo (89724). Also, a small clinical study in patients with sulfur mustard-induced chronic pruritus shows that taking a specific combination product (C3 Complex, Sami Labs LTD) containing curcumin 1 gram plus extract from black pepper or long pepper (Bioperine) daily for 4 weeks reduces pruritus severity and improves quality of life when compared with placebo (81120,81176).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Neither oral turmeric nor its constituent curcumin appears to improve cognitive function or attenuate cognitive decline in adults with this condition. Details: A small clinical trial shows that taking the turmeric constituent, curcumin, 1-4 grams daily for 6 months does not improve mental state examination scores when compared with placebo (17096). Furthermore, a meta-analysis of this study and another small clinical study in patients with Alzheimer disease shows that the turmeric group experienced greater cognitive decline when compared with placebo (100261). While this research is limited by small study sizes and heterogeneous patient populations, the current evidence does not support the use of turmeric in patients with this condition.
• Peptic ulcers. Oral turmeric does not seem to improve the healing of peptic or gastric ulcers when compared with placebo or liquid antacids. Details: Some clinical research shows that taking turmeric 2 grams three times daily for 8 weeks does not improve the healing of peptic ulcers when compared with placebo in Vietnamese patients (81444). Also, taking powdered turmeric rhizome 250 mg four times daily for 6 weeks seems to be less effective than a liquid aluminum-magnesium-hydroxide antacid for promoting gastric ulcer healing (81284).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical turmeric for acne, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Age-related cognitive decline. Some small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve cognition in elderly patients experiencing cognitive decline. Details: A meta-analysis of three small clinical trials shows that curcumin modestly improves cognition in the elderly (100261). One of these clinical trials shows that taking a specific brand of curcumin (Theracurmin, Theravalues Corp.) 90 mg twice daily for 18 months improves long-term memory and attention when compared with placebo in middle-aged and older adults with or without mild cognitive impairment (96161).
• Amenorrhea. Although there has been interest in using oral turmeric for amenorrhea, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Ankylosing spondylitis. Although there has been interest in using oral turmeric for ankylosing spondylitis, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Aromatase inhibitor-induced arthralgia. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for aromatase inhibitor-induced arthralgia. Details: A small clinical trial in patients experiencing aromatase inhibitor-induced arthralgia shows that taking curcuminoids as a nanoemulsion (Curcumin C3 Complex, Sabinsa Corporation) 200 mg daily for 3 months does not improve grip strength or joint symptoms when compared with placebo (113345). However, this study may have been underpowered to detect a difference between groups.
• Asthma. Some small clinical studies suggest that oral turmeric, as an adjunct to conventional asthma treatment, does not improve lung function or symptoms in adults and children with asthma. Details: One small clinical study in adults with mild to moderate asthma shows that adjuvant therapy with turmeric as curcumin 500 mg twice daily for 30 days does not improve lung function based on FEV1, or improve symptoms such as dyspnea, wheezing, cough, or tightness, when compared to standard treatment alone (99349). A small clinical trial in children 7-18 years of age with moderate to severe asthma shows that adding turmeric 500-1000 mg (containing 20-40 mg curcuminoids) daily for 6 months to standard therapy does not improve overall asthma symptoms when compared with placebo and standard therapy, although it may decrease the frequency of nighttime awakenings and the use of rescue inhalers (99348). Due to their small sizes and high drop-out rates, these studies may have been underpowered to detect a difference between groups.
• Athletic performance. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for athletic performance. Details: Preliminary clinical research in middle-aged male long-distance runners shows that taking a turmeric extract providing 2 grams of curcumin 95% and piperine 5% daily for 6 weeks does not improve aerobic capacity when compared with placebo (109286).
• Benign prostatic hyperplasia (BPH). It is unclear if oral curcumin, a constituent of turmeric, is beneficial in BPH. Details: A clinical study in patients with BPH shows that taking curcumin 2250 mg once daily along with tamsulosin and finasteride for 6 months improves lower urinary tract symptoms related to storage, but not overall symptoms or symptoms related to voiding, by about 35%, compared with 25% in those receiving tamsulosin and finasteride alone. Periprostatic fat thickness, quality of life, and erectile function also were improved (106799).
• Beta-thalassemia. It is unclear if oral turmeric is beneficial for iron overload in patients with beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia major and iron overload shows that taking turmeric extract containing curcumin 500 mg twice daily for 12 weeks modestly reduces non-transferrin bound iron (NTBI) by 0.6 micromol/L, but not hemoglobin, transferrin saturation, total iron binding capacity, ferritin, or hepcidin, when compared with placebo (99306). Another small clinical study in adult males with beta-thalassemia intermedia and iron overload shows that taking a higher dose of curcumin 500 mg three times daily for 12 weeks modestly reduces serum iron and ferritin turmeric levels and transferrin saturation when compared with placebo (108871).
• Bruises. Although there has been interest in using topical turmeric to alleviate bruising, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Cachexia. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for cancer cachexia. Details: A small clinical trial in patients with cancer anorexia-cachexia syndrome shows that taking curcumin 800 mg twice daily for 8 weeks does not reduce weight loss or improve body composition or handgrip strength when compared with placebo (109283).
• Canker sores. Some preliminary research suggests that topical curcumin, a constituent of turmeric, is beneficial for minor canker sores. Details: Preliminary clinical research in young adults with minor canker sores shows that applying a 2% curcumin oral gel for 6 months reduces ulcer size, pain, and recurrence rate and increases healing rate similarly to 0.1% triamcinolone oral paste (104962). The validity of the study is limited by a lack of investigator blinding and the lack of an intention to treat analysis. Another small clinical study shows that applying a 1% curcumin nanomicelle gel (SinaCurcumin Pharmaceuticals) on lesions three times daily for one week is modestly more effective than applying a 2% curcumin gel for reducing pain and ulcer size (109282). The validity of this finding is limited by the lack of a non-curcumin comparator group.
• Carpal tunnel syndrome. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is unclear if topical curcumin, a constituent of turmeric, is beneficial for carpal tunnel syndrome. Details: A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing turmeric, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and vitamins C, E, B1, B2, B6, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to turmeric, other ingredients, or the combination. Topical turmeric has also been investigated. A small clinical study in patients with mild to moderate carpal tunnel syndrome shows that applying a 1% curcuminoid gel (Sinanomin) to the wrists twice daily for 8 weeks modestly decreases symptom severity and improves function when compared with a placebo gel. However, there was no change in electrodiagnostic testing of the injury. All patients also used a night splint (113356).
• Chemotherapy-induced acral erythema. It is unclear if oral or topical turmeric reduces the risk for acral erythema from capecitabine. Details: A small clinical trial in adults with cancer shows that taking turmeric 4 grams daily for 6 weeks starting at the beginning of treatment with capecitabine does not reduce the incidence of acral erythema overall; however, it does seem to reduce acral erythema grade 2 or higher when compared with expected incidence rates (99309). Topical turmeric has also been evaluated. A clinical study in patients with colorectal, gastric, pancreatic, or breast cancer receiving capecitabine shows that applying a specific ointment (Alpha) standardized to contain curcumin extract 0.5% and henna extract 10% to the soles and palms twice daily, beginning on day 1 of chemotherapy and continued for 4 cycles, does not prevent acral erythema or improve World Health Organization severity scores when compared with placebo. A post-hoc analysis suggests that there may have been a trend toward delayed onset and progression; however, this study was not structured to assess these outcomes (108874).
• Chemotherapy-induced constipation. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced constipation. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks does not reduce symptoms of constipation when compared with placebo (107111).
• Chemotherapy-induced diarrhea. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced diarrhea. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks does not reduce symptoms of diarrhea when compared with placebo (107111).
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral curcumin reduces CINV. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks modestly reduces symptoms of nausea, but not vomiting, in the second and third months after the start of treatment when compared with placebo (107111).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced peripheral neuropathy. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks modestly reduces symptoms of chemotherapy-induced peripheral neuropathy over a three-month period when compared with placebo (107111).
• Chronic kidney disease (CKD). It is unclear if oral turmeric is beneficial for CKD. Details: A meta-analysis of four small clinical trials in patients with CKD related to diabetic nephropathy or lupus nephritis shows that taking curcumin or turmeric for 0.5-4 months moderately reduces proteinuria when compared with placebo (109276). Also, a small clinical trial in children and young adults ages 6-25 years with vascular dysfunction related to autosomal dominant polycystic disease (PKD) shows that curcumin powder 25 mg/kg daily for 12 months does not improve vascular function or kidney function when compared with placebo (107117).
• Colorectal adenoma. It is unclear if oral turmeric is beneficial for managing colorectal adenoma. Details: Preliminary clinical research in adults with familial adenomatous polyposis shows that taking curcumin 1500 mg twice daily for 12 months does not reduce the quantity or size of lower intestinal adenomatous polyps when compared with placebo (97427). A very small clinical trial in patients with familial adenomatous polyposis shows that taking 8 capsules daily of a turmeric extract, in a formulation also containing pepper fruit, spirulina, seaweed, and ginger root, for 6 months does not affect total polyp number or burden when compared with placebo. However, both number and burden were modestly reduced in the left colon. Each capsule provided curcuminoids 123.65 mg and turmerones 26.79 mg (110223).
• Colorectal cancer. It is unclear if oral turmeric is beneficial for the prevention or treatment of colorectal cancer. Details: A small clinical trial in patients undergoing chemotherapy following colorectal cancer surgery shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily for 8 weeks modestly improves some measures of quality of life when compared with placebo (107109). In addition, a small clinical study in people at high risk for colorectal cancer, such as those who smoke, shows that taking the turmeric constituent, curcumin, 4 grams daily for 30 days can reduce the number of precancerous rectal aberrant crypt foci (18204). It is not clear if this results in a reduced risk for colorectal cancer.
• Coronary artery bypass graft (CABG) surgery. One small study suggests that oral turmeric may reduce the risk for myocardial infarction after CABG surgery. Details: Preliminary clinical research shows that taking the turmeric constituent, curcuminoids, 4 grams daily in four divided doses, beginning 3 days prior to surgery and continuing for 5 days post-surgery, decreases the relative risk of myocardial infarction following CABG by approximately 56% when compared with placebo (81143).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral turmeric or its constituent, curcumin, is beneficial for reducing symptoms of COVID-19. Details: Small studies have evaluated curcumin as an adjunctive therapy in adults hospitalized with confirmed COVID-19. Patients in these studies also received treatments such as antimicrobials, anti-inflammatory medications, anticoagulants, antiretrovirals, and immunosuppressants (104966,105393,107119). One study shows that adding curcumin reduces the duration of shortness of breath by 6-9 days when compared with patients who received other treatments in combination with probiotics. However, there were no differences in the duration of other symptoms, including fever, cough, or sore throat. Subgroup analyses suggest that taking curcumin may improve oxygenation and reduce the need for supplemental oxygen or ventilation (105393). Another study shows that adding curcumin modestly reduces the time to resolution of COVID-19 symptoms, the length of supplemental oxygen use, and the likelihood for deterioration in the patients' condition when compared with patients who received other treatments alone (104966). A third study shows some benefit of curcumin on fever and cough when compared with baseline; however, it is unclear if any changes were significant when compared with placebo (107119). Doses of curcumin used in these studies include curcumin 525 mg with piperine 2.5 mg (C3 Complex, SamiDirect) twice daily, starting at admission and continuing for 14 days (105393), or a specific nanocurcumin product (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 2 weeks or 240 mg daily in divided doses for 7 days (104966,107119). Limitations of these studies include the small number of patients with severe symptoms, the large number of outcomes evaluated, the inconsistencies in other treatments used, the lack of clarity related to presentation of some results, and, in most cases, a lack of blinding. Turmeric has also been evaluated in adults in the outpatient setting with suspected or confirmed mild to moderate COVID-19. One small clinical study shows that taking curcumin (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 14 days in addition to other COVID-19 treatments (mainly hydroxychloroquine and azithromycin) reduces the duration of cough, chills, myalgia, and smell and taste disturbance, but not dyspnea, fever, sore throat, or others, by 1-2 days when compared with placebo with other treatments (106802). The validity of this study is limited by the lack of confirmatory diagnosis at baseline and lack of consistency with other treatments, as well as the unclear reporting of symptom duration in relation to the initiation of treatment. Another small clinical study in outpatients confirmed to have COVID-19 shows that taking curcumin 1000 mg plus piperine 10 mg (Sami Labs Limited) daily for 14 days modestly improves weakness, but not cough, pain, headache, difficulty breathing, or biochemical indices, when compared with placebo (109278). Some research has also examined the effect of turmeric as part of a polyherbal combination. Clinical research in patients hospitalized for moderate COVID-19 symptoms shows that using an Ayurvedic formulation 1776 mg twice daily containing turmeric, ashwagandha, ginger, and Boswellia serrata (BV-4051) for 14 days modestly reduces the duration of illness and reduces the severity of fever, cough, and smell and taste dysfunction when compared to placebo. There was no beneficial effect on other symptoms, including nasal congestion, breathing difficulty, headache, and gastrointestinal symptoms. More than half of the patients were also treated with remdesivir which did not impact the majority of these findings (109899).
• Crohn disease. It is unclear if oral turmeric is beneficial for improving symptoms of active Crohn disease. Details: Some clinical research shows that taking the turmeric constituent, curcumin, 1.08 grams daily for one month, then 1.44 grams daily for one month, can reduce bowel movements, diarrhea, and abdominal pain when compared to baseline in patients with Crohn disease (79730). The validity of these findings is limited by the lack of a comparator group.
• Denture stomatitis. Topical turmeric may be beneficial for treating denture stomatitis. Details: A small clinical study in patients with denture stomatitis shows that applying topical curcumin gel (Curenext, Abbott Laboratories) three times daily for 2 weeks resolves denture stomatitis lesions similarly to clotrimazole ointment (106797).
• Diabetes. Low-quality clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve glycemic control in patients with diabetes. Details: A meta-analysis of small clinical trials in patients with diabetic kidney disease shows that curcumin reduces levels of fasting glucose by approximately 8.3 mg/dL when compared with placebo. Curcumin was used in doses of 66.3-1670 mg daily for 2-6 months (107114). Preliminary clinical research included in the analysis shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 12 weeks reduces fasting blood glucose by about 20 mg/dL (104149). Other meta-analyses of low- to moderate-quality clinical studies in patients with a variety of conditions including type 2 diabetes show that taking turmeric extract, curcumin, or curcuminoids for 4-36 weeks improves glycated hemoglobin (HbA1c) by 0.4-0.7% and reduces fasting glucose by approximately 13 mg/dL when compared with placebo or conventional treatment (106806,108877,113604). The validity of these findings is limited by the heterogeneity of the included studies and broad curcuminoid doses ranging from 46-1500 mg daily. Conversely, other meta-analyses in patients with type 2 diabetes show that curcumin does not reduce HbA1c or insulin levels when compared with placebo (104965,108877,113604).
• Diabetic foot ulcers. It is unclear if oral curcumin is beneficial in patients with diabetic foot ulcers. Details: Preliminary clinical research in patients with grade 3 diabetic foot ulcers shows that taking nanocurcumin 80 mg orally daily for 12 weeks does not improve glycated hemoglobin (HbA1c) or change the rate of ulcer healing when compared with placebo. Taking turmeric did result in modest decreases in fasting blood glucose, insulin levels, and insulin resistance (104972).
• Diabetic nephropathy. It is unclear if oral curcumin is beneficial in patients with diabetic nephropathy. Details: Meta-analyses of two to four small clinical trials in patients with diabetic kidney disease show that curcumin modestly improves serum levels of creatinine, total cholesterol, and fasting glucose, and reduces systolic blood pressure by 4 mmHg, when compared with placebo. However, there was no effect on diastolic blood pressure, proteinuria, or serum levels of other plasma lipids or blood urea nitrogen. Curcumin was used in doses of 66.3-1670 mg daily for 2-6 months (107114). One small study included in this analysis, which evaluated patients receiving hemodialysis, shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 12 weeks reduces fasting blood glucose by about 20 mg/dL when compared with placebo (104149).
• Dysmenorrhea. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in university students aged 18 to 24 in Iran with mild to severe primary dysmenorrhea and premenstrual syndrome (PMS) shows that taking a specific combination product containing curcumin 500 mg plus extract from black pepper 5 mg (C3 Complex, Sami Labs) daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation for 3 consecutive menstrual cycles, does not improve the severity of symptoms when compared with placebo (106805). Conversely, a small clinical study in adults with moderately painful dysmenorrhea shows that taking a single dose of a combination product containing turmeric, Boswellia serrata, 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). However, it is unclear if these effects are due to turmeric, other ingredients, or the combinations.
• Endometriosis. It is unclear if oral turmeric is beneficial for reducing pain due to endometriosis. Details: A small clinical study in adults with endometriosis shows that taking the turmeric constituent, curcumin, 500 mg twice daily for 8 weeks does not affect pain associated with endometriosis or quality of life when compared with placebo (113603).
• Erythema. Although there has been interest in using topical turmeric for reducing erythema, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Exercise-induced muscle soreness. It is unclear if oral turmeric is beneficial for reducing muscle soreness from exercise. Details: A small clinical study in healthy males shows that taking turmeric capsules containing curcumin 2.5 grams twice daily for 5 days, starting 2.5 days before exercise, slightly reduces pain from certain movements when compared with placebo (98998). Another small crossover clinical study in professional male soccer players shows that taking curcumin 500 mg (Elite Opti-Turmeric, Health Span) immediately, 12 hours, and 36 hours after a match accelerates muscle recovery and reduces delayed-onset muscle soreness when compared with medium chain triglyceride oil 1000 mg (111356). Turmeric has also been examined in combination with other ingredients. Clinical research in healthy active adults with moderate to severe exercise-induced muscle pain shows that taking a single, 1000-mg dose of turmeric and Boswellia serrata 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).
• Gingivitis. Small clinical studies suggest that oral turmeric and turmeric mouthwash may reduce the severity of gingivitis. Turmeric mouthwash appears to be similarly effective to chlorhexidine mouthwash. Details: A meta-analysis of generally preliminary clinical research shows that rinsing with a mouthwash containing curcumin for 3-4 weeks is as effective as rinsing with chlorhexidine for reducing the severity of gingivitis or plaque (106059). Mouthwashes in these studies contained 0.05% to 20% curcumin and were usually used twice daily for 3-4 weeks (81127,89723,106059). One mouthwash contained 0.05% turmeric extract and 0.005% eugenol (89723). Another small clinical trial shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily by mouth after breakfast for 4 weeks reduces the severity of gingivitis and gingival bleeding, but not plaque, when compared with placebo in patients with gingivitis and mild periodontitis (104146).
• Gout. Although there is interest in using oral turmeric for gout, there is insufficient reliable information about the clinical effects of turmeric for this condition.
• Gulf war syndrome. It is unclear if oral curcumin is beneficial in patients with Gulf war syndrome. Details: A small preliminary clinical trial in patients with Gulf war syndrome shows that taking curcumin (Meriva, Indena, S.p.A.) 500 mg twice daily for 30 days reduces overall symptoms, including pain, fatigue, gastrointestinal distress, and others, by 19% when compared with baseline. Taking a higher dose of 2000 mg twice daily for an additional 30 days appears to be no more effective than the lower dose (105395).
• Helicobacter pylori. Small clinical studies suggest that oral turmeric is not beneficial for eradicating H. pylori when used alone or in combination with standard triple therapy or famotidine. Details: One small clinical study in patients with H. pylori gastritis shows that taking turmeric 2.1 grams daily for 4 weeks is less effective for eradicating H. pylori than taking an omeprazole-based triple regimen for one week (80957). Another small study in adults with peptic ulcers shows that taking a specific curcumin product (C3 Complex, Sami Labs LTD) 500 mg daily for 7 days, in conjunction with standard triple therapy, does not improve H. pylori eradication rates when compared with standard triple therapy alone. The addition of curcumin increased the resolution of dyspepsia symptoms by an additional 21%, but the clinical significance of this outcome is unclear (97420). In patients with dyspepsia, most of whom tested positive for fecal H. pylori antigen, clinical research shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily in addition to famotidine 40 mg daily for 30 days is no more effective for reducing fecal H. pylori antigen levels than taking famotidine alone (106063).
• Hypertension. It is unclear if oral curcumin is beneficial in patients with hypertension. Details: A meta-analysis of approximately 30 clinical studies in healthy adults or patients with a variety of conditions shows that taking turmeric, curcumin, curcuminoids, or nano-curcumin for 4 to 24 weeks reduces systolic blood pressure by about 2 mmHg and diastolic blood pressure by about 0.8 mmHg when compared with placebo (113602). However, these blood pressure reductions may not be clinically meaningful. In addition, most of the included studies were small and utilized heterogeneous dosing regimens.
• Impaired glucose tolerance (prediabetes). Oral turmeric may modestly improve glucose control in some patients with prediabetes. Details: In overweight or obese individuals with prediabetes, clinical research shows that taking a turmeric extract (BCM95 or Cucugreen; M/s Arjuna Natural Pvt Ltd.) 500 mg daily, providing 95% curcuminoids and at least 65% curcumin, for 90 days, either alone or in combination with zinc 30 mg as zinc gluconate, results in a small reduction in fasting glucose and glycated hemoglobin (HbA1c) when compared with placebo. There was also a small benefit in insulin sensitivity (105391). Other preliminary clinical research in adults with prediabetes shows that taking 500 mg of a combination of turmeric extract and Indian gooseberry extract in a 1:2 ratio along with phosphatidylcholine (EmbliQur) twice daily for 6 months modestly reduces fasting glucose and improves insulin resistance, when compared with placebo. However, changes in most other endpoints were not significantly different from placebo. Each 500 mg capsule contained turmeric extracts 29.86% and turmeric oil 1.27% (113355). The effect of turmeric on progression to type 2 diabetes in patients with prediabetes has also been investigated. Preliminary clinical research shows that taking a turmeric extract containing curcumin 750 mg twice daily for 9 months reduces the percentage of patients with prediabetes who develop type 2 diabetes when compared with placebo (81163).
• Irritable bowel syndrome (IBS). It is unclear if oral turmeric is beneficial for improving symptoms of IBS. Details: Preliminary clinical research in otherwise healthy adults with IBS shows that taking a turmeric extract (Cynara Turmeric, Lichtwer Pharma) 72-144 mg daily for 8 weeks reduces IBS symptoms by about 40% to 60% when compared to baseline (79565). The validity of this finding is limited by the lack of a comparator group. Taking a combination product (CU-FEO, Alfa Wasserman S.p.A.) containing curcumin 42 mg and fennel essential oil 25 mg per capsule twice daily for 60 days improves overall ratings of abdominal pain, abdominal distention, and quality of life by 24% when compared with placebo (97422). It is unclear if these effects are due to turmeric, fennel, or the combination. Observational research suggests that adding a supplement (Enterofytol PLUS) providing curcumin 42 mg and berberine 200 mg twice daily for 2 months to conventional IBS treatment is associated with improvements in symptoms, such as abdominal discomfort, distension, and stool status, by up to 48% when compared with conventional treatment alone. Use of the supplement was also associated with a 64% reduced need for conventional treatments (113354).
• Joint pain. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 1500 mg, methylsulfonylmethane 500 mg, white willow bark extract 250 mg, ginger root concentrate 50 mg, Boswellia extract 125 mg, turmeric root extract 50 mg, cayenne 40 m H.U. 50 mg, and hyaluronic acid 4 mg in three divided doses daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, it does not improve joint stiffness or function when compared with placebo (89560). It is unclear if these effects are due to turmeric, other ingredients, or the combination.
• Juvenile idiopathic arthritis (JIA). Although there is interest in using oral turmeric for JIA, there is insufficient reliable information about the clinical effects of turmeric for this condition.
• Knee pain. It is unclear if oral turmeric is beneficial for knee pain. Details: Clinical research in individuals with knee pain not related to existing arthritis shows that taking turmeric extract (TurmXTRA 60N; Inventia Healthcare Ltd. and Laila Nutraceuticals) 250 mg, providing 60% curcuminoids, once daily for 90 days modestly reduces pain associated with walking 80 meters when compared with placebo. The time taken to walk 80 meters and to climb nine steps was reduced by 4-5 seconds (105396).
• Lichen planus. Evidence is conflicting on whether turmeric is beneficial for lichen planus. Details: A meta-analysis of several small, heterogeneous, mostly low-quality clinical and observational studies in adults with oral lichen planus shows that oral or topical curcumin with or without corticosteroids for 2-12 weeks does not improve erythema, lesion size, or pain when compared with control (113605). Similarly, a network meta-analysis of small clinical trials in patients with oral lichen planus shows that applying topical turmeric gel does not improve symptoms, clinical resolution, clinical scores, or reduce pain when compared with other available interventions (111640). However, small individual clinical studies have shown some benefit in using turmeric for lichen planus. A small clinical study shows that taking a specific turmeric extract (Curcumin C3 Complex, Sabinsa Corporation) containing curcuminoids 6000 mg daily in three divided doses for 12 days can reduce erythema and ulceration associated with lichen planus when compared with placebo (81109). Another small clinical study shows that taking a nanocurcumin product (SinaCurcumin, ExirNanoSina) 80 mg orally once daily for 1 month reduces oral lichen planus lesion size, pain, and burning similarly to prednisolone 10 mg taken orally once daily for 1 month (104961).
• Metabolic syndrome. It is unclear if oral turmeric is beneficial for metabolic syndrome. Details: Research is conflicting on how turmeric, curcumin, and other formulations affect various measures of metabolic syndrome. Some clinical research and a meta-analysis of 13 clinical studies in patients with metabolic syndrome show that taking turmeric or curcumin decreases low-density lipoprotein (LDL) cholesterol, waist circumference by 2 cm, fasting blood glucose by 9 mg/dL, and diastolic blood pressure by 3 mmHg and increases high-density lipoprotein (HDL) cholesterol by 5 mg/dL when compared with placebo. However, other research shows that turmeric or curcumin have no effect on body weight, lipids, blood pressure, or blood glucose when compared with placebo (98999,99311,105400,109284,111347,112118). The validity of these effects is limited by high heterogeneity within the included studies and incomplete information about randomization and blinding. Studies have used turmeric, curcumin, and curcumin extract 80-2400 mg, in divided doses, daily for 4-12 weeks, nano-curcumin 80 mg daily for 12 weeks, or calebin A (CurCousin, Sabinsa), which is a constituent of turmeric, 25 mg twice daily for 3 months (98999,99311,105400,109284,111347,112118). Also, taking crude or phosphorylated curcuminoids 1 gram daily for 6 weeks does not improve sleep or reduce weight in these patients (105397).
• Migraine headache. It is unclear if oral curcumin is beneficial for migraine headache. Details: A small clinical trial in females with regular migraines shows that taking curcumin 500 mg twice daily for 8 weeks reduces the severity and duration, but not the frequency, of migraine headaches when compared with placebo. In individuals taking curcumin, the duration of headache per month was reduced by approximately 10.3 hours from baseline (107116).
• Myocardial infarction (MI). It is unclear if oral curcumin is beneficial for reducing myocardial injury following a MI. Details: Clinical research in patients with an acute MI shows that taking curcuminoids 500 mg plus piperine (Bioperine) 5 mg daily (Sami Labs) for 8 weeks does not improve ejection fraction, serum levels of cardiac troponin 1, blood pressure, levels of fasting blood glucose, or kidney function parameters when compared to placebo. However, there were some modest benefits on levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, glycated hemoglobin, and certain liver enzymes such as aspartate aminotransferase (AST) and alkaline phosphatase (ALP) (107115). The validity of this study is limited by its short duration and relatively small sample size.
• Obesity. Oral turmeric might modestly improve weight loss, although any effect is unlikely to be clinically significant. Details: Multiple meta-analyses of small, mostly low-quality clinical studies in adults with a variety of comorbid conditions show that taking various forms and doses of turmeric or curcumin results in an average weight loss of about 0.6-1 kg, a decrease in body mass index (BMI) of about 0.2-0.5 kg/m2, and a decrease in waist circumference of about 1.3 cm when compared with control (102345,111351,111352). A sub-analysis of dose and duration shows that a reduction in waist circumference only occurs with curcumin daily doses above 1000 mg, and duration of treatment longer than 8 weeks (102345).
• Oral submucous fibrosis. Small studies suggest that topical or oral curcumin might be beneficial for oral submucous fibrosis. However, the research is heterogenous with respect to outcomes, comparators, and the turmeric preparations, doses, and routes of administration utilized. Details: A meta-analysis of 3 small clinical trials shows that turmeric modestly improves mouth opening when compared with control. In addition, a systematic review of 11 studies shows that turmeric improves overall symptoms, including mouth opening, tongue protrusion, burning sensation, and cheek flexibility. However, studies were small with short duration and used variable dosing strategies. Most trials have studied oral turmeric 300-400 mg, either alone or with black pepper 100 mg or piperine 5 mg, for 3-6 months. Less commonly, turmeric was provided in lozenge form (105399). Also, a network meta-analysis suggests that the turmeric constituent curcumin with or without piperine is most the effective for reducing tongue protrusion when compared indirectly with various medical and antioxidant therapies; however, this analysis suggests that curcumin does not rank among the most effective interventions for improving mouth opening, burning sensation, or cheek flexibility (113514). Other preliminary clinical research shows that taking a specific oral product containing curcumin 300 mg and piperine 5 mg (Turmix tablets, Sanat Products), three times daily for 12 weeks, improves mouth opening, burning sensation, and tongue protrusion when compared with baseline, but not when compared with an antioxidant product containing alpha-lipoic acid, beta-carotene, copper, lycopene, selenium, and zinc. Mouth opening is further improved by concurrent use of a mouthwash (Turmix mouthwash, Sanat Products), containing 0.1% w/v turmeric extract (standardized to 95% curcumin), with thymol, eucalyptol, clove oil, mentha oil, and tea tree oil, twice daily for 12 weeks (102347). A small clinical study shows that applying topical curcumin gel (Curenext, Abbott Laboratories) 5 mg daily in 3-4 divided doses for 6 weeks, in combination with oral physical therapy, improves mouth opening similarly to using an aloe vera gel in combination with oral physical therapy. However, decreases in burning sensation are greater with aloe gel than curcumin gel (104967). It is not clear whether the gels, oral physical therapy, or the combination of both is responsible for the outcome. Finally, clinical research shows that applying a paste providing turmeric and holy basil 10 grams each, mixed in 10 mL of honey, to the oral mucosa 4 times daily for 3 months modestly improves mouth opening, tongue protrusion, and burning sensation and reduces the presence of fibrous bands when compared with taking a vitamin B supplement. There was no effect on the shape of the uvula (113325).
• Pain (acute). Oral turmeric 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 turmeric and Boswellia serrata 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.
• Periodontitis. There is limited evidence on the oral or topical use of turmeric or its constituent curcumin in patients with periodontitis. Details: A meta-analysis of heterogenous clinical studies in patients with chronic periodontitis suggests that use of local delivery gel products, usually turmeric 2% or a specific product containing curcumin (Curenext), modestly reduces pocket depth when compared with routine products, such as chlorhexidine. However, limited research suggests that curcumin products do not affect plaque or gingivitis measures, and curcumin irrigation does not affect pocket depth based on limited research (107108). A small preliminary clinical study in patients with severe chronic periodontitis shows that placing curcumin gel 2 mg on one side of the mouth along with scaling and root planing (SRP) reduces plaque and probing pocket depth, but not gingival index, when compared with SRP alone (101339). The use of oral curcumin has also been investigated. A small clinical trial in patients with gingivitis and mild periodontitis shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily after breakfast for 4 weeks reduces the severity of gingivitis and gingival bleeding, but not plaque, when compared with placebo (104146).
• Physical performance. It is unclear if oral turmeric may be beneficial for improving physical performance in older adults. Details: A very small clinical study in moderately functioning, sedentary adults over age 65 with low-grade chronic inflammation shows that that taking a specific turmeric extract (Curcumin C3 Complex, Sabinsa Corporation) 500 mg twice daily for 12 weeks does not improve measures of physical function, walking speed, or muscle strength when compared with placebo (111357). However, this study may have been inadequately powered to detect any possible differences between groups.
• Polycystic ovary syndrome (PCOS). Small clinical studies suggest that oral curcumin may improve some metabolic parameters in patients with PCOS, but these improvements may not be considered clinically significant. Details: Clinical research in patients with PCOS shows that taking curcumin 500 mg one to three times daily for 6-12 weeks improves some metabolic parameters (104968,105394,106795). Conversely, a small clinical study in patients aged 18 to 45 with PCOS in Iran shows that taking curcumin 1000 mg daily for 12 weeks modestly reduces fasting glucose but does not improve other metabolic parameters when compared with placebo. Taking curcumin also did not improve testosterone levels or hirsutism scores (111355). Meta-analyses show that taking curcumin modestly decreases body mass index (BMI) and improves measures of glycemic control, including fasting glucose and insulin resistance, and levels of total cholesterol when compared with placebo or metformin alone. However, effects on high-density lipoprotein (HDL) cholesterol levels were mixed and there was no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels (105394,106795,110219). Other preliminary clinical research shows that taking curcumin decreases plasma dehydroepiandrosterone and fasting plasma glucose levels when compared with placebo (104968). Some clinical research also shows that taking nano-curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 3 months is beneficial in patients already taking metformin 1500 mg daily. Taking curcumin had modest beneficial effects on fasting insulin and insulin resistance, as well as levels of testosterone, LDL cholesterol, HDL cholesterol, and triglycerides, when compared with metformin alone. There was no effect of curcumin on body weight, fasting blood glucose, or other hormones (106060).
• Postoperative pain. Small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly reduce pain in various postoperative recovery settings. Details: One small clinical study in patients undergoing laparoscopic cholecystectomy shows that taking curcumin 2 grams daily reduces postoperative pain, fatigue, and the need for analgesics by the second postoperative week when compared with placebo (81099). In patients undergoing surgery for inguinal hernia and/or hydrocele, taking curcumin 1.2 grams daily for 5 days reduces inflammation and tenderness by the sixth postoperative day when compared with placebo (81206). Curcumin was taken in 3-4 divided doses daily in these studies. Finally, taking a single dose of curcumin 200 mg after surgical removal of impacted third molars modestly reduces acute postoperative pain when compared with taking mefenamic acid 500 mg (99305).
• Premenstrual syndrome (PMS). It is unclear if oral turmeric may be beneficial for improving symptoms of PMS. Details: Some preliminary clinical research in patients with PMS shows that taking curcumin 100 mg twice daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation, improves physical, behavioral, and mood symptoms, as well as overall severity of symptoms, when compared with placebo (97433). Conversely, in university students aged 18 to 24 in Iran with mild to severe PMS and primary dysmenorrhea, a clinical study shows that taking a specific combination product containing curcumin 500 mg plus extract from black pepper 5 mg (C3 Complex, Sami Labs) daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation for 3 consecutive menstrual cycles, does not improve the severity of symptoms when compared with placebo (106805).
• Prostate cancer. It is unclear if oral turmeric is beneficial for the prevention or treatment of prostate cancer. Details: One small clinical study shows that taking curcumin 1.8 grams orally three times daily for 7 days, starting 4 days prior to docetaxel and prednisone treatment and continuing for up to 6 cycles, reduces PSA levels by at least half in 59% of patients when compared to baseline. Also, all patients with measurable lesions showed at least stable disease after treatment, and 40% of patients showed partial response when compared with baseline (96132). It is unclear if the addition of turmeric is beneficial when compared with docetaxel and prednisone alone. In contrast, an additional small clinical trial shows that taking curcumin 6 grams daily for 7 days every 3 weeks, starting four days before docetaxel, does not improve PSA levels or progression-free or overall survival when compared with docetaxel alone (105392).
• Psoriasis. Evidence is limited to one small study of topical use in patients with scalp psoriasis. Details: Preliminary clinical research in adults with scalp psoriasis shows that applying a tonic of turmeric to the scalp twice daily for 9 weeks modestly improves overall symptoms and quality of life when compared with a placebo tonic (97429).
• Quality of life. Some preliminary clinical research suggests that oral curcumin might improve quality of life in patients with various chronic conditions. Details: Small or low-quality clinical trials in various patient populations show that taking curcumin improves at least some measures of quality of life when compared with placebo. Research has been conducted in patients with cancer, sulfur mustard-induced chronic pruritus, benign prostatic hyperplasia (BPH), or irritable bowel syndrome (IBS). Studies have evaluated curcumin 2250 mg once daily for 6 months, a specific combination product (C3 Complex, Sami Labs LTD) containing curcumin 500-1000 mg plus piperine (Bioperine) daily for 4-9 weeks, or a combination product (CU-FEO, Alfa Wasserman S.p.A.) containing curcumin 42 mg and fennel essential oil 25 mg per capsule twice daily for 60 days (81120,81176,97422,106799,107109,107111). Also, in patients with scalp psoriasis, applying a tonic of turmeric to the scalp twice daily for 9 weeks modestly improves quality of life when compared with a placebo tonic (97429).
• Radiation dermatitis. It is unclear if oral or topical turmeric is beneficial for reducing the severity of radiation dermatitis. Details: A meta-analysis of 4 clinical studies in patients with breast cancer shows that taking curcumin 500-2000 mg three times daily for 3-7 weeks or applying curcumin gel 500 mg three times daily for 7 weeks reduces the radiation dermatitis severity score by about 0.5 points (on a 4-point scale) when compared with placebo or other control (111354). The validity of this analysis is limited by the heterogeneity of the included studies. However, a small clinical study in patients with breast cancer shows that taking nanocurcumin 80 mg twice daily during and for up to 2 weeks after treatment does not reduce skin reaction severity overall, but does modestly reduce pain, when compared with taking placebo. Also, there was a small reduction in skin reaction severity near the end of the study. All patients also used aloe vera leaf as part of the hospital protocol (109281). Another small preliminary clinical study in head and neck cancer patients shows that a specific cream (Vicco turmeric cream, Vicco Laboratories) containing turmeric and sandalwood oil, applied 5 times daily during radiation therapy, seems to reduce frequency and severity of radiation dermatitis when compared with baby oil (99307).
• Radiation proctopathy. It is unclear if oral turmeric is beneficial for preventing proctitis or cystitis in patients receiving radiotherapy for prostate cancer. Details: A small clinical study in patients with prostate cancer shows that taking a specific nanocurcumin product (SinaCurcumin, ExirNanoSina) 120 mg daily, for 3 days before and also during a course of radiotherapy, does not reduce the occurrence of proctitis or cystitis when compared with placebo (100259). This study may have been underpowered to detect small treatment effects.
• Respiratory tract infections. Although there is interest in using oral turmeric for various respiratory tract infections, including bronchitis and the common cold, it has not been clinically evaluated.
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve some symptoms of RA. Details: Meta-analyses of small clinical trials in patients with RA show that taking curcumin alone or with other treatments modestly reduces overall RA symptoms, pain, and markers of inflammation when compared with control groups, including placebo or other treatments. However, some research shows that there is no beneficial effect on tender or swollen joint count from the limited available clinical research (109280,111358), while other research shows that there is a benefit (112117). Clinical studies have evaluated curcumin 120-1200 mg daily for 2 weeks to 3 months (11149,18205,96129). The validity of these findings is limited by the small size of the studies, and in some cases, the lack of a comparator group.
• Sarcopenia. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in elderly patients with sarcopenia shows that taking a specific slow-release product containing turmeric, protein, carbohydrate, and fiber (Cureit, Aurea Biolabs), 500 mg orally daily for 3 months, increases handgrip strength by about 1% and distance walked before feeling tired by about 6% when compared with placebo. It also increases weightlifting capacity by about 6% from baseline, compared with a 5% decrease from baseline in those taking placebo (104973). It is unclear whether these small changes are clinically meaningful.
• Schizophrenia. Although there is interest in using oral turmeric for improving cognitive function in patients with schizophrenia, there is insufficient reliable information about the clinical effects of turmeric for this use.
• Sepsis. It is unclear if oral curcumin, a constituent of turmeric, is beneficial in patients with sepsis. Details: A small clinical trial in patients admitted to the intensive care unit (ICU) with sepsis shows that a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina), 80 mg dissolved in water and administered via gastric tube following lavage twice daily for 10 days does not affect length of ICU stay, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, blood pressure, or heart rate when compared with placebo (108873).
• Smoking cessation. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing turmeric 50 mg, ashwagandha, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, and holy basil (Smotect, Smotect India) daily for 3 months reduces the number of cigarettes smoked by approximately 3 per day when compared with placebo. This product also reduces levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity (112115). However, only data from patients who completed treatment were analyzed, which limits the validity of this study. It is unclear if these effects are due to turmeric, other ingredients, or the combination.
• Stress. It is unclear if oral turmeric is beneficial for reducing occupational stress in healthy adults. Details: A small clinical trial in healthy adults with occupational stress-related anxiety and fatigue shows that taking a specific type of turmeric (CurQfen, Akay Flavours and Aromatics Pvt Ltd.) that contains fenugreek dietary fiber for improved bioavailability at a dose of 500 mg twice daily for 30 days reduces stress and fatigue and improves quality of life when compared with placebo, and also when compared with a standard curcumin supplement with lower bioavailability (99308).
• Stroke. It is unclear if oral turmeric is beneficial for stroke. Details: A small clinical study conducted in Iran in adults with a recent ischemic stroke shows that taking curcumin 500 mg and piperine, a pepper constituent, 5 mg (Sami Lans, India) daily for 12 weeks reduces carotid intima-media thickness, triglycerides, total cholesterol, and systolic and diastolic blood pressure, but does not improve low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or quality-of-life indicators when compared with placebo (113601). The validity of this study is limited by the lack of statistical adjustment for multiple comparisons which can lead studies to erroneously show differences between treatment groups.
• Systemic lupus erythematosus (SLE). There is limited evidence on the oral use of turmeric in adults with lupus nephritis. Details: Preliminary clinical research in adults with lupus nephritis shows that taking turmeric 1.5 grams daily in three divided doses for 3 months reduces systolic blood pressure and improves kidney function when compared to baseline (81104). The validity of this finding is limited by the lack of a comparator group.
• Tuberculosis. It is unclear if oral turmeric is beneficial in patients receiving treatment for tuberculosis. Details: A small clinical study in adults receiving antituberculosis treatment shows that taking a formulation containing turmeric 0.5 grams and Tinospora cordifolia 0.5 grams twice daily for 4 months can reduce levels of Mycobacterium tuberculosis in the sputum and improve lesion healing when compared with antituberculosis treatment alone. Also, liver toxicity associated with the antituberculosis treatment seems to be reduced when administered with this formulation (80424). It is unclear if these effects are due to turmeric, Tinospora cordifolia, or the combination.
• Ulcerative colitis. It is unclear if oral or rectal turmeric, or its constituent, curcumin, is beneficial in adults with ulcerative colitis. Details: Although two small clinical studies in adults with ulcerative colitis show that taking oral turmeric extract 2-3 grams daily for 1-6 months improves the rate of remission and reduces relapse rate (79966,97423), a meta-analysis of these studies and one additional clinical study shows that turmeric does not improve remission rates when compared with placebo (99000). A specific product (Cur-Cure, Bara Herbs Inc) was used in some of these studies. Reasons for the conflicting findings are unclear, but may be due to small patient populations, concerns about blinding, and the inclusion of patients who were also taking immunomodulating drugs. It may also be due to differences in how a study measures remission. A meta-analysis of small clinical studies in patients with mild to moderate ulcerative colitis shows that adding oral curcumin 0.5-3 grams daily to standard treatment for 1-6 months may improve clinical remission rates, but not endoscopic remission rates, when compared with placebo (108872). However, the validity of this finding is limited by the small number of studies that evaluated endoscopic remission. A small clinical study shows that administering an enema form of turmeric extract (NCB-02, Himalaya Drug Company) as 20 mL, containing turmeric extract 140 mg, daily for 8 weeks increases response rate from 50% to about 93% and increases remission rate from about 31% to 71% when compared with placebo in patients with active ulcerative colitis. However, patients using the turmeric extract enema for shorter durations did not improve when compared with placebo (89729). Turmeric has also been investigated in combination with the Mediterranean diet. A small clinical trial shows that taking curcumin (VeNatura Curcumin Supplement) 800 mg twice daily while following the Mediterranean diet for 8 weeks is no more effective for improving ulcerative colitis symptom severity than following the Mediterranean diet without supplemental curcumin (113339).
• Uveitis. It is unclear if oral curcumin is beneficial for uveitis. Details: Observational research in patients with acute non-infectious uveitic macular edema shows that taking a specific hydrophilic curcumin product (Cucrcuwin, Diabec, Alfa Intes) 60 mg twice daily for 6 months, in conjunction with standard corticosteroid treatment, and then alone for an additional 6 months, modestly improves best corrected visual acuity, but not macular thickness or intraocular pressure, when compared with standard treatment alone for 6 months (107110).
• Wound healing. Although there is interest in using topical turmeric for wound healing, there is insufficient reliable information about the clinical effects of turmeric for this condition. More evidence is needed to rate turmeric for these uses.

(Read more about TURMERIC)

LIKELY SAFE ...when aloe gel is used topically and appropriately. Aloe gel-containing formulations have been safely applied in clinical trials (101,11982,12096,12098,12159,12160,12163,12164,17418)(90123,90124,90127,90128,90129,90131,97320,98816,103305). When included in topical cosmetics, the Cosmetic Ingredient Review Expert Panel concluded that aloe-derived anthraquinone levels should not exceed 50 ppm (90122).

POSSIBLY SAFE ...when aloe gel is used orally and appropriately, short-term. Aloe gel has been safely used in a dose of 15 mL daily for up to 42 days or 100 mL of a 50% solution twice daily for up to 4 weeks (11984,12164). Also, a specific aloe gel complex (Aloe QDM complex, Univera Inc.) has been safely used at a dose of approximately 600 mg daily for up to 8 weeks (90121). ...when aloe extract is used orally and appropriately, short-term. Aloe extract has been used with apparent safety in a dose of 500 mg daily for one month (101579). Also, an aloe extract enriched in aloe sterols has been used with apparent safety in a dose of 500 mg daily for 12 weeks (101577).

POSSIBLY UNSAFE ...when aloe latex is used orally. There is some evidence that anthraquinones in aloe latex are carcinogenic or promote tumor growth, although data are conflicting (6138,16387,16388,91596,91597). In 2002, the US FDA banned the use of aloe latex in laxative products due to the lack of safety data (8229). ...when aloe whole-leaf extract is used orally. Aloe whole-leaf extract that has not been filtered over charcoal still contains anthraquinones. This type of aloe whole-leaf extract is referred to as being "nondecolorized". The International Agency for Research on Cancer has classified this type of aloe whole-leaf extract as a possible human carcinogen (91598,91908). Although filtering aloe whole-leaf extract over charcoal removes the anthraquinones, some animal research suggests that this filtered extract, which is referred to as being "decolorized", may still cause gene mutations (91598). This suggests that constituents besides anthraquinones may be responsible for the carcinogenicity of aloe whole-leaf extract. It should be noted that commercial products that contain aloe whole-leaf extract may be labeled as containing "whole leaf Aloe vera juice" or "aloe juice" (91908).

LIKELY UNSAFE ...when aloe latex is used orally in high doses. Ingesting aloe latex 1 gram daily for several days can cause nephritis, acute kidney failure, and death (8,8961).

CHILDREN: POSSIBLY SAFE
when aloe gel is used topically and appropriately. Aloe gel-containing formulations have been safely applied in clinical trials (90124,90131).

CHILDREN: POSSIBLY UNSAFE
when aloe latex and aloe whole leaf extracts are used orally in children. Children younger than 12 years may experience abdominal pain, cramps, and diarrhea (4).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Anthraquinones present in aloe latex and aloe whole leaf extracts have irritant, cathartic, and possible mutagenic effects (4,16387,16388,90122). There are also anecdotal reports and evidence from animal research that anthraquinones or aloe whole leaf extracts might induce abortion and stimulate menstruation; avoid using (4,8,19,90122).

LACTATION: POSSIBLY UNSAFE
when aloe preparations are used orally. Cathartic and mutagenic anthraquinones present in aloe latex and aloe whole leaf extracts might pass into milk; avoid using (4,19).

(Read more about ALOE)

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

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

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

(Read more about GLUCOSAMINE)

LIKELY SAFE ...when used orally and appropriately. Glutamine has been safely used in clinical research in doses up to 40 grams per day or 1 gram/kg daily (2334,2337,2338,2365,5029,5462,7233,7288,7293), (52288,52307,52308,52311,52313,52337,52349,52350,96516,97366). A specific glutamine product (Endari) is approved by the US Food and Drug Administration (FDA) (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 600 mg/kg daily in clinical trials (2363,2366,5448,5452,5453,5454,5458,7293,52272,52275), (52283,52289,52304,52306,52316,52341), (52359,52360,52371,52377,52381,52284,52385,52408,96637,96507,96516).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Glutamine has been shown to be safe in clinical research when used in amounts that do not exceed 0.7 grams/kg daily in children 1-18 years old (11364,46657,52321,52323,52363,86095,96517). A specific glutamine product (Endari) is approved by the US Food and Drug Administration for certain patients 5 years of age and older (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 0.4 grams/kg daily in clinical research (52338,96508). There is insufficient reliable information available about the safety of glutamine when used in larger amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods. There is insufficient reliable information available about the safety of glutamine when used in larger amounts as medicine during pregnancy or lactation.

(Read more about GLUTAMINE)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Licorice has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when licorice products that do not contain glycyrrhizin (deglycyrrhizinated licorice) are used orally and appropriately for medicinal purposes. Licorice flavonoid oil 300 mg daily for 16 weeks, and deglycyrrhizinated licorice products in doses of up to 4.5 grams daily for up to 16 weeks, have been used with apparent safety (6196,11312,11313,17727,100984,102960). ...when licorice products containing glycyrrhizin are used orally in low doses, short-term. Licorice extract 272 mg, containing glycyrrhizin 24.3 mg, has been used daily with apparent safety for 6 months (102961). A licorice extract 1000 mg, containing monoammonium glycyrrhizinate 240 mg, has been used daily with apparent safety for 12 weeks (110320). In addition, a syrup providing licorice extract 750 mg has been used twice daily with apparent safety for 5 days (104558). ...when applied topically. A gel containing 2% licorice root extract has been applied to the skin with apparent safety for up to 2 weeks. (59732). A mouth rinse containing 5% licorice extract has been used with apparent safety four times daily for up to one week (104564).

POSSIBLY UNSAFE ...when licorice products containing glycyrrhizin are used orally in large amounts for several weeks, or in smaller amounts for longer periods of time. The European Scientific Committee on Food recommends that a safe average daily intake of glycyrrhizin should not exceed 10 mg (108577). In otherwise healthy people, consuming glycyrrhizin daily for several weeks or longer can cause severe adverse effects including pseudohyperaldosteronism, hypertensive crisis, hypokalemia, cardiac arrhythmias, and cardiac arrest. Doses of 20 grams or more of licorice products, containing at least 400 mg glycyrrhizin, are more likely to cause these effects; however, smaller amounts have also caused hypokalemia and associated symptoms when taken for months to years (781,3252,15590,15592,15594,15596,15597,15599,15600,16058)(59731,59740,59752,59785,59786,59787,59792,59795,59805,59811)(59816,59818,59820,59822,59826,59828,59849,59850,59851,59867)(59882,59885,59888,59889,59895,59900,59906,97213,110305). In patients with hypertension, cardiovascular or kidney conditions, or a high salt intake, as little as 5 grams of licorice product or 100 mg glycyrrhizin daily can cause severe adverse effects (15589,15593,15598,15600,59726).

PREGNANCY: UNSAFE
when used orally. Licorice has abortifacient, estrogenic, and steroid effects. It can also cause uterine stimulation. Heavy consumption of licorice, equivalent to 500 mg of glycyrrhizin per week (about 250 grams of licorice per week), during pregnancy seems to increase the risk of delivery before gestational age of 38 weeks (7619,10618). Furthermore, high intake of glycyrrhizin, at least 500 mg per week, during pregnancy is associated with increased salivary cortisol levels in the child by the age of 8 years. This suggests that high intake of licorice during pregnancy may increase hypothalamic-pituitary-adrenocortical axis activity in the child (26434); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about LICORICE)

LIKELY SAFE ...when marshmallow root and leaf are used in amounts commonly found in foods. Marshmallow root has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when marshmallow root and leaf are used orally in medicinal amounts (4,12). ...when used topically (4,62020). There is insufficient reliable information available about the safety of marshmallow flower.

PREGNANCY AND LACTATION:
Insufficient reliable information available.

(Read more about MARSHMALLOW)

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

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

(Read more about METHYLSULFONYLMETHANE (MSM))

POSSIBLY SAFE ...when used orally and appropriately, short-term. Quercetin has been used with apparent safety in doses up to 1 gram daily for up to 12 weeks (481,1998,1999,16418,16429,16430,16431,96774,96775,96782)(99237,102539,102540,102541,104229,104679,106498,106499,107450,109620)(109621). ...when used intravenously and appropriately. Quercetin has been used with apparent safety in doses less than 945 mg/m2. Higher doses have been reported to cause nephrotoxicity (9564,16418). There is insufficient reliable information available about the safety of quercetin when used topically.

POSSIBLY UNSAFE ...when used intravenously in large amounts. Doses greater than 945 mg/m2 have been reported to cause nephrotoxicity (9564,16418).

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

(Read more about QUERCETIN)

POSSIBLY SAFE ...when used orally and appropriately (4,12,272,512,1740).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Slippery elm bark has historically been inserted into the cervix to induce abortion. As a result, slippery elm has been reported in some sources to have abortifacient activity. However, there is no reliable information available about whether slippery elm has abortifacient activity when taken orally.

(Read more about SLIPPERY ELM)

LIKELY SAFE ...when used orally and appropriately, short-term. Turmeric products providing up to 8 grams of curcumin have been safely used for up to 2 months (10453,11144,11150,17953,79085,89720,89721,89724,89728,101347)(81036,101349,107110,107116,107117,107118,107121,109278,109283). Turmeric in doses up to 3 grams daily has been used with apparent safety for up to 3 months (102350,104146,104148,113357). ...when used topically and appropriately (11148).

POSSIBLY SAFE ...when used as an enema, short-term. Turmeric extract in water has been used as a daily enema for up to 8 weeks (89729). ...when used topically as a mouthwash, short-term. A mouthwash containing 0.05% turmeric extract and 0.05% eugenol has been used safely twice daily for up to 21 days (89723).

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in food.

PREGNANCY: LIKELY UNSAFE
when used orally in medicinal amounts; turmeric might stimulate the uterus and increase menstrual flow (12).

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in food. There is insufficient reliable information available about the safety of using turmeric in medicinal amounts during lactation.

(Read more about TURMERIC)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, aloe gel might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details In vitro research shows that aloe gel can inhibit platelet aggregation. This inhibition was greater than that seen with celecoxib, but less than that seen with aspirin (105501).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Aloe might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Preliminary clinical research suggests aloe gel might lower blood glucose levels (11983,12164,19756) and have additive effects when used with antidiabetes drugs. Monitor blood glucose levels closely.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, aloe might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research shows that aloe extract induces CYP1A2 enzymes (111404).

DIGOXIN (Lanoxin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, aloe latex might increase the risk of adverse effects when taken with cardiac glycosides.  Details Overuse of aloe latex can increase the risk of adverse effects from cardiac glycoside drugs, such as digoxin, due to potassium depletion. Overuse of aloe, along with cardiac glycoside drugs, can increase the risk of toxicity (19).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, aloe latex might increase the risk of hypokalemia when taken with diuretic drugs.  Details Overuse of aloe latex might compound diuretic-induced potassium loss, increasing the risk of hypokalemia (19).

STIMULANT LAXATIVES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, aloe latex might increase the risk for fluid and electrolyte loss when taken with stimulant laxatives.  Details Due to cathartic laxative effects of aloe latex, concomitant use with other stimulant laxatives might compound fluid and electrolyte loss (19,19742,19743,19744).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, aloe latex might increase the risk of bleeding when taken with warfarin.  Details Aloe latex has stimulant laxative effects. In some people aloe latex can cause diarrhea. Diarrhea can increase the effects of warfarin, increase international normalized ratio (INR), and increase the risk of bleeding. Advise patients who take warfarin not to take excessive amounts of aloe vera.

(Read more about ALOE)

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

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

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

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

(Read more about GLUCOSAMINE)

ANTICONVULSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, glutamine might antagonize the effects of anticonvulsant medications.  Details Glutamine is metabolized to the excitatory neurotransmitter glutamate. Glutamate might have antagonistic effects with anticonvulsant drugs (7292,7293,7294). However, this interaction has not yet been reported in humans.

(Read more about GLUTAMINE)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, licorice might reduce the effects of antihypertensive drugs.  Details In human research, licorice increases blood pressure in a dose-dependent manner (1372,7620,59877).

CISPLATIN (Platinol-AQ) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might reduce the effects of cisplatin.  Details In animal research, licorice diminished the therapeutic efficacy of cisplatin (59763).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of licorice and corticosteroids might increase the side effects of corticosteroids.  Details Case reports suggest that concomitant use of licorice and oral corticosteroids, such as hydrocortisone, can potentiate the duration of activity and increase blood levels of corticosteroids (3252,12672,20040,20042,48429,59756). Additionally, in one case report, a patient with neurogenic orthostatic hypertension stabilized on fludrocortisone 0.1 mg twice daily developed pseudohyperaldosteronism after recent consumption of large amounts of black licorice (108568).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase levels of drugs metabolized by CYP2B6.  Details In vitro research shows that licorice extract and glabridin, a licorice constituent, inhibit CYP2B6 isoenzymes (10300,94822). Licorice extract from the species G. uralensis seems to inhibit CYP2B6 isoenzymes to a greater degree than G. glabra extract in vitro (94822). Theoretically, these species of licorice might increase levels of drugs metabolized by CYP2B6; however, these interactions have not yet been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase levels of drugs metabolized by CYP2C19.  Details In vitro, licorice extracts from the species G. glabra and G. uralensis inhibit CYP2C19 isoenzymes in vitro (94822). Theoretically, these species of licorice might increase levels of drugs metabolized by CYP2C19; however, this interaction has not yet been reported in humans.

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase levels of drugs metabolized by CYP2C8.  Details In vitro, licorice extract from the species G. glabra and G. uralensis inhibits CYP2C8 isoenzymes (94822). Theoretically, these species of licorice might increase levels of drugs metabolized by CYP2C8; however, this interaction has not yet been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase or decrease levels of drugs metabolized by CYP2C9.  Details There is conflicting evidence about the effect of licorice on CYP2C9 enzyme activity. In vitro research shows that extracts from the licorice species G. glabra and G. uralensis moderately inhibit CYP2C9 isoenzymes (10300,94822). However, evidence from an animal model shows that licorice extract from the species G. uralensis can induce hepatic CYP2C9 activity (14441). Until more is known, licorice should be used cautiously in people taking CYP2C9 substrates.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, licorice might increase or decrease levels of drugs metabolized by CYP3A4.  Details Pharmacokinetic research shows that the licorice constituent glycyrrhizin, taken in a dosage of 150 mg orally twice daily for 14 days, modestly decreases the area under the concentration-time curve of midazolam by about 20%. Midazolam is a substrate of CYP3A4, suggesting that glycyrrhizin modestly induces CYP3A4 activity (59808). Animal research also shows that licorice extract from the species G. uralensis induces CYP3A4 activity (14441). However, licorice extract from G. glabra species appear to inhibit CYP3A4-induced metabolism of testosterone in vitro. It is thought that the G. glabra inhibits CYP3A4 due to its constituent glabridin, which is a moderate CYP3A4 inhibitor in vitro and not present in other licorice species (10300,94822). Until more is known, licorice should be used cautiously in people taking CYP3A4 substrates.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of licorice with digoxin might increase the risk of cardiac toxicity.  Details Overuse or misuse of licorice with cardiac glycoside therapy might increase the risk of cardiac toxicity due to potassium loss (10393).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of licorice with diuretic drugs might increase the risk of hypokalemia.  Details Overuse of licorice might compound diuretic-induced potassium loss (10393,20045,20046,59812). In one case report, a 72-year-old male with a past medical history of hypertension, type 2 diabetes, hyperlipidemia, arrhythmia, stroke, and hepatic dysfunction was hospitalized with severe hypokalemia and uncontrolled hypertension due to pseudohyperaldosteronism. This was thought to be provoked by concomitant daily consumption of a product containing 225 mg of glycyrrhizin, a constituent of licorice, and hydrochlorothiazide 12.5 mg for 1 month (108577).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase or decrease the effects of estrogen therapy.  Details Theoretically, licorice might interfere with estrogen therapy due to estrogenic and anti-estrogenic effects (7860,16058).

LOOP DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, loop diuretics might increase the mineralocorticoid effects of licorice.  Details Theoretically, loop diuretics might enhance the mineralocorticoid effects of licorice by inhibiting the enzyme that converts cortisol to cortisone; however, bumetanide (Bumex) does not appear to have this effect (3255).

METHOTREXATE (Trexall, others) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, licorice might increase levels of methotrexate.  Details Animal research suggests that intravenous administration of glycyrrhizin, a licorice constituent, and high-dose methotrexate may delay methotrexate excretion and increase systemic exposure, leading to transient elevations in liver enzymes and total bilirubin (108570). This interaction has not yet been reported in humans.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, licorice might decrease levels of midazolam.  Details In humans, the licorice constituent glycyrrhizin appears to moderately induce the metabolism of midazolam (59808). This is likely due to induction of cytochrome P450 3A4 by licorice. Until more is known, licorice should be used cautiously in people taking midazolam.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease the absorption of P-glycoprotein substrates.  Details In vitro research shows that licorice can increase P-glycoprotein activity (104561).

PACLITAXEL (Abraxane, Onxol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease plasma levels and clinical effects of paclitaxel.  Details Multiple doses of licorice taken concomitantly with paclitaxel might reduce the effectiveness of paclitaxel. Animal research shows that licorice 3 grams/kg given orally for 14 days before intravenous administration of paclitaxel decreases the exposure to paclitaxel and increases its clearance. Theoretically, this occurs because licorice induces cytochrome P450 3A4 enzymes, which metabolize paclitaxel. Notably, a single dose of licorice did not affect exposure or clearance of paclitaxel (102959).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease plasma levels and clinical effects of warfarin.  Details Licorice seems to increase metabolism and decrease levels of warfarin in animal models. This is likely due to induction of cytochrome P450 2C9 (CYP2C9) metabolism by licorice (14441). Advise patients taking warfarin to avoid taking licorice.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, marshmallow flower might have antiplatelet effects.  Details Animal research suggests that marshmallow flower extract has antiplatelet effects (92846). However, the root and leaf of marshmallow, not the flower, are the plant parts most commonly found in dietary supplements. Theoretically, use of marshmallow flower with anticoagulant/antiplatelet drugs can have additive effects, and might increase the risk for bleeding in some patients.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, due to potential diuretic effects, marshmallow might reduce excretion and increase levels of lithium.  Details Marshmallow is thought to have diuretic properties. To avoid lithium toxicity, the dose of lithium might need to be decreased when used with marshmallow.

ORAL DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, mucilage in marshmallow might impair absorption of oral drugs.  Details Marshmallow contains mucilage which can affect oral drug absorption (1,11,12,19). To avoid changes in absorption, take marshmallow 30-60 minutes after oral medications.

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(Read more about METHYLSULFONYLMETHANE (MSM))

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of quercetin and antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that a combination of quercetin, myricetin, and chlorogenic acid reduce levels of fasting glucose in patients with type 2 diabetes, including those already taking antidiabetes agents (96779). The effect of quercetin alone is unknown.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking quercetin with antihypertensive drugs might increase the risk of hypotension.  Details Quercetin can modestly decrease blood pressure in people with mild hypertension (16424,96780). Theoretically, it might have additive blood pressure lowering effects when used with antihypertensive drugs.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of cyclosporine.  Details A small study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine, possibly due to inhibition of p-glycoprotein or cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporin (16434).

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of CYP2C8 substrates.  Details In vitro research shows that quercetin inhibits CYP2C8 (16432,16435). Inhibition of paclitaxel (Taxol) metabolism via CYP2C8 has been reported in vitro (16436). However, a small study in humans found no effect of quercetin on rosiglitazone (Avandia), which is also a CYP2C8 substrate (16432).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of CYP2C9 substrates.  Details A small clinical study in healthy volunteers shows that taking quercetin 500 mg twice daily for 10 days prior to taking diclofenac, a CYP2C9 substrate, increases diclofenac plasma levels by 75% and prolongs the half-life by 32.5% (97931). Animal research also shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar), a substrate of CYP2C9 (100968). Furthermore, laboratory research shows that quercetin inhibits CYP2C9 (15549,16433).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of CYP2D6 substrates.  Details In vitro research show that quercetin inhibits CYP2D6 (15549,16433). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might alter the effects and adverse effects of CYP3A4 substrates.  Details A small clinical study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine (Neoral, Sandimmune), a substrate of CYP3A4 (16434). Animal research also shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar) and quetiapine (Seroquel), substrates of CYP3A4 (100968,104228). Other laboratory research also shows that quercetin inhibits CYP3A4 (15549,16433,16435). However, one clinical study shows that quercetin can increase the metabolism of midazolam, a substrate of CYP3A4, and decrease serum concentrations of midazolam by about 24% in some healthy individuals, suggesting possible induction of CYP3A4 (91573).

DICLOFENAC (Voltaren, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of diclofenac.  Details A small clinical study in healthy volunteers shows that taking quercetin 500 mg twice daily for 10 days prior to taking diclofenac increases diclofenac plasma levels by 75% and prolongs the half-life by 32.5%. This is thought to be due to inhibition of CYP2C9 by quercetin (97931).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of losartan and decrease the effects of its active metabolite.  Details Animal research shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar) while decreasing plasma levels of losartan's active metabolite. This metabolite, which is around 10-fold more potent than losartan, is the result of cytochrome P450 (CYP) 2C9- and CYP3A4-mediated transformation of losartan. Additionally, in vitro research shows that quercetin may inhibit P-glycoprotein-mediated efflux of losartan from the intestines, resulting in increased absorption of losartan (100968). These results suggest that concomitant use of quercetin and losartan might increase systemic exposure to losartan while also decreasing plasma concentrations of losartan's active and more potent metabolite.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might decrease the levels and effects of midazolam.  Details A small clinical study in healthy volunteers shows that quercetin can increase the metabolism of midazolam, with a decrease in AUC of about 24% (91573).

MITOXANTRONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of mitoxantrone.  Details In vitro research shows that quercetin increases the intracellular accumulation and cytotoxicity of mitoxantrone, possibly through inhibition of breast cancer resistance protein (BCRP), of which mitoxantrone is a substrate (107897). So far, this interaction has not been reported in humans.

ORGANIC ANION TRANSPORTER 1 (OAT1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of OAT1 substrates.  Details In vitro research shows that quercetin is a strong non-competitive inhibitor of OAT1, with half-maximal inhibitory concentration (IC50) values less than 10 mcM (104454). So far, this interaction has not been reported in humans.

ORGANIC ANION TRANSPORTER 3 (OAT3) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of OAT3 substrates.  Details In vitro research shows that quercetin is a strong non-competitive inhibitor of OAT3, with half-maximal inhibitory concentration (IC50) values as low as 0.75 mcM (104453,104454). So far, this interaction has not been reported in humans.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of OATP substrates.  Details In vitro evidence shows that quercetin can inhibit organic anion-transporting peptide (OATP) 1B1-mediated uptake of estrone-3-sulfate and pravastatin (91581). Furthermore, clinical research in healthy males shows that intake of quercetin along with pravastatin increases the AUC of pravastatin by 24%, prolongs its half-life by 14%, and decreases its apparent clearance by 18%, suggesting that quercetin modestly inhibits the uptake of pravastatin in hepatic cells (91581).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might alter the effects and adverse effects of P-glycoprotein substrates.  Details There is preliminary evidence that quercetin inhibits the gastrointestinal P-glycoprotein efflux pump, which might increase the bioavailability and serum levels of drugs transported by the pump (16433,16434,16435,100968,104228). A small study in healthy volunteers reported that pretreatment with quercetin increased bioavailability and plasma levels after a single dose of cyclosporine (Neoral, Sandimmune) (16434). Also, two small studies have shown that quercetin might decrease the absorption of talinolol, a substrate transported by the gastrointestinal P-glycoprotein efflux pump (91579,91580). However, in another small study, several days of quercetin treatment did not significantly affect the pharmacokinetics of saquinavir (Invirase) (16433). The reason for these discrepancies is not entirely clear (91580). Until more is known, use quercetin cautiously in combination with P-glycoprotein substrates.

PRAVASTATIN (Pravachol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of pravastatin.  Details In vitro evidence shows that quercetin can inhibit OATP 1B1-mediated uptake of pravastatin (91581). Also, preliminary clinical research in healthy males shows that intake of quercetin along with pravastatin increases the maximum concentration of pravastatin by 24%, prolongs its half-life by 14%, and decreases its apparent clearance by 18%, suggesting that quercetin modestly inhibits the uptake of pravastatin in hepatic cells (91581).

PRAZOSIN (Minipress) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of prazosin.  Details In vitro research shows that quercetin inhibits the transcellular efflux of prazosin, possibly through inhibition of breast cancer resistance protein (BCRP), of which prazosin is a substrate. BCRP is an ATP-binding cassette efflux transporter in the intestines, kidneys, and liver (107897). So far, this interaction has not been reported in humans.

QUETIAPINE (Seroquel) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of quetiapine.  Details Animal research shows that pretreatment with quercetin can increase plasma levels of quetiapine and prolong its clearance, possibly due to inhibition of cytochrome P450 3A4 (CYP3A4) by quercetin. Additionally, the brain-to-plasma ratio of quetiapine concentrations increased, possibly due to inhibition of P-glycoprotein at the blood-brain barrier (104228). This interaction has not been reported in humans.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might inhibit the effects of quinolone antibiotics.  Details In vitro, quercetin binds to the DNA gyrase site on bacteria (481), which may interfere with the activity of quinolone antibiotics.

SULFASALAZINE (Azulfidine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of sulfasalazine.  Details Animal research shows that quercetin increases the maximum serum concentration (Cmax) and area under the curve (AUC) of sulfasalazine, possibly through inhibition of breast cancer resistance protein (BCRP), of which sulfasalazine is a substrate (107897). So far, this interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin may increase the risk of bleeding if used with warfarin.  Details Animal and in vitro studies show that quercetin might increase serum levels of warfarin (17213,109619). Quercetin and warfarin have the same human serum albumin (HSA) binding site, and in vitro research shows that quercetin has stronger affinity for the HSA binding site and can theoretically displace warfarin, causing higher serum levels of warfarin (17213). Animal research shows that taking quercetin for 2 weeks before initiating warfarin increases the maximum serum level of warfarin by 30%, the half-life by 10%, and the overall exposure by 63% when compared with control. Concomitant administration of quercetin and warfarin, without quercetin pre-treatment, also increased these measures, but to a lesser degree. Researchers theorize that inhibition of CYP3A4 by quercetin may explain these effects (109619). So far, this interaction has not been reported in humans.

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ORAL DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, slippery elm may slow the absorption and reduce serum levels of oral drugs.  Details Slippery elm inner bark contains mucilage, which may interfere with the absorption of orally administered drugs (19).

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ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric has antioxidant effects. Theoretically, this may reduce the activity of chemotherapy drugs that generate free radicals. However, research is conflicting.  Details In vitro research suggests that curcumin, a constituent of turmeric, inhibits mechlorethamine-induced apoptosis of breast cancer cells by up to 70%. Also, animal research shows that curcumin inhibits cyclophosphamide-induced tumor regression (96126). However, some in vitro research shows that curcumin does not affect the apoptosis capacity of etoposide. Also, other laboratory research suggests that curcumin might augment the cytotoxic effects of alkylating agents. Reasons for the discrepancies may relate to the dose of curcumin and the specific chemotherapeutic agent. Lower doses of curcumin might have antioxidant effects while higher doses might have pro-oxidant effects (96125). More evidence is needed to determine what effect, if any, turmeric might have on alkylating agents.

AMLODIPINE (Norvasc) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking turmeric with amlodipine may increase levels of amlodipine.  Details Animal research shows that giving amlodipine 1 mg/kg as a single dose following the use of turmeric extract 200 mg/kg daily for 2 weeks increases the maximum concentration and area under the curve by 53% and 56%, respectively, when compared with amlodipine alone (107113). Additional animal research shows that taking amlodipine 1 mg/kg with a curcumin 2 mg/kg pretreatment for 10 days increases the maximum concentration and area under the curve by about 2-fold when compared with amlodipine alone (103099).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Turmeric may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs. However, research is conflicting.  Details Curcumin, a constituent of turmeric, has demonstrated antiplatelet effects in vitro (11143,81204,81271). Furthermore, two case reports have found that taking turmeric along with warfarin or fluindione was associated with an increased international normalized ratio (INR) (89718,100906). However, one clinical study in healthy volunteers shows that taking curcumin 500 mg daily for 3 weeks, alone or with aspirin 100 mg, does not increase antiplatelet effects or bleeding risk (96137). It is possible that the dose of turmeric used in this study was too low to produce a notable effect.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking turmeric with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research and case reports suggest that curcumin, a turmeric constituent, can reduce blood glucose levels in patients with diabetes (79692,79984,80155,80313,80315,80476,80553,81048,81219). Furthermore, clinical research in adults with type 2 diabetes shows that taking curcumin 475 mg daily for 10 days prior to taking glyburide 5 mg decreased postprandial glucose levels for up to 24 hours when compared with glyburide alone, despite the lack of a significant pharmacokinetic interaction (96133). Another clinical study in patients with diabetes on hemodialysis shows that taking curcumin 80 mg daily for 12 weeks can reduce blood glucose levels when compared with placebo (104149).

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric has antioxidant effects. Theoretically, this may reduce the activity of chemotherapy drugs that generate free radicals. However, research is conflicting.  Details In vitro and animal research shows that curcumin, a constituent of turmeric, inhibits doxorubicin-induced apoptosis of breast cancer cells by up to 65% (96126). However, curcumin does not seem to affect the apoptosis capacity of daunorubicin. In fact, some research shows that curcumin might augment the cytotoxic effects of antitumor antibiotics, increasing their effectiveness. Reasons for the discrepancies may relate to the dose of curcumin and the chemotherapeutic agent. Lower doses of curcumin might have antioxidant effects while higher doses might have pro-oxidant effects (96125). More evidence is needed to determine what effects, if any, antioxidants such as turmeric have on antitumor antibiotics.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase or decrease levels of drugs metabolized by CYP1A1. However, research is conflicting.  Details Most in vitro and animal research suggests that the turmeric constituent, curcumin, INHIBITS CYP1A1, primarily in the liver (15823,21495,80876,81411). However, some evidence from in vitro research suggests that curcumin may INDUCE CYP1A1 in the intestines (21500).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase levels of drugs metabolized by CYP1A2. However, research is conflicting.  Details In vitro and animal research show that the turmeric constituent, curcumin, inhibits CYP1A2 (15823,21497,81304). However, other in vitro research suggests that curcumin does not significantly affect CYP1A2 (22000).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric might increase levels of drugs metabolized by CYP3A4.  Details In vitro and animal research show that turmeric and its constituents curcumin and curcuminoids inhibit CYP3A4 (21497,21498,21499). Also, 8 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking turmeric and cancer medications that are CYP3A4 substrates, including everolimus, ruxolitinib, ibrutinib, and palbociclib, and bortezomib (111644). In another case report, a transplant patient presented with acute nephrotoxicity and elevated tacrolimus levels after consuming turmeric powder at a dose of 15 or more spoonfuls daily for ten days prior. It was thought that turmeric increased levels of tacrolimus due to CYP3A4 inhibition (93544). Conversely, other in vitro research suggests that turmeric induces CYP3A4 activity, leading to reduced levels of CYP3A4 substrates (111404). However, this interaction has not been reported in humans.

DOCETAXEL (Taxotere) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase blood levels of oral docetaxel.  Details Animal research suggests that the turmeric constituent, curcumin, enhances the oral bioavailability of docetaxel (80999). However, the significance of this interaction is unclear, as this drug is typically administered intravenously in clinical settings.

ESTROGENS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, large amounts of turmeric might interfere with hormone replacement therapy through competition for estrogen receptors.  Details In vitro research shows that curcumin, a constituent of turmeric, displaces the binding of estrogen to its receptors (21486).

GLYBURIDE (Diabeta, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking turmeric and glyburide in combination might increase the risk of hypoglycemia.  Details Clinical research shows that taking curcumin 475 mg daily for 10 days prior to taking glyburide 5 mg increases blood levels of glyburide by 12% at 2 hours after the dose in patients with type 2 diabetes. While maximal blood concentrations of glyburide were not affected, turmeric modestly decreased postprandial glucose levels for up to 24 hours when compared to glyburide alone, possibly due to the hypoglycemic effect of turmeric demonstrated in animal research (96133).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the risk of liver damage when taken with hepatotoxic drugs.  Details There is concern that turmeric might cause hepatotoxicity, especially when highly bioavailable formulations are used in high doses (103633,107122,109288,110221).

LOSARTAN (Cozaar) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the effects of losartan.  Details Research in hypertensive rats shows that taking turmeric can increase the hypotensive effects of losartan (110897).

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might have additive effects when used with hepatotoxic drugs such as methotrexate.  Details In one case report, a 39-year-old female taking methotrexate, turmeric, and linseed oil developed hepatotoxicity (111644).

NORFLOXACIN (Noroxin) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the effects and adverse effects of norfloxacin.  Details Animal research shows that taking curcumin, a turmeric constituent, can increase blood levels of orally administered norfloxacin (80863).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase blood levels of OATP4C1 substrates.  Details In vitro research shows that the turmeric constituent curcumin competitively inhibits OATP4C1 transport. This transporter is expressed in the kidney and facilitates the renal excretion of certain drugs (113337). Theoretically, taking turmeric might decrease renal excretion of OATP substrates.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the absorption of P-glycoprotein substrates.  Details In vitro and animal research shows that curcuminoids and other constituents found in turmeric can inhibit P-glycoprotein expression and activity (21472,21473,21474,21475,21476,21477,21478,21479,21480)(21482,21484,111644).

PACLITAXEL (Abraxane, Onxol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might alter blood levels of paclitaxel, although any effect may not be clinically relevant.  Details Clinical research in adults with breast cancer receiving intravenous paclitaxel suggests that taking turmeric may modestly alter paclitaxel pharmacokinetics. Patients received paclitaxel on day 1, followed by either no treatment or turmeric 2 grams daily from days 2-22. Pharmacokinetic modeling suggests that turmeric reduces the maximum concentration and area under the curve of paclitaxel by 12.1% and 7.7%, respectively. However, these changes are not likely to be considered clinically relevant (108876). Conversely, animal research suggests that curcumin, a constituent of turmeric, enhances the oral bioavailability of paclitaxel (22005). However, the significance of this interaction is unclear, as this drug is typically administered intravenously in clinical settings.

SULFASALAZINE (Azulfidine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Turmeric might increase the effects and adverse effects of sulfasalazine.  Details Clinical research shows that taking the turmeric constituent, curcumin, can increase blood levels of sulfasalazine by 3.2-fold (81131).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric might increase the effects and adverse effects of tacrolimus.  Details In one case report, a transplant patient presented with acute nephrotoxicity and elevated tacrolimus levels of 29 ng/mL. The patient previously had tacrolimus levels within the therapeutic range at 9.7 ng/mL. Ten days prior to presenting at the emergency room the patient started consumption of turmeric powder at a dose of 15 or more spoonfuls daily. It was thought that turmeric increased levels of tacrolimus due to cytochrome P450 3A4 (CYP3A4) inhibition (93544). In vitro and animal research show that turmeric and its constituent curcumin inhibit CYP3A4 (21497,21498,21499).

TALINOLOL Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Turmeric may reduce the absorption of talinolol in some situations.  Details Clinical research shows that taking curcumin for 6 days decreases the bioavailability of talinolol when taken together on the seventh day (80079). The clinical significance of this effect is unclear.

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, turmeric might reduce the levels and clinical effects of tamoxifen.  Details In a small clinical trial in patients with breast cancer taking tamoxifen 20-30 mg daily, adding curcumin 1200 mg plus piperine 10 mg three times daily reduces the 24-hour area under the curve of tamoxifen and the active metabolite endoxifen by 12.8% and 12.4%, respectively, as well as the maximum concentrations of tamoxifen, when compared with tamoxifen alone. However, in the absence of piperine, the area under the curve for endoxifen and the maximum concentration of tamoxifen were not significantly reduced. Effects were most pronounced in patients who were extensive cytochrome P450 (CYP) 2D6 metabolizers (107123).

TOPOISOMERASE I INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric has antioxidant effects. There is some concern that this may reduce the activity of chemotherapy drugs that generate free radicals. However, research is conflicting.  Details In vitro research shows that curcumin, a constituent of turmeric, inhibits camptothecin-induced apoptosis of breast cancer cells by up to 71% (96126). However, other in vitro research shows that curcumin augments the cytotoxic effects of camptothecin. Reasons for the discrepancies may relate to the dose of curcumin and the chemotherapeutic agents. Lower doses of curcumin might have antioxidant effects while higher doses might have pro-oxidant effects (96125). More evidence is needed to determine what effect, if any, turmeric might have.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric might increase the risk of bleeding with warfarin.  Details One case of increased international normalized ratio (INR) has been reported for a patient taking warfarin who began taking turmeric. Prior to taking turmeric, the patient had stable INR measurements. Within a few weeks of starting turmeric supplementation, the patient's INR increased to 10 (100906). Additionally, curcumin, the active constituent in turmeric, has demonstrated antiplatelet effects in vitro (11143,81204,81271), which may produce additive effects when taken with warfarin.

(Read more about TURMERIC)

General ...Orally and topically, aloe products are generally well tolerated when used in typical doses. However, oral aloe latex is associated with a greater risk of adverse effects, especially when used in high doses or long-term.
Most Common Adverse Effects:
Orally: Aloe latex may cause abdominal pain, cramps, and diarrhea.
Topically: Burning, erythema, and itching. Contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Aloe latex is associated with serious adverse effects when taken in high doses or long-term. Cases of acute hepatitis due to a hypersensitivity reaction to aloe leaf extract has been reported.

Dermatologic ...Topically, aloe gel has occasionally been associated with burning (12164,19741,30697,30706), itching (12164,19741,30697), eczema (90122), erythema (19748,30706,90123), contact dermatitis (12163,12164,30695,30736,30737,30738,30740), popular eruption (30732), and urticaria (30712). Also, a case of generalized nummular and popular dermatitis attributed to hypersensitivity has been reported for a 47-year-old male who used aloe leaf gel, both topically and orally, for 4 years (30740).

Endocrine ...A case of severe hypokalemia has been reported for a male breast cancer patient who was undergoing chemotherapy and using aloe vera 1 liter daily orally for 2 weeks. The hypokalemia was attributed to the cathartic effects of aloe and resolved once aloe use was discontinued (30704).

Gastrointestinal ...Orally, aloe latex can cause abdominal pain and cramps. Long-term use or abuse of aloe latex can cause diarrhea, sometimes with hypokalemia, albuminuria, hematuria, muscle weakness, weight loss, arrhythmia, and pseudomelanosis coli (pigment spots in intestinal mucosa). Pseudomelanosis coli is believed to be harmless, and usually reverses with discontinuation of aloe. It is not directly associated with an increased risk of developing colorectal adenoma or carcinoma (6138). Orally, aloe gel may cause nausea, stomach cramps, and other gastrointestinal complaints in some patients (104174,111921,111663).
Topically, applying aloe gel in the mouth may cause nausea within 5 minutes of application in some patients (90124).

Hematologic ...A case of Henoch-Schonlein purpura, characterized by abdominal pain, purpura, and severe arthralgia, has been reported in a 52-year-old male who drank aloe juice prepared from four to five leaflets for 10 days prior to symptom development (91598).

Hepatic ...Cases of acute hepatitis have been reported after ingestion of aloe leaf extracts for between 3 weeks and 5 years. This is thought to be a hypersensitivity reaction (15567,15569,16386,17419,90126,91598). A case of acute hepatitis has also been reported for a 45-year-old female who drank two ounces of Euforia juice (Nuverus International), a product containing green tea, noni, goji, and aloe, daily for one month (90125). However, one small clinical trial in healthy individuals shows that taking aloe gel 2 ounces twice daily for 60 days does not impair liver function (104174).

Renal ...Orally, aloe latex can cause hemorrhagic gastritis, nephritis, and acute kidney failure following prolonged use of high doses (1 gram daily or more) (8961).

(Read more about ALOE)

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about GLUCOSAMINE)

General ...Orally and intravenously, glutamine is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, constipation, cough, diarrhea, flatulence, gastrointestinal pain, headache, musculoskeletal pain, nausea, and vomiting.

Endocrine ...One case of hot flashes has been reported in a patient taking glutamine 5-15 grams orally twice daily for up to 1 year (96520).

Gastrointestinal ...Orally, glutamine has been associated with belching, bloating, constipation, flatulence, nausea, vomiting, diarrhea, and gastrointestinal (GI) pain. Nausea, vomiting, constipation, diarrhea, and GI pain have been reported in clinical trials using high-dose glutamine 10-30 grams (0.3 grams/kg) in two divided doses daily to treat sickle cell disease (99414). One case of dyspepsia and one case of abdominal pain have been reported in patients taking glutamine 5-15 grams twice daily orally for up to 1 year (96520). In a small trial of healthy males, taking a single dose of about 60 grams (0.9 grams/kg of fat free body mass [FFM]) was associated with a 50% to 79% incidence of GI discomfort, nausea, and belching, compared with a 7% to 28% incidence with a lower dose of about 20 grams (0.3 gram/kg FFM). Flatulence, bloating, lower GI pain, and urge to regurgitate occurred at similar rates regardless of dose, and there were no cases of heartburn, vomiting, or diarrhea/constipation (105013). It is possible that certain GI side effects occur only after multiple doses of glutamine.

Musculoskeletal ...Orally, glutamine 30 grams daily has been associated with cases of musculoskeletal pain and non-cardiac chest pain in clinical trials for patients with sickle cell disease (99414).

Neurologic/CNS ...Orally, glutamine has been associated with dizziness and headache. A single case of dizziness has been reported in a patient treated with oral glutamine 0.5 grams/kg. However, the symptom resolved after reducing the dose to 0.25 grams/kg (91356). Mania and hypomania have been reported in 2 patients with bipolar disorder taking commercially purchased glutamine up to 4 grams daily (7291). Glutamine is metabolized to glutamate and ammonia, both of which might have neurological effects in people with neurological and psychiatric diseases or in people predisposed to hepatic encephalopathy (7293).

Oncologic ...There is some concern that glutamine might be used by rapidly growing tumors and possibly stimulate tumor growth. Although tumors may utilize glutamine and other amino acids, preliminary research shows that glutamine supplementation does not increase tumor growth (5469,7233,7738). In fact, there is preliminary evidence that glutamine might actually reduce tumor growth (5469).

Other ...Orally, glutamine has been associated with cough when a powdered formulation is used. It is unclear if this was due to accidental inhalation. One case of a burning sensation and one case of hypersplenism has been reported in a patient taking glutamine 5-15 grams twice daily orally for up to 1 year (96520).

(Read more about GLUTAMINE)

General ...Orally, licorice is generally well tolerated when used in amounts commonly found in foods. It seems to be well tolerated when licorice products that do not contain glycyrrhizin (deglycyrrhizinated licorice) are used orally and appropriately for medicinal purposes or when used topically, short-term.
Most Common Adverse Effects:
Orally: Headache, nausea, and vomiting.
Topically: Contact dermatitis.
Intravenously: Diarrhea, itching, nausea, and rash.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about acute renal failure, cardiac arrest, cardiac arrhythmias, hypertension, hypokalemia, muscle weakness, paralysis, pseudohyperaldosteronism, and seizure associated with long-term use or large amounts of licorice containing glycyrrhizin.

Cardiovascular ...Orally, excessive licorice ingestion can lead to pseudohyperaldosteronism, which can precipitate cardiovascular complications such as hypertension and hypertensive crisis, ventricular fibrillation or tachycardia, sinus pause, and cardiac arrest. These effects are due to the licorice constituent glycyrrhizin and usually occur when 20-30 grams or more of licorice product is consumed daily for several weeks (781,15590,15592,15594,15596,15597,15599,15600,16835,97213) (104563,108574,108576,110305,112234). In one case report, an 89-year-old female taking an herbal medicine containing licorice experienced a fatal arrhythmia secondary to licorice-induced hypokalemia. The patient presented to the hospital with recurrent syncope, weakness, and fatigue for 5 days after taking an herbal medicine containing licorice for 2 months. Upon admission to the hospital, the patient developed seizures, QT prolongation, and ventricular arrhythmia requiring multiple defibrillations. Laboratory tests confirmed hypokalemia and pseudohyperaldosteronism (112234).
However, people with cardiovascular or kidney conditions may be more sensitive, so these adverse events may occur with doses as low as 5 grams of licorice product or glycyrrhizin 100 mg daily (15589,15593,15598,15600,59726). A case report in a 54-year-old male suggests that malnutrition might increase the risk of severe adverse effects with excessive licorice consumption. This patient presented to the emergency room with cardiac arrest and ventricular fibrillation after excessive daily consumption of licorice for about 3 weeks. This caused pseudohyperaldosteronism and then hypokalemia, leading to cardiovascular manifestations. In spite of resuscitative treatment, the patient progressed to kidney failure, refused dialysis, and died shortly thereafter (103791).

Dermatologic ...There have been reports of contact allergy, resulting in an itchy reddish eruption, occurring in patients that applied cosmetic products containing oil-soluble licorice extracts (59912). There have also been at least 3 cases of allergic contact dermatitis reported with the topical application of glycyrrhizin-containing products to damaged skin. In one case report, a 31-year-old female with acne presented with a 2-year history of pruritic erythematous-scaly plaques located predominantly on the face and neck after the use of a cosmetic product containing licorice root extract 1%. The patient had a positive skin patch test to licorice root extract, leading the clinicians to hypothesize that the use of benzoyl peroxide, a strong irritant, might have sensitized the patient to licorice (108578). Burning sensation, itching, redness, and scaling were reported rarely in patients applying a combination of licorice, calendula, and snail secretion filtrate to the face. The specific role of licorice is unclear (110322).
In rare cases, the glycyrrhizin constituent of licorice has caused rash and itching when administered intravenously (59712).

Endocrine ...Orally, excessive licorice ingestion can cause a syndrome of apparent mineralocorticoid excess, or pseudohyperaldosteronism, with sodium and water retention, increased urinary potassium loss, hypokalemia, and metabolic alkalosis due to its glycyrrhizin content (781,10619,15591,15592,15593,15594,15595,15596,15597,15598)(15600,16057,16835,25659,25660,25673,25719,26439,59818,59822)(59832,59864,91722,104563,108568,108574,110305,112234). These metabolic abnormalities can lead to hypertension, edema, EKG changes, fatigue, syncope, arrhythmias, cardiac arrest, headache, lethargy, muscle weakness, dropped head syndrome (DHS), rhabdomyolysis, myoglobinuria, paralysis, encephalopathy, respiratory impairment, hyperparathyroidism, and acute kidney failure (10393,10619,15589,15590,15593,15594,15596,15597,15599)(15600,16057,16835,25660,25673,25719,26439,31562,59709,59716)(59720,59740,59787,59820,59826,59882,59889,59900,91722,97214,100522) (104563,108576,108577). These effects are most likely to occur when 20-30 grams of licorice products containing glycyrrhizin 400 mg or more is consumed daily for several weeks (781,15590,15592,15594,15596,15597,15599,15600,16835,108574). However, some people may be more sensitive, especially those with hypertension, diabetes, heart problems, or kidney problems (15589,15593,15598,15600,59726,108576,108577) and even low or moderate consumption of licorice may cause hypertensive crisis or hypertension in normotensive individuals (1372,97213). The use of certain medications with licorice may also increase the risk of these adverse effects (108568,108577). One case report determined that the use of large doses of licorice in an elderly female stabilized on fludrocortisone precipitated hypokalemia and hypertension, requiring inpatient treatment (108568). Another case report describes severe hypokalemia necessitating intensive care treatment due to co-ingestion of an oral glycyrrhizin-specific product and hydrochlorothiazide for 1 month (108577). Glycyrrhetinic acid has a long half-life, a large volume of distribution, and extensive enterohepatic recirculation. Therefore, it may take 1-2 weeks before hypokalemia resolves (781,15595,15596,15597,15600). Normalization of the renin-aldosterone axis and blood pressure can take up to several months (781,15595,108568). Treatment typically includes the discontinuation of licorice, oral and intravenous potassium supplementation, and short-term use of aldosterone antagonists, such as spironolactone (108574,108577).
Chewing tobacco flavored with licorice has also been associated with toxicity. Chewing licorice-flavored tobacco, drinking licorice tea, or ingesting large amounts of black licorice flavored jelly beans or lozenges has been associated with hypertension and suppressed renin and aldosterone levels (12671,12837,97214,97215,97217,108574). One case report suggests that taking a combination product containing about 100 mg of licorice and other ingredients (Jintan, Morishita Jintan Co.) for many decades may be associated with hypoaldosteronism, even up to 5 months after discontinuation of the product (100522). In another case report, licorice ingestion led to hyperprolactinemia in a female (59901). Licorice-associated hypercalcemia has also been noted in a case report (59766).

Gastrointestinal ...Nausea and vomiting have been reported rarely following oral use of deglycyrrhizinated licorice (25694,59871). Intravenously, the glycyrrhizin constituent of licorice has rarely caused gastric discomfort, diarrhea, or nausea (59712,59915).

Immunologic ...There have been reports of contact allergy, resulting in an itchy reddish eruption, occurring in patients that applied cosmetic products containing oil-soluble licorice extracts (59912). There have also been at least 3 cases of allergic contact dermatitis reported with the topical application of glycyrrhizin-containing products to damaged skin. In one case report, a 31-year-old female with acne presented with a 2-year history of pruritic erythematous-scaly plaques located predominantly on the face and neck after the use of a cosmetic product containing licorice root extract 1%. The patient had a positive skin patch test to licorice root extract, leading the clinicians to hypothesize that the use of benzoyl peroxide, a strong irritant, might have sensitized the patient to licorice (108578).

Musculoskeletal ...In a case report, excessive glycyrrhizin-containing licorice consumption led to water retention and was thought to trigger neuropathy and carpal tunnel syndrome (59791).

Neurologic/CNS ...Orally, licorice containing larger amounts of glycyrrhizin may cause headaches. A healthy woman taking glycyrrhizin 380 mg daily for 2 weeks experienced a headache (59892). Intravenously, the glycyrrhizin constituent of licorice has rarely caused headaches or fatigue (59721). In a case report, licorice candy ingestion was associated with posterior reversible encephalopathy syndrome accompanied by a tonic-clonic seizure (97218).

Ocular/Otic ...Orally, consuming glycyrrhizin-containing licorice 114-909 grams has been associated with transient visual loss (59714).

Pulmonary/Respiratory ...Orally, large amounts of licorice might lead to pulmonary edema. In one case report, a 64-year old male consumed 1020 grams of black licorice (Hershey Twizzlers) containing glycyrrhizin 3.6 grams over 3 days, which resulted in pulmonary edema secondary to pseudohyperaldosteronism (31561). Intravenously, the glycyrrhizin constituent of licorice has caused cold or flu-like symptoms, although these events are not common (59712,59721).

(Read more about LICORICE)

General ...Orally and topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about MARSHMALLOW)

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).

(Read more about METHYLSULFONYLMETHANE (MSM))

General ...Orally and intravenously, quercetin seems to be well tolerated in appropriate doses. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

Gastrointestinal ...Intravenous administration of quercetin is associated with nausea and vomiting (9564).

Neurologic/CNS ...Orally, quercetin may cause headache and tingling of the extremities (481,111500). Intravenously, quercetin may cause pain at the injection site. Injection pain can be minimized by premedicating patients with 10 mg of morphine and administering amounts greater than 945 mg/m² over 5 minutes (9564). In addition, intravenous administration of quercetin is associated with flushing and sweating (9564).

Pulmonary/Respiratory ...Intravenous administration of quercetin at doses as high as 2000 mg/m² is associated with dyspnea that may persist for up to 5 minutes (9564).

Renal ...Intravenously, nephrotoxicity has been reported with quercetin in amounts greater than 945 mg/m² (9563,9564,70304).

(Read more about QUERCETIN)

General ...Orally, slippery elm seems to be well tolerated. A thorough evaluation of safety outcomes with topical use of slippery elm has not been conducted.

Dermatologic ...Topically, slippery elm extracts can cause contact dermatitis. The pollen is an allergen (6). Contact dermatitis and urticaria have been reported after exposure to slippery elm or an oleoresin contained in the slippery elm bark (75131).

(Read more about SLIPPERY ELM)

General ...Orally and topically, turmeric is generally well tolerated.
Most Common Adverse Effects:
Orally: Constipation, dyspepsia, diarrhea, distension, gastroesophageal reflux, nausea, and vomiting.
Topically: Curcumin, a constituent of turmeric, can cause contact urticaria and pruritus.

Cardiovascular ...Orally, a higher dose of turmeric in combination with other ingredients has been linked to atrioventricular heart block in one case report. It is unclear if turmeric caused this adverse event or if other ingredients or a contaminant were the cause. The patient had taken a combination supplement containing turmeric 1500-2250 mg, black soybean 600-900 mg, mulberry leaves, garlic, and arrowroot each about 300-450 mg, twice daily for one month before experiencing atrioventricular heart block. Heart rhythm normalized three days after discontinuation of the product. Re-administration of the product resulted in the same adverse effect (17720).

Dermatologic ...Following occupational and/or topical exposure, turmeric or its constituents curcumin, tetrahydrocurcumin, or turmeric oil, can cause allergic contact dermatitis (11146,79270,79470,79934,81410,81195). Topically, curcumin can also cause rash or contact urticaria (79985,97432,112117). In one case, a 60-year-old female, with no prior reactivity to regular oral consumption of turmeric products, developed urticaria after topical application of turmeric massage oil (97432). A case of pruritus has been reported following topical application of curcumin ointment to the scalp for the treatment of melanoma (11148). Yellow discoloration of the skin has been reported rarely in clinical research (113356). Orally, curcumin may cause pruritus, but this appears to be relatively uncommon (81163,97427,104148). Pitting edema may also occur following oral intake of turmeric extract, but the frequency of this adverse event is less common with turmeric than with ibuprofen (89720). A combination of curcumin plus fluoxetine may cause photosensitivity (89728).

Gastrointestinal ...Orally, turmeric can cause gastrointestinal adverse effects (107110,107112,112118), including constipation (81149,81163,96135,113355), flatulence and yellow, hard stools (81106,96135), nausea and vomiting (10453,17952,89720,89728,96127,96131,96135,97430,112117,112118), diarrhea or loose stool (10453,17952,18204,89720,96135,110223,112117,112118), dyspepsia (17952,89720,89721,96161,112118), gastritis (89728), distension and gastroesophageal reflux disease (18204,89720), abdominal fullness and pain (81036,89720,96161,97430), epigastric burning (81444), and tongue staining (89723).

Hepatic ...Orally, turmeric has been associated with liver damage, including non-infectious hepatitis, cholestasis, and hepatocellular liver injury. There have been at least 70 reports of liver damage associated with taking turmeric supplements for at least 2 weeks and for up to 14 months. Most cases of liver damage resolved upon discontinuation of the turmeric supplement. Sometimes, turmeric was used concomitantly with other supplements and medications (99304,102346,103094,103631,103633,103634,107122,109288,110221). The Drug-Induced Liver Injury Network (DILIN) has identified 10 cases of liver injury which were considered to be either definitely, highly likely, or probably associated with turmeric; none of these cases were associated with the use of turmeric in combination with other potentially hepatotoxic supplements. Most patients (90%) presented with hepatocellular pattern of liver injury. The median age of these case reports was 56 years and 90% identified as White. In these case reports, the carrier frequency on HLAB*35:01 was 70%, which is higher than the carrier frequency found in the general population. Of the ten patients, 5 were hospitalized and 1 died from liver injury (109288).
It is not clear if concomitant use with other supplements or medications contributes to the risk for liver damage. Many case reports did not report turmeric formulation, dosing, or duration of use (99304,103094,103631,103634,109288). However, at least 10 cases involved high doses of curcumin (250-1812.5 mg daily) and the use of highly bioavailable formulations such as phytosomal curcumin and formulations containing piperine (102346,103633,107122,109288,110221).

Neurologic/CNS ...Orally, the turmeric constituent curcumin can cause vertigo, but this effect seems to be uncommon (81163).

Psychiatric ...Orally, the turmeric constituent curcumin or a combination of curcumin and fluoxetine can cause giddiness, although this event seems to be uncommon (81206,89728).

Renal ...Orally, turmeric has been linked to one report of kidney failure, although the role of turmeric in this case is unclear. A 69-year-old male developed kidney failure related to calcium oxalate deposits in the renal tubules following supplementation with turmeric 2 grams daily for 2 years as an anti-inflammatory for pelvic pain. While turmeric is a source of dietary oxalates, pre-existing health conditions and/or chronic use of antibiotics may have contributed to the course of disease (113343).

Other ...There is a single case report of death associated with intravenous use of turmeric. However, analysis of the treatment vial suggests that the vial contained only 0.023% of the amount of curcumin listed on the label. Also, the vial had been diluted in a solution of ungraded polyethylene glycol (PEG) 40 castor oil that was contaminated with 1.25% diethylene glycol. Therefore the cause of death is unknown but is unlikely to be related to the turmeric (96136).

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