Meal Replacement Plant Protein Chocolate by plnt

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Although there is interest in using oral or topical acai to prevent aging skin, there is insufficient reliable information about the clinical effects of acai for this purpose.
• Athletic performance. It is unclear if oral acai is beneficial for improving athletic performance. Details: Preliminary clinical research in amateur cyclists shows that consuming 400 grams of pasteurized acai pulp daily for 15 days prevents oxidative damage and decreases levels of blood lactate during exercise by 28% when compared with placebo. Consuming acai pulp also seems to increase anaerobic threshold intensity, but does not improve maximum workload or measures of exertion, when compared to baseline (102860).
• Erectile dysfunction (ED). Although there is interest in using oral acai for ED, there is insufficient reliable information about the clinical effects of acai for this condition.
• Hypercholesterolemia. Although there is interest in using oral acai for hypercholesterolemia, there is insufficient reliable information about the clinical effects of acai for this condition.
• Metabolic syndrome. Although there is interest in using oral acai for metabolic syndrome, there is insufficient reliable information about the clinical effects of acai for this condition.
• Obesity. It is unclear if oral black seed is beneficial for improving metabolic indices in overweight individuals. Details: In overweight individuals, preliminary clinical research shows that consuming 100 mg of acai pulp (Sambazon Acai Smoothie Pack, Sambazon Inc.) twice daily for one month reduces fasting glucose and total cholesterol levels when compared with baseline. However, no effect was seen on levels of low density lipoprotein (LDL) cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, or blood pressure (17731). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there is interest in using oral acai for osteoarthritis, there is insufficient reliable information about the clinical effects of acai for this condition.
• Tinnitus. It is unclear if oral acai is beneficial for chronic tinnitus. Details: A small clinical study in adults with unilateral or bilateral chronic tinnitus, with either normal hearing or mild hearing loss, shows that taking dried acai pulp extract 100 mg daily for 3 months decreases tinnitus discomfort when compared with baseline (107846). However, the validity of this finding is limited by the lack of statistical comparison to the placebo group, which reported a numerically similar improvement in tinnitus discomfort. More evidence is needed to rate acai for these uses.

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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.

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POSSIBLY INEFFECTIVE

• Hypercholesterolemia. Preliminary clinical research shows that eating muffins made with amaranth flour or taking oral doses of amaranth oil 3-18 mL daily while following a reduced fat diet for 3-4 weeks does not reduce serum cholesterol levels more than the reduced fat diet alone (6188,31069). Similarly, two clinical trials in overweight and obese adults show that taking amaranth oil 20 mL daily for 3 weeks does not decrease low-density lipoprotein (LDL) cholesterol or triglyceride levels or increase high-density lipoprotein (HDL) cholesterol levels when compared with either rapeseed oil 20 mL daily or no intervention (104834,104837). In one of these trials, amaranth oil 20 mL increased LDL levels when compared to baseline (104834).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Iron deficiency anemia. Preliminary clinical research in children shows that consuming 150 grams of bread made with 70% amaranth grain, providing approximately 22.3 mg iron, for 6 months decreases the prevalence of anemia by 61% and increases hemoglobin levels by 8% when compared with consuming bread containing 100% maize grain. The amaranth used in this study was processed to reduce phytic acid content in order to improve iron absorption (104835).
• Peptic ulcers. Preliminary clinical research shows that taking amaranth oil from Amaranthus cruentus seeds 1 mL daily for 27 days immediately following standard treatment with lansoprazole, amoxicillin, and clarithromycin for 7 days does not improve clinical outcomes with Helicobacter pylori-associated peptic ulcers more than standard treatment alone (99235). More evidence is needed to rate amaranth for these uses.

(Read more about AMARANTH)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if apple juice consumption is beneficial in patients with Alzheimer disease. Details: A small clinical study in adults with moderate to severe Alzheimer disease shows that drinking 4 ounces of apple juice twice daily for one month does not improve cognitive function when compared with baseline. However, according to caregiver assessment, it seems to improve aspects of mood and behavior, such as anxiety, depression, apathy, delusion, and agitation, when compared with baseline (94422). The validity of this finding is limited by the lack of a comparator group.
• Cancer. It is unclear if apple consumption is beneficial for preventing cancer. Details: Some population research has found that eating one or more apples daily may be associated with a decreased risk of esophageal, colorectal, larynx, or breast cancer when compared with eating less than 1 apple daily (31688). Also, a case-control study in adults with lung cancer has found that increased apple consumption may be associated with a reduced risk of lung cancer (3470).
• Dental plaque. It is unclear if apple consumption is beneficial for reducing dental plaque. Details: A small clinical study in healthy patients shows that eating an apple is less effective for reducing plaque than brushing teeth. Eating an apple actually increases plaque when compared with baseline, although it decreases the measure of bacterial vitality (99447).
• Diabetes. It is unclear if consumption of powdered, dehydrated apple is beneficial in patients with type 2 diabetes. Details: A small clinical study in patients with type 2 diabetes shows that substituting 26-52 grams of white wheat flour in bread with powdered, dehydrated apple and consuming the bread daily for up to 4 weeks does not improve fasting blood glucose or postprandial glucose levels when compared with a low-fiber white bread control (13141).
• Diarrhea. It is unclear if apple juice consumption is beneficial in infants with severe diarrhea. Details: A clinical study in infants with severe diarrhea shows that drinking apple juice 15 mL/kg twice daily during episodes of diarrhea results in more fecal loss when compared with drinking water (31687).
• Metabolic syndrome. Although there has been interest in using apple for metabolic syndrome, there is insufficient reliable information about the clinical effects of apple for this purpose.
• Muscle strength. Oral apple extract has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: Small clinical studies in resistance trained males show that taking a specific blend of ancient peat and apple extract (elevATP, VDF FutureCeuticals Inc.) 150 mg daily as a liquid with liposomes (QuSomes, BioZone Laboratories Inc.) for 12 weeks modestly increases lower body and total strength, improves lower body power output, and increases cross-sectional area of muscle when compared with placebo (94418,94419).
• Obesity. It is unclear if apple consumption is beneficial in patients with overweight or obesity. Details: A small clinical study in females with hypercholesterolemia and overweight or obesity shows that eating apples three times daily for 12 weeks is associated with weight loss of 1.2 kg, compared with weight loss of 0.9 kg in those consuming oat cookies (17997). More evidence is needed to rate apple for these uses.

(Read more about APPLE)

POSSIBLY EFFECTIVE

• Constipation. Oral Bacillus coagulans seems to be beneficial for constipation. Details: Clinical research in individuals with mild intermittent constipation shows that taking B. coagulans SNZ 1969 (CTCBIO, Inc.) 1 billion colony-forming units (CFUs) daily for 8 weeks reduces colonic transit time, increases the number of weekly complete spontaneous bowel movements, and improves bowel discomfort when compared with placebo. Colonic transit time was reduced by at least 25% in 58% of patients taking B. coagulans, compared with 32% of patients taking placebo (107613). Other clinical research in patients with functional constipation shows that taking B. coagulans Unique IS2 (Unique Biotech Limited) 2 billion CFUs daily for 4 weeks modestly increases the number of bowel movements and reduces abdominal pain and pain with defecation when compared with placebo. Also, 98% of patients achieved normal stool consistency, compared with 74% of those taking placebo (107612). Adding lactulose 10 grams to this regimen increases stool frequency when compared with placebo, but not when compared with lactulose alone. However, normal stool consistency was achieved earlier and by more patients in those taking lactulose plus B. coagulans when compared with lactulose alone. The combination was also more beneficial for reducing defecation pain, abdominal pain, and sensations of incomplete evacuation (107614). Also, a small clinical study in adults with constipation-dominant functional bowel disorders shows that taking a specific supplement containing B. coagulans 1 billion CFUs twice daily for 4 weeks modestly improves abdominal pain and abdominal distention, as well as discomfort and effort during defecation, when compared with baseline (104232). However, the validity of the findings in this study is limited by the lack of a comparator group.
• Irritable bowel syndrome (IBS). Oral Bacillus coagulans seems to be beneficial for IBS. Details: Clinical research in adults with diarrhea-predominant IBS shows that taking B. coagulans daily for 56-90 days improves quality of life and decreases bloating, nausea, vomiting, abdominal pain, and stool frequency when compared with placebo. Improvements in headache, anxiety, and constipation have also been shown (92730,92735,92740,105169). In addition, meta-analyses show that taking B. coagulans reduces overall symptom, straining, and/or abdominal pain severity when compared with placebo (107594,110866). In one study, taking B. coagulans for 80 days resulted in no symptoms in 63% of individuals, compared with only 21% of those taking placebo (105169). Doses used in some of this clinical research have included a specific B. coagulans MTCC5856 product (Lactospore, Sabinsa Corporation) 2 billion colony-forming units (CFUs) daily for 90 days (92730), another specific B. coagulans product (GanedenBC30, Ganeden Biotech Inc.) 300 million to 2 billion CFUs daily for 8 weeks (92735,92740), B. coagulans LBSC (Advanced Enzyme Technologies Ltd.) 2 billion CFUs three times daily for 80 days (105169), or B. coagulans Unique IS2 2 billion CFUs daily for 8 weeks (110866). Other clinical research in adults with IBS shows that taking a specific combination product (Colinox, DMG Italia SRL) containing B. coagulans and simethicone after each meal three times daily for 4 weeks improves bloating and discomfort, but not pain, when compared with placebo (92726).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antibiotic-associated diarrhea. Although there has been interest in using oral Bacillus coagulans for antibiotic-associated diarrhea, there is insufficient reliable information about the clinical effects of B. coagulans for this condition.
• Athletic performance. It is unclear if oral Bacillus coagulans is beneficial for athletic performance. Details: A small clinical trial shows that taking an inactivated B. coagulans GBI-30, 6086 product (Staimune, Kerry, Inc) 1 billion cells daily for 2 weeks does not improve jump power or muscle endurance when compared with placebo (107610). This study might not have been adequately powered to detect differences between groups. A larger study in resistance-trained males shows that taking B. coagulans Unique IS-2 2 billion colony-forming units daily for 60 days in combination with 20 grams of an 80% whey protein concentrate modestly improves some measures of power and muscle strength when compared with taking whey protein alone. However, some measures of strength were not improved, and there was no effect on maximum oxygen consumption, muscle hypertrophy, or body composition (110878).
• Cancer. Although there has been interest in using oral Bacillus coagulans for cancer prevention, there is insufficient reliable information about the clinical effects of B. coagulans for this purpose.
• Cirrhosis. Oral Bacillus coagulans has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with liver cirrhosis who are at increased risk for developing spontaneous bacterial peritonitis (SBP) shows that taking a combination of B. coagulans, Enterococcus faecalis, Clostridium butyricum, and Bacillus mesentericus three times daily, in conjunction with norfloxacin for 6 months, does not reduce the risk of developing SBP when compared with norfloxacin alone (92731).
• Clostridioides difficile infection. Although there has been interest in using oral Bacillus coagulans for C. difficile infection, there is insufficient reliable information about the clinical effects of B. coagulans for this purpose.
• Depression. Although there has been interest in using oral Bacillus coagulans for depression, there is insufficient reliable information about the clinical effects of B. coagulans for this condition.
• Diabetes. Oral Bacillus coagulans has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that taking B. coagulans GBI-30, 6086 (GanedenBC30) 100 billion CFUs, Lactobacillus acidophilus 1 billion colony-forming units (CFUs), Lacticaseibacillus rhamnosus 10 billion CFUs, and fructo-oligosaccharides 500 mg daily for 12 weeks modestly reduces fasting blood glucose and insulin and improves measures of insulin resistance when compared with placebo. There was no effect on plasma lipids (107731).
• Diarrhea. It is unclear if oral Bacillus coagulans is beneficial for acute diarrhea or diarrhea-dominant functional bowel disorders. Details: Clinical research in infants 6-24 months of age with acute diarrhea of various causes shows that taking B. coagulans 120 million colony-forming units (CFUs) twice daily for up to 5 days in conjunction with oral rehydration solution does not decrease duration, frequency, or volume of diarrhea when compared with oral rehydration solution and placebo (92738). However, a small clinical study in adults with acute diarrhea shows that taking a specific supplement (Lactic Acid Bacillus) containing B. coagulans 2 billion CFUs, three times daily for 7 days, reduces diarrhea and improves abdominal pain when compared with placebo (100853). Preliminary clinical research in adults with diarrhea-dominant functional bowel disorders shows that taking a specific supplement containing B. coagulans 1 billion CFUs twice daily for 4 weeks reduces abdominal pain, abdominal distention, discomfort and effort during defecation, and the number of stools classified as diarrhea when compared with baseline (104232). The validity of these findings is limited by the lack of a comparator group.
• Dyspepsia. It is unclear if oral Bacillus coagulans is beneficial for dyspepsia. Details: Several small studies show that B. coagulans can improve symptoms of dyspepsia (104231,104232,104233,107611). In one study, 1 billion colony-forming units (CFUs) were taken twice daily for 4 weeks, resulting in an improvement in abdominal pain and abdominal distention when compared with placebo (104232). Some studies have used B. coagulans in combination with other probiotics. In adults with functional dyspepsia, taking a combination of B. coagulans MY01 and Bacillus subtilis MY02 as 1.25 billion CFUs each twice daily for 8 weeks improves postprandial distress scores of at least 0.7 in 48% of patients, compared with only 20% of those taking placebo (107611). A small clinical study in older adults aged 55-75 years with indigestion, abdominal pain, and flatulence shows that taking a probiotic syrup containing B. coagulans 500 million CFUs with digestive enzymes (alpha amylase 25 mg, pepsin 10 mg, and lipase 1.5 mg) 5 mL twice daily for 5 days reduces symptoms of dyspepsia when compared with placebo (104233). Also, a small study in adults with non-specific gastrointestinal discomfort shows that taking a specific combination supplement (SNZ TriBac, Sanzyme Biologics) containing B. coagulans SNZ 1969, Bacillus clausii SNZ 1971, and B. subtilis SNZ 1972, 2 billion CFUs daily for 30 days, decreases self-reported symptoms of burping, belching, and sour taste when compared with placebo (104231). It is unclear if these effects are due to B. coagulans, other ingredients, or the combinations.
• Flatulence. It is unclear if oral Bacillus coagulans is beneficial for flatulence. Details: Clinical research in children aged 6-8 years shows that taking B. coagulans GBI-30, 6086 (GanedenBC30, Ganeden, Inc.) 1 billion colony-forming units (CFUs) daily for 3 months modestly decreases the incidence of flatulence when compared with taking placebo (107615). However, preliminary clinical research in patients with postprandial intestinal gas-related symptoms shows that taking a specific combination supplement (Digestive Advantage Gas Defense Formula, Ganeden Biotech) containing this same strain of B. coagulans and an enzyme blend daily for 4 weeks does not improve bloating or gas when compared with placebo (92736).
• Gingivitis. Although there has been interest in using oral Bacillus coagulans for gingivitis, there is insufficient reliable information about the clinical effects of B. coagulans for this condition.
• Helicobacter pylori. It is unclear if oral Bacillus coagulans is beneficial for H. pylori. Details: In patients with H. pylori, preliminary clinical research shows that taking B. coagulans (Donghai Pharmaceutical Co Ltd) 1050 mg three times daily for 8 weeks results in a 20% eradication rate 1-2 weeks after treatment. This was as effective as taking Clostridium butyricum 1050 mg twice daily, alone or in combination with B. coagulans (105168). This study is limited by lack of blinding and the lack of a placebo group. Also, it is unclear how B. coagulans compares to standard H. pylori eradication treatments.
• HIV/AIDS. Although there has been interest in using oral Bacillus coagulans for HIV/AIDS, there is insufficient reliable information about the clinical effects of B. coagulans for this condition.
• Hypercholesterolemia. Although there has been interest in using oral Bacillus coagulans for cholesterol reduction, there is insufficient reliable information about the clinical effects of B. coagulans for this purpose.
• Inflammatory bowel disease (IBD). Although there has been interest in using oral Bacillus coagulans for IBD, there is insufficient reliable information about the clinical effects of B. coagulans for this purpose.
• Necrotizing enterocolitis (NEC). It is unclear if oral Bacillus coagulans is beneficial or safe for NEC prevention. Details: Preliminary clinical research in infants with a gestational age of less than 33 weeks or a very low birth weight shows that taking B. coagulans 350 million colony-forming units daily until hospital discharge does not reduce the risk of NEC or death when compared with placebo. However, taking B. coagulans reduced the incidence of feeding intolerance in these newborns (92733). The US Food and Drug Administration (FDA) warns that preterm infants given probiotics are at risk of serious infections caused by the bacteria or fungi contained in probiotics due to cases reported in very preterm or very low birth weight infants under 1000 grams (111610). Also, The American Academy of Pediatrics does not support the routine administration of probiotics to preterm infants, particularly those with a birth weight below 1000 grams, due to conflicting data on safety and efficacy and potential for harm in this vulnerable population (111608).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral Bacillus coagulans is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD shows that taking 1 capsule containing B. coagulans 1 billion colony-forming units plus 400 mg inulin for 8 weeks may be beneficial for treating inflammation associated with NAFLD when compared with placebo. However, this combination did not improve lipid profiles or glycemic indices. Inulin was used in this study as a prebiotic to ensure bacterial growth in the gut lumen (104230).
• Postoperative ileus. It is unclear if oral Bacillus coagulans is beneficial for postoperative ileus. Details: A small clinical study in patients undergoing gynecological laparoscopic surgery shows that taking B. coagulans TBC169 105 million or 175 million colony-forming units the night before surgery, and then every 8 hours starting 8 hours after surgery, reduces time to first flatus by up to 10 hours when compared with placebo. There were also modest reductions in the rates of postoperative gastrointestinal adverse events such as nausea, vomiting, distension, and ileus. However, there was no difference in time to first defecation or length of hospital stay (110879).
• Rheumatoid arthritis (RA). It is unclear if oral Bacillus coagulans is beneficial for RA. Details: Preliminary clinical research in adults with RA shows that taking B. coagulans GBI-30, 6086 (GanedenBC30, Ganeden Biotech Inc.) 2 billion colony-forming units daily for 60 days, in conjunction with standard therapy, reduces overall pain when compared with placebo. However, it does not reduce the number of painful or swollen joints or improve activities of daily living (92734).
• Rotaviral diarrhea. It is unclear if oral Bacillus coagulans is beneficial for rotaviral diarrhea. Details: Preliminary clinical research in newborns shows that taking B. coagulans 100 million colony-forming units daily for one year reduces the incidence of acute rotaviral diarrhea. Taking B. coagulans decreases the incidence of diarrheal episodes by around 5 per year and reduces duration of diarrhea by around 3 days per episode when compared with placebo. However, taking B. coagulans does not reduce the occurrence of mild to moderate dehydration (92729).
• Small intestinal bacterial overgrowth (SIBO). Oral Bacillus coagulans has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with SIBO who were previously treated for 3 weeks with broad spectrum antibiotics shows that taking a specific probiotic product (Lactol, Bioplus Life Sciences Pvt. Ltd.) containing B. coagulans spores and fructo-oligosaccharides twice daily on 15 days per month for 6 months, in conjunction with minocycline, modestly decreases stomach pain and flatulence (91145).
• Travelers' diarrhea. Although there has been interest in using oral Bacillus coagulans for travelers' diarrhea, there is insufficient reliable information about the clinical effects of B. coagulans for this condition.
• Upper respiratory tract infection (URTI). It is unclear if oral Bacillus coagulans is beneficial for URTI prevention. Details: Clinical research in children aged 6-8 years shows that taking B. coagulans GBI-30, 6086 (GanedenBC30, Ganeden, Inc.) 1 billion colony-forming units (CFUs) daily for 3 months modestly decreases the incidence of some URTI symptoms, including nasal congestion, bloody nasal mucus, itchy nose, and hoarseness, but not others such as dry cough and sore throat, when compared with placebo (107615). More evidence is needed to rate Bacillus coagulans for these uses.

(Read more about BACILLUS COAGULANS)

POSSIBLY EFFECTIVE

• Diarrhea. Low-quality evidence shows that oral cooked green bananas might be helpful for the management of acute and persistent diarrhea due to various causes in children. There is insufficient reliable information about the clinical effects of banana for treatment of diarrhea in adults. Details: A meta-analysis of nine blinded or open label clinical studies in children aged 8 to 34 months with acute and persistent diarrhea shows that consuming cooked green bananas along with standard treatment, such as fluids, for 1 to 14 days increases rates of resolution for acute and persistent diarrhea when compared with control. Furthermore, consuming green banana increases the likelihood of diarrhea resolution by day 3 and reduces the risk of dehydration and related complications when compared with control (115475). Several clinical trials used cooked green bananas 50-100 grams per day in children aged 6-12 months, 100-200 grams per day in children aged 12-24 months, and 300 grams per day aged 24 months to 5 years (93451,93462,93463,106469,115475). A moderate size, open label clinical study among children aged 6-35 months hospitalized with persistent diarrhea in Bangladesh shows that consuming a diet of green banana mixed with rice suji increases the number of children who recover within 5 days when compared with a full-strength rice suji diet but is equivalent to the standard treatment (control) of 75% strength rice suji diet (112150). Duration of hospital stay is also similar with green banana and 75% strength rice suji and shorter than with full strength rice suji. There is also less relapse at home among children who had been given the green banana rice suji diet in hospital compared with the 75%-strength rice suji. The validity of the study is limited by the lack of blinding. Clinical research also shows that bananas might be beneficial for diarrhea associated with enteral feeding in adults with critical illness. Adding banana flakes (Kanana Banana, Corpak Co) 1-3 tablespoons every 8 hours to the feeding tube seems to be as effective as routine medical treatment involving feeding rate adjustments and use of antidiarrheal agents for reducing symptoms and duration of diarrhea. After 7 days of treatment, 57% of patients in the banana group were free of diarrhea compared with only 24% of patients in the group receiving routine treatment (93453).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral banana flower for allergic rhinitis, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Athletic performance. It is unclear if oral banana is beneficial for athletic performance. Details: Preliminary clinical research in trained male cyclists shows that consuming 0.4 grams/kg carbohydrate orally from ripe bananas with water 10-20 minutes prior to a 75 km cycling time trial, and 0.15-0.2 grams/kg carbohydrate from bananas with water every 15 minutes during the trial, modestly improves cycling time and oxygen consumption when compared with water alone. This regimen is equally effective to the same dose of carbohydrate from a 6% carbohydrate beverage (Gatorade) (93459,93465). However, another study from the same group of researchers found conflicting results with the use of carbohydrates from banana for this purpose (100995). It is possible that the consumption of carbohydrates in general, not the use of bananas specifically, is beneficial for athletic performance. However, other preliminary clinical research in trained male runners shows that consuming a banana and drinking plain water does not improve the time to run 10 km on a treadmill when compared with plain water alone. No benefit was seen with the consumption of other carbohydrate drinks when compared with plain water; it is possible that the duration of exercise was too short to identify an improvement in performance (93457). Further research is needed to clarify the benefits of banana, if any, for athletic performance.
• Burns. It is unclear if topical banana leaf is beneficial in patients with burns. Details: Preliminary clinical research in adults and children with partial thickness burns shows that daily changes of a banana leaf dressing with povidone iodine reduces pain during dressing changes. Furthermore, wound healing is as effective as a boiled potato peel bandage with povidone iodine, with no increased need for skin grafting (93454). When compared with Vaseline gauze dressing for 8 days following skin graft treatment for burns in adults, banana leaf dressing increases speed of epithelization from 11.7 days to 8.7 days, and improves average pain, pain during dressing removal, and ease of dressing removal. By the 8th day, complete epithelization was present in 57% of the wounds dressed with banana leaves when compared with 0% of the wounds dressed with Vaseline gauze (93455).
• Cancer. Although there has been interest in using topical banana green fruit for cancer, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Constipation. It is unclear if oral green banana is beneficial in patients with constipation. Details: Preliminary clinical research in children with functional constipation shows that consuming cooked green bananas, 30 grams daily for 8 weeks, improves stool consistency and abdominal pain and reduces straining and pain during defecation when compared with baseline. Consuming cooked green bananas with a conventional laxative such as polyethylene glycol plus electrolytes or sodium picosulfate also appears to decrease the dose of laxative needed in these children when compared with baseline (100996). The validity of these findings is limited by the lack of a comparator group.
• Contraception. Although there has been interest in using oral banana root for contraception, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Cough. Although there has been interest in using oral banana flower for cough, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Depression. It is unclear if oral banana is beneficial in patients with depression. Details: A large cross-sectional study in the general Chinese adult population has found that moderate, but not high, banana consumption is associated with a lower likelihood of depressive symptoms in males. However, high banana consumption is associated with a higher likelihood of depressive symptoms in females (106471).
• Diabetes. It is unclear if oral banana starch is beneficial in patients with diabetes. Details: Two small clinical studies in adults with type 2 diabetes shows that taking banana starch 24-57.2 grams orally daily for 4-28 days does not improve serum glucose levels, glucose variability, glucose control scores, or insulin levels when compared with control starches (110619,93448).Other preliminary clinical research in obese patients with type 2 diabetes shows that taking banana starch 24 grams in 240 mL of water each day for 4 weeks reduces body weight when compared with a taking soymilk powder in water. However, banana starch did not improve lipid levels or body fat (93448). Other preliminary clinical research in patients with type 2 diabetes shows that taking desiccated banana 250 grams daily for 12 weeks does not improve lipid levels or glycemic response when compared to baseline (93452).
• Exercise-induced muscle soreness. It is unclear if oral banana is beneficial for exercise-induced muscle soreness. Details: Preliminary clinical research in trained cyclists shows that consuming 0.4 grams/kg of carbohydrates orally from mini-yellow bananas with water 20 minutes prior to a 75 km cycling time trial, and 0.2 grams/kg of carbohydrates from banana every 15 minutes during the trial, decreases muscle soreness ratings 1.5 hours after the time trial when compared with water alone. Consuming carbohydrates from Cavendish bananas in the same manner did not decrease delayed onset muscle soreness, although cyclists reported less muscle cramping with both types of bananas when compared with water (100995). It is unclear whether carbohydrates from banana are any more effective than other carbohydrate sources or whether these results are generalizable to other types of exercise.
• Gastroesophageal reflux disease (GERD). Although there has been interest in using oral banana fruit for GERD, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Hangover. Although there has been interest in using oral banana fruit for hangover, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Headache. Although there has been interest in using topical banana leaves for headache, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Hypercholesterolemia. It is unclear if oral banana is beneficial in patients with hypercholesterolemia. Details: Preliminary clinical research shows that taking desiccated banana 500 grams orally daily for 12 weeks reduces levels of total cholesterol by 7.5% when compared with baseline in patients with hypercholesterolemia. Taking 250 grams daily does not seem to reduce total cholesterol levels; however, high-density lipoprotein (HDL) cholesterol levels increase by 14.5% (93452). The validity of these findings is limited by the lack of a comparator group.
• Hypertension. Although there has been interest in using oral banana fruit for hypertension, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Hypokalemia. Although there has been interest in using oral banana fruit for hypokalemia, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Inflammatory bowel disease (IBD). Although there has been interest in using oral banana fruit for IBD, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Joint pain. Although there has been interest in using oral banana flower for joint pain, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Kidney stones (nephrolithiasis). Oral banana stem has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with calculi of at least 5 mm shows that taking a specific Ayurvedic product (Herbmed) containing banana stem 250 mg and Crateva nurvala 250 mg orally daily for 3 months moderately improves symptoms associated with urinary calculi and reduces the size of the calculi by 11% to 33% when compared with baseline (93460). It is not clear if this is due to banana stem, Crateva nurvala, or the combination. Also, the validity of this finding is limited by the lack of a comparator group.
• Menorrhagia. Although there has been interest in using oral banana fruit for menorrhagia, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Obesity. It is unclear if oral banana is beneficial in patients with obesity. Details: Preliminary clinical research in obese patients with type 2 diabetes shows that taking banana starch 24 grams in 240 mL of water orally each day for 4 weeks reduces body weight by 1 kg more when compared to a control group consuming soymilk powder in water (93448).
• Peptic ulcers. Although there has been interest in using oral banana fruit for peptic ulcers, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Shigellosis. It is unclear if oral green banana is beneficial in patients with shigellosis. Details: Clinical research in children 6-60 months of age who are being treated with antibiotics for shigellosis shows that eating cooked green banana 250 grams per liter of a rice-based diet for 5 days improves symptoms of diarrhea, including the presence of fecal mucus and blood, when compared with a rice-based diet alone. Adding banana to the diet decreased the number of daily stools by 70% in those consuming banana compared to 50% in children consuming the rice diet alone (93461).
• Skin grafts. Although there has been interest in using topical banana leaves for skin grafts, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Smoking cessation. Although there has been interest in using oral banana fruit for smoking cessation, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Stroke. Although there has been interest in using oral banana fruit for stroke, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Tuberculosis. Although there has been interest in using oral banana flower for tuberculosis, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Vaginitis. Although there has been interest in using oral banana root for vaginitis, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Vitamin A deficiency. Although there has been interest in using oral banana fruit for vitamin A deficiency, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Warts. Although there has been interest in using topical banana leaves or peels for warts, there is insufficient reliable information about the clinical effects of banana for this purpose.
• Wound healing. Although there has been interest in using topical banana leaves, peels, or green fruit for wound healing, there is insufficient reliable information about the clinical effects of banana for this purpose. More evidence is needed to rate banana for these uses.

(Read more about BANANA)

POSSIBLY EFFECTIVE

• Athletic performance. Oral beet may improve athletic performance associated with aerobic activities. However, it is not clear who is most likely to benefit, for which type of competition it is most useful, or what dose or duration of use is most appropriate. Details: Several small clinical trials, most of which enrolled elite athletes, recreational athletes, and sedentary males, as well as meta-analyses of some of these and other studies, show that beet improves various measures of athletic performance, including ability, muscular endurance, power output, sprinting, and strength (93844,94464,94468,94469,100143,100150,100152,105761,113422). Clinical research also shows that drinking beetroot juice improves the use of oxygen during exercise testing in recreationally-trained athletes, especially with severe exercise testing (94460,94463,94467,100147,105762). Also, in obese adolescents, taking beetroot juice daily for 6 days increases the time to exhaustion from severe exercise, but does not improve moderate exercise (100145). Not all research shows that beet supplementation benefits athletic performance. Another meta-analysis of several small clinical studies, including some of the studies above, shows that taking beetroot does not improve performance in high-intensity or sprint interval training (111159). Additionally, the majority of research in elite athletes does not support the use of beetroot juice to decrease the time needed to complete a task, aid in some sort of graded exercise test, or improve the use of oxygen during exercise testing (94455,94458,94460,94461,94464,94465,94466,94469,94473,100142,100153,105763). The supposed lack of effect of beetroot juice in elite athletes might be related to the natural production of nitrates and nitrites in the body or the increased ability to use oxygen that comes from extensive training (94458,94463). Alternatively, any changes might be very small (<1%) and not identified with statistical comparisons, although even very small changes might be beneficial in competition (94464). The most commonly used doses in all studies, regardless of effect, have included an acute dose of beetroot juice 70-500 mL up to 3 hours prior to exercise (93844,94463,94464,94466,94467,94473,97726,100142,100143,105761)(105762,111159,113422) or chronic dosing of up to 500 mL daily for 3-6 days (94459,94464,94469,100145,100147,100153,111159,113422). Less commonly, beetroot juice 70-140 mL daily, betalain-rich concentrate 100 mg daily, or a beetroot-based nutritional gel 100 grams daily, have been taken for longer dosing schedules of 7-15 days (97720,100144,100148,100152,105763,113422). Benefits in elite athletes, most often related to time trials, are usually limited to studies using chronic dosing of 7-15 days, which is longer than the duration of 6 days used in the majority of studies (94473,97720,100144,100148). Brands of juice used in clinical trials have included Beet It Sport (James White Drinks Ltd.) (94455,94458,94465,100142,100143,100144,100148,105761,105763), Beet It Stamina Shot (James White Drinks Ltd.) (93844), Beet It (James White Drinks Ltd) (94457,94459,94460,94467,94469,97726,100145,100153,105762,111159), and Love Beets Beetroot Juice (Gs Fresh Ltd.) (94461,94462). Although plasma levels have not been analyzed in all studies, the majority of studies suggest that these doses are adequate to increase levels of nitrates or nitrites, which is thought to be essential for increasing athletic potential (93844,94455,94458,94459,94460,94465,94467,94469,94466,94473,97726). The evidence also suggests benefit in both normoxic and hypoxic environments (94465,100148,105763).
• Exercise-induced muscle soreness. Drinking beetroot juice 7-8 times over 48 hours after strenuous exercise may reduce exercise-induced muscle soreness, but evidence is conflicting. Details: Some clinical research shows drinking beetroot juice (Love Beets Beetroot Juice, Gs Fresh Ltd.) 125 mL or 250 mL seven times over 48 hours after strenuous box jumps improves muscle soreness when compared with placebo and sodium nitrite (96964,97722). Other small clinical studies show that drinking beetroot juice 50-250 mL as eight separate doses over 48 hours after strenuous exerciseimproves muscle soreness and reduces tissue edema when compared with placebo (94461,113424). However, drinking beetroot juice 250 mL as seven separate doses over 48 hours after running a marathon does not appear to reduce muscle soreness when compared with placebo (94462). A meta-analysis of 4 small studies, mostly in healthy or physically active males, shows that drinking beetroot juice improves the pressure pain threshold, which is a measure of muscle soreness, at 48- and 72-hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not improve subjective muscle soreness scores (111160). The validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies. Further, these results should not be generalized to elite athletes.

POSSIBLY INEFFECTIVE

• Chronic obstructive pulmonary disease (COPD). Drinking beetroot juice for up to 14 days may not improve exercise capacity in patients with COPD. Details: A meta-analysis of eight small clinical trials in patients with COPD shows that taking nitrate-rich beetroot juice does not improve most measures of exercise capacity, including the 6-minute walk test, cycling ergometry endurance time, and maximum rate of oxygen consumption (VO2 max), when compared with placebo. Additionally, beetroot juice did not reduce blood pressure or heart rate. However, the analysis did show a significant improvement in scores on the Borg Rating of Perceived Exhaustion scale with beetroot juice over placebo. Nitrate-rich beetroot juice doses ranged from 70-140 mL daily for up to 14 days (104200).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cognitive function. It is unclear if drinking beetroot juice is beneficial for cognitive function. Details: A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves the time to complete part B of the trail making test, which is a test of cognitive function, but not part A, when compared with controls (111158). However, the duration and size of this study limits its validity. Further, it is unclear whether any improvement is clinically significant. The effect of acute beet administration on cognitive function has also been studied. A very small clinical study in healthy adults shows that taking beet extract (RedNite, Enovate Biolife) chewable tablets 3 grams 90 minutes prior to neuropsychological testing improves immediate and delayed memory capacity, frontal lobe function, and lexical flexibility but does not improve working memory, information processing speed, or subjective reports of memory performance when compared with placebo (113427).
• Coronary heart disease (CHD). It is unclear if oral beetroot extract is beneficial in patients with CHD. Details: A small clinical trial in patients with CHD shows that taking red beetroot extract 500 mg, containing around 25 mg betalains, twice daily for 2 weeks reduces total cholesterol and low-density lipoprotein (LDL) cholesterol by 15 mg/dL and reduces triglycerides by 8 mg/dL when compared to baseline. Slight improvements in blood pressure and blood glucose were also reported, but these changes were not clinically significant (103883). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear whether beetroot can reduce the risk of cardiovascular events in patients with CHD.
• Dyslipidemia. It is unclear if oral beetroot is beneficial in patients with dyslipidemia. Details: A meta-analysis of small clinical studies in healthy individuals or patients with dyslipidemia, cardiovascular disease, or overweight or obesity, shows that consuming beetroot juice or leaves does not improve levels of triglycerides or total, low-density lipoprotein, or high-density lipoprotein cholesterol when compared with controls (111163). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the enrolled patients and beetroot regimens.
• Exercise-induced muscle damage. It is unclear if oral beetroot juice improves recovery from muscle damage after exercise. Details: A meta-analysis of 4 small clinical studies in healthy or physically active individuals, most of which enrolled males only, shows that drinking beetroot juice improves measures of muscle recovery at 72 hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not consistently improve recovery at earlier time points post-exercise, nor does it reduce levels of creatine kinase or markers of inflammation (i.e., interleukin-6, interleukin-8, c-reactive protein, or tumor necrosis factor-alpha) (111160). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies, which usually varied from 210-250 mg of nitrate in 7-11 servings over 3-7 days. Further, these results should not be generalized to elite athletes. Another very small clinical study in semi-professional female athletes shows that ingesting beetroot juice 50 mL 8 times over 48 hours after exercise-induced muscle damage enhances the recovery of some functional parameters such as muscle endurance but not others such as flexibility and vertical jump performance when compared with placebo (113424).
• Hypertension. Oral beet may slightly reduce blood pressure in healthy individuals, but it is unclear if it is beneficial in patients with hypertension. Details: Meta-analyses of small studies show the potential for a minor reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in healthy adults taking beetroot juice (94470,97718,97728). The average reduction in SBP and DBP with beetroot juice consumption is about 4 mmHg and 1 mmHg, respectively, which is greater than the effect seen with consuming blackcurrant juice or nitrate-depleted beetroot juice. The most benefit is seen when beetroot juice is taken for at least 2 weeks or at doses of 500 mL daily (97728). The effect of acute beet supplementation on blood pressure is conflicting. A small clinical study in healthy adults shows that drinking beet juice (Beet It, James White Company) 140 mL two hours prior to cardiovascular measurements reduces resting SBP by about 4 mmHg but does not improve resting or post-exercise DBP, central blood pressure, or arterial stiffness nor does it improve post-exercise SBP when compared with placebo. Subgroup analysis suggests that the reductions in resting SBP were only observed in males, not females (113423). Another small clinical study shows that consuming beet 100 grams baked into bread modestly decreases DBP over a 6-hour period when compared with white bread (97725). It is possible that genetics might play a role in the magnitude of effect seen with beetroot consumption. Adults with a specific gene polymorphism, eNOS Glu298Asp, experienced a greater reduction in DBP after consuming beet-containing bread (97724). Despite positive findings in studies of healthy individuals, research on the use of beetroot juice in patients with hypertension is unclear. A small clinical study in adults with hypertension who were taking antihypertensive medications shows that drinking nitrate-rich beetroot juice (Beet it; James White Drinks Ltd.) 70 mL twice daily for one week does not lower blood pressure when compared with nitrate-depleted beetroot juice (94457). Also, in patients with mild to moderate hypertension, clinical research shows that taking a combination of beetroot powder (Sensient) 300 mg, olive leaf extract 1000 mg, and green coffee bean extract 200 mg daily for 6 weeks does not lower blood pressure when compared with placebo (97723). However, some evidence suggests that at least part of the blood pressure lowering effects of beet might be independent of nitrate (97728). Furthermore, some research suggests that identifying effects on blood pressure might be dependent on the method of measurement, including clinic resting measurements, 24-hour monitoring, or morning/evening home resting measurements (97729).
• Hypertriglyceridemia. It is unclear if oral beet is beneficial in patients with hypertriglyceridemia. Details: A small clinical study in overweight or obese individuals with dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not lower triglyceride levels when compared with nutritional guidance alone (100146). Beet has also been evaluated in combination with other ingredients. A small clinical trial in patients at risk for heart disease shows that a specific combination of beet and hawthorn berry (Neo40-Daily, Neogenis Labs), taken twice daily for 30 days, can modestly reduce blood triglyceride levels when compared to baseline (18222). It is unclear if these findings are due to beet, hawthorn berry, or the combination.
• Liver disease. Although there has been interest in using oral beet for liver disease, there is insufficient reliable information about the clinical effects of beet for this purpose.
• Muscle strength. It is unclear if oral beetroot juice is beneficial for muscle strength. Details: A meta-analysis of 18 clinical studies in healthy males shows that taking beetroot juice or beetroot gel 2-3 hours before exercise improves muscular strength when compared with placebo. Subgroup analysis suggests that beetroot-based supplements improve muscular strength in a fatigued but not resting state (113422). A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves handgrip strength by approximately 18% compared with 4% in controls (111158). However, it is unclear whether any improvement is clinically significant.
• Obesity. It is unclear if oral beet leaf or beetroot juice is beneficial for weight loss. Details: A small clinical study in patients with overweight or obesity and dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not reduce body weight or body mass index (BMI) when compared with nutritional guidance alone (100146). Similarly, a small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days does not improve weight loss when compared with controls (111158). However, the size and duration of this study may have been inadequate to detect differences between groups.
• Pregnancy-induced hypertension. It is unclear if oral beetroot juice is beneficial in patients with pregnancy-induced hypertension. Details: A small clinical trial in pregnant patients with hypertension who are at approximately 22-35 weeks gestation shows that taking beetroot juice (James White Drinks Ltd) 70 mL daily for 8 days does not reduce blood pressure when compared with a nitrate-depleted beetroot juice (100151). However, the study was small and designed to investigate the feasibility of using beetroot juice in this population.
• Pulmonary hypertension. It is unclear if oral beetroot juice is beneficial in patients with pulmonary hypertension. Details: A small clinical study shows that taking beetroot juice (Beet-It Sport; James White Drinks Ltd) 70 mL twice daily for 7 days does not improve right ventricular systolic function when compared with nitrate-depleted beetroot juice in patients with pulmonary hypertension (100149). However, this study was small and not adequately powered to detect differences between groups.
• Raynaud syndrome. It is unclear if oral beetroot juice is beneficial in patients with Raynaud syndrome. Details: A small clinical study in patients with Raynaud syndrome undergoing cold sensitivity tests shows that drinking beetroot juice (Beet-It, James White Drinks Ltd) 70 mL daily for 13 days, followed by 140 mL prior to testing, does not reduce pain in the hands or feet, but might improve thermal comfort in the feet, when compared to baseline (103884). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate beet for these uses.

(Read more about BEET)

POSSIBLY INEFFECTIVE

• Night vision. Most research suggests that oral bilberry does not improve night vision in healthy individuals. Details: There is contradictory evidence about the effectiveness of bilberry for improving night vision; however, much of the research is of poor quality. In general, the most rigorous research shows that bilberry is not effective for improving night vision in healthy individuals (8139,9739,14280,35446). Whether bilberry can improve night vision in patients with night blindness is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of elderly Norwegian males with subjective cognitive impairment shows that drinking 330 mL of bilberry and red grape juice twice daily for 9 weeks does not improve measures of memory or motor skills when compared with placebo (110641).
• Age-related macular degeneration (AMD). Although there has been interest in using oral bilberry for AMD, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Asthenopia (eye strain). Small clinical studies suggest that oral bilberry fruit extract may improve objective measures of asthenopia, but it is unclear if oral bilberry improves subjective symptoms of asthenopia. Details: Two small clinical studies in adults who report general eye strain or those who look at computer or other display screens at work for long periods of time show that taking bilberry-derived anthocyanins 43.2 mg daily for 6 weeks or bilberry extract 240 mg daily for 12 weeks improves objective measures of eye strain after staring at computer screens when compared with placebo (103190,104195). However, bilberry extract did not improve subjective measures of eye strain in the study that evaluated these outcomes (104195). This study may have been underpowered to detect significant differences between groups. Bilberry has also been evaluated in combination with other ingredients for improving eye strain. A small clinical trial in patients with eye strain shows that a combination of fish oil, lutein, and bilberry extract containing bilberry anthocyanidins 59 mg, taken daily for 4 weeks, reduces dry eye, lower back pain, shoulder stiffness, and stuffy head when compared with placebo (35470). It is unclear if these effects are due to bilberry, other ingredients, or the combination.
• Atherosclerosis. Although there has been interest in using oral bilberry for atherosclerosis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Cataracts. Although there has been interest in using oral bilberry for cataracts, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Chronic venous insufficiency (CVI). It is unclear if oral bilberry is beneficial in patients with CVI. Details: One small clinical study in patients with CVI shows that taking bilberry extract containing anthocyanins 173 mg daily for 30 days reduces symptoms of CVI when compared with placebo (35510).
• Diabetes. It is unclear if oral bilberry is beneficial in patients with diabetes. Details: One small clinical trial in patients with type 2 diabetes shows that taking a specific extract of bilberry fruit (Mirtoselect, Indena S.p.A) 470 mg once, prior to taking an oral glucose tolerance test, lowers plasma glucose levels when compared with placebo (91507). However, a small crossover trial in Chinese patients with type 2 diabetes shows that taking bilberry fruit extract 700 mg twice daily for 4 weeks does not improve glycated hemoglobin (HbA1c), body weight, blood pressure, or lipid levels when compared with placebo (104194). The validity of the HbA1c-related findings is limited due to the short study duration.
• Diabetic retinopathy. It is unclear if oral bilberry is beneficial in patients with diabetic retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also reduced flow velocity in those with high-flow, diabetic retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Dry eye. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with severe dry eye symptoms suggests that taking bilberry extract 600 mg and docosahexaenoic fish oil 240 mg once daily for 3 months may modestly improve measures of tear quality and patient-reported scores for dry eye symptoms when compared with control (112415). However, the validity of these results is limited by the lack of a statistical comparison between groups. Additionally, it is unclear if these effects are due to bilberry, fish oil, or the combination.
• Dysmenorrhea. It is unclear if oral bilberry is beneficial in patients with dysmenorrhea. Details: One small clinical study in patients with dysmenorrhea shows that a specific bilberry product (Tegens) containing bilberry anthocyanoside 160 mg, taken twice daily beginning 3 days prior to menses and continuing for 8 days, reduces pelvic pain, lumbosacral pain, breast pain, nausea, vomiting, and headache when compared with placebo (35512).
• Exercise-induced muscle soreness. It is unclear if oral bilberry is beneficial for reducing exercise-induced muscle soreness. Details: A small clinical study in trained athletes shows that drinking 200 mL of bilberry juice, containing about 744 mg phenols and 80 mg anthocyanins, twice daily for 5 days prior to running a half-marathon modestly worsens muscle soreness immediately after the run when compared with placebo. There was no longer a difference in muscle soreness between groups within 1-2 days after the run (99540).
• Glaucoma. Small clinical studies suggest that oral bilberry fruit extract, when taken with maritime pine extract, may lower intraocular pressure in patients with glaucoma. It is unclear if oral bilberry alone is beneficial in patients with glaucoma. Details: One small, uncontrolled clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing bilberry fruit extract 90 mg and maritime pine extract 40 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). Another small clinical study in patients with high intraocular pressure shows that taking a specific product (Mirtogenol) containing bilberry fruit extract (Mirtoselect, Indena S.p.A.) 80 mg and maritime pine extract (Pycnogenol, Horphag Research) 40 mg twice daily for 6 months lowers intraocular pressure and improves intraocular blood flow when compared with no treatment (35456). It is unclear if these findings are due to bilberry, maritime pine, or the combination. A retrospective chart review of patients with normal tension glaucoma has found that taking bilberry anthocyanin 60 mg twice daily for at least 12 months is associated with improvements in visual function when compared to pretreatment (35472).
• Hemorrhoids. Although there has been interest in using oral bilberry for hemorrhoids, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Hyperlipidemia. It is unclear if oral bilberry is beneficial in patients with hyperlipidemia. Details: A small clinical study in adults with hyperlipidemia shows that taking bilberry-derived anthocyanins 320 mg daily for 4 weeks does not improve total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, or triglyceride levels. Further, no improvements in other biomarkers of cardiovascular disease were reported (110640). The validity of this study is limited by its short duration.
• Hypertension. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with hypertension shows that consuming 500 mL of a juice containing bilberry, red grape, and chokeberry, with or without black currant (MANA Blue, TINE SA), daily for 12 weeks does not improve blood pressure when compared with placebo (92371).
• Hypertensive retinopathy. It is unclear if oral bilberry is beneficial in patients with hypertensive retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also increased flow velocity for those with ischemic, hypertensive retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Impaired glucose tolerance (prediabetes). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with impaired glucose tolerance and two markers of metabolic syndrome shows that consuming a diet high in whole grain products, fatty fish, and bilberries three times daily for 12 weeks reduces levels of plasma glucose when compared to baseline (35468). However, it is unclear if these findings are due to bilberry, another component of the diet, or the combination.
• Irritable bowel syndrome (IBS). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in adults with IBS shows that consuming a formula containing powdered bilberry fruit, aerial agrimony parts, cinnamon quills, and slippery elm bark modestly improves bowel movement frequency and reduces symptoms such as abdominal pain, bloating, flatulence, and straining when compared to baseline (35462). It is unclear if these findings are due to bilberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral bilberry is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that consuming a diet containing 400 grams of fresh bilberries daily does not affect body weight, glucose metabolism, or lipid metabolism when compared with a control diet (35473).
• Myopia. It is unclear if oral bilberry is beneficial in patients with myopia. Details: One small clinical trial in adults with myopia shows that a specific fermented bilberry fruit extract (Fermented Blueberry, Ajinomoto, Co., Inc.) 200 mg, taken twice daily for 4 weeks, improves night vision as well as the eye's ability to adjust focus when compared with placebo. The amplitude of accommodation was also significantly increased from 4.62 to 5.33 (91505).
• Obesity. It is unclear if oral bilberry is beneficial in patients with obesity. Details: One small clinical study in obese and overweight females shows that consuming 100 grams of frozen, whole bilberries daily for 33-35 days decreases weight and waist circumference when compared to baseline (35463). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there has been interest in using oral bilberry for osteoarthritis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Ulcerative colitis. It is unclear if oral bilberry is beneficial in patients with ulcerative colitis. Details: One small, open-label clinical study in adults with mild-to-moderate ulcerative colitis shows that consuming sieved bilberries and concentrated bilberry juice (Symrise GmbH & Co) 160 grams daily for 6 weeks induces remission in 46% of patients. Furthermore, 91% of patients achieved remission at the end of treatment, and 72% of patients achieved remission at the end of the study (91506). The validity of these findings is limited by the lack of a comparator group.
• Urinary tract infections (UTIs). Although there has been interest in using oral bilberry for UTIs, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Varicose veins. Although there has been interest in using oral bilberry for varicose veins, there is insufficient reliable information about the clinical effects of bilberry for this purpose. More evidence is needed to rate bilberry for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Common cold. Although there is interest in using oral black mustard for the common cold, there is insufficient reliable information about the clinical effects of black mustard for this condition.
• Osteoarthritis. Although there is interest in using oral or topical black mustard for osteoarthritis, there is insufficient reliable information about the clinical effects of black mustard for this condition.
• Pain (acute). Although there is interest in using oral or topical black mustard for acute pain, there is insufficient reliable information about the clinical effects of black mustard for this purpose. More evidence is needed to rate black mustard for these uses.

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POSSIBLY INEFFECTIVE

• Hypertension. Most clinical research suggests that consuming freeze-dried blueberries or blueberry powder does not lower blood pressure in patients with hypertension, prehypertension, or other risk factors for cardiovascular disease. Details: Although conflicting results exist (92386,99139), a meta-analysis of 6 clinical trials including approximately 200 patients with hypertension, prehypertension, or other risk factors for cardiovascular disease shows that consuming freeze dried blueberries or blueberry powder 22-50 grams daily for 6-8 weeks does not significantly lower systolic or diastolic blood pressure when compared with placebo (92390).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if oral blueberry can improve symptoms of anxiety. Details: A small clinical study in healthy adults shows that drinking 30 mL of blueberry juice diluted in 100 mL of water twice daily for 20 days reduces measures of state and trait anxiety when compared with placebo (111235).
• Age-related cognitive decline. Small clinical studies suggest that oral blueberry products may slightly improve some measures of cognitive function in older adults with age-related cognitive decline. Details: Most clinical evidence shows that blueberry can improve some aspects of cognitive decline, but it has minimal effect on other measures. One small clinical trial in older patients with self-reported cognitive decline shows that taking freeze-dried blueberry powder 12.5 grams twice daily for 6 months modestly improves cognitive performance in daily activities but most measures of cognitive function did not improve (97181). Another small clinical study in patients 60 years of age and older with self-reported memory complaints shows that taking a wild blueberry extract (ThinkBlue, Naturex Inc) 100 mg daily with cysteine and glutathione modestly improves episodic memory at 3 months, but not at 6 months, when compared with placebo. However, taking this same blueberry extract or a wild blueberry powder 450 mg or 900 mg daily with cysteine and glutathione does not improve sequence recall, working memory, or executive function (99139). Other small clinical studies show a benefit in some, but not all measures of executive functioning and memory (96467,111234)
• Aging. It is unclear if consuming blueberry can improve functional mobility in adults 60 years of age and older. Details: One small clinical study in adults over 60 years of age shows that consuming 2 cups of frozen blueberries daily for 6 weeks improves some measures of functional mobility, such as foot placement and balance, when compared with drinking carrot juice. However, blueberry does not seem to improve hand grip strength, executive function, or other measurements of gait speed when compared with carrot juice (92387). Another small clinical study in this same age group shows that consuming 12 grams of powdered blueberry mixed with liquid twice daily for 3 months does not improve measures of functional mobility when compared with placebo (96467).
• Athletic performance. Small clinical studies suggest that oral freeze-dried blueberry powder may not reduce exertion or improve long-distance running performance in trained runners. Details: Two small clinical studies in adults with running experience show that taking freeze-dried blueberry powder 24 grams three times daily for four days does not improve perceived exertion, the time to run 8 km, or distance run over 30 minutes when compared with placebo. However, blueberry does appear to modestly attenuate increases in blood lactate after running (101963,107282).
• Cancer. Although there has been interest in using oral blueberry for preventing cancer, there is insufficient reliable information about the clinical effects of blueberry for this purpose.
• Cardiovascular disease (CVD). Small clinical studies suggest that oral blueberry supplementation might modestly improve body weight and triglyceride levels, but not body mass index (BMI), glycemic control, or cholesterol levels, in patients at risk for CVD. Details: A meta-analysis of 11 small and low-quality clinical studies involving a total of 497 adults with various risk factors for CVD shows that taking blueberry for 4-16 weeks modestly reduces weight and triglyceride levels, but does not improve other risk factors for CVD, including BMI, glycemic indices, cholesterol levels, and certain inflammatory mediators, when compared with placebo or other control. In a sub-group analysis, weight reduction was slightly more favorable in studies of longer than 6 weeks' duration (mean reduction of 0.91 kg) and in studies using blueberry powder or freeze-dried blueberry (mean reduction of 0.86 kg) (105702). The validity of these findings is limited by the heterogeneity and small size of the included studies. Additionally, it is unclear if blueberry is beneficial for reducing the risk for CVD or CVD-related complications.
• Cataracts. Although there has been interest in using oral blueberry for preventing cataracts, there is insufficient reliable information about the clinical effects of blueberry for this purpose.
• Cognitive function. Small clinical studies suggest that oral blueberry products may improve some, but not most, measures of cognitive function in children and adults. Details: Several small clinical studies in children 7-10 years of age show that drinking a blueberry drink containing 30 grams of freeze-dried blueberries or 200 grams of fresh blueberries as a single dose does not improve most measures of cognitive function when compared with placebo. These trials showed small improvements in some measures of cognitive function, including auditory-verbal learning, word recognition, and delayed memory, but these specific findings were not consistent across all studies (92394,96465,101961). Additionally, a small clinical trial in healthy young adults shows that taking a combination of blueberry and grape extracts (Memophenol, Activ'Inside) 600 mg increases the ability to complete serial three subtraction by 2.5-fold when compared with placebo. However, there were no other improvements in working memory or attention during a sustained cognitive effort (101960).
• Depression. It is unclear if oral blueberry extract or freeze-dried powder is beneficial in patients with depression. Details: One small clinical study in adults with cerebral venous thrombosis (CVT)-associated depression and depression-associated gastrointestinal infection shows that taking blueberry extract 10 mg daily for 3 months reduces symptoms of depression by 49% and gastrointestinal infection rates by 84% when compared to baseline; when compared with placebo, these changes are significant (96464). Another small clinical study in healthy adults shows that drinking 30 mL of blueberry juice diluted in 100 mL of water twice daily for 20 days reduces symptoms of depression when compared with placebo (111235). A small clinical study in healthy adolescents 11-17 years of age without diagnosed mental health issues at baseline shows that drinking freeze-dried wild blueberry powder 13 grams daily for 4 weeks improves self-reported depressive symptoms, but not anxiety symptoms or transient affect, when compared with placebo. The adolescents enrolled in this study were found to have suboptimal fruit and vegetable intake at baseline (105703).
• Diabetes. It is unclear if oral freeze-dried blueberry powder is beneficial in patients with diabetes. Details: A small clinical study in males 45-75 years of age with type 2 diabetes shows that drinking 11 grams of freeze-dried highbush blueberry powder mixed with water twice daily with a meal for 8 weeks reduces glycated hemoglobin (HbA1c) values and triglyceride levels, but not body weight, fasting plasma glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or blood pressure, when compared with placebo. This study may have been inadequately powered to detect a difference between groups (105701). Blueberry has also been evaluated for the prevention of gestational diabetes. A small clinical study in patients with a history of gestational diabetes shows that consuming 280 grams of blueberries plus 12 grams of soluble fiber daily for 18 weeks, starting at less than 20 weeks' gestation, along with standard care reduces maternal weight gain and blood glucose levels after glucose challenge testing when compared with standard care alone. However, neither gestational diabetes incidence nor infant birth weight was lower with blueberry supplementation when compared with standard care alone (107281).
• Hyperlipidemia. It is unclear if oral blueberry is beneficial in patients with hyperlipidemia. Details: One small clinical study in healthy adults shows that drinking blueberry juice 30 mL twice daily for 20 days reduces total cholesterol and low-density lipoprotein (LDL) cholesterol when compared with placebo (111235). Additionally, drinking a combination of blueberry, apple, chokeberry, and cranberry juice 300 mL daily for 6 weeks appears to decrease total cholesterol and increase high-density lipoprotein (HDL) cholesterol when compared to baseline in females with overweight or obesity and at least one risk factor for cardiovascular disease (111233). However, the validity of the study is limited by its small size, short duration, and lack of a comparator group. It is unclear if these effects are due to blueberry, other ingredients, or the combination. In contrast, other small clinical studies suggest that blueberry does not improve lipid levels (105701,111234). A small clinical study in males 45-75 years old shows that blueberry has no effect on total cholesterol, HDL cholesterol, and LDL cholesterol, but may reduce triglycerides, when compared with placebo. However, in a sub-group of patients also taking lipid-lowering medications, blueberry reduced levels of total cholesterol and LDL cholesterol when compared with placebo (105701). Another small clinical study in middle-aged adults with overweight shows that taking oral blueberry powder daily for 12 weeks does not impact total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides when compared with placebo (111234). However, these studies may have been inadequately powered to detect a difference between groups.
• Hypertriglyceridemia. It is unclear if oral blueberry leaf extract is beneficial in patients with hypertriglyceridemia. Details: A small clinical trial in patients with mild to moderate hypertriglyceridemia shows that taking a single dose of a blueberry leaf extract 300 mg along with a high-fat meal reduces postprandial triglyceride levels, but not postprandial glucose or insulin levels, when compared with placebo (101959).
• Juvenile idiopathic arthritis (JIA). It is unclear if oral blueberry juice is beneficial in children with JIA. Details: A small clinical study in children with JIA shows that adding 50 mL of blueberry juice daily to treatment with etanercept 50 mg twice weekly for 6 months increases the percentage of patients who achieve a 20% improvement in symptoms based on American College of Rheumatology criteria when compared with taking etanercept along with placebo juice. About 75% of patients in the blueberry juice group experienced a 20% improvement in symptoms, compared with 51% of patients in the placebo group, suggesting that for every four patients that drink blueberry juice along with etanercept therapy, one additional patient will experience a 20% or greater improvement in symptoms. Drinking blueberry juice also appears to reduce side effects caused by etanercept, including weight gain, infection, diarrhea, and anorexia (92388).
• Metabolic syndrome. Small clinical studies in patients with metabolic syndrome, along with an analysis of studies in patients at risk for metabolic syndrome, suggest that oral freeze-dried blueberries do not improve body weight or glycemic control, but may slightly lower blood pressure and cholesterol levels. Details: A small clinical study in patients with metabolic syndrome shows that taking freeze-dried blueberry powder 26 grams daily for 6 months improves flow-mediated dilation by 45% when compared with placebo, but does not affect low-density lipoprotein (LDL) cholesterol levels, insulin resistance, or blood pressure. In a sub-group of patients not taking statins, blueberry increased levels of high-density lipoprotein (HDL) cholesterol by 3 mg/dL; however, a lower dose of 13 grams daily had no beneficial effects (101958). Another small clinical trial in patients with metabolic syndrome shows that consuming freeze-dried blueberries 25 grams twice daily for 8 weeks reduces systolic blood pressure by around 4% and diastolic blood pressure by around 3% when compared with placebo, but does not affect body weight, lipid levels, or glycemic control (107278). Additionally, a small clinical trial in patients with metabolic syndrome shows that drinking a smoothie containing freeze-dried blueberry powder 22.5 grams twice daily for 6 weeks does not improve blood pressure, body weight, glycemic control, or lipid levels when compared with placebo, although it does improve measures of endothelial function (107279). A meta-analysis evaluating the studies above, along with 9 small clinical trials in patients at risk for metabolic syndrome, shows that blueberry supplementation does not improve body weight, glycemic control, triglyceride levels, or systolic blood pressure. However, it reduces total cholesterol by around 8 mg/dL, low-density lipoprotein (LDL) cholesterol by around 9 mg/dL, and diastolic blood pressure by around 2 mmHg when compared with placebo (107280).
• Muscle strength. Oral blueberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in young, healthy males shows that taking blueberry extract 200 mg plus phosphocreatine disodium salts 5 grams daily for 28 days improves peak torque and average power during leg extension exercises when compared to baseline, while individuals taking placebo saw no improvements in these measures (107284). It is unclear if these findings are due to blueberry, phosphocreatine, or the combination.
• Night vision. Although there has been interest in using oral blueberry for improving night vision, there is insufficient reliable information about the clinical effects of blueberry for this purpose.
• Obesity. Oral blueberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with overweight or obesity and at least one risk factor for cardiovascular disease shows that drinking a combination of blueberry, apple, chokeberry, and cranberry juice 300 mL daily for 6 weeks does not reduce body weight, body mass index (BMI), or blood pressure but might improve total cholesterol and high-density lipoprotein (HDL) cholesterol when compared to baseline (111233). However, the validity of these findings is limited by the small study size, short duration, and lack of a comparator group. It is unclear if these effects are due to blueberry, other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there has been interest in using oral blueberry for preventing UTIs, there is insufficient reliable information about the clinical effects of blueberry for this purpose. More evidence is needed to rate blueberry for these uses.

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POSSIBLY EFFECTIVE

• Colorectal cancer. Consumption of cruciferous vegetables, including broccoli, seems to reduce the risk of developing colorectal cancer. Details: Epidemiological research suggests that the highest intakes of cruciferous vegetables, including broccoli, are associated with an 18% to 20% reduced risk of developing colorectal neoplasms when compared with the lowest intakes (14148,96187,96189).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. It is unclear if consumption of broccoli reduces the risk of developing bladder cancer. Details: Epidemiological research suggests that eating about 1.75 cups daily of cruciferous vegetables, such as broccoli or cabbage, is associated with a 30% reduced risk of developing bladder cancer (14864).
• Breast cancer. It is unclear if consumption of broccoli reduces the risk of developing breast cancer. Details: Epidemiological research suggests that consumption of broccoli is associated with a modestly reduced risk of developing breast cancer in premenopausal adults. However, broccoli consumption does not seem to be associated with breast cancer risk in postmenopausal adults (14146).
• Fibromyalgia. Broccoli has only been evaluated in combination with ascorbigen; its effect when used alone is unclear. Details: A small clinical study in females with fibromyalgia shows that taking one capsule containing ascorbigen 100 mg and broccoli powder 400 mg once daily for one month improves pain by 18% and reduces physical impairment by 20% when compared to baseline (19605). It is unclear if this effect is due to broccoli, ascorbigen, or the combination. The validity of these findings is limited by the lack of a comparator group.
• Gastric cancer. It is unclear if consumption of broccoli reduces the risk of developing gastric cancer. Details: A small epidemiological study suggests that higher consumption of broccoli is associated with a reduced risk of developing gastric cancer when compared with lower consumption (14148).
• Helicobacter pylori. It is unclear if consumption of broccoli is beneficial for treating Helicobacter pylori infection. Details: A moderate-sized clinical study in adults with Helicobacter pylori infection shows that taking broccoli seed extract 200 mg, containing 16% glucosinolates, daily before bedtime for 2 months does not improve Helicobacter pylori eradication rate when compared with placebo (112445,112446).
• Hypercholesterolemia. Broccoli has only been evaluated in combination with cabbage; its effect when used alone is unclear. Details: A small clinical study in patients with mild to moderate hypercholesterolemia shows that consuming 160 grams of a beverage containing broccoli, cabbage, and fruit twice daily for 12 weeks reduces levels of low-density lipoprotein (LDL) cholesterol by 8.5% when compared to baseline. It is unclear if the improvement from baseline differed when compared with those consuming a similar beverage without broccoli and cabbage (19607). It is unclear if this effect is due to broccoli, other ingredients, or the combination.
• Hypertension. It is unclear if consumption of broccoli can prevent hypertension in healthy adults. Details: A meta-analysis of 3 prospective cohort studies in healthy adults suggests that eating 100 grams of broccoli daily is associated with a 12% reduced risk of hypertension. However, 2 other studies in the meta-analysis suggest that broccoli, consumed as part of a larger group of cruciferous vegetables, is associated with an 11% increased risk of hypertension per 100 grams eaten daily (112087).
• Prostate cancer. It is unclear if consumption of broccoli reduces the risk of developing prostate cancer; the available research is conflicting. In patients with prostate cancer, broccoli has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some epidemiological research suggests that consumption of Brassica vegetables, such as broccoli, Brussels sprouts, cauliflower, and cabbage, is associated with a reduced risk of developing prostate cancer (14145). However, other epidemiological research has found no association (14147,15172). Clinical research in adults with prostate cancer shows that taking a whole food formulation containing broccoli powder 100 mg, turmeric powder 100 mg, pomegranate whole fruit powder 100 mg, and green tea extract 20 mg three times daily for 6 months prevents an increase in prostate specific antigen (PSA) levels. Mean PSA levels increased by 15% in the whole food formulation group, compared with 79% in the placebo group. Also, 46% of those taking the whole food formulation showed final PSA levels that were the same or lower than initial PSA levels, compared with 14% of those in the placebo group (89730). However, it is not yet known whether the whole food formulation reduces the risk of prostate cancer progression or recurrence. It is unclear if these effects are due to broccoli, other ingredients, or the combination. More evidence is needed to rate broccoli for these uses.

(Read more about BROCCOLI)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral bromelain for allergic rhinitis, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Aromatase inhibitor-induced arthralgia. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with aromatase inhibitor-induced arthralgia shows that taking a specific combination product (Opera, Gam Farma), providing bromelain 20 mg, alpha-lipoic acid 240 mg, Boswellia serrata 40 mg, and methylsulfonylmethane 200 mg, daily for 6 months reduces arthralgia symptoms when compared to baseline (109570). The validity of these findings is limited by a lack of placebo control group. Further, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Burns. Preliminary clinical research shows that topical bromelain is beneficial for burn debridement. However, it is unclear if topical bromelain is beneficial for scar prevention. Details: Preliminary clinical research and chart reviews show that gels formulated with proteolytic enzymes derived from bromelain (Debridase or NexoBrid, MediWound Ltd.) applied under an occlusive dressing for 4 hours help debride burns, including chemical and electrical burns, in children and adults (18275,91113,103297,108149). Further, a meta-analysis of up to 5 lower- to moderate-quality clinical and observational studies in children and adults with deep burns shows that enzymatic debridement with a specific bromelain based proteolytic enzyme gel applied once or twice for a 4 hour period reduces eschar time by approximately 7 days and reduces the relative risk of surgical excision, and autografts by 83%, and 60%, respectively, when compared with standard of care (e.g., surgical and non-surgical procedures) (115870). The validity of these results is limited by significant heterogeneity across clinical studies, including differences in the location of burns and extent of total body surface area affected.
• Cancer. Although there has been interest in using oral bromelain for cancer, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Chemotherapy-induced peripheral neuropathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chemotherapy-induced peripheral neuropathy shows that taking a specific product (Opera, Gamfarma s.r.l.) containing bromelain 20 mg, alpha-lipoic acid 240 mg, methylsulfonylmethane (MSM) 200 mg, and boswellia 40 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 control group. Additionally, it is not clear if benefit is due to alpha-lipoic acid, the other ingredients, or the combination.
• Chronic venous insufficiency. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in adults with chronic venous insufficiency using compression stockings shows that taking a specific supplement containing bromelain dry extract 50-200 mg, Baikal skullcap, and horse chestnut (Lenidase, Enfarma), dose adjusted based on severity, daily for up to 90 days, improves severity of lower extremity symptoms (e.g., inflammation, pain, varicose veins, vessel induration) when compared with the use of compression stockings alone (115869). It is unclear if these benefits are due to bromelain, the other ingredients, or the combination.
• Diabetes. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with a family history of type 1 diabetes found that taking a specific product (Mucos Pharma) containing bromelain 90 mg. rutin 100 mg, and trypsin 48 mg daily for 24 months is not associated with reduced incidence of type 1 diabetes at 8 years (99472).
• Diabetic foot ulcers. Although there has been interest in using topical bromelain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Exercise-induced muscle soreness. It is unclear if oral bromelain is beneficial for preventing exercise-induced muscle soreness. Details: One small clinical study shows that taking bromelain 300 mg three times daily, immediately following an intense exercise regimen, does not reduce delayed onset muscle soreness and has no effect on pain, flexibility, or skeletal weakness when compared with either ibuprofen 400 mg three times daily or placebo (10622). However, a small clinical study shows that taking a combination protease tablet containing bromelain 50 mg, trypsin 75 mg, papain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, can improve recovery of contractile muscle function and decrease muscle soreness when compared with placebo (67838). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
• Exercise-induced respiratory infections. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in non-elite male runners shows that taking a combination product (Wobenzym Plus, Mucos Pharma) providing bromelain 540-1080 mg, rutin 600-1200 mg, and trypsin 288-576 mg daily for 3 weeks, starting one week before a marathon, does not reduce the risk of a post-race respiratory tract infection when compared with placebo (96766).
• Kidney stones (nephrolithiasis). It is unclear if oral bromelain is beneficial for kidney stone expulsion. Details: Observational research in patients with 4-10 mm kidney stones found that adding bromelain to tamsulosin is associated with a 12% increased rate of spontaneous stone expulsion when compared to tamsulosin alone (100752).
• Knee pain. It is unclear if oral bromelain is beneficial for knee pain. Details: Preliminary clinical research shows that taking bromelain (Bromelin, Lichtwer Pharma Ltd.) orally for 30 days can reduce mild, acute (duration of less than 3 months) knee pain in otherwise healthy patients when compared to baseline. A daily dose of 400 mg seems to be more effective than 200 mg daily for relieving pain, stiffness, and physical function of the knee, with reductions in symptom scores of 59% and 41%, respectively (11457).
• Lymphedema. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research in patients who have undergone a mastectomy shows that taking a specific combination product containing bromelain, rutin, pancreatin, papain, trypsin, and chymotrypsin (Wobenzym N, Mucos Pharma) daily for 7 weeks reduces arm swelling associated with lymphedema when compared with diuretics (24560). Other preliminary clinical research in patients with primary or secondary lymphedema of the upper or lower limbs shows that taking a different combination product containing bromelain 100 mg, rutin 300 mg, and sweet clover 100 mg daily for 6 months decreases pitting, limb volume, pain, and quality of life when compared to baseline (103298). The validity of these results is limited by the lack of a control group. Additionally, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Multiple sclerosis (MS). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with relapsing-remitting MS shows that taking an enzyme combination containing bromelain 90 mg, rutin 100 mg, and trypsin 48 mg per tablet for at least 3 months does not affect the progression of disability, relapse rate, or central nervous system lesions when compared with placebo (99468). The validity of these results is limited by the short duration of treatment.
• Ocular floaters. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in patients with spontaneous symptomatic vitreous opacities (ocular floaters) shows that taking oral mixed fruit enzyme capsules containing bromelain 190 mg, papain, and ficin once, twice, or three times daily for 3 months eliminates floaters in 55%, 63%, and 70% of patients, respectively, when compared with an elimination rate of 5% with vitamin C as a control. Additionally, patients with vitreous hemorrhage-induced symptomatic vitreous opacities taking the mixed fruit enzyme capsules 3 times daily for 3 months reduced intraocular blood by 56% and improved visual acuity, but these effects were not found for lower doses and shorter durations when compared with a control (111650). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
• Osteoarthritis. It is unclear if oral bromelain is beneficial for osteoarthritis. Details: A small clinical trial shows that taking bromelain 800 mg daily for 12 weeks as an adjunctive treatment for moderate to severe knee osteoarthritis is no more effective than placebo for improving symptom scores (18274). Other preliminary clinical research shows that taking bromelain 500 mg daily for 4 weeks for mild to moderate knee osteoarthritis is less effective than diclofenac 100 mg daily for improving quality of life, joint pain, and joint function (96216). However, preliminary clinical research shows that oral combination products containing bromelain can reduce pain and improve function in knee osteoarthritis (6252,91104,91106,99467,99477,103299). Bromelain 180 mg has been used in combination with trypsin 144 mg and rutin 200 mg (Phlogenzym, Mucos Pharma GMBH; Wobenzym, Mucos Pharma GmbH) three times daily for 3-12 weeks, with effects comparable to diclofenac, usually taken as 50 mg three times daily for one week, then twice daily thereafter. This product also reduces the need for rescue analgesics by 95% when compared with placebo (6252,91104,99467,99477). Other studies have used a specific combination supplement (AINAT, Laboratoire de Rhumatologie Appliquée) containing Devil's claw 600 mg, turmeric 400 mg, and bromelain 300 mg, taken 2-3 times daily for 2-8 weeks (91106) or a combination of bromelain 250 mg and papain 250 mg (Nature's Life Bromelain & Papain, NutraMarks, Inc.) twice daily, plus aceclofenac 100 mg twice daily for 6 weeks (103299).
• Pain (acute). It is unclear if oral bromelain is beneficial for acute pain. Details: A meta-analysis of 9 small clinical studies in patients experiencing acute pain due to various etiologies shows that taking bromelain slightly improves subjective pain scores and allows patients to open their mouth wider after oral operations when compared with a control (113513).
• Parturition. Although there has been interest in using oral bromelain for shortening the duration of labor, there is insufficient reliable information about the clinical effects of bromelain for this purpose.
• Periodontitis. It is unclear if oral bromelain is beneficial for periodontitis. Details: A very small clinical study in adults with periodontitis shows that taking bromelain 500 mg (Anaheal) twice daily for one week after undergoing pocket elimination surgery reduces bleeding on probing but does not improve gingival index, plaque index, or probing pocket depth when compared with placebo when assessed five weeks after surgery (111691). The validity of these effects is limited by a very small sample size and inadequate statistical power.
• Pityriasis lichenoides chronica (PLC). It is unclear if oral bromelain is beneficial for PLC. Details: A case series suggests that taking bromelain 40 mg orally three times daily for one month, then twice daily for a second month, then once daily for a third month, helps treat episodes of PLC when compared to baseline (18280).
• Postoperative pain. While evidence is mixed, some small clinical studies suggest that oral bromelain reduces postoperative pain aftersome oral surgeries. Details: Meta-analyses and clinical research in a small number of patients undergoing wisdom tooth extraction shows that bromelain modestly reduces pain for up to 8 days when compared with control (91109,91110,100750,100751). In contrast, several other small clinical studies show that taking bromelain does not reduce pain after wisdom tooth extraction when compared with placebo (91107,96214,96215). These studies might not have been sufficiently powered to detect a smaller effect. Meta-analyses also suggest that bromelain does not appear to have a significant effect on postoperative swelling or trismus (100750,100751). Additionally, multiple clinical studies in patients undergoing oral procedures, including crown lengthening or root canal surgery, shows that bromelain 160-1500 mg, taken in 2-4 divided doses daily for up to 6 days, reduces dental pain, swelling, and trismus similarly to taking non-steroidal anti-inflammatories (e.g., ketoprofen, diclofenac sodium, aceclofenac, and ibuprofen) (91109,91110,110546,113898,115871,110546). Bromelain, in combination with other ingredients, has also been evaluated for reducing pain after surgery. Several clinical trials in adults undergoing a variety of surgery types, including facial trauma, hernioplasty, oral surgery, and shoulder surgery, show that taking specific combination products (Siben, Brovas, Tenosan) containing bromelain and other ingredients (e.g., freeze-dried pineapple, methylsulfonylmethane, Boswellia serrata) daily for 1 week to 3 months reduces postoperative pain (115868,19322,114687,115304). However, clinical significance is unclear. Additionally, it is unclear if the effect is due to bromelain, other ingredients, or the combination.
• Postoperative swelling. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical study in patients undergoing surgery of the jaw shows that taking an enzyme combination of bromelain 180 mg, rutin 200 mg, and trypsin 96 mg twice daily for 5 days in addition to standard treatment reduces soft-tissue thickness (indicating the amount of swelling) at most of the nine assessed facial points when compared to control (99476).
• Rhinosinusitis. It is unclear if oral bromelain is beneficial for rhinosinusitis. Details: Several small clinical trials show that short-term and long-term use of bromelain reduces symptoms of acute and chronic sinusitis, especially nasal mucosal inflammation and edema (18276,18277,18278,18279,91105). The trials used bromelain 40 mg orally (usually the product Ananase) four times daily for six days as an adjunct to antibiotics (18276,18278,18279) or 6 bromelain tablets each containing enzymes of 500 International Pharmaceutical Federation (FIP) units for 12 weeks (91105). Bromelain is usually taken in combination with decongestants, antihistamines, and/or antibiotics. However, the studies have a number of methodological problems, and results are inconsistent. Bromelain has also been evaluated as part of a combination product. A small study in patients over 12 years old with chronic sinusitis shows that taking a combination product containing bromelain 200 mg, Boswellia serrata, black currant, and vitamin D (Flogostop Forte, Humana Italia S.p.A) 1-2 times daily for 15-30 days as an adjunctive therapy to inhaled corticosteroids modulates hyperemia of the mucosa, rhinorrhea, and local inflammation when compared with inhaled corticosteroids alone and baseline (111501). It is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Sprains. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with a sprained ankle shows that taking a specific enzyme combination (Phlogenzym, Mucos Pharma) containing bromelain 90 mg, trypsin 48 mg, and rutin 100 mg, or taking different combinations of the individual enzymes three times daily for 10 days, is no more effective for relieving pain than placebo (99473).
• Tendinopathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with Achilles tendon insertional tendinopathy shows that taking two sachets of a specific supplement (Tenosan, Agave, Prato, Italy) containing a total of bromelain 100 mg, arginine-L-alpha-ketoglutarate 1000 mg, methylsulfonylmethane (MSM) 1100 mg, hydrolyzed collagen type I 600 mg, vitamin C 120 mg, and Vinitrox 25 mg orally for 60 days improves function and pain when compared with placebo (19321).
• Urinary tract infections (UTIs). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of bromelain 50 mg and trypsin 1 mg (Kimotab, Mochida Pharmaceutical), taken in a dose of 8 tablets daily for 2 days, does not improve subjective symptoms of UTIs when compared with placebo (18282).
• Venous leg ulcers. Although there has been interest in using topical bromelain for venous leg ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Wound healing. It is unclear if enzymatic debridement with bromelain improves the healing of various types of chronic wounds. Details: A meta-analysis of 12 small clinical studies shows that topical bromelain reduces time to complete debridement by around 6 days but has no effect on time to healing when compared with a control (113513). However, the validity of these effects is limited by significant publication bias and a small number of studies per outcome. One small clinical study, included in the analysis above, of patients with chronic wounds related to diabetes, surgery, trauma, or venous insufficiency shows that use of bromelain-based enzymatic debridement (EscharEx, MediWound Ltd), administered as up to ten daily applications of 4 hours each, increases the incidence of complete debridement over the next 6 months to 55% of patients, compared with only 29% of those using the bromelain-free gel. However, there was no difference in changes in wound area, non-viable tissue area, or the incidence or time to complete wound closure (108148). More evidence is needed to rate bromelain for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). A meta-analysis of clinical research shows that taking buckwheat seems to improve some, but not all, markers of CVD risk. Buckwheat was found to decrease total cholesterol by 19 mg/dL, triglycerides by 22 mg/dL, and blood glucose by 15 mg/dL, but had no effect on blood pressure, body weight, insulin, or low-density lipoprotein (LDL) cholesterol when compared with a control group (100947). The patient populations included in this analysis ranged from healthy adults to those with diabetes or hyperlipidemia; it's unclear whether the results are consistent across patient groups or if the benefits are more pronounced in certain types of patients. The effects of buckwheat on cardiovascular events, such as myocardial infarction, stroke, or cardiovascular death, in patients with CVD, are unknown.
• Chronic venous insufficiency (CVI). Preliminary clinical research shows that drinking common buckwheat tea for 3 months attenuates leg swelling compared with placebo in patients with chronic venous insufficiency (37351).
• Diabetes. Preliminary clinical research shows that patients with type 2 diabetes who replace a portion of white rice or white flour with tartary buckwheat 50 grams three times daily for 4 weeks show a 3% reduction in fasting insulin and a 7% reduction in low-density lipoprotein (LDL) cholesterol compared to baseline. Patients who consume the standardized recipe containing white rice and/or white flour three times daily for 4 weeks show no significant changes in these measurements. Neither groups show improvement in fasting blood glucose or hemoglobin A1c levels (96063).
• Diabetic retinopathy. Preliminary clinical research shows that taking common buckwheat 1 gram three times daily for 3 months does not significantly improve visual acuity compared with baseline in patients with diabetic retinopathy (37358). More evidence is needed to rate the effectiveness of buckwheat for these uses.

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POSSIBLY EFFECTIVE

• Breast engorgement. Most research shows that applying cabbage leaves to engorged breasts reduces pain and hardness to the same degree as cold compresses in lactating females with breast engorgement. Details: Several small clinical studies suggest that applying whole cabbage leaves to the engorged breasts of lactating females produces subjective relief similar to the use of chilled gel-packs (6781,6784,93677). Both chilled and room temperature cabbage leaves seem to provide the same relief (6782). Another small clinical study shows that whole cabbage leaves also seem to improve breast pain and hardness when compared with general nursing care (93673). When compared with hot and cold compresses, one small clinical study found that using chilled cabbage leaves reduces postnatal breast engorgement to a similar degree, but is not as effective for reducing pain (101966). The preparation of cabbage leaves for this purpose sometimes includes stripping out the large vein of the cabbage leaf and cutting a hole for the nipple. Cabbage leaves are rinsed and chilled. The chilled cabbage leaf is worn inside the bra or as a compress under a cool towel. This procedure is typically repeated 1-4 times daily for 1-3 days (6781,6784,93673,93677,101966). A cabbage leaf extract applied as a cream has also been tried. The cabbage leaf extract cream seems to provide subjective relief when compared to baseline, but it does not provide superior relief when compared with a placebo cream (6783).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. It is unclear if consuming cabbage is effective for the prevention of bladder cancer. Details: Observational research has found that eating about 1.75 cups of cruciferous vegetables such as cabbage or broccoli is associated with a 30% reduced risk of bladder cancer in men and women (14864).
• Colorectal cancer. It is unclear if consuming cabbage is effective for the prevention of colorectal cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing colorectal cancer (6792).
• Gastric cancer. It is unclear if consuming cabbage is effective for the prevention of gastric cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing stomach cancer (6792).
• Gastritis. Although there has been interest in using oral cabbage for gastritis, there is insufficient reliable information about the clinical effects of cabbage for this purpose.
• Hyperlipidemia. It is unclear if oral cabbage is beneficial in patients with hyperlipidemia. Details: A small clinical study in Japanese adults with hyperlipidemia shows that adding broccoli and cabbage to a beverage consisting of fruits and vegetables for 3-9 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 8.5% when compared to baseline. The reduction in LDL cholesterol was significant when compared with the same beverage without broccoli and cabbage added (25423).
• Knee pain. It is unclear if topical cabbage is beneficial in patients with knee pain. Details: A small clinical study in males with an acute mild to moderate traumatic knee ligament injury shows that use of crushed fresh cabbage leaf and cooling dressing wraps improves recovery over the first 24 hours of use by a moderate amount when compared with the cooling dressing alone. Normal fluid release occurred in 67% to 80% of patients using crushed cabbage leaf compared with 47% to 50% of those given the cooling dressing alone (101969).
• Lung cancer. It is unclear if consuming cabbage is effective for the prevention of lung cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing lung cancer (6792).
• Osteoarthritis. Small clinical studies suggest that topical cabbage leaf modestly improves pain and other symptoms in patients with osteoarthritis of the knee. Details: A small clinical study in patients with osteoarthritis of the knee shows that applying cabbage leaf wraps to the knees for at least 2 hours daily for 4 weeks decreases pain by around 12 points on a 100 mm visual analog scale when compared with usual care. The analgesic effect of cabbage leaf wraps in these patients appears to be similar to treatment with topical gel containing the nonsteroidal anti-inflammatory drug diclofenac 10 mg/gram (93671). Another small, open-label clinical study in patients with moderate to severe osteoarthritis of the knee shows that applying cabbage leaf wraps to the knees for 1 hour daily for 4 weeks reduces knee pain and improves symptom severity when compared with diclofenac gel applied four times daily. Improvements in pain and overall symptoms were similar between cabbage leaf and the use of cooling gel pads (110558). The validity of these findings is limited by a lack of blinding.
• Pancreatic cancer. It is unclear if consuming cabbage is effective for the prevention of pancreatic cancer. Details: Observational research in elderly and middle-aged individuals has found that consuming one or more servings of cabbage per week is associated with a 38% lower risk of developing pancreatic cancer when compared with those who do not eat cabbage (25422).
• Peptic ulcers. Although there has been interest in using oral cabbage for peptic ulcers, there is insufficient reliable information about the clinical effects of cabbage for this purpose.
• Prostate cancer. It is unclear if consuming cabbage is effective for the prevention of prostate cancer. Details: Some observational research has found that consuming higher amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is not associated with a lower risk of prostate cancer (25417,25419). However, other observational studies have found that consuming higher amounts of cabbage and other Brassica vegetables is associated with a lower risk of developing prostate cancer (25418,25420,25421). More evidence is needed to rate cabbage for these uses.

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EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount in adults with or without hypertension. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies, including a meta-analysis of 18 high-quality clinical trials, show that intake of calcium supplements or dietary calcium modestly reduces systolic blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as those who are salt-sensitive or have low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221,113920,113925). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplemental sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367). Research evaluating the effect of calcium supplementation during pregnancy on the child's blood pressure has yielded conflicting findings. A systematic review of 2 clinical studies and 3 observational studies found that calcium intake during pregnancy is associated with a 1-2 mmHg reduction in the systolic blood pressure of the offspring between the ages of 1-7 years (38852). However, a separate meta-analysis of 3 clinical studies shows that calcium intake during pregnancy does not reduce systolic or diastolic blood pressure in the offspring (113923).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia, especially in high-risk individuals and those with low baseline dietary calcium intake. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces the risk of pre-eclampsia (973,1833,8828,39043,39319,39426,97348,113919). A large clinical trial of 11,000 pregnant individuals in India and Tanzania shows that supplementation with 500 mg daily is similarly effective to 1500 mg daily (113908). Multiple meta-analyses which include 16-30 clinical studies have found that varying doses of calcium supplementation reduce the relative risk of pre-eclampsia by 46% to 51% when compared with placebo (97348,113909,113919). One of these meta-analyses found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (97348). Additionally, one of these meta-analyses found that calcium reduces the relative risk of pre-eclampsia by 51%, regardless of whether it is taken at a dose above or below 1000 mg daily (113919). Some research suggests that calcium supplementation may have a greater effect in individuals at high risk of pre-eclampsia or with low baseline dietary calcium intake, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,97348,99714,113919). However, another meta-analysis of 30 clinical studies found a similar benefit of calcium in both high- and low-risk individuals (113919). A separate meta-analysis of 6 clinical studies conducted in China evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy. This combination was associated with an 80% lower relative risk of pre-eclampsia and an 83% lower relative risk of pre-eclampsia with gestational hypertension when compared with routine care (113913). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely (102366). Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low (97347).
• Pregnancy-induced hypertension. Oral calcium may reduce the risk of pregnancy-induced hypertension. Details: A meta-analysis of 17 clinical studies shows that calcium supplementation during pregnancy may reduce the relative risk of pregnancy-induced hypertension by 30% when compared with control (113909). A separate meta-analysis of 6 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of pregnancy-induced hypertension by 85% when compared with routine care (113913).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium, via supplementation or as part of the diet, does not seem to be beneficial for breast cancer prevention. Details: Although some studies disagree (15631,39041,95811,107237,113917), most population research suggests that increased calcium intake is not associated with overall breast cancer risk (15631,16715,98895,107236,107237,113917). However, one meta-analysis of observational studies shows that although higher total calcium intake is not associated with breast cancer risk, higher dietary calcium intake, specifically, may be associated with a slightly reduced risk (113917). Also, some analyses suggest that calcium intake may be associated with the risk for certain breast cancer sub-types. Some subgroup analyses suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237) and that dietary calcium intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: Robust meta-analyses of mostly large, high-quality clinical studies show that calcium supplementation 500-1600 mg daily for 0.5-7 years with or without vitamin D does not reduce total fractures, hip fractures, vertebral fractures, or non-vertebral fractures in older adults without osteoporosis (95822,112486). A large-scale study in postmenopausal females aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) suggests that calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the WHI study found that, in older females with the lowest genetic susceptibility to low BMD, taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss in adults or children with overweight or obesity. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905,113918), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). A meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308,113584).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Brain tumor. It is unclear if dietary calcium intake is associated with risk of brain tumor. Details: A meta-analysis of 4 case-control studies has found that higher dietary calcium intake is associated with a lower odds of brain tumor when compared with lower dietary intake (113922). The validity of this finding is limited by the exploratory nature of the included studies, which analyzed all dietary ingredients for any potential associations.
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if dietary calcium intake is associated with type 2 diabetes risk. Details: Some population research has found that a higher intake of calcium from the diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473,113929). One meta-analysis of cohort and cross-sectional studies found that the highest level of dietary calcium intake is associated with an 18% relative reduction in risk of type 2 diabetes when compared with the lowest level of intake. A dose-response analysis suggests that each 300, 600, and 1000 mg per day increase in dietary calcium intake is associated with a 7%, 14%, and 23% reduced risk of type 2 diabetes, respectively (113929). However, population research is often limited by confounding variables. For example, one analysis suggests that any beneficial effect might be influenced by concomitant magnesium intake (96473,113929), while another suggests that any benefit from increased intake may be more pronounced in females, adults aged 50 years or older, and Asian populations (113929). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis (95815).
• Dyslipidemia. It is unclear if oral calcium is beneficial for dyslipidemia. Details: One clinical study in adults with mild to moderate hypercholesterolemia shows that adding calcium carbonate 400 mg three times daily to a low-fat diet (American Heart Association Step 1) for 6 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% when compared with the low-fat diet and placebo (2557). In contrast, a clinical study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years INCREASES total cholesterol levels and carotid intima-media thickness in postmenopausal, but not premenopausal, females when compared with placebo (97350). Calcium supplementation has also been evaluated in combination with vitamin D. A meta-analysis of randomized controlled trials including adults with normolipidemia and dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is most beneficial in patients with dyslipidemia at baseline (107227). The relationship between dietary calcium intake and serum lipid levels has also been evaluated in observational research. A meta-analysis of 7-11 observational studies found that dietary calcium intake is not associated with total cholesterol levels, although small differences in individual lipid parameters were identified. Additionally, a meta-analysis of 4-9 observational studies suggests that calcium intake is not associated with the risk of developing hypertriglyceridemia, hypercholesterolemia, or low HDL. A subgroup analysis found that higher calcium intake may be associated with lower triglyceride levels in Asian populations (113927). Overall, these findings are limited by significant heterogeneity and the cross-sectional nature of the included studies.
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Exercise-induced muscle damage. It is unclear if oral calcium is beneficial for reducing exercise-induced muscle damage. Details: A very small clinical study in resistance-trained adults shows that taking calcium carbonate 500 mg 4 times daily for 3 weeks does not attenuate exercise-induced muscle damage from bench presses when compared with placebo (113933). This study may have been inadequately powered to detect a difference between groups.
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prematurity. It is unclear if supplemental calcium is beneficial for the growth and development of preterm infants. Details: A small clinical study in preterm infants consuming human milk shows that supplementation with calcium 45 mg/kg daily and phosphorus 25 mg/kg daily does not affect infant weight, length, head circumference, or risk of osteopenia after 6 weeks when compared with human milk alone (113924). However, the duration and size of this study may have been too limited to detect any difference between groups.
• Preterm labor. It is unclear if oral calcium reduces the risk of preterm labor. Details: A meta-analysis of 10 clinical studies shows that taking calcium supplements during pregnancy does not reduce the risk of preterm labor when compared with placebo (113909). A separate meta-analysis of 7 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of preterm labor by 74% when compared with routine care (113913).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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There is insufficient reliable information available about the effectiveness of camu camu.

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POSSIBLY EFFECTIVE

• Vitamin A deficiency. Some preliminary clinical research shows that consuming one spoonful of carrot jam daily for 10 weeks improves growth velocity when compared with control in children with vitamin A deficiency (25819). Other preliminary research shows that consuming 100 grams of grated carrot daily for 60 days improves vitamin A status when compared with placebo in lactating women at risk for vitamin A deficiency (67861).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Breast cancer. A meta-analysis of observational research has found that consuming a diet highest in carrots is associated with a 21% decreased odds of developing breast cancer when compared with consuming a diet lowest in carrots (101715).
• Colorectal cancer. A large observational study in older Danish adults shows that self-reported high consumption of raw carrot (2-4 carrots weekly or greater than 32 grams daily) is associated with a 17% lower likelihood of colorectal cancer diagnosis, whereas lower carrot consumption is not associated with a decreased risk. The validity of these findings may be limited by selection bias, recall bias, and other confounding factors (106559).
• Fibromyalgia. Preliminary clinical research shows that consuming a mostly raw, pure vegetarian diet that includes two to four 240 mL servings of carrot juice daily for 7 months might improve fibromyalgia symptoms in some people (98057). The effect of carrot alone on fibromyalgia is unknown.
• Prostate cancer. Population research has found that higher intake of carrot is associated with an 18% decrease in the odds of developing prostate cancer. Increasing carrot consumption by 10 grams daily or 1 serving per week is associated with a 4% to 5% decrease in the odds of developing prostate cancer (96307). More evidence is needed to rate carrot for these uses.

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POSSIBLY INEFFECTIVE

• Hyperlipidemia. A meta-analysis of small clinical studies suggests that consuming chia seeds, flour, powder, or oil for 7-24 weeks does not improve lipid levels in patients with conditions associated with hyperlipidemia. Details: A meta-analysis of 10 small clinical trials in patients with various metabolic conditions, including diabetes, metabolic syndrome, nonalcoholic fatty liver disease, and obesity, shows that consuming chia seeds, flour, or powder 15-60 grams daily for 7-24 weeks, or taking chia oil 6 grams daily for 8 weeks, does not reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels or increase high-density lipoprotein (HDL) cholesterol levels when compared with control groups consuming wheat bran, oat bran, dietary fiber, poppy seeds, or soybean oil (106657). While the patient populations in the studies analyzed are more likely to develop hyperlipidemia, it is unclear if these findings can be generalized to patients diagnosed with hyperlipidemia.
• Obesity. Small clinical studies suggest that consuming chia seeds for up to 12 weeks does not reduce body weight in overweight or obese adults. Details: One small clinical study in overweight or obese individuals shows that ingesting chia seeds 25 grams mixed in 0.25 liters of water twice daily before meals for 12 weeks does not improve body composition or reduce blood pressure when compared with placebo (25533). Another small clinical study in overweight, postmenopausal females shows that ingesting milled or whole chia seeds 25 grams daily for 10 weeks does not improve body composition or blood pressure when compared to baseline (25532).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral chia is beneficial for improving athletic performance. Details: A small clinical study in trained athletes shows that drinking a beverage containing 50% of calories from chia seeds (Greens Plus Omega 3 Chia seeds) and 50% of calories from a carbohydrate-containing beverage (Gatorade) for 2 days prior to participating in an endurance exercise lasting more than 90 minutes leads to similar performance when compared with Gatorade alone (25531).
• Cardiovascular disease (CVD). Although there has been interest in using oral chia for CVD, there is insufficient reliable information about the clinical effects of chia for this purpose.
• Diabetes. Small clinical studies suggest that consuming chia for 4-6 months might reduce systolic blood pressure (SBP) in patients with type 2 diabetes, although it does not appear to improve glycemic control or lipid levels and has shown mixed effects on body weight and inflammatory markers. Details: One small clinical trial in patients with type 2 diabetes shows that consuming bread containing a specific, selectively bred type of chia (Salba, Salba Smart Natural Products LLC), providing 37 grams of chia daily for 12 weeks reduces SBP, C-reactive protein, and vonWillebrand factor, but not lipid levels, when compared with consuming bread containing wheat bran. This form of chia also significantly reduced glycated hemoglobin (HbA1c) when compared to baseline, but not when compared with a wheat bran control (16124). Another small clinical study in adults with type 2 diabetes and obesity shows that consuming Salba chia 40 grams daily, either baked into bread or as a powder, in conjunction with a restricted calorie diet for 6 months reduces weight by 1.6 kg and waist circumference by 2.8 cm when compared with an oat bran control. However, consuming chia had no effect on body fat percentage, HbA1c, or fasting glucose levels (97940). Also, a small clinical study in adults with type 2 diabetes shows that consuming chia seeds 40 grams daily for 12 weeks reduces SBP, but does not improve body weight, HbA1c, or levels of fasting glucose, lipids, or C-reactive protein, when compared with those not consuming chia (106658).
• Hypertension. It is unclear if oral chia is beneficial in patients with hypertension. Details: A very small clinical study in patients with mild hypertension shows that consuming chia flour 35 grams daily for 12 weeks reduces systolic blood pressure (SBP) by around 10 mm Hg and diastolic blood pressure (DBP) by almost 9 mm Hg when compared to baseline. In patients already taking antihypertensive drugs, chia seems to have an even greater impact on SBP and DBP. However, in patients not being treated with antihypertensive drugs, chia flour modestly reduces SBP by 6.5%, but does not significantly reduce DBP. No improvements in blood pressure were reported in patients consuming a wheat bran control (91516).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral chia is beneficial in patients with NAFLD. Details: Small, uncontrolled clinical studies in patients with NAFLD show that consuming milled chia seeds 25 grams daily for 8 weeks may reduce hepatic steatosis, as measured by the liver: spleen attenuation ratio, in up to 43% of subjects with prediabetes and 100% of subjects with diabetes when compared to baseline. Chia seed supplementation may also modestly reduce visceral fat, body mass index, and waist circumference in patients with prediabetes when compared to baseline, but does not seem to improve lipid levels (104530,110438). The validity of these findings is limited by the lack of a comparator group in both studies.
• Metabolic syndrome. Oral chia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with metabolic syndrome shows that reducing daily caloric intake by 500 kcal and drinking a beverage containing chia seed 4 grams, soy protein 32 grams, dehydrated nopal 7 grams, and oat 22 grams daily for 2 months reduces body weight, body mass index, and waist circumference when compared to baseline, but not when compared with following a reduced calorie diet alone. However, following the reduced calorie diet and drinking this beverage appears to lower serum triglycerides and C-reactive protein and improve glucose tolerance when compared with a reduced calorie diet alone (25534). It is unclear if these findings are due to chia, other ingredients, or the combination.
• Muscle strength. It is unclear if oral chia is beneficial for increasing muscle strength and muscle mass during resistance training. Details: A very small clinical trial in healthy, non-resistance trained males shows that drinking a supplemental beverage containing chia flour 50 grams, providing 20 grams of protein and 3 grams of omega-3 fatty acids, is no more effective than whey protein 20 grams or placebo for augmenting the increases in muscle strength and fat-free mass that occur with an 8-week whole body resistance training program (112385). The habitual baseline diet of the study participants already contained dietary protein intakes recommended for strength training, and the beverage was only consumed three times per week immediately after training sessions.
• Pruritus. It is unclear if topical chia seed oil is beneficial in patients with pruritus. Details: One very small, uncontrolled clinical study in patients with xerotic pruritus or pruritus caused by kidney failure or diabetes shows that applying lotion containing chia seed oil 4% for 8 weeks improves skin hydration and reduces the severity of lichen simplex chronicus and prurigo nodularis when compared to baseline (25537). The validity of these findings is limited by the small study size and lack of a comparator group. More evidence is needed to rate chia for these uses.

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POSSIBLY EFFECTIVE

• Ventilator-associated pneumonia (VAP). Clove mouthwash might reduce the risk of acquiring pneumonia in patients on mechanical ventilation. Details: A large clinical trial in adults in the intensive care unit on mechanical ventilation shows that administration of a clove extract 6.66% mouthwash, 15 mL twice daily for 5 days, results in a 2-fold lower incidence of ventilator-associated pneumonia when compared with chlorhexidine mouthwash (112151).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alveolar osteitis. Although there has been interest in using topical clove for alveolar osteitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Anal fissures. It is unclear if topical clove oil is beneficial in patients with anal fissures. Details: Preliminary clinical research in patients with chronic anal fissures shows that applying clove oil 1% cream for 6 weeks heals fissures in 60% of patients by the 3-month follow-up, compared with only 12% of patients who used topical lidocaine 5% cream and stool softeners (43487).
• Cough. Although there has been interest in using oral clove for cough, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dental plaque. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a specific toothpaste (Sudantha, Link Natural Products Ltd.) containing a combination of clove, Acacia chundra Willd., malabar nut, bullet wood tree, black pepper, Indian beech, gall oak, Terminalia, and ginger twice daily for 12 weeks can reduce dental plaque, bleeding, and bacteria counts in the mouth when compared with placebo (43570). Other clinical research shows that administration of a mouth rinse containing clove, tea tree oil, and basil 10 mL twice daily for 21 days is as effective as a commercially available mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate in reducing dental plaque and gum inflammation (92160). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Diarrhea. Although there has been interest in using oral clove for diarrhea, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dyspepsia. Although there has been interest in using oral clove for dyspepsia, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Flatulence. Although there has been interest in using oral clove for flatulence, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Gingivitis. Although there has been interest in using topical clove for gingivitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Halitosis. Although there has been interest in using oral clove for halitosis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Hangover. It is unclear if oral clove flower extract is beneficial for reducing hangover severity. Details: Preliminary clinical research in a very small number of healthy males with a history of hangovers shows that taking a clove flower bud polyphenol extract 250 mg prior to drinking brandy (42.8% alcohol) decreases hangover severity scores by around 55% when compared with placebo (100597).
• Hyperhidrosis. It is unclear if topical clove oil is beneficial in patients with hyperhidrosis. Details: Preliminary clinical research in patients with hyperhidrosis of the palms shows that topical application of clove oil 45% in liposome base twice daily for 2 weeks improves hyperhidrosis severity and decreases the rate of sweating by around 34% when compared with a saline control (100596). The validity of these findings is limited by a lack of subject randomization.
• Impaired glucose tolerance (prediabetes). It is unclear if oral clove flower extract is beneficial in patients with prediabetes. Details: Preliminary clinical research in a very small number of patients with prediabetes shows that taking a polyphenolic extract from clove flower buds 250 mg daily for 30 days decreases pre-prandial plasma glucose by 14 mg/dL and postprandial plasma glucose by 40 mg/dL when compared to baseline (100595). The validity of these findings is limited by the very small size of the study and the lack of a control group.
• Mosquito repellent. Small clinical studies suggest that topical clove oil may repel mosquitos for up to 4-5 hours. Details: Preliminary clinical research shows that topical application of undiluted clove oil can repel 100% of mosquitoes for up to 4 hours (43427). Other preliminary research shows that topical application of gel containing clove oil 20% can repel 86% to 97% of mosquitoes for 5 hours (43411).
• Nausea and vomiting. Although there has been interest in using oral clove for nausea and vomiting, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Oral mucositis. Although there has been interest in using topical clove for oral mucositis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Pain (acute). It is unclear if topical clove is beneficial in patients with acute pain. Details: Preliminary clinical research shows that topical application of a gel containing ground cloves, applied as 4 grams of gel for 5 minutes prior to dental anesthesia injection, can reduce needle stick pain when compared with placebo. The effect of the clove gel on pain seems to be comparable to benzocaine 20% gel (43448).
• Premature ejaculation. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that administration of a multi-ingredient cream preparation (SS Cream) containing clove flower, Panax ginseng root, Angelica root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, Asiasari root, cinnamon bark, and toad venom to the glans penis, one hour prior to intercourse and washed off immediately before intercourse, increases ejaculatory latency time by over 4-fold when compared with placebo in adults with premature ejaculation (2537). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Pruritus. There is limited evidence on the topical use of clove oil in patients with chronic pruritus. Details: Preliminary clinical research in patients with chronic pruritus shows that applying clove oil 10% in petroleum jelly to the skin twice daily for 2 weeks reduces the daily duration of itching by 48 minutes and improves symptom severity and disability scores when compared with placebo (96950).
• Smoking cessation. Oral clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults in India with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing clove 30 mg, ashwagandha, cowhage, ginger, turmeric, and other herbal extracts (Smotect, Smotect India) twice daily for 3 months reduces the number of cigarettes smoked daily and levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity when compared with placebo (112115). It is unclear if these effects are due to clove, other ingredients, or the combination. More evidence is needed to rate clove for these uses.

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LIKELY EFFECTIVE

• Mental alertness. Consumption of caffeinated coffee attenuates changes in alertness and cognitive capacity that occur throughout the day. It also improves mental performance and alertness following sleep deprivation. Details: Consumption of coffee and other caffeinated beverages seems to prevent a decline in alertness and cognitive capacity when consumed throughout the day (4221,4224). Caffeine can improve mental performance and alertness following prolonged sleep deprivation (10205). With respect to mental alertness while driving, some research shows that drinking a single cup of coffee containing 80 mg caffeine in 180 mL during a 15-minute rest after simulated driving for 2 hours reduces the amount of weaving and increases speed consistency in the 3rd and 4th hours of driving when compared with drinking decaffeinated coffee. Overall, the mental effort needed to drive, driving quality, and feelings of sleepiness appear to improve with caffeine consumption (93875).

POSSIBLY EFFECTIVE

• Diabetes. Population research has found that consumption of caffeinated coffee is associated with a reduced risk of developing type 2 diabetes. Consumption of coffee also seems to be associated with a reduced risk of mortality in patients with type 2 diabetes. Details: Population research suggests that consumption of caffeinated coffee is associated with a dose-dependent reduced risk of developing type 2 diabetes (11353,11731,14313,38174,91040,91055,111040). Some research suggests that increasing coffee consumption by 1 cup daily is associated with a 6% to 9% reduction in the incidence of type 2 diabetes (91040,91055). In North American adults, consuming 6 or more cups of coffee daily is associated with a 29% lower risk of developing diabetes in females and a 54% lower risk in males (11353). Research in European adults suggests that drinking 5-6 cups of coffee daily appears to reduce diabetes risk by 61% in females and 30% in males. Drinking 10 or more cups daily reduces diabetes risk by 79% in females and 55% in males (11731). Additional research suggests that drinking 3-4 cups of coffee daily reduces the risk of diabetes by 23% to 42% when compared with drinking just 1 cup daily (14343,38174). An analysis of these and other cohort studies involving over 457,000 patients suggests that drinking 3-4 cups of coffee or decaffeinated coffee daily is associated with a 25% to 35% reduced risk of type 2 diabetes when compared with drinking 2 cups or less daily. Each additional cup of coffee consumed each day is associated with a 5% to 10% reduction in the incidence of type 2 diabetes (97368). Some population research in patients with previous gestational diabetes has also investigated the association between consumption of coffee and risk of developing type 2 diabetes. Research suggests that consumption of at least 4 cups of caffeinated coffee daily is associated with a 54% reduced risk of type 2 diabetes when compared with drinking no coffee. There is no association between consumption of decaffeinated coffee and type 2 diabetes risk (111040). Coffee consumption has also been evaluated in patients with type 2 diabetes, with mixed findings. Most population research suggests that coffee consumption is associated with a reduced risk of mortality in patients with type 2 diabetes. In one meta-analysis of observational studies, drinking high amounts of coffee was associated with a 24% reduction in mortality risk, with a 9% reduction for each additional cup of coffee (104595). In another meta-analysis, drinking up to 4 cups of coffee daily was associated with a 19% reduction in all-cause mortality and a 34% reduction in coronary heart disease (CHD) mortality when compared with not drinking coffee. Reductions in cardiovascular disease (CVD) mortality were only significant when one large study was excluded during sensitivity analyses (107836). Results of individual studies are conflicting (37805,97374,104589,104594). Additionally, a cross-sectional study in older adults with type 2 diabetes has examined the relationship between coffee consumption and CVD risk factors. This study suggests that higher coffee consumption is associated with lower fasting plasma glucose and diastolic blood pressure and higher high-density lipoprotein (HDL) cholesterol and triglyceride levels (107825). Population research has examined the relationship between coffee consumption and change in kidney function in patients with type 2 diabetes. One study in patients with normal kidney function suggests that drinking any coffee is associated with up to a 25% prevention in kidney function decline when compared with no coffee consumption. Kidney function decline was based on estimated glomerular function rate (eGFR) measurements (111043).
• Heart failure. Consumption of caffeinated coffee seems to reduce the long-term risk of heart failure in those without cardiovascular disease (CVD) at baseline. Details: A meta-analysis of three large population studies, the Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and Atherosclerosis Risk in Communities (ARIC) study, has found that increased daily coffee consumption is associated with a reduced long-term risk of heart failure in individuals without CVD at baseline. Drinking at least 2 cups of coffee daily is associated with a 29% to 31% reduced risk of heart failure. In the analysis, total caffeine intake, but not decaffeinated coffee intake, was associated with a reduced risk of heart failure (104597).
• Overall mortality. Consumption of coffee seems to reduce all-cause mortality. The effects of coffee on specific causes of mortality are variable. Details: Population research conducted in almost 4 million international individuals suggests that long-term, daily consumption of coffee is associated with an 8% to 28% reduction in all-cause mortality when compared to low or no coffee consumption (97373,97374,103997,103998,104594,104595,105308,105311,105314,107826)(107833,107839,111033), though not all research agrees (107822). The strongest association is seen for individuals consuming 2-4 cups of coffee daily and in never smokers. Most research suggests that consuming ground, instant, or decaffeinated coffee is associated with similar reductions in mortality (97373,97374,103997,103998,104594,104595,105308,105311,105314,107833)(111033). The use of sweeteners might affect the association of coffee consumption with all-cause mortality. Population research suggests that consumption of unsweetened coffee, in amounts ranging from any to up to 4.5 cups daily depending on type of coffee, is associated with a reduction in mortality of 14% to 39% when compared with no coffee consumption. Consumption of 1.5 to 3.5 cups of sugar-sweetened coffee is associated with a reduction in mortality of approximately 30%; however, this association does not occur with higher coffee intakes or the consumption of decaffeinated coffee. Any association between the consumption of artificially sweetened coffee and mortality is unclear. When subgroup analyses were conducted to determine the association of coffee consumption with cause-specific mortality, coffee consumption was associated with a reduction in cardiovascular mortality. In some analyses, this association is for ground or decaffeinated, but not sweetened, instant, or unfiltered, coffee (97373,97374,103997,103998,104594,104595,105308,105311,105314,107833)(111032). In another analysis, consumption of coffee was inversely associated with deaths from chronic respiratory diseases, diabetes, pneumonia and influenza, and intentional self-harm. There were no associations between coffee consumption and deaths from accidents, Alzheimer disease, or kidney disease (105311). The association between coffee consumption and cancer-related mortality is less clear. Although one large meta-analysis of population research suggests that consumption of approximately 2 cups of coffee daily is associated with a 4% decrease in cancer-related mortality, the results of individual studies are mixed. One large population cohort suggests that ground or instant caffeinated coffee consumption is associated with up to a 27% reduction in cancer mortality (97374), while other analyses show no association (97373,103994,105308,105311,107822). The reasons for this discrepancy are not clear but may be related to smoking status or use of sweeteners. In one meta-analysis, consumption of each additional cup of coffee daily is associated with a 2% decrease in cancer-related mortality in non-smokers, as opposed to an increased risk in smokers (105308). Other population research suggests that only intake of unsweetened coffee, and not sugar-or artificially-sweetened coffee, is associated with a reduced risk of cancer-related mortality (111032).
• Parkinson disease. Consumption of coffee seems to reduce the risk of developing Parkinson disease. This effect seems to be dose related in males, but not in females. Details: There is evidence that the risk of Parkinson disease is lower in people who consume caffeinated beverages such as coffee, tea, and cola. For males, the effect seems to be dose related. Males consuming the greatest amount of caffeinated coffee, 28 ounces (three to four cups) or a total of 421-2716 mg of caffeine from any source daily, seem to have the greatest reduction in risk. However, a significant reduction in risk exists even with consumption of as little as approximately 1-2 cups of coffee, or 124-208 mg of caffeine, daily (6022). In females, the effect does not seem to be dose related. Moderate consumption of caffeinated coffee, 1-3 cups daily, provides the greatest reduction in risk (1238). Coffee does not appear to provide additional protection from Parkinson disease in cigarette smokers (9236).
• Postoperative ileus. Consumption of coffee seems to decrease the time to first stool and first flatus, and possibly time to discharge, after gynecological or colorectal surgeries. Details: Meta-analyses of mainly small clinical trials in patients who have undergone gynecological or colorectal surgeries show that drinking coffee decreases the time to the first stool and time to tolerating solid food by about 10-15 hours when compared with no treatment or drinking water or tea (103991,111035,112732). Although one meta-analysis found that drinking coffee does not reduce the length of hospital stay (103991), other research shows that hospital stay is reduced by up to 1.5 days; however, the validity of these results are limited by high heterogeneity. In addition, sub-analyses suggest that benefit is limited to gynecological surgery and not colorectal surgery or caesarian section (97386,111035,112732). Sub-analyses also suggest that drinking coffee does not improve bowel function after caesarian section (103991,111035). Caffeinated coffee has been most commonly consumed as 100 mL three times daily starting after surgery and until the first stool. Some studies have used decaffeinated coffee (93876,97386,103991,111035,111039).

POSSIBLY INEFFECTIVE

• Esophageal cancer. Consumption of coffee does not seem to be associated with a reduced risk of esophageal cancer. Details: Population research has found that coffee intake is not associated with the incidence of esophageal cancer (9222,90186,100874). However, subgroup analyses have found coffee consumption may be associated with a reduced risk of esophageal cancer in patients from East Asia (100874).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in consuming coffee for ADHD, there is insufficient reliable information about the clinical effects of coffee for this purpose.
• Atherosclerosis. It is unclear if consuming coffee is beneficial for atherosclerosis. Details: Population research has found that drinking coffee is not associated with prevalent coronary-artery calcium, a subclinical marker of atherosclerosis, in patients without known coronary heart disease (97371).
• Atrial fibrillation. It is unclear if consuming coffee affects the risk of atrial fibrillation. The available research is conflicting. Details: A meta-analysis of observational research suggests that coffee intake is not associated with the incidence of atrial fibrillation (100860). However, a more recent observational study suggests that drinking at least 1 cup of coffee per week is associated with a 40% increased risk of atrial fibrillation, with the highest incidence of atrial fibrillation occurring in adults consuming at least 6 cups daily. A sub-analysis found that this association remained only for White participants and not other ethnicities (111042). This study was limited by its relatively small sample size and a higher than general proportion of smokers. Some observational research in elderly persons following the Mediterranean diet suggests that consuming 4-28 cups of coffee monthly (up to 1 cup daily) is associated with a lower risk of atrial fibrillation when compared with 3 cups or less monthly. Consuming more than 1 cup of coffee daily was not associated with reduced risk (103988). However, it is unclear if this association was due to moderate coffee consumption, the Mediterranean diet, or other, unidentified factors.
• Bladder cancer. Population research suggests that coffee consumption does not reduce the risk of bladder cancer. Details: Although earlier evidence has been conflicting (97375,97376), the most comprehensive analysis of cohort and case control studies has found that coffee consumption is not associated with bladder cancer risk. In subgroup analyses of females, males, or non-smokers, coffee did not affect risk (103992).
• Brain tumor. It is unclear if consuming coffee reduces the risk of brain cancer. Details: Observational research has found that consumption of coffee is associated with a lower risk of brain cancer in Asian populations, but not in American populations (100870).
• Breast cancer. Population research suggests that coffee consumption does not reduce the risk of breast cancer. Details: Population research has found that consumption of coffee is not associated with a reduced incidence of breast cancer (9235,97377,107823).
• Cancer. Although there has been interest in using rectal coffee enemas for the treatment of cancer, there is insufficient reliable information about the clinical effects of coffee for this purpose.
• Cardiovascular disease (CVD). Some population research has found that drinking coffee is associated with a reduced risk of heart failure, but not with a reduced risk of major adverse cardiac events, coronary heart disease, or CVD in general. In patients with a history of CVD, coffee consumption may reduce CVD-related mortality. However, at least some evidence suggests that there is a J-shaped association between coffee consumption and the risk of acute coronary syndromes. Details: A meta-analysis of three large population studies, the Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and Atherosclerosis Risk in Communities (ARIC) study, suggests that increased daily coffee consumption is associated with a reduced long-term risk of heart failure in individuals without CVD at baseline. Drinking at least 2 cups of coffee daily is associated with a 29% to 31% reduced risk of heart failure. However, there was no association between coffee consumption and risk of stroke, coronary heart disease, or CVD in general. In the analysis, total caffeine intake, but not decaffeinated coffee intake, was associated with a reduced risk of heart failure (104597). In one cohort study, there was no association between past coffee-drinking and the prevalence of having coronary heart disease as determined by a coronary angiography (104588). However, a large population study suggests that drinking up to 5 cups daily of instant, ground, or decaffeinated coffee is associated with a reduced risk of incident CVD, including coronary heart disease, cardiac failure, and/or ischemic stroke, of approximately 11% (111033). The association between coffee consumption and arrhythmia has also been investigated. In one population study, there was a 3% reduced risk of arrhythmia for each additional cup of habitual coffee consumed. Similar effects were seen when atrial fibrillation and supraventricular tachycardia, but not ventricular tachycardia, were independently analyzed (105310). More recent population research suggests that consuming 1-5 cups daily of ground or instant coffee, but not decaffeinated coffee, is associated with up to a 17% reduced risk of arrhythmia when compared with not consuming coffee. Intake of more than 5 cups was no longer associated with a reduced risk of arrhythmia (111033). Some population research suggests a J-shaped association between regular coffee consumption and the risk of developing acute coronary syndromes. Moderate consumption of less than 300 mL daily (about 1.3 cups) was associated with a lower risk of developing acute coronary syndromes, whereas regular consumption of 300 mL daily or more was associated with an increased risk (11318). However, other population research in people without a history of CVD suggests that drinking more than 6 cups of coffee daily does not appear to be associated with an increased risk of developing coronary heart disease (14343). The association between coffee consumption and CVD-related mortality has also been evaluated in people with CVD. Population research suggests that coffee consumption is associated with a reduction in CVD-related mortality. In some analyses, this association is for ground or decaffeinated coffee only (97373,97374,103997,103998,104594,104595,105308,105311,105314). A meta-analysis of a small number of population studies suggests that consuming coffee for at least 1 year after a myocardial infarction (MI) is associated with a small reduction in risk of CVD-related mortality and no increased risk of all-cause mortality or major cardiac events, such as a recurrent MI or stroke (104882). In patients with a history of acute coronary syndrome, including acute MI or unstable angina, consumption of 1-3 cups of coffee daily is associated with a reduced risk of overall mortality over a 4-year period, especially in never or former smokers. However, in those who are current smokers, consuming more than 3 cups daily is associated with a more than 2-fold increased risk of overall mortality (8533,105313). A large observational study which followed patients with stable coronary artery disease for 5 years also suggests that there is no association between coffee consumption and CVD-related mortality, myocardial infarction, or stroke (112735).
• Chronic kidney disease (CKD). It is unclear if consuming coffee is beneficial for the prevention or management of CKD. Details: A small meta-analysis of population research has found that coffee consumption is associated with a 14% reduced incidence of CKD; drinking at least 2 cups daily seems to have the most benefit. Coffee consumption is also associated with an 18% reduced incidence of progression to kidney failure, as well as lower odds of having albuminuria. In addition, coffee consumption is associated with a reduced risk of CKD-related death, with at least 4 cups daily providing the most benefit when compared with drinking no coffee (104586). The validity of these findings is limited by the heterogeneous definitions of CKD, kidney failure, and albuminuria in the individual studies, as well as the comparisons of coffee consumption.
• Cognitive function. It is unclear if consuming coffee is beneficial for cognitive function. Details: Some population research has found that higher lifetime coffee consumption might positively affect cognitive function among females aged 80 years or older (10620). Additionally, a small clinical study in healthy adults shows that consuming a single dose of regular coffee 220 mL containing 100 mg of caffeine improves reaction time and working memory, but not episodic memory, when compared with placebo (100864).
• Colorectal cancer. It is unclear if consuming coffee is beneficial for the prevention or treatment of colorectal cancer. Details: A meta-analysis of cohort studies conducted in North America and Europe suggests that there is no association between coffee intake and the incidence of colorectal cancer (97385). However, population research conducted in Japan and Korea suggests that drinking coffee is associated with a lower risk of colorectal cancer, with the greatest reduction seen in patients consuming 3 or more cups of coffee daily (9222,97384,107832,111041). In one study, risk reduction increased from 32% to 78% when adjusted for the use of coffee additives, including cream and sugar (107832). In addition, drinking coffee is associated with a reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Each additional cup daily is associated with a 5% reduced risk of cancer progression and a 7% reduced risk of death. The greatest benefits were associated with drinking at least 4 cups daily when compared with no coffee consumption (104591).
• Constipation. Although there has been interest in consuming coffee for constipation, there is insufficient reliable information about the clinical effects of coffee for this purpose.
• Dementia. It is unclear if consuming coffee is beneficial for preventing dementia. Details: One meta-analysis of observational studies including nearly 329,000 adults has found that drinking coffee is not associated with a lower risk of dementia or Alzheimer disease (100866). Conversely, other observational research has found evidence of benefit, but results are conflicting. A meta-analysis of observational studies in nearly 334,000 adults has found a reduced risk of any cognitive deficit (including mild cognitive impairment and dementia) or dementia alone in those drinking less than 2.8 or 2.3 cups of coffee daily, respectively, when compared with not drinking coffee (107829). The validity of these findings is limited by a lack of discussion of heterogeneity and variability in sensitivity analyses. An individual observational study in nearly 14,000 adults has found that coffee and caffeine consumption is associated with dose-dependent reductions in dementia risk, especially in males, and that drinking at least 3 cups of coffee daily is associated with a 50% lower risk of dementia when compared with not drinking coffee (107841). Coffee consumption has also been studied in combination with tea. An observational study has found that drinking 0.5-1 cup of coffee with at least 4 cups of tea or 2-3 cups of coffee and tea each daily is associated with a 28% to 30% reduced risk of dementia when compared with not drinking coffee and tea (107204).
• Depression. It is unclear if consuming coffee is beneficial for reducing the risk of depression. Details: Observational research has found that higher coffee consumption is associated with a 24% lower risk of depression when compared with lower coffee consumption. Drinking 400-600 mL of coffee daily is associated with 16% lower risk of depression when compared with not consuming coffee (100863).
• Endometrial cancer. It is unclear if consuming coffee is beneficial for the prevention of endometrial cancer; the available research is conflicting. Details: One meta-analysis of prospective cohort studies suggests that drinking coffee is associated with a dose-dependent reduction in the risk of endometrial cancer. Increasing coffee consumption by 4 cups daily is associated with a 20% reduction in endometrial cancer risk (97381). Another meta-analysis of population research suggests that the highest intake of caffeinated coffee, but not decaffeinated coffee, is associated with a 34% reduced risk of endometrial cancer when compared with the lowest. A sub-analysis suggests that this association is limited to individuals with a high body mass index (111036). In contrast, earlier meta-analyses and one large prospective cohort study conducted in the United Kingdom suggests that drinking coffee is not associated with a reduced risk of endometrial cancer in general; however, there may be some protection in obese females drinking at least 2 cups of caffeinated coffee daily (93873,97381,97382).
• Fractures. It is unclear if consuming coffee is beneficial for fracture prevention. Details: Multiple meta-analyses of observational research suggest that the highest intake of coffee is not associated with a difference in the odds of fracture when compared with the lowest intake. However, any association may be dependent on the dose of coffee and/or the location of research (111034,112734). A dose-response analysis in one meta-analysis suggests that consuming 0.5 to 4 cups daily, but not higher amounts, is associated with a small reduction in the incidence of hip fracture when compared with no coffee consumption. Additional sub-analyses suggest that while the highest coffee consumption was associated with a 25% reduced risk of fracture in studies conducted in Europe and North America, the opposite is true in studies conducted in Asia where the risk is increased by 37% (111034).
• Gallbladder disease. Population research suggests that consuming coffee may reduce the risk of developing symptomatic gallstone disease. Details: Population research has found that the consumption of caffeinated beverages, including coffee, that provide at least 400 mg of caffeine (two or more cups of coffee) daily is associated with a significantly reduced risk of developing symptomatic gallstone disease (3345,8032). The effect seems to be dose-dependent; consumption of 800 mg caffeine (four or more cups of coffee) daily is associated with the greatest reduction in risk (3345).
• Gastric cancer. It is unclear if consuming coffee reduces the risk of gastric cancer. Details: Overall, meta-analyses of observational research suggest that coffee consumption does not affect gastric cancer risk. However, subgroup analyses of patients living in the United States suggest that consuming coffee is associated with an increased risk of gastric cancer (100873,111038). One sub-analysis suggests that consuming 6.5 or more cups of coffee daily was associated with a 36% greater risk of gastric cancer (100873).
• Gout. It is unclear if consuming coffee is beneficial for preventing gout. Details: Epidemiological research has found that the risk of developing gout over a 12-year period is 40% lower in males aged 40-75 years who drink 4-5 cups of caffeinated coffee daily, compared with those who don't drink coffee. In people who drink 6 cups or more daily, the risk of developing gout is 59% lower. Drinking decaffeinated coffee is also associated with a reduced risk of developing gout, but the risk reduction is more modest than with caffeinated coffee (15540).
• Headache. Although caffeine is an established treatment for certain types of headache, there is insufficient reliable information about the clinical effects of coffee, specifically, for this purpose.
• Hearing loss. It is unclear if consuming coffee is beneficial for hearing loss. Details: Population research has found that consuming at least one cup of coffee daily is associated with a reduced risk of hearing impairment in males, but not females, when compared with less than one cup of coffee daily. In males, each additional cup consumed daily was associated with a 15% lower risk of hearing impairment (104592).
• Hepatitis B. It is unclear if consuming coffee is beneficial for hepatitis B. Details: Population research in patients being treated for chronic hepatitis B suggests that drinking at least 3 cups of coffee a day is associated with a reduced risk of having liver fibrosis when compared to not consuming coffee. However, this association was not present in untreated patients (111044). This study is limited by its cross-sectional design and use of blood markers, rather than the gold standard liver biopsy, for diagnosing fibrosis.
• Hyperlipidemia. It is unclear if consuming caffeinated coffee is beneficial for hyperlipidemia. Details: A meta-analysis of small, randomized, controlled trials shows that consuming caffeinated coffee for up to about 11 weeks reduces total cholesterol by 8 mg/dL, low-density lipoprotein (LDL) cholesterol by 5 mg/dL, and triglycerides by 13 mg/dL when compared with a control group. These effects appear to be dose-dependent, with the greatest reduction observed in individuals consuming 6-8 cups of coffee daily. Every additional cup of caffeinated coffee consumed daily is associated with a 3-4 mg/dL additional reduction in total and LDL cholesterol and a 6-7 mg/dL additional reduction in triglyceride levels. Decaffeinated coffee had no effect on any markers of cholesterol (97370). However, population research has found that coffee consumption is associated with slightly higher total cholesterol, LDL cholesterol, and triglyceride levels when compared with no coffee consumption (104590).
• Hypertension. Epidemiologic research suggests that consuming coffee reduces the risk of developing hypertension. Details: Some epidemiological research suggests that coffee consumption might reduce the risk of developing hypertension. A meta-analysis of epidemiologic research suggests that long-term coffee intake is associated with a modest 9% reduction in the risk of developing hypertension. However, smoking may diminish any potential benefit (97372). This analysis did not investigate the likelihood of a dose-response relationship and did not adjust for smoking status. Another epidemiologic study in a Brazilian population that did adjust for sociodemographic factors such as smoking suggests that drinking 1-3 cups of coffee daily is associated with a reduced risk of hypertension by about 18% when compared with never or almost never drinking coffee. Drinking more than 3 cups of coffee did not impact risk (103993). However, this study defined 1 cup of coffee as 50 mL; it is unclear how this intake compares with typical use in other countries. The best evidence comes from a meta-analysis of observational research which suggests that coffee intake was not associated with hypertension risk. However, coffee intake was associated with a modest reduction in hypertension risk in studies conducted in the United States (111037). In patients with hypertension, a meta-analysis of epidemiologic research suggests that habitual coffee intake is not associated with the risk of developing CVD (105312). However, other prospective population research in patients with severe hypertension, but not mild hypertension, suggests that drinking at least two cups of coffee daily is associated with a 2-fold increase in CVD mortality compared with non-coffee drinkers (111027).
• Hypotension. It is unclear if consuming caffeinated coffee is beneficial in older adults with postprandial hypotension. Details: Preliminary clinical research in older adults with postprandial hypotension shows that consuming caffeinated beverages like coffee seems to increase blood pressure (11835).
• Irritable bowel syndrome (IBS). It is unclear if consuming coffee is beneficial for preventing IBS. Details: A meta-analysis of mostly small, low-quality, observational and population research suggests that coffee consumption is associated with a modestly lower odds of developing IBS when compared with no coffee consumption. However, the validity of this result is limited by high heterogeneity (112739).
• Kidney failure. It is unclear if consuming coffee is beneficial for preventing progression to kidney failure or reducing the risk of chronic kidney disease (CKD)-related death. Details: A small meta-analysis of population research has found that coffee consumption is associated with an 18% reduced incidence of progression from CKD to kidney failure. Coffee consumption is also associated with a reduced risk of CKD-related death, with at least 4 cups daily providing the most benefit when compared with not drinking coffee (104586). This analysis is limited by the heterogeneous definitions of CKD and kidney failure in the individual studies, as well as the comparisons of coffee consumption.
• Liver cancer. It is unclear if consuming coffee reduces the risk of liver cancer. Details: A meta-analysis of observational research in approximately 2.5 million adults in Asia, North America, and Europe suggests that consuming at least 1 cup of coffee daily is associated with a 27% to 48% reduced risk of liver cancer (111016). An earlier meta-analysis of observational research suggests that regular coffee consumption is associated with a 31% lower risk of hepatocellular carcinoma when compared with no consumption. Higher coffee consumption seems to have a greater preventative effect when compared with lower coffee consumption (103989).
• Liver disease. It is unclear if consuming coffee reduces the risk of chronic liver disease. Details: Observational research has found that regular coffee consumption is associated with a 38% lower risk of chronic liver disease when compared with no consumption. Higher coffee consumption seems to have a greater preventative effect when compared with lower coffee consumption (100862).
• Lung cancer. It is unclear if consuming caffeinated coffee reduces the risk of lung cancer; the available research is conflicting. Details: Epidemiological research has found that males who consume a higher amount of dietary phytoestrogens, such as the lignan precursors found in coffee and tea, have up to a 27% lower risk of developing lung cancer when compared with those who consume smaller amounts (13190). However, conflicting evidence suggests that people who consume 2-4 or more cups of caffeinated coffee daily have a significantly increased risk of developing lung cancer (13191,90177). But drinking decaffeinated coffee seems to be associated with a decreased risk of lung cancer (13191).
• Melanoma. It is unclear if consuming coffee reduces the risk of malignant melanoma. Details: Population research has found that high coffee intake is associated with a 19% to 25% reduction in the risk of malignant melanoma when compared with low consumption. However, after adjusting for confounders, most data show no significant reduction. Drinking decaffeinated coffee is not associated with a reduced incidence of malignant melanoma (97378,97379).
• Metabolic syndrome. It unclear if consuming decaffeinated coffee is beneficial in patients with metabolic syndrome. Details: A meta-analysis of mostly small randomized controlled studies in patients with metabolic syndrome shows that consumption of decaffeinated coffee modestly reduces systolic and diastolic blood pressure when compared with control. The validity of these findings is limited by the high heterogeneity and small size of the included studies (107830).
• Nonalcoholic fatty liver disease (NAFLD). Observational research suggests that consuming coffee may reduce the risk of NAFLD. Observational and clinical research on liver fibrosis is conflicting. Details: A meta-analysis of observational research in over 50,000 patients has found that drinking 1-2 cups of coffee daily does not affect NAFLD incidence when compared with drinking less than 1 cup of coffee. However, drinking more than 3 cups of coffee daily was associated with a reduced risk of NAFLD when compared with less than 2 cups daily (103990). Other observational research has found a reduced risk of NAFLD and/or fibrosis in those who drink coffee when compared with those who do not drink coffee (100872,107831). However, the validity of these findings is limited by a relatively small population size and the lack of dose-response analyses. Two of the primary bioactive constituents of coffee, caffeine and chlorogenic acid, also have been evaluated. A small study in patients with NAFLD and type 2 diabetes shows that taking caffeine 200 mg and/or chlorogenic acid 200 mg for 6 months has no effect on the reduction of hepatic fat and fibrosis when compared with placebo (107835).
• Nonmelanoma skin cancer. It is unclear if consuming caffeinated coffee reduces the risk of nonmelanoma skin cancer. Details: Population research has found that the highest intake of coffee or caffeine is associated with an 18% reduction in nonmelanoma skin cancer risk when compared with the lowest intake. However, the benefit appears to be limited to the incidence of basal cell carcinoma. Drinking decaffeinated coffee is not associated with a reduced incidence of nonmelanoma skin cancer. The effect, if any, appears to be due to caffeine rather than coffee (97380).
• Obesity. It is unclear if consuming coffee is beneficial for weight loss in patients who are overweight or obese; the available research is conflicting. Details: Some clinical research in males who are overweight or obese and are receiving dietary counseling shows that taking coffee mannooligosaccharides 2 grams twice daily for 12 weeks reduces body weight by 6%, compared with 2.3% with placebo. The product also reduces body fat in males, but not females (93877). Additional clinical research in patients with pre-obesity shows that drinking a dark roast coffee 500 mL daily, enriched with N-methylpyridinium ions, for 4 weeks results in weight loss of 3.5%, compared with 0% with a light roast coffee enriched in chlorogenic acids. The dark roast coffee appears to reduce caloric intake (93874). However, other clinical research in adults who are overweight or obese shows that drinking caffeinated or decaffeinated coffee 885 mL daily for 8 weeks does not appear to improve glycemic control or reduce weight (93879).
• Osteoporosis. It is unclear if consuming coffee is beneficial for osteoporosis prevention. Details: A meta-analysis of observational research suggests that the highest coffee consumption is associated with a 21% reduced odds of osteoporosis when compared with the lowest (111034).
• Pancreatitis. It is unclear if consuming coffee reduces the risk of pancreatitis. Details: Observational research has found that drinking three or more cups of coffee daily is associated with a 22% lower risk of pancreatitis when compared with drinking less coffee (100871).
• Pharyngeal cancer. It is unclear if consuming coffee reduces the risk of pharyngeal cancer. Details: Observational research has found that high coffee consumption is associated with a 28% reduced odds of pharyngeal cancer when compared with low coffee consumption (100869).
• Pregnancy-induced hypertension. It is unclear if consuming coffee reduces the risk of pregnancy-induced hypertension. Details: A large prospective cohort study in pregnant patients in Japan has found that the highest total caffeine intake is associated with a 26% increased risk of pregnancy-induced hypertension when compared with no intake, but that a higher coffee intake (at least 2 cups daily) is associated with a 21% reduced risk of pregnancy-induced hypertension when compared with no intake, even when adjusted for total caffeine intake (107827). The validity of these findings may be limited by the fact that detailed information on proteinuria and hypertension were unavailable.
• Pneumonia. It is unclear if consuming coffee is beneficial for reducing the risk of pneumonia. Details: A case-control study in elderly patients has found a 50% reduced risk of pneumonia in those consuming 2 or more cups of coffee daily over the past month (107840). The validity of this finding may be limited by differences in the baseline characteristics between the matched control subjects and the cases, specifically the higher prevalence of hypertension and diabetes in the control group.
• Prostate cancer. Population research has found that coffee consumption is associated with a modestly reduced risk of prostate cancer. Details: Although some individual studies disagree (107834), population research has found that the highest coffee consumption is associated with a small reduction in the risk of prostate cancer when compared with the lowest consumption (97383,97384,104587). Sub-analyses show that coffee consumption is associated with a 7% reduced risk of localized, but not advanced or fatal, prostate cancer (97383,97384,104587).
• Stroke. It is unclear if coffee consumption, alone or in combination with tea, is beneficial for stroke, post-stroke dementia, all-cause mortality, or stroke-related mortality. The available research is conflicting. Details: Several meta-analyses of population research in patients with and without cardiovascular disease (CVD) have found no association between coffee consumption and risk of stroke (104597,104882). However, another meta-analysis of population research and an individual observational study have found that coffee consumption (e.g., 2-3 cups of coffee daily) is associated with an 8% to 12% reduced risk of stroke, especially ischemic stroke, when compared with no consumption (107204,107828). The validity of the findings from the meta-analysis is limited by the lack of a dose-response analysis. Additionally, this analysis found that consumption of 2-3 cups of coffee daily is associated with a 20% reduced risk of post-stroke dementia when compared with not drinking coffee (107204). The consumption of coffee in combination with tea has also been evaluated. An observational study has found that consumption of 2-3 cups daily each of coffee and tea, including black tea, is associated with a 32% reduced risk of stroke when compared with not drinking coffee and tea. Additionally, consumption of 0.5-1 cup of coffee and 2-3 cups of tea, including black tea, daily is associated with a 50% reduced risk of post-stroke dementia when compared with not drinking coffee and tea (107204). Coffee consumption has also been evaluated for its effects on stroke-related and all-cause mortality. One observational study has found that consumption of 1-2 cups of coffee daily is associated with a 50% reduced risk of stroke-related mortality (107822). However, another observational study in patients with a history of stroke has found no association between coffee consumption and all-cause mortality (107839).
• Thyroid cancer. It is unclear if consuming coffee reduces the risk of thyroid cancer. Details: Population research has found that high coffee consumption is associated with a 25% lower risk of thyroid cancer when compared with low consumption. Every additional cup of coffee was associated with a 5% reduction in risk (103996). More evidence is needed to rate coffee for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Crohn disease. Observational research over a period of 24-28 days in a small group of patients with active inflammatory bowel disease (50% ulcerative colitis and 50% Crohn disease) suggests that taking a specific combination product containing coffee charcoal 50 mg, myrrh 100 mg, and chamomile extract 70 mg per tablet (MYRRHINIL-INTEST, Repha GmbH) results in symptom resolution in 16-26 days. The probability of being free of symptoms did not differ between patients using other treatments, the coffee charcoal product alone, or a combination of the coffee charcoal product with other treatments. Overall efficacy was rated as good to very good by patients and physicians (104593). The effect of coffee charcoal alone is unclear.
• Diarrhea. Observational research over a period of 7-14 days in a group of patients with active diarrhea related to an acute inflammatory disorder suggests that taking a specific combination product containing coffee charcoal 50 mg, myrrh 100 mg, and chamomile extract 70 mg per tablet (MYRRHINIL-INTEST, Repha GmbH), alone or in combination with other therapies, improves overall symptoms of diarrhea. The median time to symptom resolution was 4 days. The probability of symptom resolution with use of the coffee charcoal combination product was similar to that observed when other treatments were used. Overall efficacy was rated as good to very good by patients and physicians (104593). The effect of coffee charcoal alone is unclear.
• Irritable bowel syndrome (IBS). Observational research over a period of 24-28 days in a group of patients with IBS suggests that taking a specific combination product containing coffee charcoal 50 mg, myrrh 100 mg, and chamomile extract 70 mg per tablet (MYRRHINIL-INTEST, Repha GmbH), alone or in combination with other therapies, improves overall symptoms of diarrhea. The probability of being free of symptoms did not differ between patients using other treatments or when the coffee charcoal combination product was used in combination with other treatments. Overall efficacy was rated as good to very good by patients and physicians (104593). The effect of coffee charcoal alone is unclear.
• Ulcerative colitis. Preliminary clinical research shows that taking a specific combination product containing coffee charcoal 50 mg, myrrh 100 mg, and chamomile extract 70 mg per tablet (MYRRHINIL-INTEST, Repha GmbH) four tablets three times daily for 12 months is non-inferior to mesalamine therapy for maintaining remission in patients with inactive ulcerative colitis (93653). In addition, observational research over a period of 24-28 days in a small group of patients with active inflammatory bowel disease (50% ulcerative colitis and 50% Crohn disease) suggests that taking this same product results in symptom resolution in 16-26 days. The probability of being free of symptoms did not differ between patients using other treatments, the coffee charcoal product alone, or a combination of the coffee charcoal product with other treatments. Overall efficacy was rated as good to very good by physicians (104593). The effect of coffee charcoal alone is unclear. More evidence is needed to rate coffee charcoal for these uses.

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POSSIBLY EFFECTIVE

• Urinary tract infections (UTIs). Cranberry products may possibly reduce the risk of repeat, symptomatic UTI in females with recurrent UTI, in children, and in people susceptible to UTI following kidney transplant, urogenital surgery, or radiation therapy near the urogenital system. While some positive evidence exists, most research suggests that cranberry products do not seem to reduce the risk of UTI in older adults in institutions, pregnant patients, or adults with neuromuscular dysfunction of the bladder. Cranberry is not recommended for the treatment of UTI in any population. Details: Cranberry appears to reduce the risk of UTI in some populations but not others. In healthy females at an increased risk of UTI or history of recurrent UTI, meta-analyses of clinical trials show that cranberry products decrease the overall risk of recurrent or first-time UTI by 26% to 35% (46473,92578,96739,111407). In 2019, the American Urological Association published guidelines stating that, based on low certainty evidence, clinicians may offer cranberry tablets or juice as prophylaxis for females with recurrent UTIs. Due to a lack of compelling evidence for any specific product, the guidelines recommend choosing formulations based on availability and tolerability (100855). In 2020, the US Food and Drug Administration (FDA) approved qualified health claims stating that consuming cranberry juice in doses of at least 8 ounces daily, or cranberry supplements in doses of at least 500 mg daily, may help reduce the risk of recurrent UTI in healthy females. However, the FDA has concluded that there is limited scientific evidence to support these claims (103302). The benefits of cranberry for prevention of UTI during pregnancy are unclear. Subgroup analysis of meta-analyses suggest that cranberry supplementation does not reduce the risk of UTI in pregnant adults compared with placebo or no treatment (100855,111407). A preliminary clinical study shows that drinking cranberry juice 240 mL three times daily until delivery does not reduce the frequency of asymptomatic bacteriuria or symptomatic UTI during pregnancy, although the study was not adequately powered to detect a difference in these outcomes (16415). In contrast, one preliminary clinical trial shows that UTI frequency was reduced in 70.5% of those ingesting cranberry juice 250 mL four times daily, compared with only 32% of those taking placebo (93670). In children, a meta-analysis shows that taking cranberry products probably reduces the risk of subsequent symptomatic UTIs by up to 54% compared with placebo or no treatment, but does not specify a particular formulation (111407). Clinical trials show that daily consumption of cranberry syrup (Pharmatoka), cranberry juice (Cranberry UR-50, Kikkoman Company) 100 mL, cranberry-lingonberry juice 50 mL, and cranberry extract (Anthocran) 120 mg reduce the risk of UTI recurrence in children (46452,96733,96737,108055). In contrast, another clinical trial shows that drinking cranberry juice (Ocean Spray Cranberries, Inc) 5 mL/kg daily for 6 months does not reduce the incidence of recurrent UTI when compared with placebo, although it does decrease the total number of UTI episodes and length of antimicrobial therapy per child (46470). In older, institutionalized adults, a meta-analysis of 5 studies evaluating the effectiveness of cranberry products shows little or no benefit in preventing symptomatic, culture-verified UTIs (111407). A clinical study in females residing in long-term care (LTC) facilities shows that taking a specific cranberry supplement (Ellura, Pharmatoka) once daily for 1 year does not reduce the incidence of UTI or asymptomatic bacteriuria (92517). However, clinical trials of cranberry products in elderly patients in LTC facilities suggest that cranberry may be more effective in patients at a higher risk for UTIs, such as those with diabetes, long-term catheterization, or recurrent UTIs (90041,108055), and in patients with E. coli-related UTIs (46389,46472). In one small study, providing all patients living in a LTC facility with 4 ounces of cranberry juice or six tablets of a specific concentrated cranberry product (Azo-Cranberry, i-Health, Inc.) daily for 13 months decreased the facility's overall monthly UTI rate from 27.7 to 20.7 (46492). In another clinical trial, taking cranberry juice cocktail (Ocean Spray Cranberries, Inc) 300 mL daily for 6 months decreased the rate of asymptomatic bacteriuria plus pyuria by 13% in older females living in institutional settings (7008). In another clinical trial, taking a cranberry capsule 500 mg, standardized to 1.8% PACs, twice daily for 12 months decreased the risk of UTI by around 26% in patients at high-risk for UTI, including those with catheters, diabetes, or at least one UTI in the previous 12 months (90041). Meta-analyses and clinical research show that cranberry products do not reduce the risk of UTI associated with neurogenic bladder, neuromuscular dysfunction, or insufficient bladder emptying in adults or children (2811,6759,11980,46379,46425,46473,90044,92578,96737,108055,111407). However, one study found benefit in patients with neurogenic bladder due to spinal cord injury taking cranberry capsules (Cran-Max, Proprietary Nutritionals, Inc.) 500 mg daily (46443). Cranberry products have also been evaluated in a variety of other high-risk populations, with mixed results. A meta-analysis of 7 studies shows that cranberry products reduce the risk of UTIs in people with increased susceptibility to UTI due to an intervention (e.g., kidney transplant, radiotherapy to urogenital system, or urogenital surgery) when compared with placebo (111407). Cranberry extracts do not seem to reduce the risk of UTIs in individuals undergoing hysterectomy and/or anterior vaginal repair (46465), pelvic floor surgery (104245), or in patients with multiple sclerosis (46496,111407). Taking cranberry powder capsules (NurtiCran90, Petefa AB) 550 mg three times daily for 5 days does not reduce the UTI rate at days 5 or 14 when compared with placebo in postoperative females with hip fracture receiving a urinary catheter; however, the study was not adequately powered to detect a difference in this outcome (96734). Other preliminary clinical research in elderly males with benign prostatic hyperplasia and a recent UTI shows that taking a standardized cranberry extract (Anthocran) 120 mg daily for 60 days reduces the UTI recurrence rate by about 62% when compared with placebo (96735). Cranberry supplements have been studied in a variety of formulations, but it is unclear whether certain cranberry formulations are better than others (111407). Most positive studies utilized oral cranberry EXTRACTS in tablet, powder, or capsule form (6760,17210,46366,46432,93669,111407). Some products (Cranberry Supreme, GNC; Cranpac, IPCA Laboratories), taken as 200 mg twice daily, were standardized to provide 100-120 mg of proanthocyanidins (PACs) daily (46432). Some of these studies used capsules containing 400 mg cranberry solids twice daily (6760) or Natural Cranberry Extract (Solgar Vitamin and Herb Co.) 800 mg twice daily (17210). However, a clinical study in healthy females with a history of UTIs shows that taking a specific cranberry extract product (Urophenol; Diana Food) does not reduce the risk of symptomatic UTI when taken at a dose of 120 mg twice daily, standardized to 15% PACs, or at a dose of 1 mg twice daily, standardized to 1% PACs. A subgroup analysis suggests that the high dose may have modest benefit in those with less than 5 UTIs a year (108054). Cranberry JUICE or syrup has yielded mixed results for the prevention of UTI in patients with a history of recurrent UTIs, with some showing significant benefit (8253,46366,96736,111407). These studies used cranberry juice 240-250 mL 1-3 times daily (46366,96736), cranberry syrup, or a combination beverage containing cranberry juice plus lingonberry juice (Maija) 50 mL daily (8253). However, other studies found no significant improvement when compared with placebo (17524,46471,90047), although some of these studies may have been inadequately powered to detect a difference (17524,46471). Cranberry products have also been compared with other treatments including antibiotics and probiotics for preventing recurrent UTI, but the results are unclear. A meta-analysis suggests that cranberry products reduce the risk of symptomatic UTIs compared to probiotics. The analysis also showed no difference in the risk of UTI between cranberry products and antibiotics, but the precision of included studies was poor (111407). In one study, taking cranberry extract capsules (Cran-Max; Proprietary Nutritionals, Inc) 500 mg daily for 6 months was as effective as trimethoprim 100 mg daily in elderly females with recurrent UTI (16720). However, taking this same cranberry product twice daily for 12 months was less effective than trimethoprim-sulfamethoxazole 480 mg once daily in younger premenopausal individuals (17176). Additional research in children with vesicoureteral reflux (VUR) shows that daily consumption of cranberry products results in UTI recurrence rates equivalent to those obtained with prophylactic antibiotics. Cranberry juice (Cranberry UR-50, Kikkoman Company) 100 mL daily was equally effective to cefaclor 5-10 mg/kg daily; cranberry syrup (Pharmatoka) 0.2 mL/kg daily was equally effective to trimethoprim 0.2 mL/kg daily (96737).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral cranberry is beneficial for age-related cognitive decline. Oral cranberry may be beneficial for improving visual episodic memory in healthy, elderly adults, but its effects on other aspects of cognition are unclear. Details: A clinical study in healthy adults aged 50-80 years shows that taking a freeze-dried cranberry powder 4.5 grams twice daily (standardized to provide 281 mg proanthocyanidins daily), provided as a sachet and added to food or beverage for 12 weeks, improves visual episodic memory performance during a memory and recall test (Rey Complex Figure Test), but does not appear to affect other measures such as attention, orientation, fluency, language, processing speed, or short-term memory, when compared with placebo (108564). Cranberry supplementation also does not appear to affect grey matter structure; however, due to the low number of patients who completed a baseline and follow-up MRI, this study may not have been adequately powered to detect a difference between groups.
• Benign prostatic hyperplasia (BPH). Preliminary clinical research suggests that oral cranberry is beneficial for reducing BPH symptoms. Details: Preliminary clinical research shows that taking powdered dried cranberry fruit 500 mg three times daily for 6 months improves lower urinary symptoms and reduces prostate specific antigen (PSA) levels when compared with no treatment in patients 45 years of age or older with elevated PSA levels, a negative prostate biopsy, and clinically confirmed non-bacterial prostatitis (17126). Another small study in those 45 years of age and older without elevated PSA levels shows that taking a specific dried cranberry powder (Flowens, Naturex-DBS, LLC) 250-500 mg daily for 6 months reduces lower urinary tract symptoms and improves voiding and storage symptoms when compared with placebo (96738).
• Cancer. Although there has been interest in using oral cranberry for cancer, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Cardiovascular disease (CVD). Although some research suggests that oral cranberry may modestly improve some CVD risk factors, it is unclear if it is beneficial for CVD prevention. Details: A meta-analysis of 10 clinical studies shows that cranberry juice or cranberry extract seems to reduce systolic blood pressure by 3.6 mmHg and body mass index by 0.3 kg/m2 when compared with placebo. However, these improvements are unlikely to be clinically significant, and cranberry does not appear to improve diastolic blood pressure, lipid levels, glycemic control, or waist circumference (102849). The generalizability of these results is limited, as the study populations ranged from healthy adults to those with type 2 diabetes, metabolic syndrome, or coronary heart disease. A clinical crossover study in patients who are overweight or obese and have elevated blood pressure shows that drinking cranberry juice 250 mL twice daily for 8 weeks reduces ambulatory diastolic blood pressure by 2 mmHg during daytime hours, but does not improve systolic blood pressure, glycemic control, or lipid levels, when compared with placebo (108059). The validity of these findings is limited due to short duration of treatment and broad heterogeneity of patient baseline characteristics.
• Catheter-related infections. Although there has been interest in using oral cranberry for catheter-related infections, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral cranberry for CFS, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Diabetes. It is unclear if oral cranberry is beneficial for diabetes. Details: A small clinical trial shows that taking cranberry supplements orally does not improve fasting serum glucose, glycated hemoglobin (HbA1C), fructosamine, triglycerides, high-density lipoprotein (HDL) cholesterol, or low-density lipoprotein (LDL) cholesterol levels in patients with type 2 diabetes (11328).
• Helicobacter pylori. There is conflicting evidence regarding the use of oral cranberry for Helicobacter pylori eradication, either as a standalone treatment or in combination with standard triple therapy. Details: Two small clinical studies show that taking cranberry juice 480-500 mL, containing 88 mg proanthocyanidins (PACs), daily in two divided doses for 2-3 months can modestly increase the H. pylori eradication rate at 8 weeks, but not at 2 weeks, when compared with placebo. However, the eradication rate was only 20% or less, which is much lower than that obtained with conventional triple therapy (46388,104248). Lower doses, as either cranberry juice or cranberry powder, do not seem to improve H. pylori eradication rates. Cranberry juice containing only 23 mg or 44 mg PACs or cranberry powder containing 36 mg or 72 mg PACs did not demonstrate benefit when compared with placebo (104248). Cranberry juice has also been studied in combination with standard triple therapy. Preliminary clinical research shows that taking cranberry juice 250 mL daily for 3 weeks along with omeprazole, amoxicillin, and clarithromycin for one week does not increase the eradication rate when compared with triple therapy plus placebo. However, the combination treatment increased the rate of H. pylori eradication when only females were considered (46439). A meta-analysis of 4 small clinical studies, including three studies already discussed, shows that taking cranberry, either as a juice or a dried powder, does not improve H. pylori eradication rate when compared with placebo, regardless of treatment duration (108060). The validity of these findings is limited by the high heterogeneity of the included studies and incomplete reporting. In asymptomatic children aged 6-16 years old with H. pylori, one clinical study shows that drinking cranberry juice 200 mL, with live or heat-killed Lactobacillus johnsonii 80 mL, daily for 3 weeks eradicates H. pylori in 15% to 22% of patients, compared with 1.5% of those receiving placebo. However, these rates are lower than those typically obtained with conventional triple therapy (46441).
• Hyperlipidemia. Oral cranberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Drinking a combination of cranberry, blueberry, apple, and chokeberry juice 300 mL daily for 6 weeks appears to decrease total cholesterol and increase high-density lipoprotein (HDL) cholesterol when compared to baseline in females with overweight or obesity and at least one risk factor for cardiovascular disease (111233). However, the validity of the study is limited by its small size, short duration, and lack of a comparator group. It is unclear if these effects are due to cranberry, other ingredients, or the combination.
• Kidney stones (nephrolithiasis). It is unclear if oral cranberry is beneficial for reducing the risk of kidney stones. Details: Although some preliminary clinical research shows that drinking cranberry juice 500 mL diluted in 1500 mL water daily for 2 weeks can decrease urinary excretion of oxalate in healthy males, which suggests a decreased risk of kidney stone formation (46371), other preliminary clinical research shows that both cranberry juice and concentrated cranberry extracts can increase urinary oxalate levels, suggesting an increased risk of stone formation (7074,46393).
• Memory. It is unclear if oral cranberry is beneficial for memory. Details: Preliminary clinical research in cognitively intact older adults shows that taking cranberry juice 16 ounces twice daily for 6 weeks does not improve memory when compared with placebo (46390).
• Metabolic syndrome. It is unclear if oral cranberry is beneficial for metabolic syndrome. Details: Preliminary clinical research shows that drinking cranberry juice 240 mL twice daily for 8 weeks can increase plasma antioxidant capacity when compared with placebo in adults with metabolic syndrome. However, cranberry juice does not appear to affect blood pressure, blood glucose, serum lipids, or markers of inflammation when compared with placebo in these patients (46467).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral cranberry is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD shows that adding cranberry extract 288 mg daily to a weight loss diet for 12 weeks does not appear to affect body weight, liver enzymes, lipid levels, or steatosis grade when compared with placebo. Cranberry extract may moderately reduce insulin levels and insulin resistance (104249). However, the clinical impact of these reductions is unclear. Another clinical trial in adults with NAFLD shows that taking dried cranberry powder 144 mg daily after lunch for 6 months improves steatosis grade as measured by ultrasound, insulin sensitivity, and levels of total cholesterol and triglycerides, but does not affect liver enzyme levels, when compared with placebo. All patients also consumed a reduced-calorie diet and an undefined dose of supplemental vitamin E (108058).
• Obesity. Oral cranberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with overweight or obesity and at least one risk factor for cardiovascular disease shows that drinking a combination of cranberry, blueberry, apple, and chokeberry juice 300 mL daily for 6 weeks does not reduce body weight, body mass index (BMI), or blood pressure but might improve total cholesterol and high-density lipoprotein (HDL) cholesterol when compared to baseline (111233). However, the validity of these findings is limited by the small study size, short duration, and lack of a comparator group. It is unclear if these effects are due to cranberry, other ingredients, or the combination.
• Overactive bladder. It is unclear if oral cranberry is beneficial for overactive bladder. Details: Preliminary clinical research in otherwise healthy females shows that taking dried cranberry powder 500 mg daily for 24 weeks can reduce daily micturition by 16% and urgency episodes by 57% when compared with placebo. Patients taking cranberry powder also reported an improvement in their own perception of their bladder condition when compared with placebo (104246). Limitations of this study include a short duration, lack of a run-in period, and high drop-out rate, which interfered with the ability to meet power.
• Periodontitis. Topical cranberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chronic periodontitis shows that applying a topical combination gel product containing cranberry extract 2.5 grams and garcinia extract after scaling and root planing reduces plaque index, gingival index, probing pocket depth, clinical attachment level, and salivary biomarkers of periodontal disease when compared with scaling and root planing alone and similarly to scaling and root planing with tetracycline fibers (112272). It is unclear if these effects are due to cranberry, garcinia, or the combination.
• Peristomal lesions. Although there has been interest in using oral cranberry for peristomal lesions, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Prostate cancer. It is unclear if cranberry is beneficial for preventing prostate cancer recurrence. Details: Clinical research shows that taking cranberry powder (Pacran, Naturex) 1500 mg for a mean of 30 days prior to radical prostatectomy for prostate cancer does not improve prostate tissue markers when compared with taking placebo. However, levels of prostate tissue antigen decreased by approximately 22% when compared with baseline (105127).
• Radiation-induced cystitis. Evidence for the use of cranberry juice in the prevention of radiation-induced cystitis is conflicting. Details:One small clinical study in individuals with prostate cancer shows that taking 200 mg of a cranberry extract standardized to 30% proanthocyanidins (Monoselect Macrocarpon; PharmExtracta) once daily during external beam radiotherapy for 6-7 weeks reduces the risk of lower UTI by 64% when compared with placebo (92579). However, other preliminary clinical research shows that taking cranberry capsules, standardized to contain a total of 72 mg proanthocyanidins, daily during radiation treatment for prostate cancer and for two weeks post-treatment, does not improve pain, burning, nocturia, or urinary flow symptoms from radiation-induced cystitis when compared with a beetroot placebo (104247). Additionally, preliminary clinical research in patients receiving radiotherapy for bladder or cervical cancer shows that consuming cranberry juice 250 mL daily for 2 weeks does not seem to reduce the incidence of UTIs (46469).
• Rheumatoid arthritis (RA). It is unclear if oral cranberry is beneficial in RA. Details: A clinical study in adults with RA shows that drinking reduced-calorie cranberry juice 250 mL twice daily in addition to taking fish oil 1 gram three times daily for 90 days improves disease activity score (DAS28-CRP) when compared with no supplementation. However, this combination was similarly effective to patients taking fish oil alone, suggesting that any benefits may be due to fish oil, as opposed to cranberry juice (108057). In contrast, another small study in adults with RA shows that drinking reduced-calorie cranberry juice 500 mL daily for 90 days does not improve disease activity score or clinically relevant biologic markers of RA such as rheumatoid factor, anti-cyclic citrullinated peptide antibodies, erythrocyte sedimentation rate, or C-reactive protein when compared with a control group (112273).
• Upper respiratory tract infection (URTI). It is unclear if oral cranberry is beneficial for the prevention or treatment of URTIs. Details: Clinical research shows that drinking a cranberry juice beverage 450 mL daily for 70 days does not decrease the incidence of cold or flu, but may reduce cold and flu symptoms, when compared with placebo in healthy adults (90046).
• Urinary odor. It is unclear if oral cranberry is beneficial for urinary odor. Details: Preliminary clinical research shows that cranberry juice cocktail might reduce urinary odors when given orally on a regular basis to patients with urinary incontinence (3333,3334,8254). Cranberry juice cocktail up to 237 mL three times daily for up to 4 weeks has been used (3334). More evidence is needed to rate cranberry for these uses.

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POSSIBLY EFFECTIVE

• Influenza. Although some small clinical studies show that elderberry extracts can improve influenza symptoms in otherwise healthy adults, a small clinical study enrolling adults and children with or without high risk medical conditions shows it does not reduce the duration of symptoms. Details: Small clinical studies in otherwise healthy adults with influenza presenting within 48 hours of symptom onset show that taking elderberry extract syrup (Sambucol, Nature's Way) 15 mL four times daily for 5 days improves patient ratings of symptoms such as aches and pains, cough, and nasal congestion an average of 4 days earlier than in control groups. It also reduced the use of rescue medications (5260,12235). Another small clinical study in adults shows that taking an elderberry extract lozenge (ViraBLOC, HerbalScience) 175 mg four times daily for 2 days, starting within 24 hours of symptom onset, improves flu-like symptoms, typically within 48 hours, when compared with placebo (17022). However, in a small clinical study in children and adults 5 years and older with influenza, including those with high-risk conditions such as asthma, chronic lung disease, and heart disease, using Sambucol for 5 days starting within 48 hours of symptom onset did not reduce the time to complete resolution of symptoms for a 24-hour period when compared with placebo (103831). These negative findings may be due to the age and baseline health status of the enrolled patients, as well as the use of symptom resolution, as opposed to symptom improvement, as the primary outcome. Elderberry has also been evaluated in combination with echinacea for treating influenza symptoms (95650), but it is not clear whether the combination is better than either ingredient alone.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there is interest in using oral elderberry for allergic rhinitis, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Asthenopia (eye strain). Oral elderberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults without dry eye disease with occupations requiring the use of video display terminals shows that taking a specific combination product containing elderberry fruit extract 300 mg, zinc 10 mg, L-carnitine 50 mg, currant 100 mg, and Eleutherococcus root 50 mg (Meramirt CM) once daily for 1 month improves measures of eye strain and contrast sensitivity when compared to baseline. Improvements in these measures were lacking in the control group (111295). Statistical comparison between the two groups was not reported. It is unclear if these effects are due to elderberry, other ingredients, or the combination.
• Cardiovascular disease (CVD). It is unclear whether elderberry has any benefit in CVD. In one small study it did not alter disease markers. Details: Preliminary clinical research in postmenopausal women shows that taking elderberry extract 500 mg daily for 12 weeks does not significantly improve markers of CVD, including inflammatory biomarkers, vascular activity, or plasma lipid or glucose levels, when compared with placebo (21141).
• Chronic obstructive pulmonary disease (COPD). Elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in men aged 40-70 years with a history of smoking and Stage 2 COPD, shows that a combination of elderberry 165 mg, heart's ease herb 165 mg, and calendula flowers 165 mg (Inflaminat, INAT-Farma), 3 capsules daily for 6 months modestly improves the score on the 5-point breathlessness, cough, and sputum scale (BCSS) and modestly increases the mean forced expiratory volume in 1 second (FEV1), compared with no changes in the placebo group. However, the number of COPD exacerbations per month is not affected (103629). It is unclear if these effects are due to elderberry, the other ingredients, or the combination.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral elderberry for CFS, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Cognitive function. Oral elderberry extract 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 consuming a multi-ingredient beverage containing elderberry extract 50 mg, carob extract, green tea powder, and guarana seed extract improves some measures of cognitive function such as rapid visual information processing and multitasking 120 minutes later when compared with placebo (113940). It is unclear if this effect is due to elderberry, other ingredients, or the combination.
• Common cold. Oral elderberry extract does not seem to PREVENT colds when taken prophylactically, but it may reduce the duration and severity of existing colds. Details: Clinical research in healthy adults shows that taking capsules containing elderberry extract (BerryPharma, Iprona AG) 600 mg daily for 8 days before overseas air travel, and then 900 mg daily starting 1 day before traveling and continuing for 4-5 days after arriving at the destination, does not reduce the number of colds or impact quality of life when compared with placebo. However, this product does reduce the duration of colds by about 2 days and the severity of colds by about 58% when compared with placebo (91374).
• Constipation. Oral elderberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial among airline flight crew shows that taking a specific product (ACTIVE) containing elderberry extract 70 mg and a specific probiotic formulation (SYNBIO) daily for 1 month improves constipation, stool volume and consistency, ease of defecation, intestinal regularity, flatulence, and diarrhea compared to baseline, but not when compared with placebo (112134). It is unclear if these effects are due to elderberry, the probiotics, or the combination.
• Gingivitis. Elderberry has been evaluated as a mouthwash or patch in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a mouth rinse (HM-302, Izun Pharmaceuticals) containing elderberry, echinacea, and gotu kola 15 mL three times daily for 14 days might prevent worsening of gingivitis when compared with a placebo rinse. However, it only minimally improves symptoms (20069). Other preliminary clinical research shows that applying a periodontal patch (PerioPatch, Izun Pharmaceuticals) containing elderberry, echinacea, and gotu kola either as a single dose, or three times daily for 1 day then once daily for 2 days, reduces some, but not all, measures of inflammation and gingivitis when compared with no treatment (20068,20070).
• HIV/AIDS. Although there has been interest in using oral elderberry for HIV/AIDS, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Hyperlipidemia. It is unclear if elderberry is beneficial for the treatment of hyperlipidemia. Details: One preliminary clinical study in patients with hyperlipidemia shows that taking capsules containing spray-dried elderberry 400 mg, providing 10% anthocyanins, three times daily for 2 weeks does not reduce serum lipids when compared with placebo (21142).
• Lower respiratory tract infections. Oral elderberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children aged 2-6 years with recurrent respiratory tract infections shows that adding a specific combination product (Stimunex gocce) containing elderberry extract, beta-glucans, zinc, and vitamin D3 to standard therapy does not reduce the number or duration of lower respiratory tract infections when compared with standard therapy alone. In the four months after treatment completion, the number of infections was reduced by about 50%; however, the total number of infections in each group was small. The dose was 1 drop/kg daily for one month, followed by 1 drop/kg daily for 15 consecutive days each month for the next three months (109212). The validity of this study is limited by lack of blinding.
• Obesity. Elderberry has been studied for weight loss in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in overweight adults shows that replacing all meals for 8 days with a kit containing elderberry juice (from 120 grams of elderberries/day), dried elderberry (225 mg/day), dried elderflower (3.9 grams/day), elderflower extract (600 mg/day), and dried asparagus (40.5 grams/day), while also taking psyllium 2-3 teaspoons daily for 2 weeks, is associated with a mean decrease in body weight of 3.2 kg over 14 days when compared with baseline (94939). The validity of this study is limited by the lack of a comparator group. Also, it is unclear whether this effect is due to elderberry, other ingredients, the combination, or fasting from regular food.
• Psychological well-being. Oral elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial among airline flight crew shows that taking a specific product (ACTIVE) containing elderberry extract 70 mg and a specific probiotic formulation (SYNBIO) daily for 1 month improves scores on the Psychological General Well Being Index when compared with placebo. The index measures symptoms of anxiety and depression, general health status, and feelings of vitality and general self-control (112134). It is unclear if these effects are due to elderberry, the probiotics, or the combination.
• Respiratory tract infections. Oral elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children aged 2-6 years with recurrent respiratory tract infections shows that adding a specific combination product (Stimunex gocce) containing elderberry extract, beta-glucans, zinc, and vitamin D3 to standard therapy reduces the duration of respiratory tract infections by about 1.7 days and modestly improves parent-perceived symptom severity when compared with standard therapy alone. However, there was no effect on the number of total, upper, or lower respiratory tract infections, the use of antibiotics or antipyretics, or the number of days missed from school. The product was dosed as 1 drop/kg daily for one month, followed by 1 drop/kg daily for 15 consecutive days each month for the next three months (109212). The validity of this study is limited by lack of blinding.
• Rhinosinusitis. Although there has been interest in using oral elderberry for rhinosinusitis, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Upper respiratory tract infection (URTI). Oral elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children aged 2-6 years with recurrent respiratory tract infections shows that adding a specific combination product (Stimunex gocce) containing elderberry extract, beta-glucans, zinc, and vitamin D3 to standard therapy does not reduce the number or duration of upper respiratory tract infections when compared with standard therapy alone. At four months after treatment completion, the number of infections was reduced by about 44%; however, the total number of infections in both groups was small. The product was dosed as 1 drop/kg daily for one month, followed by 1 drop/kg daily for 15 consecutive days each month for the next three months (109212). The validity of this study is limited by lack of blinding. More evidence is needed to rate elderberry for these uses.

(Read more about ELDERBERRY)

POSSIBLY EFFECTIVE

• Constipation. Oral flaxseed is a bulk forming laxative that helps to relieve constipation. Details: Flaxseed is a source of dietary fiber and has a bulk forming laxative effect (6803,12910). One clinical study in healthy young adults shows that consuming muffins containing 25 grams of milled flaxseed twice daily for 4 weeks increases weekly bowel movements by 30% when compared to a control group (6803). Other clinical research in diabetic patients with constipation shows that taking flaxseed 10 grams twice daily for 12 weeks improves stool form and reduces constipation by a moderate amount when compared with placebo (101950). Furthermore, a small clinical study in patients in China with functional constipation shows that consuming brown flaxseed flour 50 grams in divided doses with meals daily for 4 weeks seems to modestly improve frequency of bowel movements and pain and reduce failure to evacuate when compared with taking lactulose 15 mL every morning (105474). Flaxseed has also been evaluated in combination with other natural ingredients. A preliminary clinical trial in elderly patients with mild constipation shows that eating yogurt containing galacto-oligosaccharide syrup (Elixor, Borculo Whey Products) 6 grams, prunes 6 grams, and flaxseed 3 grams twice daily for 3 weeks increases stool frequency when compared with a control yogurt (21191). It is unclear if the effects were due to flaxseed, other constituents, or the combination.
• Diabetes. Oral ground flaxseed modestly reduces blood glucose in patients with diabetes and pre-diabetes. It is unclear if oral whole flaxseed reduces blood glucose. Details: Most evidence from meta-analyses and clinical research in adults with prediabetes and diabetes shows that taking ground flaxseed reduces fasting blood glucose and insulin levels (21194,21196,26479,101950,111061). A meta-analysis of 7 small to moderate clinical trials shows that taking flaxseed, usually ground, 13 to 40 grams daily for 8-12 weeks has a small beneficial effect on fasting blood glucose, insulin, insulin resistance, and glycated hemoglobin (HbA1c), compared with no intervention or another fiber source. A sub-analysis shows that the benefit of flaxseed on fasting glucose levels remains in patients with type 2 diabetes (111061). Other research disagrees. A meta-analysis of three small clinical trials in patients with type 2 diabetes shows that taking flaxseed does not improve fasting blood glucose, insulin resistance, or HbA1c (111062). Another meta-analysis of 24 clinical studies involving 1,879 patients with and without diabetes shows that whole and ground flaxseed seem to reduce blood glucose levels by an average of 6 mg/dL and insulin levels by an average of 1 mIU/mL and modestly reduce insulin resistance when compared with control treatments such as wheat germ or raw rice. Whole and ground flaxseed were not shown to significantly reduce HbA1c when compared with control, although there was a non-significant trend towards a reduction (96428). Significant heterogeneity in study size and study population limit the validity of these findings. The effects of flaxseed lignan extract in patients with type 2 diabetes is unclear. A small clinical study in Chinese adults with type 2 diabetes show that using a specific standardized flaxseed lignan extract (Flax Essence, Jarrow Formulas) 600 mg three times daily, providing 360 mg secoisolariciresinol diglucoside, slightly reduces HbA1c when compared with placebo (16768). However, a small meta-analysis including this study shows that taking flaxseed lignans does not reduce fasting blood glucose or HbA1c (111062).
• Hypercholesterolemia. Oral whole and ground flaxseed modestly reduce lipid levels. Details: Most research shows that taking various flaxseed preparations 30-50 grams daily reduces total cholesterol by 5% to 15% and low-density lipoprotein (LDL) cholesterol by 8% to 18%, but does not seem to affect high-density lipoprotein (HDL) cholesterol, when compared with control (6808,10952,22179,26478,65866,101944,101947,101949,108044,108046)(111064). Apolipoprotein A-1 and apolipoprotein B may be reduced by 6% and 7.5%, respectively (10952). A meta-analysis of clinical studies shows reductions in apolipoprotein A and apolipoprotein B following whole flaxseed supplementation (108046). The cholesterol-lowering effect of flaxseed has been shown in various populations, including those with hypercholesterolemia with/or without diabetes, postmenopausal patients, and patients with chronic kidney disease or cardiovascular risk factors (6808,10952,10978,12910,22180,22181,26478,26480,26488,101944)(101949,101950,111064). One large meta-analysis suggests that the most consistent effect occurs in patients with hypercholesterolemia (101947). Another large meta-analysis suggests that patients with hypercholesterolemia and healthy patients with a body mass index greater than 25 kg/m2 may benefit the most from treatment (108044). Most research shows that flaxseed reduces triglyceride levels (101947,108046,111064). However, there are certain preparations, such as partially defatted flaxseed (which lacks alpha-linolenic acid content) or flaxseed incorporated into bread products, which might increase triglyceride levels by up to 26% (6808,26488).
• Hypertension. Daily oral flaxseed consumption, especially for longer than 12 weeks, seems to modestly reduce blood pressure. Details: Meta-analyses of mainly small clinical studies in patients with and without hypertension show that taking flaxseed reduces systolic and diastolic blood pressure by an average of 1.1 to 1.8 and 1.0 to 1.3 mmHg, respectively, when compared with control (96426,111063). The effect of flaxseed lignan is unclear. One meta-analysis shows that flaxseed lignan does not seem to reduce blood pressure when compared with control (96426). However, a more recent meta-analysis shows that taking flaxseed lignan has a small effect on systolic, but not diastolic, blood pressure (111063). The length of supplementation may play a role as studies lasting longer than 12 weeks seemed to lower blood pressure to a slightly greater degree than studies lasting less than 12 weeks (96426). The validity of these findings is limited due to the short duration of treatment, the variation in study size, the inclusion of patients with and without hypertension, and the range of doses used. Some clinical research also shows that taking flaxseed may be beneficial for blood pressure reduction in patients with hypertension (111063). One individual clinical study in adults with hypertension shows that taking flaxseed 10 grams or 30 grams daily affects blood pressure in a dose-dependent manner when compared with placebo. After 12 weeks of treatment, systolic and diastolic blood pressure decreased by 12 mmHg and 6 mmHg, respectively, in the high-dose group, compared with 10 mmHg and 7 mmHg, respectively, in the low-dose group (108043).
• Mastalgia. Oral flaxseed seems to reduce symptoms of cyclic mastalgia. Details: Clinical research in healthy Iranian women with cyclic mastalgia shows that taking flaxseed powder 25 grams daily for 2 months reduces breast pain intensity from moderate to mild and also reduces duration of pain when compared with placebo (96250). Other preliminary clinical research shows that eating a muffin containing ground flaxseed 25 grams daily for 3 months reduces symptoms of severe cyclic mastalgia (16766).
• Obesity. Oral flaxseed and flaxseed mucilage seem to modestly improve weight loss in patients who are obese or overweight. However, flaxseed lignan extract does not seem to be beneficial. Details: A meta-analysis of 45 clinical studies including 2,561 overweight or obese adults shows that flaxseed consumption reduces body weight by 1.8 kg, body mass index (BMI) by 0.6 kg/m2, and waist circumference by 1.2 cm when compared with control in adults. The most benefit is seen in adults with a baseline BMI greater than or equal to 27 (96427). Flaxseed consumption of at least 30 grams daily for durations of at least 12 weeks demonstrated the greatest efficacy (96427,101949). The soluble fiber, flaxseed mucilage, has also been studied. A clinical trial in overweight or obese adults shows that taking oral flaxseed mucilage 1280 or 2560 mg mixed in water twice daily with meals for 12 weeks decreases body weight, waist circumference, and BMI in a dose-dependent manner when compared with placebo. After 12 weeks, a 5 kg and 4 kg weight reduction was observed in the high- and low-dose groups, respectively, compared to a 1 kg reduction in the placebo group (108047). The validity of this finding is limited due to short duration of treatment and lack of follow-up. Conversely, flaxseed lignan extract does not appear to be effective in reducing weight, BMI, or waist circumference (96427). Some research has investigated whether variants in genes related to satiety and appetite play a role in any effect of flaxseed on weight loss and appetite. A small clinical trial in adults with overweight or obesity shows that taking defatted flaxseed flour in biscuits daily for 8 weeks modestly reduces body weight, BMI, triglycerides, or blood glucose only in those with specific gene variants when compared with control biscuits (111066). More information is needed to determine how these gene variants play a role in the connection between nutrition and obesity.
• Systemic lupus erythematosus (SLE) nephritis. Oral flaxseed might be beneficial for improving kidney function in SLE. Details: Some small clinical studies suggest that taking whole or ground flaxseed orally might improve serum creatinine levels in people with SLE nephritis (6802,8021).

POSSIBLY INEFFECTIVE

• Osteoporosis. Oral flaxseed does not seem to be beneficial in osteoporosis. Details: Clinical research shows that consuming ground flaxseed 40 grams daily for up to one year does not affect markers of bone metabolism or improve bone mineral density in healthy, postmenopausal adults (10952,12910). Similarly, taking flaxseed extract 550 mg three times daily for 6 months does not appear to improve bone mineral density when compared with placebo in older adults (21197).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral flaxseed for acne, there is insufficient reliable information about the clinical effects of flaxseed for this purpose.
• Benign prostatic hyperplasia (BPH). It is unclear if oral flaxseed lignan improves symptoms of BPH. Details: A small clinical study in patients with BPH shows that taking a specific flaxseed lignan extract (BeneFlax, Archer Daniels Midland Co.) 300 mg or 600 mg daily for 4 months improves lower urinary tract symptom scores when compared with placebo. Additionally, the 600 mg dose was associated with improved quality of life when compared with placebo (21193).
• Breast cancer. It is unclear if oral flaxseed reduces the risk for breast cancer or the progression of breast cancer. Details: A small clinical study in females newly diagnosed with breast cancer shows that consuming a muffin containing ground flaxseed 25 grams daily for about 40 days reduces markers of tumor cell proliferation when compared with baseline, but not when compared with placebo (16765). The effect of flaxseed intake on breast cancer outcomes was not assessed. Dietary lignans, which occur in flaxseed, have been linked with a lower risk of developing breast cancer. Most large-scale population studies have found that high intake of dietary lignans and serum levels of the lignan enterolactone are associated with a reduced risk of developing breast cancer (16775,16776,16777,16779,16781,16782,16783,16785). It is unclear if flaxseed lignan, specifically, is beneficial for reducing the risk of breast cancer.
• Burning mouth syndrome. Flaxseed has only been evaluated in a mouthwash in combination with German chamomile; its effect when used alone is unclear. Details: A small clinical study in female patients with burning mouth syndrome shows that using a homemade mouthwash containing boiled whole flaxseed 10 grams and German chamomile 1 gram in 200 mL of water 3-4 times daily for 3 months decreases subjective burning and dry mouth symptoms, increases salivary flow rate, and decreases saliva viscosity when compared with baseline (104807). However, the validity of these results is limited by the lack of a control group and product standardization, as the mouthwash was prepared by each patient from ingredients they purchased.
• Cardiovascular disease (CVD). It is unclear if oral flaxseed or flaxseed lignans reduce the development or progression of CVD. Details: A small clinical study in older adults that were also given dietary advice shows that taking flaxseed 30 grams daily for 12 weeks, starting 4 weeks after percutaneous coronary intervention (PCI), more than doubles flow mediated dilation when compared with a group not taking flaxseed (101945). However, population research has found that total dietary intake of lignans, including flaxseed lignans, is not associated with a reduced risk of coronary heart disease or all-cause mortality (16787). This research did not specifically assess the effect of flaxseed intake on CVD.
• Chronic kidney disease (CKD). Although there is interest in using oral flaxseed for CKD, there is insufficient reliable information about the clinical effects of flaxseed for this condition.
• Colorectal cancer. It is unclear if oral flaxseed reduces the risk of colorectal cancer. Details: Flaxseed is one source of dietary lignans. Population research has found that serum levels of lignans are not associated with risk of developing colorectal cancer (16778). However, other population research has found that high dietary intake of lignans is associated with a reduced risk of colorectal cancer (16784), and that higher serum levels of dietary lignans are associated with a reduced risk of colorectal adenomas (16788). It is unclear if flaxseed lignan, specifically, is beneficial for reducing the risk of colorectal cancer.
• Endometrial cancer. It is unclear if oral flaxseed reduces the risk of endometrial cancer. Details: Flaxseed is one source of dietary lignans. A large-scale population study has found that serum levels of lignans are not associated with risk of developing endometrial cancer (16786).This research did not specifically assess the effect of flaxseed intake on endometrial cancer risk.
• Fatigue. It is unclear if oral ground flaxseed reduces fatigue in overweight children. Details: A small non-blinded clinical study in overweight healthy children ages 7-18 shows that consuming ground flaxseed 20 grams in divided doses with food daily for 4 weeks seems to modestly reduce mental fatigue but not physical fatigue when compared with puffed wheat 25 grams daily (105473).
• Impaired glucose tolerance (prediabetes). It is unclear if oral flaxseed is beneficial in prediabetes. Details: A small clinical study in adults with prediabetes shows that consuming milled flaxseed 20 grams or 40 grams daily for 12 weeks does not improve glycemic control, but modestly reduces systolic blood pressure, when compared with no intervention (96434).
• Irritable bowel syndrome (IBS). It is unclear if oral flaxseed improves IBS symptoms. Details: A small open-label clinical study in patients with IBS suggests that consuming whole or ground flaxseed 24 grams daily for 4 weeks does not improve quality of life, severity of IBS symptoms, or number of bowel movements when compared with no intervention (21198).
• Lung cancer. It is unclear if oral flaxseed reduces the risk of lung cancer. Details: Observational research has found that consuming a higher amount of dietary phytoestrogens, such as the lignan metabolites and precursors found in flaxseed, is associated with a lower risk of developing lung cancer when compared to those who consume smaller amounts (13190). It is unclear if flaxseed, specifically, is beneficial for reducing the risk of lung cancer.
• Menopausal symptoms. There is contradictory evidence about the effects of flaxseed for reducing menopausal symptoms. Details: Some preliminary clinical research in postmenopausal adults shows that taking either flaxseed meal 90 grams daily or a specific flaxseed extract (Biogalenica, Medicinal Compounding Pharmacy) 1000 mg daily for 6 months reduces menopausal symptoms and the frequency of hot flashes when compared to baseline (21200). Other small clinical studies in postmenopausal adults show that consuming ground flaxseed orally 40 grams daily reduces symptoms of hot flashes by about 35% and night sweats by about 44% when compared to baseline (10978,12910). However, similar reductions have been observed with placebos, such as wheat germ (12910,18224). Higher quality studies of flaxseed used in food products have yielded negative results. One clinical trial in postmenopausal adults shows that taking a specific flaxseed-containing bar (Glambia Nutritionals) providing 7 grams of flaxseed and 410 mg of lignans reduces hot flash frequency by 28% and hot flash scores by 50% when compared to baseline, but not when compared with placebo (18224). In another small clinical study, consuming muffins containing flaxseed 25 grams daily providing 50 mg lignans did not improve hot flashes or measures of quality of life when compared with placebo in a similar patient population (16762). Eating flaxseed-enriched bread providing 25 grams of flaxseed daily for 12 weeks also did not improve menopausal symptoms or reduce the frequency of hot flashes when compared to control (22176).
• Metabolic syndrome. Small studies suggest that oral flaxseed is beneficial for metabolic syndrome. Details: One small clinical study in older adults shows that taking a specific flaxseed lignan extract (BeneFlax, Archer Daniels Midland Co.) 550 mg three times daily for 6 months reduces metabolic syndrome risk scores when compared with placebo in males, but not females (21197). Another small open-label clinical trial in patients with metabolic syndrome suggests that taking flaxseed powder 30 grams daily for 12 weeks modestly reduces the number of people meeting the criteria for metabolic syndrome when compared with no supplementation (105276). However, food containing flaxseed does not seem to be as beneficial. Some clinical research in Asian Americans with metabolic syndrome shows that eating bread containing flaxseed 30 grams daily plus lifestyle counseling for 12 weeks does not improve markers of metabolic syndrome when compared with lifestyle counseling alone (21199).
• Nonalcoholic fatty liver disease (NAFLD). Small clinical studies suggest that oral flaxseed may modestly reduce markers of liver disease progression in patients with NAFLD. Details: A small clinical pilot study in adults with NAFLD shows that taking brown milled flaxseed 30 grams daily for 12 weeks along with lifestyle modification reduces fibrosis by 21% and steatosis by about 15.3%, compared with reductions of 9.7% and 5.5%, respectively, in those following lifestyle modifications alone (96249). A larger follow-up clinical study in patients with NAFLD shows that taking brown milled flaxseed 30 grams daily for 12 weeks in addition to lifestyle modification reduces steatosis by about 28%, compared with a 16% reduction in the lifestyle modification group (105275).
• Osteoarthritis. It is unclear if topical flaxseed is beneficial in patients with osteoarthritis. Details: A small clinical study in patients with hand osteoarthritis who are using routine treatments shows that using a flaxseed poultice compress once daily for 7 days improves pain by 63% and hand function by 66% when compared with a hot compress or no compress in combination with routine treatments. Some of the benefit was maintained for at least a week following treatment (101946).
• Peripheral arterial disease (PAD). It is unclear if oral flaxseed is beneficial in patients with PAD. Details: Clinical research in patients with PAD shows that taking milled flaxseed 30 grams daily mixed with a variety of foods for one year does not reduce the incidence of cardiac arrhythmias or improve the distance walked until claudication when compared with placebo (101942). This study may have been inadequately powered to detect differences between groups.
• Pharyngitis. Although there is interest in using oral flaxseed for pharyngitis, there is insufficient reliable information about the clinical effects of flaxseed for this purpose.
• Polycystic ovary syndrome (PCOS). It is unclear if oral flaxseed is beneficial in patients with PCOS. Details: A small open-label clinical study in patients with PCOS shows that taking flaxseed 30 grams daily for 12 weeks in conjunction with receiving lifestyle modification advice reduces triglyceride and insulin levels and improves insulin resistance when compared with lifestyle modification advice alone. About 69% of those in the treatment group who had irregular menstrual cycles at baseline had a regular cycle at the end of treatment, compared with no significant improvement in the control group. Flaxseed did not affect body weight, low-density lipoprotein (LDL) cholesterol, or blood glucose when compared with control (101943).
• Prostate cancer. Small clinical studies suggest that oral flaxseed may modestly improve biomarkers of prostate cancer. Details: A very small clinical trial in patients with prostatic intraepithelial neoplasia (PIN), a precancerous proliferation of prostatic epithelial cells, shows that adding ground flaxseed (Alena, Enreco) 30 grams daily to a fat-restricted diet for 6 months lowers prostate specific antigen (PSA) levels and slows prostate epithelium proliferation when compared with baseline (12908). This finding is limited by the lack of a placebo group. A clinical study in patients with prostate cancer awaiting prostatectomy shows that taking ground flaxseed (Alena, Enreco) 30 grams daily with or without a fat-restricted diet for about 30 days reduces tissue proliferation rate, but does not reduce PSA, when compared with control (16761).
• Radiation-induced pneumonitis. It is unclear if oral flaxseed is beneficial for preventing radiation-induced pneumonitis in patients with non-small cell lung cancer (NSCLC). Details: A very small, clinical trial in adults with locally advanced or metastatic NSCLC currently undergoing chemoradiation therapy shows that taking ground flaxseed (Golden Valley Flax; Hylden Farms) 40 grams daily, starting one week prior to radiotherapy and continuing until completion of treatment, may reduce the risk of radiation-induced pneumonitis when compared with baseline, with only 1 patient (5%) developing a grade ≥3 event and no cases of grade 2 events (108042). The validity of these findings is limited by the lack of a comparator group and a low adherence rate due to tolerability issues.
• Rheumatoid arthritis (RA). It is unclear if oral flaxseed is beneficial in patents with RA. Details: A clinical study in adults with RA shows that following either a regular or anti-inflammatory diet supplemented with oral flaxseed 30 grams daily for 12 weeks improves disease activity score 28-joint (DAS28-ESR), as well as pain and quality of life outcomes, such as emotional well-being and vitality, when compared with baseline (108048). The validity of these findings is limited by the lack of a comparator group.
• Ulcerative colitis. It is unclear if oral flaxseed is beneficial in patients with ulcerative colitis. Details: A small open-label clinical study in patients with ulcerative colitis shows that taking ground flaxseed 30 grams daily for 12 weeks seems to modestly reduce inflammatory markers and disease severity and improve quality of life when compared with control (101941). A nonblinded, clinical study in adults with mild to moderate ulcerative colitis shows that taking brown milled flaxseed 15 grams twice daily for 12 weeks improves disease severity scores when compared with placebo (108045). The validity of these findings is limited by the lack of blinding and short duration of treatment. More evidence is needed to rate flaxseed for these uses.

(Read more about FLAXSEED)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Constipation. Small clinical studies suggest that oral FOS may modestly improve symptoms in patients with constipation when used in combination with probiotics. The benefits of FOS when used alone are unclear. Details: Most clinical research has evaluated the use of FOS for constipation in conjunction with probiotics. Preliminary clinical research in adults with chronic functional constipation shows that taking an unspecified dose of a specific product (Hexbio) consisting of FOS, Lactobacillus acidophilus, Lacticaseibacillus casei, Lactococcus lactis, Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium infantis orally twice daily for 7 days increases defecation frequency by 3-fold when compared with placebo. Taking this product also improved patient reported symptoms of straining, lumpy hard stools, and incomplete evacuation sensations (90266). Other clinical research in adult females with constipation shows that taking a different product (Lactofos, SKL Functional Nutrition Ltda.) containing FOS 6 grams and Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus acidophilus, and Bifidobacterium lactis 0.1-1 billion colony-forming units each, orally twice daily for 30 days, modestly increases the frequency of evacuation and decreases constipation severity when compared with placebo (90300). It is unclear if these effects are due to FOS, other ingredients, or the combination. In children aged 4-8 years with functional constipation, preliminary clinical research shows that taking a mixture of FOS 0.45 grams and polydextrose 4.17 grams orally daily for 45 days improves the weekly frequency of bowel movements, clinical manifestations of constipation, and quality of stool type when compared with baseline (106482). It is unclear if these effects are due to FOS, polydextrose, or the combination. Additionally, the validity of these findings is limited by the lack of a comparator group. Clinical research evaluating the use of FOS alone is limited. Preliminary clinical research in elderly males shows that taking FOS alone 3-10 grams daily for 30 days increases the frequency of defecation by 1.5-fold when compared with baseline (8505). The validity of this study is limited by the lack of a comparator group. In non-breastfeeding infants 6-24 months of age with constipation, preliminary clinical research shows that fortifying formula or milk with FOS daily for 4 weeks increases the frequency of soft stools by 33% and decreases the frequency of straining by 55% when compared with placebo. However, the use of FOS did not increase the percentage of infants who achieved normal bowel pattern. The daily dose of FOS was 6 grams for infants 6-8.9 kg, 9 grams for infants 9-11.9 kg, and 12 grams for infants over 12 kg (98651).
• Diabetes. Oral FOS has only been evaluated in combination with probiotics; its effect when used alone is unclear. Details: Preliminary clinical research in adults with type 2 diabetes shows that taking a combination product containing FOS 500 mg, Bacillus coagulans 100 billion spores, Lacticaseibacillus rhamnosus 10 billion colony-forming units (CFUs), and Lactobacillus acidophilus 1 billion CFUs once daily for 12 weeks reduces fasting blood glucose by 17 mg/dL, compared with an increase of 3 mg/dL with placebo. However, taking this product did not affect body weight, waist circumference, or cholesterol levels. It is unclear if this effect is due to FOS, other ingredients, or the combination (107731).
• Hematopoietic stem cell transplant (HSCT). It is unclear if oral FOS is beneficial in patients undergoing HSCT. Details: Preliminary clinical research in patients undergoing an allogeneic HSCT shows that taking a specific oral FOS supplement, (Fibrulose F97, Cosucra Groupe) 5-15 grams daily for 21 days, beginning 5 days before transplant, does not reduce acute graft-versus-host disease, blood stream infections, or Clostridioides difficile infections or improve overall survival when compared with control (107931). However, this study may have been inadequately powered to detect a difference between groups.
• Hypercholesterolemia. Although there has been interest in using oral FOS for hypercholesterolemia, there is insufficient reliable information about the clinical effects of FOS for this purpose.
• Obesity. Although there has been interest in using oral FOS for obesity, there is insufficient reliable information about the clinical effects of FOS for this purpose.
• Osteoporosis. Oral FOS has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking a specific FOS product (NutraFlora, Ingredion Inc.) 3.2 grams plus calcium 800 mg daily for 24 months reduces the decline in total-body bone mineral density (BMD) when compared with calcium alone, but not when compared with a maltodextrin control. In a subgroup of patients with osteopenia, this combination reduced the decline in BMD in the lumbar vertebrae when compared with calcium alone or a maltodextrin control (94931).
• Travelers' diarrhea. It is unclear if oral FOS is beneficial for preventing traveler's' diarrhea. Details: Preliminary clinical research shows that taking FOS 10 grams orally daily for 4 weeks, starting 2 weeks before traveling to a medium- to high-risk destination, does not reduce the incidence of travelers' diarrhea when compared with placebo (10373). However, the study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate FOS for these uses.

(Read more about FRUCTO-OLIGOSACCHARIDES (FOS))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral goji berry reduces the risk of developing AMD. Details: A small, unblinded clinical study in healthy adults aged 45 to 65 years shows that consuming goji berries 28 grams five times a week for 90 days improves macular pigment optical density, which is a marker for AMD, when compared to baseline (110767). The validity of this finding is limited by the lack of statistical comparison to the other study group that received a supplement containing lutein and zeaxanthin.
• Cancer. Although there is interest in using oral goji for cancer, there is insufficient reliable information about the clinical effects of goji for this condition.
• Cardiovascular disease (CVD). It is unclear if oral goji improves risk factors for CVD. Details: A meta-analysis of 6 mostly small clinical studies of adults in China shows that consuming goji as polysaccharide extract or juice for 1-3 months modestly improves triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and fasting blood glucose but does not impact total cholesterol when compared with no treatment or placebo (110765). Another meta-analysis of 4 small clinical studies in adults also shows that consuming goji polysaccharide extract or goji berries for 1-4 months modestly improves triglycerides and HDL but does not impact total or LDL cholesterol when compared with placebo or healthy eating. Goji also had no impact on systolic or diastolic blood pressure, or markers of oxidative stress (110768). However, the interpretation of the findings from these meta-analyses is limited by the use of variable goji forms and doses, as well as inclusion of studies in heterogeneous patients, including healthy people, patients with diabetes, and patients with metabolic syndrome. Furthermore, most studies were conducted in China; it is unclear if these benefits can be extrapolated to other geographic locations.
• Cognitive function. It is unclear if oral goji berry improves cognition in healthy young individuals. Details: A small clinical crossover study in healthy participants 14-24 years of age shows that taking goji berry fruit water extract (BIOMIX Company) 3600 mg in 3 divided doses daily for 4 weeks might improve certain cognitive measures such as verbal learning, short-term memory, and attention when compared with baseline (105488). The validity of these findings are limited due to incomplete outcome reporting and a lack of statistical comparisons between the treatment and placebo groups.
• Cough. Although there is interest in using oral goji for cough, there is insufficient reliable information about the clinical effects of goji for this purpose.
• Depression. It is unclear if oral goji berry polysaccharide is beneficial for adolescents with subthreshold depression. Details: A small clinical study in adolescents aged approximately 15 years with subthreshold depression in China shows that taking goji berry polysaccharide extract 300 mg daily for 6 weeks modestly improves clinician-assessed depression scores (i.e. Hamilton Depression Scale, HAMD-24) but does not improve self-reported depression scores (i.e. Beck Depression Inventory) or scores assessing sleep quality, psychological distress, or anxiety when compared with placebo (110769). However, these results are from an interim analysis, which limits the interpretation of these findings. Furthermore, it is unclear if results can be extrapolated to patients in other geographic locations.
• Diabetes. It is unclear if oral goji berry polysaccharides improve glycemic control in patients with diabetes. Details: One small clinical study in patients with type 2 diabetes shows that taking goji fruit polysaccharide powder 150 mg twice daily for 3 months results in a slightly lower postprandial glucose area under the curve (AUC), but does not seem to affect insulin levels or insulin resistance, when compared with placebo. A subgroup of patients who were not taking antidiabetes medications had a greater reduction in postprandial blood glucose (92117).
• Dry eye. Although there is interest in using oral goji for dry eye, there is insufficient reliable information about the clinical effects of goji for this purpose.
• Erectile dysfunction (ED). Although there is interest in using oral goji for ED, there is insufficient reliable information about the clinical effects of goji for this condition.
• Hypertension. Although there is interest in using oral goji root bark for hypertension, there is insufficient reliable information about the clinical effects of goji for this condition.
• Obesity. It is unclear if oral goji berry juice improves weight loss. Details: Preliminary clinical research in healthy, overweight adults shows that drinking a specific goji fruit juice (GoChi, FreeLife International LLC) 120 mL daily for 14 days while following a weight loss diet and participating in an exercise program decreases waist circumference by about 4.7 cm more than exercise and diet alone. However, drinking goji berry juice along with diet and exercise does not improve body weight, body mass index, or body fat when compared with diet and exercise alone (52536).
• Quality of life. Small clinical studies suggest that oral goji berry juice may modestly improve quality of life in healthy adults. Details: Small clinical studies in healthy adults suggest that taking a specific standardized goji fruit juice (GoChi, FreeLife International LLC) 120 mL daily for 14-30 days improves subjective measures of energy levels, athletic performance, sleep quality, mental acuity, calmness, feelings of well-being, and gastrointestinal regularity when compared with placebo (17082,52532,52542). These studies were funded by the juice manufacturer.
• Sunburn. It is unclear if oral goji extract can prevent sunburn. Details: A small clinical study in healthy Japanese adults shows that taking goji extract 900 mg daily for 8 weeks reduces and accelerates resolution of erythema after exposure to a standard dose of UVB irradiation when compared with placebo (110770). All study participants were highly UV-sensitive; it is unclear whether these results can be extrapolated to individuals less sensitive to UV irradiation.
• Tinnitus. Although there is interest in using oral goji for tinnitus, there is insufficient reliable information about the clinical effects of goji for this purpose. More evidence is needed to rate goji for these uses.

(Read more about GOJI)

POSSIBLY EFFECTIVE

• Chronic venous insufficiency (CVI). Oral grape leaf extract might improve CVI symptoms. It is unknown if other grape products are beneficial for CVI. Details: Some clinical trials in patients with CVI show that taking a specific grape leaf extract, known as red vine leaf extract (AS 195, Antistax, Boehringer Ingelheim), seems to improve leg edema after 6 weeks of treatment when compared with placebo. Doses of 360 mg and 720 mg daily were both effective, but the higher dose produced a slightly greater effect. Patients also reported decreases in subjective complaints such as tired or heavy legs, tension, and tingling and pain after 2-12 weeks of treatment (2538,52985,53005,53206).

POSSIBLY INEFFECTIVE

• Allergic rhinitis (hay fever). Oral grape seed extract does not seem to improve hay fever symptoms. Details: A clinical study in patients with seasonal allergic rhinitis shows that taking grape seed extract 100 mg twice daily for 8 weeks before ragweed pollen season does not seem to decrease seasonal allergic rhinitis symptoms or antihistamine usage when compared with placebo (9182).
• Chemotherapy-induced nausea and vomiting (CINV). Drinking grape juice does not seem to improve CINV. Details: Clinical research shows that taking 4 ounces of chilled Concord grape juice 30 minutes prior to meals for a week following each of four cycles of chemotherapy does not seem to reduce CINV when compared with placebo (53175).
• Lower urinary tract symptoms (LUTS). Drinking grape juice does not seem to improve LUTS. Details: Clinical research in middle-aged and older men with LUTS shows that drinking 100% Concord grade juice 240 mL daily for 3 months does not improve symptoms when compared with placebo (96190).
• Mastalgia. Oral grape seed extract does not seem to improve mastalgia symptoms. Details: Clinical research in patients treated for early breast cancer using high-dose radiotherapy shows that taking the grape seed extract constituent proanthocyanidin 100 mg orally three times daily for 6 months does not reduce breast tissue hardness, pain, or tenderness when compared with placebo (53048).
• Obesity. Oral grape products do not seem to improve weight loss. Details: Clinical research in overweight or obese individuals shows that drinking Concord grape juice 480 mL daily for 12 weeks does not improve weight or body composition when compared to baseline (53181). Furthermore, taking grape pomace alone or in combination with schisandra fruit extract daily for 4-10 weeks does not improve body composition, abdominal fat, or body weight when compared with control (96200,99269,99270). Taking grape pomace 7-8 grams daily for 4-6 weeks seems to improve insulin resistance by about 33%, but does not affect blood lipids or blood pressure, when compared with placebo in overweight or obese adults with at least one metabolic syndrome factor (99269,99270).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral grape skin extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in adults with signs of aging skin shows that taking a specific combination product (Celergen, Laboratories-Dom) containing grape skin extract 10 mg, marine collagen peptides 570 mg, coenzyme Q10 10 mg, luteolin 10 mg, and selenium 0.05 mg, one capsule with breakfast and dinner for 2 months, might improve skin elasticity when compared with baseline. However, there was no effect on moisture or biological skin age (97930). It is not clear if these effects are due to grape skin extract, the other ingredients, or the combination.
• Age-related macular degeneration (AMD). Although there is interest in using oral grape seed for AMD, there is insufficient reliable information about the clinical effects of grape for this condition.
• Atherosclerosis. Oral grape seed extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking a specific combination product (Karinat, INAT-Farma) containing grape seed extract constituent proanthocyanidin 40 mg, garlic 100 mg, hops 160 mg, green tea 115 mg, vitamin C 30 mg, silicon 8 mg, vitamin E 6.6 mg, and beta-carotene 0.5 mg three capsules daily for 12 months might slow the progression of atherosclerosis as measured by mean carotid intima thickness when compared with placebo. However, the combination product does not seem to affect the growth of existing plaques, and it does not seem to improve lipid parameters (97929). It is not clear if these effects are due to grape seed extract, the other ingredients, or the combination.
• Athletic performance. It is unclear if oral grape products are beneficial for athletic performance. Details: A small study in elite athletes shows that taking a specific grape extract (Powergrape, Naturex SA) 400 mg daily for one month can increase total power in a jumping task when compared with placebo, but has no effect on initial power and maintenance of power (53310). Another small study in recreationally active young adults shows that drinking juice prepared from 46 grams of a freeze-dried preparation of whole grapes daily for 6 weeks prior to a running exercise test does not improve maximal oxygen uptake or work capacity during exercise when compared with placebo (91540).
• Atopic dermatitis (eczema). Topical grape products have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with atopic dermatitis shows that twice daily application with a cream containing grape polyphenols, vitamin E, and epigallocatechin gallate for 28 days does not improve symptoms or reduce the affected area based on physician assessment when compared with placebo (96196).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral grape seed for ADHD, there is insufficient reliable information about the clinical effects of grape for this condition.
• Canker sores. Although there is interest in using oral grape seed for canker sores, there is insufficient reliable information about the clinical effects of grape for this condition.
• Cardiovascular disease (CVD). It is unclear if oral grape products are beneficial for reducing CVD risk. Details: There is preliminary evidence that taking grape products, such as purple grape juice or red grape juice concentrate, might improve endothelium-dependent vasodilation, prevent low-density lipoprotein (LDL) oxidation, reduce markers of inflammation, and suppress platelet-mediated thrombosis. Theoretically, chronic ingestion of these products might reduce the risk of CVD in various patient populations, including adults with type 2 diabetes or hypercholesterolemia, those undergoing hemodialysis, and children with metabolic syndrome (8745,8746,52954,53030,53062,53106,53155,53174). However, a large meta-analysis shows that although taking grape products, including grape extract, grape juice, raisins, and grape seed extract, reduces levels of blood fats by a small amount in a mixed population of adults, these effects were not present in a subgroup of patients with CVD when compared with placebo. There was a small benefit on total cholesterol and high-density lipoprotein (HDL) cholesterol (102610).
• Cognitive function. It is unclear if oral grape products improve cognitive function. Details: Clinical research in healthy adults aged 55-75 years with no cognitive decline shows that taking a specific grape fruit extract (Cognigrape, Bionap srl) 250 mg daily for 12 weeks improves cognitive functioning by 4.5%, and overall neuropsychological status, including attention, language, and recall, by 6%, compared with no change in the placebo group (96198). Also, a preliminary clinical study in middle-aged women under moderate stress shows that drinking Concord grape juice 355 mL daily for 12 weeks improves immediate spacial memory and may improve executive function and verbal recall when compared with placebo (96195).
• Cognitive impairment. Small clinical studies suggest that oral grape products may not slow cognitive decline in older patients with cognitive impairment. Details: One very small study in in patients with mild cognitive decline shows that taking a freeze-dried grape powder 36 grams twice daily for 6 months does not improve most measures of cognitive function and memory, including immediate memory, delayed memory, speed of information processing, cognitive ability, or language, when compared with placebo (96199). Another very small study in older adults with signs of memory decline shows that drinking 100% Concord grape juice 6-9 mL/kg daily for 12 weeks does not improve delayed verbal recall or spatial memory when compared with placebo, although it does seem to moderately improve verbal learning (53166).
• Colorectal cancer. Oral grape seed extract is has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with colorectal cancer shows that taking a product containing grape seed extract, turmeric extract, fermented soybean extract, green tea extract, spirulina, and Taiwanofungus camphoratus, 1920 mg three times daily for 16 weeks during a chemotherapy regimen might modestly increase the effectiveness of treatment when compared with placebo. No patients in the treatment group experienced disease progression, compared with 15.8% (6 patients) of the placebo group. However, there was no significant effect on overall survival or the best response to treatment (96183).
• Constipation. Although there is interest in using oral grape products for constipation, there is insufficient reliable information about the clinical effects of grape for this condition.
• Dental caries. Although there is interest in using topical grape seed for dental caries, there is insufficient reliable information about the clinical effects of grape for this purpose.
• Diabetes. Oral grape extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study of males with type 2 diabetes mellitus and erectile dysfunction suggests that an oral combination product containing alpha lipoic acid, Gingko biloba, and grape extract (Blunorm Forte, Uriach S.p.A.) taken for 3 months may decrease fasting plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score both alone and when combined with avanafil when compared with baseline and placebo (110707).
• Diabetic retinopathy. It is unclear if oral grape seed extract is beneficial in patients with diabetic retinopathy. Details: A preliminary clinical study in patients with non-proliferative diabetic retinopathy shows that taking a specific grape seed proanthocyanidin extract (Entelon, Hanlim Pharm) 50 mg three times daily for 12 months reduces the severity of hard exudates when compared with calcium dobesilate or placebo. Grape seed extract had a treatment success rate 3-fold and 5.5-fold higher than those of calcium dobesilate and placebo, respectively. Treatment success was defined as a 2-grade decrease in hard exudate severity. No significant improvements in retinopathy grade or visual acuity were reported (100954). However, the study may not have been adequately powered to detect a difference in these outcomes.
• Erectile Dysfunction (ED). Oral grape extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large study of males with type 2 diabetes mellitus and erectile dysfunction suggests that a specific combination product containing alpha lipoic acid, grape extract, and gingko biloba (Blunorm Forte, Uriach S.p.A.) administered orally for three months with avanafil prior to sexual acts improves International Index of Erectile Function (IIEF) scores when compared with either product alone, placebo, and baseline, and may reduce markers of ED including high sensitivity-c-reactive protein, nitrates/nitrites, and metalloproteinases-2 and -9. These results suggest that an oral combination nutraceutical consisting of alpha lipoic acid, grape extract, and gingko biloba (Blunorm Forte, Uriach S.p.A.) may react synergistically with avanafil to enhance sexual performance in males with type 2 diabetes and erectile dysfunction. It is unclear if this effect is due to the alpha lipoic acid, grape extract, or gingko biloba, but researchers theorize that it may be due to the inhibition of phosphodiesterase-5 enzymes by grape extract (110707).
• Hemorrhoids. Although there is interest in using oral grape seed for hemorrhoids, there is insufficient reliable information about the clinical effects of grape for this purpose.
• Hypercholesterolemia. Small clinical studies suggest that oral grape products reduce cholesterol levels by a small amount. Details: A large meta-analysis of heterogeneous clinical trials shows that taking grape products, including grape extract, grape juice, raisins, or grape seed extract, for 2-54 weeks reduces levels of total and low-density lipoprotein (LDL) cholesterol, as well as triglycerides, by a small amount when compared with placebo in a mixed population of adults. In a sub-group of patients with any hyperlipidemia, the mean decreases in LDL cholesterol and triglycerides were 11 mg/dL and 14 mg/dL, respectively. There was no effect on levels of high-density lipoprotein (HDL) in the mixed population or in adults with hyperlipidemia (102610). Although some individual studies disagree, the most evidence for benefit is related to use of whole grape extract or grape seed extract. It is not clear if benefit is dependent on dose or duration of use. These results suggest a benefit of grape products in patients with hypercholesterolemia, but any benefit is likely to be small (42585,96816,102610).
• Hypertension. Some research suggests that oral grape products may modestly lower blood pressure; however, results are inconsistent. Details: Some clinical trials have shown modest benefit in patients with prehypertension, mild hypertension, or metabolic syndrome (18228,53149,96197), but conflicting results exists (91541,90079). A 2016 meta-analysis including 16 trials of 810 patients shows that when compared with placebo, grape seed extract or polyphenols reduces systolic blood pressure (SBP) and diastolic blood pressure (DBP) by about 6 mmHg and 3 mmHg, respectively, with greatest improvements observed in those with obesity or metabolic syndrome. This meta-analysis suggests that a minimum treatment duration of 8 weeks may be necessary before benefit is seen (96194). However, other research in adults with hypertension shows that taking grape seed polyphenols 1000 mg daily for 6 weeks does not alter blood pressure. Also, when grape seed polyphenols were combined with vitamin C 500 mg daily, some patients experienced an increase in blood pressure and worsening of nighttime and daytime variation in blood pressure (13162,90079). The reason for these conflicting findings is unclear but may due to patient characteristics and comorbidities. A meta-analysis of clinical research in various patient populations shows that taking grape seed extract 150-2100 mg for 2-25 weeks improves DBP and heart rate when compared with control, but does not improve SBP or flow-mediated dilation, regardless of dose, duration, sex, BMI, or health status. Additionally, subgroup analyses suggest that blood pressure effects may be greater in patients who are otherwise healthy, female, overweight, and/or under 50 years of age. Also, the use of lower doses and longer treatment durations may be associated with greater benefit (108090). The validity of these findings is limited by the high heterogeneity of included studies. A clinical study in adults with mildly elevated blood pressure shows that a specific grape seed extract (Enovita; Indena SpA) standardized to provide at least 95% oligomeric proanthocyanins, taken as 150 mg twice daily for 16 weeks, does not reduce SBP or DBP when compared with placebo. However, a subgroup analysis suggests that taking grape seed extract improves blood pressure in males, but not in females, when compared with placebo (108091). Some research has also evaluated the effects of grape juice on blood pressure. Two clinical studies in patients with hypertension show that drinking grape juice can reduce blood pressure when compared to baseline; however, another study shows that drinking grape juice does not reduce blood pressure when compared with placebo in these patients (53018,53156,53199).
• Melasma. It is unclear if oral grape seed extract is beneficial in patients with melasma. Details: A very small clinical study in Japanese females with melasma shows that taking grape seed extract (Gravinol, Kikkoman Co) containing 54 mg of proanthocyanidins three times daily for 6-11 months reduces skin hyperpigmentation when compared to pretreatment (53016). The validity of this finding is limited by the lack of a control group.
• Menopausal symptoms. It is unclear if oral grape seed extract is beneficial in patients with menopausal symptoms. Details: Preliminary clinical research in adults with at least one menopausal symptom shows that taking grape seed extract (Gravinol, Kikkoman Biochemifa Co) containing proanthocyanidin 200 mg daily for 8 weeks reduces anxiety when compared with placebo. It also reduces hot flashes and other physical symptoms when compared to baseline, but not when compared with placebo. A lower dose of proanthocyanidin 100 mg daily does not appear to improve these outcomes. Neither doses improved insomnia or depression (91542).
• Metabolic syndrome. Small studies suggest that various oral grape products might improve lipid levels and blood pressure in patients with metabolic syndrome. Details: A meta-analysis of small clinical studies in adults with type 2 diabetes or metabolic syndrome shows that taking grape products, usually grape seed or grape extract, for 4-48 weeks reduces levels of total and low-density lipoprotein (LDL) cholesterol, as well as triglycerides, by a small amount when compared with placebo. The mean decreases in LDL cholesterol and triglycerides were 2.6 mg/dL and 11 mg/dL, respectively (102610). These findings are limited by significant heterogeneity of the included research. Also, a small clinical study in overweight or obese adults, most with metabolic syndrome, shows that taking grape pomace 8 grams daily for 6 weeks improves insulin resistance by about 33%, but does not affect blood lipids, blood pressure, or fasting glucose, when compared with placebo (99270). Some grape products have also shown benefit for improving blood pressure in patients with metabolic syndrome. One small clinical crossover study in males with metabolic syndrome shows that taking 46 grams daily of a freeze-dried, dehydrated preparation of grape polyphenols (equivalent to about 250 grams of fresh grapes daily) for 30 days seems to modestly lower systolic, but not diastolic, blood pressure, and increase brachial artery flow-mediated dilation (FMD) when compared with placebo (18228). Also, a small clinical study in adolescents with metabolic syndrome suggests that drinking natural grape juice 18 mL/kg daily for one month improves FMD when compared with baseline (53174).The validity of this finding is limited by the lack of a control group. A very small clinical study in patients with metabolic syndrome shows that taking a specific grape seed extract (Meganatural BP, Polyphenolics) 150-300 mg daily for 4 weeks modestly reduces blood pressure when compared with placebo (53149). The validity of this finding is limited due to small study size and because patients in the treatment groups had higher blood pressure at baseline.
• Minor bleeding. Topical grape vine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that topically applying 4 mL of a specific product (Ankaferd blood stopper) containing grape vine, alpinia, licorice, thyme, and stinging nettle reduces bleeding, but does not improve the surgical time for episiotomy repair, when compared with saline (31010). It is unclear if this effect is due to grape vine, other ingredients, or the combination.
• Muscle soreness. It is unclear if oral grape products improve muscle soreness. Details: One small study in active young adults shows that drinking juice, prepared from 46 grams of freeze-dried whole grapes, daily for 6 weeks prior to an eccentric arm exercise test does not reduce muscle inflammation or pain at 24 or 48 hours post-exercise when compared with placebo (91540).
• Night vision. Although there is interest in using oral grape seed extract for improving night vision, there is insufficient reliable information about the clinical effects of grape for purpose.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral grape seed extract reverses fatty liver in patients with NAFLD. Details: One small clinical study in adults with NAFLD shows that taking grape seed extract 1000 mg twice daily for 3 months improves some, but not all, markers of liver damage and improves the grade of fatty liver change when compared with vitamin C supplementation (53190).
• Ocular stress. Although there is interest in using oral grape seed extract for ocular stress, there is insufficient reliable information about the clinical effects of grape for this purpose.
• Premenstrual syndrome (PMS). Although there is interest in using oral grape seed extract for PMS, there is insufficient reliable information about the clinical effects of grape for this condition.
• Wound healing. Limited research suggests that topical grape seed extract might improve wound healing. Details: A small clinical study in adults undergoing surgical removal of minor skin lesions shows that applying red grape seed extract 2% cream twice daily to the affected areas reduces the time to complete wound healing by about 6 days when compared with a placebo cream (91539). Also, preliminary clinical research in patients recovering from cesarean section shows that applying grape seed extract 5% ointment twice daily to cesarean section wounds for 14 days improves wound healing, as measured by a scoring system assessing redness, edema, ecchymosis, discharge, and wound closure, when compared with a placebo ointment. A 2.5% ointment did not improve wound healing measures when compared with placebo (100955). More evidence is needed to rate grape for these uses.

(Read more about GRAPE)

LIKELY EFFECTIVE

• Human papillomavirus (HPV). A specific green tea extract ointment (Polyphenon E ointment 15%) is approved by the US Food and Drug Administration (FDA) for treating external genital warts caused by HPV. Details: A specific green tea extract ointment (Veregen, Bradley Pharmaceuticals; Polyphenon E ointment 15%, MediGene AG) providing 150 mg of sinecatechins per gram of ointment, applied three times daily to external warts, completely clears external genital and perianal warts in 24% to 60% of patients after 10-16 weeks of treatment (15067,36438,36442,53777,53907,54018). This green tea extract is an FDA-approved prescription product (15067).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Drinking green tea seems to reduce the risk of CVD and CVD-related mortality. Details: Large-scale population research in Japan suggests that consuming at least 3-5 cups of green tea daily is associated with a reduced risk of cardiovascular mortality when compared with drinking less than 1 cup daily. This association appears to be primarily related to a decrease in risk for cerebral infarction and heart disease. This association appears to be stronger in females than in males (14498,53789,100202). Population research also suggests that drinking green tea is associated with a reduced risk of CVD. One meta-analysis suggests that drinking green tea is associated with a 28% reduced risk of CAD (54017). Another meta-analysis suggests that consuming small to moderate amounts of green tea, 1-5 cups or 300 to 1500 mL daily, is associated with an 8% to 16% reduced risk of coronary heart disease over 5 to 13 years when compared with consuming no green tea (111017). One meta-analysis suggests that a 1 cup increase in green tea consumption is associated with a 5% reduced risk of CVD mortality and a 3% reduced risk of CVD events (102728). When compared with drinking less than 1 cup of green tea daily, epidemiological research in a population at high risk of coronary artery disease (CAD) suggests that drinking more than 3 cups of green tea daily is associated with a 46% reduced odds of having CAD, especially severe CAD, as determined by a coronary angiography (104588). A sub-group analysis suggests that these odds only occurred in individuals consuming fruits more than 4 times weekly and not in individuals consuming fruits less often (104588). However, some population research suggests that any association seems to be greater for males than females (53691). Other population studies suggest that general tea consumption might protect against ischemic heart disease or death from CVD; however, many of the tea drinkers in some of these studies consumed black tea rather than green tea (8119,8120,8121,102728).
• Endometrial cancer. Drinking green tea seems to be beneficial for endometrial cancer prevention. Details: Meta-analyses of epidemiological research have found that people who drink green tea often, usually more than once daily, have a 21% to 23% reduced risk of developing endometrial cancer when compared with those who never or rarely drink green tea (53919,92409,102716). One of these meta-analyses also found that increasing green tea intake by one cup per day is associated with an 11% reduced risk of developing endometrial cancer (92409).
• Hyperlipidemia. Oral green tea seems to reduce levels of low-density lipoprotein (LDL) cholesterol by a small amount. Details: Clinical research and a meta-analysis of clinical research in people with or without hyperlipidemia shows that consuming green tea or green tea extract containing 150-2500 mg catechins daily for up to 24 weeks reduces total cholesterol by about 5-24 mg/dL and LDL cholesterol by about 2-25 mg/dL when compared with control (11308,54038,54048,90146,90161,97135,104605). There is also preliminary evidence that taking a green tea extract containing catechins 676 mg daily for 12 weeks reduces oxidation of LDL cholesterol when compared with placebo, which might lead to reduced damage to the vascular endothelium and reduced arteriosclerosis (98458). Epidemiological research has found that higher consumption of green tea, especially 10 cups daily or more, is associated with improved serum lipids in males, but not females (6403,97134).
• Ovarian cancer. Drinking green tea seems to be beneficial for ovarian cancer prevention. Details: Consuming tea, including green tea or black tea, appears to significantly lower the risk of developing ovarian cancer when compared with never or seldom consuming tea (9228,13208,90144,102716). One meta-analysis of population research suggests that the highest intake of green tea is associated with a 36% reduced risk of ovarian cancer when compared with the lowest intake (102716). Also, one prospective population study found that those who consume 2 or more cups of tea daily have a 46% lower risk of ovarian cancer when compared with those who don't regularly consume tea (13208). There also appears to be a trend that suggests higher consumption of tea or longer duration of use further reduces the risk of ovarian cancer (9228,13208). However, green tea does not appear to prevent ovarian cancer recurrence. Preliminary clinical research shows that drinking 500 mL of double-brewed green tea (DBGT), prepared with 35 grams/L of tea leaves standardized to contain approximately 640 mg/L of EGCG, daily for up to 18 months does not prevent cancer recurrence in adults with a history of advanced stage serous or endometrioid ovarian cancer (90175).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical green tea might reduce acne lesions by a small amount. It is unclear if oral green tea is beneficial for acne. Details: A meta-analysis of preliminary clinical research shows that topical application of green tea extract reduces the number of inflammatory and non-inflammatory lesions by a small amount (104609). In one small study, applying a solution containing the green tea constituent epigallocathechin-3-gallate (EGCG) 1% or 5% twice daily for 8 weeks was used (54074). However, oral green tea extract had limited or no effect in one study included in a meta-analysis (104609). Higher quality studies are needed to confirm this finding.
• Age-related cognitive decline. It is unclear if oral green tea is beneficial for cognitive decline associated with age. Details: In elderly individuals living in the community, clinical research shows that taking matcha green tea powder (Yabukita, Kyoeiseicha Co., Ltd.) 3 grams daily for 12 weeks does not improve overall measures of cognitive function when compared with placebo. However, a sub-group analysis in females found a small improvement in language, but not other measures, including memory, impulsivity, and attention (104602). Other clinical research in middle aged and older adults shows that taking green tea extract (Thea-Flan 90S, ITO EN Ltd.) providing catechins 336.4 mg daily for 12 weeks does not improve most measures of cognitive function, although there was a small effect on one measure of working memory. In addition, a single dose has a small effect on errors during an attention task (104603).
• Amyloidosis. It is unclear if oral green tea is beneficial for amyloidosis. Details: Preliminary clinical research in patients with cardiac transthyretin amyloidosis shows that drinking green tea (Green Darjeeling, FTGFOP1, Teekampagne Projektwerkstatt GmbH) 1.5-2 liters standardized to contain epigallocatechin-3-gallate (EGCG) 340 mg/L and/or taking specific capsules (Praevent-loges, Dr. Loges + Co. GmbH) containing 300 mg green tea extract standardized to contain EGCG 75 mg/capsule for 12 months protects against an increase in left ventricular wall thickness and left ventricular myocardial mass (54064).
• Anxiety. Although there has been interest in using oral green tea for anxiety, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Athletic performance. The evidence on the effects of green tea constituents for athletic performance is conflicting. Details: Some preliminary clinical research shows that taking green tea extract containing up to 572.8 mg of catechins as a beverage does not improve respiration efficiency, maximal oxygen uptake, or time trial performance in individuals undergoing endurance training when compared with beverages without catechins (53987,53991). However, other preliminary research shows that taking specific pills (Teavigo, Healthy Origins) containing epigallocatechin-3-gallate (EGCG) 135 mg/pill, taken three times daily with meals for a total dose of seven pills, improves maximal oxygen uptake but not maximum work rate or respiration efficiency, in healthy adults when compared with placebo (53944). Also, a small study in untrained adults shows that taking a single dose of green tea polyphenols 640 mg, 90 minutes before exercise, increases maximal oxygen uptake. However, the effect on athletic performance was not determined (104606).
• Beta-thalassemia. It is unclear if oral green tea is beneficial for reducing iron accumulation in beta-thalassemia. Details: A small clinical trial shows that taking green tea 3 cups daily after meals for 12 months, in addition to usual treatment with blood transfusions and deferasirox, an iron chelator, reduces levels of liver iron and serum ferritin by moderate amounts when compared with usual treatment alone. Hemoglobin values did not differ between groups. Each green tea bag contained 2 grams green tea (Lipton, Unilever Gulf) (104601).
• Bladder cancer. It is unclear if drinking green tea is beneficial for bladder cancer prevention. Details: Some epidemiological evidence suggests that drinking green tea is associated with a reduced risk of bladder cancer (1458,1459,90179). However, conflicting evidence exists. A meta-analysis of some epidemiological evidence suggests that drinking green tea is not associated with a reduced risk of bladder cancer (54077,90166,102716).
• Breast cancer. Evidence evaluating the association between green tea intake and breast cancer risk is inconsistent; any association may be dependent on genotype and menopausal status. Details: Meta-analyses of cohort and case-control studies have found that green tea intake is not associated with a reduced risk of breast cancer (98460,102716). However, some individual population studies suggests that green tea intake is associated with a reduced odds of developing breast cancer in Asian-American (14427,53866), but not Asian (13189,14426,90181), populations. Any protective effect of green tea on breast cancer risk might depend on patient genotype or menopausal status. Green tea consumption does not seem to lower breast cancer risk in Asian females with low-activity angiotensin-converting enzyme (ACE) genotype, although it does seem to decrease breast cancer risk in Asian females with high-activity ACE genotype (14430). Similarly, Asian-American females who drink green tea seem to have a lower breast cancer risk if they have low-activity catechol-O-methyltransferase (COMT) genotype. However, they do not seem to benefit if they do not have the low-activity COMT genotype (14431). Additionally, some observational research suggests that there is a link between green tea and modestly reduced breast cancer risk in pre-menopausal, but not postmenopausal, females (99788). Some research has evaluated the effect of green tea on breast cancer recurrence. Population research suggests that Asian females who have had stage I or II breast cancer who drink at least 3 cups of green tea daily seem to have reduced risk of breast cancer recurrence (3926,13189,54112). However, drinking green tea does not seem to significantly reduce the risk of recurrence of later-stage breast cancer. In April 2012, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming green tea may reduce the risk of breast cancer, although the FDA has concluded that there is very little scientific evidence to support this claim (102106).
• Cervical cancer. It is unclear if oral green tea is beneficial for cervical cancer. Details: Clinical research in adults with persistent high-risk HPV (HR HPV) infection and concomitant low-grade cervical intraepithelial neoplasia shows that taking a specific green tea extract (Polyphenon E), four capsules standardized to contain epigallocatechin-3-gallate (EGCG) 200 mg/capsule, once daily for 4 months does not affect HR HPV-positive status or histological outcomes when compared with placebo (90145).
• Cervical dysplasia. It is unclear if topical green tea is beneficial for cervical dysplasia. Details: Preliminary clinical research shows that applying a specific ointment (Polyphenon E ointment 15%, MediGene AG) containing epigallocatechin-3-gallate (EGCG) to human papilloma virus (HPV)-infected cervical lesions twice weekly and/or taking a specific green tea extract (Polyphenon E) 200 mg daily containing EGCG by mouth for 8-12 weeks can improve lesion appearance when compared with control (11310).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral green tea for CFS, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Chronic obstructive pulmonary disease (COPD). It is unclear if drinking green tea reduces the risk of COPD. Details: One prospective, observational study in older adults has found that consumption of at least 3 cups daily of tea, including green tea, oolong tea, and black tea, is associated with a 23% reduction in COPD prevalence and a 65% reduced risk of developing COPD in models adjusted for potential confounders when compared with the lowest tea consumption (107201). However, green tea was only consumed by about 19% of the population included in this study and consumption of green tea itself was not associated with a reduced risk of COPD.
• Cognitive function. It is unclear if oral green tea improves cognitive function in healthy adults. Details: A small clinical study in adults ages 50-69 years shows that taking matcha powder (Hojin no shiro, Ito En, Ltd.) 9 capsules daily for 12 weeks, providing 170 mg total catechins daily, modestly improves some measures of attention and work performance when compared with taking placebo or caffeine. However, there was no effect on other measures of these outcomes, or on verbal memory tasks, visual information processing, working memory, motor function, or facial expression recognition (107168). Another small clinical study shows that taking a single dose of the green tea constituent, epigallocathechin-3-gallate (EGCG), 135 or 270 mg does not seem to improve mood or cognitive performance in healthy adults (54059). Green tea has also been evaluated in combination with other ingredients. A small clinical study in healthy adults shows that consuming a multi-ingredient beverage containing green tea powder 50 mg, elderberry extract, carob extract, and guarana seed extract improves some measures of cognitive function such as rapid visual information processing and multitasking, but not others, 120 minutes later when compared with placebo (113940). It is unclear if this effect is due to green tea, other ingredients, or the combination.
• Cognitive impairment. It is unclear if oral green tea is beneficial for the prevention or treatment of mild cognitive impairment in elderly adults. Details: Some population research in elderly individuals has found that drinking green tea at least once per week is associated with a 53% reduced incidence of dementia or mild cognitive impairment when compared to not consuming green tea (104598). In addition, drinking at least two cups of green tea daily was associated with a 54% lower prevalence of cognitive impairment (104611). Some clinical research shows that taking two capsules of a specific combination product containing green tea extract 360 mg/capsule and L-theanine 60 mg/capsule (LGNC-07, LG Household & Health Care, Ltd) twice daily after meals for 16 weeks improves memory and attention in patients with mild cognitive impairment when compared with placebo (54019).
• Colorectal adenoma. It is unclear if oral green tea extract is beneficial for reducing colorectal adenoma recurrence. Details: A large clinical trial in patients with previously removed colorectal adenomas shows that taking green tea extract (Dr. Loges + Co. GmbH) standardized to epigallocatechin gallate (EGCG) 150 mg twice daily for 3 years does not affect the risk of developing new metachronous adenomas when compared with taking placebo (111020). However, a sub-group analysis shows that taking green tea extract results in a 10% absolute reduction in risk of adenoma formation in males, but not females (111020). Also, preliminary clinical research in patients with previously removed colorectal adenomas shows that taking green tea extract 1.5 grams daily for 12 months reduces the incidence of metachronous adenomas when compared with placebo (53816).
• Colorectal cancer. It is unclear if oral green tea is beneficial for colorectal cancer prevention. Details: Although evidence from individual population studies is mixed (9222,9223,14498,90176,90178,90181,102718), meta-analyses of population research suggest that a high intake of green tea is associated with a reduced risk of colorectal cancer (36416,102716). The highest intake of green tea is associated with a 16% reduced risk when compared with the lowest; however, the benefit appears to be specific to colon cancer, not rectal cancer (102716). When subdivided according to gender, evidence from case-control research suggests that green tea is associated with a reduced risk of colon and rectal cancer for females (54096).
• Common cold. It is unclear if oral green tea is beneficial for the common cold. Details: Preliminary clinical research shows that taking two capsules of a specific formulation (ImmuneGuard, Nutraceutical Holdings LLC) containing L-theanine (Suntheanine, Taiyo International) plus epigallocatechin gallate (Sunphenon, Taiyo International) twice daily for 3 months reduces cold or flu symptoms and duration of symptoms when compared with placebo in healthy adults (53754).
• Crohn disease. Although there has been interest in using oral green tea for Crohn disease, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Dementia. It is unclear if drinking green tea is beneficial for dementia prevention. Details: A meta-analysis of observational studies in over 20,000 adults suggests that the risk of any cognitive deficit (including mild cognitive impairment and dementia) is associated with a 6% reduction per cup of green tea consumed daily (107829). Some population research in elderly individuals suggests that drinking green tea at least once per week is associated with a 53% reduced incidence of dementia or mild cognitive impairment when compared to not consuming green tea (104598). Other population research in adults ages 40-74 years suggests that drinking at least 600 mL of green tea daily is not associated with a reduced risk of developing dementia when compared with drinking less than 60 mL daily. However, there is a modest reduction in dementia risk specifically in individuals ages 60-69 years (107164). A prospective, observational study suggests that consumption of tea, including both green and black tea, of at least 4 cups, in conjunction with 0.5-1 cups of coffee, daily is associated with a 30% reduced risk of dementia when compared with not drinking tea or coffee. Also, drinking 2-3 cups daily of both tea and coffee is associated with a 28% reduced risk of dementia when compared with not drinking tea and coffee (107204). Any association between drinking green tea specifically and developing dementia cannot be determined from this study.
• Dental plaque. It is unclear if oral or topical green tea is beneficial for reducing dental plaque. Details: A meta-analysis of clinical research shows that use of oral or topical products containing green tea modestly reduces dental plaque when compared with control products, including triclosan toothpaste, placebo, and chlorhexidine rinse. However, a sub-group analysis shows that a green tea rinse is no more effective than a chlorhexidine rinse. Green tea products in these studies included mouth rinse, paste, tea, capsules, and strips (107156). Many of these studies are limited by a lack of clear blinding. A more recent clinical study in children ages 10-14 years with plaque and gingivitis shows that using a mouthwash containing green tea extract 5% twice daily, alone or at half strength with ginger extract, for 30 days reduces plaque and gingivitis severity. The mouthwash containing the combination of green tea and ginger extract was most effective, and the green tea extract alone was at least as effective as chlorhexidine (107163).
• Depression. It is unclear if drinking green tea is beneficial for depression prevention. Details: Epidemiological research suggests that consuming green tea is associated with a reduced prevalence of depression and depressive symptoms. In Japanese adults, drinking four or more cups of green tea daily is associated with a 44% to 51% lower prevalence of mild to severe depression when compared to consuming one cup or less daily (90160,90163). A meta-analysis suggests that the highest green tea consumption is associated with a 34% reduced risk of depressive symptoms when compared with the lowest (111024). Other research in a general population of Chinese adults suggests that consuming at least 1 cup of green tea daily is associated with a 22% decreased risk of depressive symptoms over 2 years when compared with almost never consuming green tea. However, there is no association between depressive symptoms and less frequent green tea consumption in this population (111023).
• Diabetes. It is unclear if drinking green tea or taking green tea extract is beneficial for the prevention of diabetes or the improvement of glycemic control. Details: Epidemiological research has found that Japanese adults who consume 6 or more cups of green tea daily have a 33% lower risk of developing type 2 diabetes when compared to those who consume one cup or less daily. The risk reduction appears to be more pronounced in females when compared with males (14313). Also, epidemiological research has found that Chinese adults who consume at least one cup of green tea per week have a 59% to 77% lower risk of impaired fasting glucose when compared to those who consume less than one cup per week (90149). Other epidemiological research has found that consumption of any amount of green tea daily by Chinese adults is associated with an 8% reduced risk of developing type 2 diabetes when compared with never drinking green tea (107165). In contrast, some epidemiological research in Chinese adults has found that green tea consumption is associated with a 20% increased risk of developing type 2 diabetes when compared with non-green tea drinkers. A dose-response relationship was found for both the amount and duration of tea consumed (107170). Also, clinical research in patients with prediabetes shows that drinking one cup of green tea three times daily for 14 weeks does not improve fasting blood glucose or glycated hemoglobin (HbA1c) when compared to control (90174). There is inconsistent evidence regarding the effects of green tea in patients with type 2 diabetes. Epidemiological research suggests that drinking at least 4 cups of green tea daily is associated with a 40% reduction in mortality risk when compared to not drinking green tea (104589). Other epidemiological research in patients with type 2 diabetes has found that consumption of any amount of green tea daily is associated with a 10% reduction in mortality risk when compared to never drinking green tea. However, there was no association between green tea intake and the incidence of developing macrovascular or microvascular complications (107165). Meta-analyses of clinical research show that green tea extract and green tea catechins reduce fasting blood glucose when compared to control when patients with type 2 diabetes, borderline diabetes, or normal blood glucose status are evaluated together (90154,90187). However, a meta-analysis of up to 15 mainly small clinical trials involving patients with type 2 diabetes shows that taking green tea does not affect fasting blood glucose or insulin or improve insulin resistance or glucose control when compared with placebo. Most included studies used green tea or its extract in doses of 400-10,000 mg daily for 8-16 weeks (104604). Also, clinical research shows that taking green tea extract daily for up to 16 weeks does not improve blood glucose, HbA1c, or insulin when compared with placebo in patients with type 2 diabetes or borderline diabetes (37678,37781,54035). Some research has evaluated the effect of green tea on other outcomes in patients with type 2 diabetes. One meta-analysis shows that taking green tea extract modestly reduces fasting triglyceride levels when compared with control. This benefit was seen with doses of at least 800 mg daily taken for longer than 8 weeks. This dose and duration reduces levels of total cholesterol, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol levels (102715). Another meta-analysis shows that taking green tea modestly reduces body weight, body mass index (BM), and body fat. A sub-analysis shows that these benefits occur in studies lasting more than 8 weeks, using doses of up to 800 mg daily, and in patients who were overweight. There was no effect on waist circumference. Most patients included in the analysis were overweight or had obesity (104610).
• Diabetic neuropathy. It is unclear if oral green tea is beneficial for improving diabetic neuropathy symptoms. Details: Clinical research in patients with mild-to-moderate diabetic peripheral neuropathy shows that taking decaffeinated green tea extract 500 mg three times daily for 16 weeks modestly reduces neural pain and dysfunction, as well as overall symptom severity, when compared with placebo (107159).
• Down syndrome. It is unclear if oral green tea is able to alter facial morphology in children with Down syndrome.
• Down syndrome. There was no effect in children aged 4-18 years (107167). This study is limited by its observational design. The dosage, time of onset, and duration of treatment differed between individuals.
• Dry eye. It is unclear if oral green tea is beneficial for improving dry eye symptoms. Details: In patients with mild to moderate dry eye and meibomian gland dysfunction, preliminary clinical research shows that applying green tea extract into the eyes three times daily for one month, in addition to artificial tears three times daily, improves symptoms of dry eye. Symptoms of itching, burning, foreign body sensation, and redness were improved by a moderate amount over artificial tears alone (104612).
• Dysmenorrhea. It is unclear if drinking green tea is beneficial for preventing dysmenorrhea symptoms. Details: Population research has found that drinking green tea is associated with a 37% reduced odds of experiencing dysmenorrhea and a 58% reduced odds of having moderate-to-severe dysmenorrhea when compared with not drinking green tea (102729).
• Esophageal cancer. It is unclear if drinking green tea is beneficial for preventing esophageal cancer; the available research is conflicting. Details: Although some epidemiological evidence and observational studies have found that drinking green tea is associated with a reduced risk of esophageal cancer, most meta-analyses do not support this finding in a mixed group of adults (1457,36542,90169,90185,90186,102004,102716,107154). Meta-analyses of epidemiological studies suggest that drinking green tea is associated with a 54% reduction in the risk of esophageal cancer, or a 21% reduced odds per cup of green tea consumed daily, only in females (90169,90185,102004,107154). Also, some epidemiological research found that drinking green tea that is very hot is associated with an increased risk of esophageal cancer (53828). In addition, drinking decaffeinated green tea 5 mg daily for 12 months does not seem to be an effective treatment for patients diagnosed with esophageal precancerous lesions (53702).
• Fractures. It is unclear if drinking green tea reduces fracture risk. Details: Population research has found that consumption of green tea is associated with a 12% lower risk of any fracture and 20% lower risk of hip fracture when compared with no tea consumption (99800).
• Gastric cancer. Evidence evaluating an association between green tea consumption and gastric cancer risk is conflicting. Details: Most meta-analyses of epidemiological studies suggest that green tea consumption is not associated with gastric cancer risk (53767,53813,90181,102716). Although the most recent meta-analysis of epidemiological research suggests that drinking green tea regularly is associated with up to a 9% reduced risk of gastric cancer when compared with non-regular consumption, sub-analyses suggest that there is no association between gastric cancer and intake of specific amounts of green tea up to at least 3 cups daily (111025). Also, other population research suggests that drinking 10 or more cups of green tea daily is associated with a reduced risk of gastric cancer (8903,9222,9225,9226,9227), while consuming less than 10 cups daily is not consistently associated with a reduced risk (7033,9223,54090). The association between drinking green tea and gastric cancer-related mortality has also been investigated, A large-scale population study in Japan suggests that drinking 5 or more cups of green tea daily is not associated with a reduced risk of gastric cancer-related mortality when compared to drinking less than one cup daily (14498). Discrepancies might be related to the temperature of the green tea. The most recent meta-analysis suggests that intake of cold or warm green tea, and not hot green tea, is associated with a modest reduction in gastric cancer risk (111025).
• Gingivitis. It is unclear if oral or topical green tea is beneficial for gingivitis. Details: A meta-analysis of clinical research shows that use of oral or topical products containing green tea modestly reduces gingivitis and gingival bleeding when compared with control products, including triclosan toothpaste, placebo, and chlorhexidine rinse. However, a sub-group analysis shows that a green tea rinse is no more effective than a chlorhexidine rinse. Green tea products used in these studies were heterogeneous and included mouth rinse, gel, paste, tea, strips, and capsules (107156). Many of these studies are limited by a lack of clear blinding. A more recent clinical study in children ages 10-14 years with plaque and gingivitis shows that using a mouthwash containing green tea extract 5% twice daily, alone or at half-strength with ginger extract, for 30 days reduces plaque and gingivitis severity. The mouthwash containing the combination of green tea and ginger extract was most effective, and the green tea extract alone was at least as effective as chlorhexidine (107163).
• Headache. Although there has been interest in using oral green tea for headache, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Hypertension. The evidence is mixed as to whether drinking green tea reduces the risk of hypertension and whether oral green tea lowers blood pressure in patients with hypertension. Details: Some epidemiological research from China shows that drinking 120-599 mL of green tea or oolong tea daily is associated with a 46% lower risk of developing hypertension when compared with non-habitual tea drinkers; drinking more than 600 mL daily is associated with a 65% reduced risk (12518). In contrast, drinking green tea daily is associated with a 38% increased odds of having hypertension when compared with never drinking green tea in elderly Chinese males, but not females (107166). Green tea may help lower blood pressure in patients with or without hypertension; however, the evidence is mixed, and any reductions appear to be small. A meta-analysis of two clinical trials in patients with hypertension shows that drinking green tea for 4-16 weeks reduces systolic, but not diastolic, blood pressure by about 6 mmHg (104583). Meta-analyses in patients with or without hypertension, including overweight or obese adults, suggest that green tea reduces systolic and diastolic blood pressure by 1-3 mmHg (90146,90155,90161,98423,102726,111018). Some studies used green tea, made by boiling a 3 gram tea bag with 150 mL water and then waiting for 5 minutes and consuming three times daily approximately 2 hours after each meal for 4 weeks (90159), or green tea extract up to 1500 mg daily for up to 12 weeks (111018), including a specific product (Olimp Labs) 379 mg, taken daily with the morning meal for 3 months (54068).
• Hypotension. It is unclear if oral green tea is beneficial for postprandial hypotension in elderly adults. Details: Some research shows that consuming caffeinated beverages increases blood pressure in elderly people with postprandial hypotension (11834,11835). Also, preliminary clinical research shows that drinking 400 mL of green tea before lunch increases postprandial systolic and diastolic blood pressure by 15 mmHg and 6 mmHg, respectively, in older elderly people with postprandial hypotension (89482).
• Infertility. Oral green tea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with a history of problems conceiving shows that taking three capsules daily of a proprietary blend of Vitex agnus-castus extract (standardized to 0.5% agnusides), green tea extract (standardized to 50% phenols), L-arginine, vitamins E, B6, and B12, folate, iron, magnesium, zinc, and selenium (FertilityBlend, The Daily Wellness Company) for three menstrual cycles increases the rate of pregnancy at three months by 61% when compared with placebo (41479).
• Influenza. It is unclear if oral green tea is beneficial for preventing the flu. Details: A meta-analysis of five clinical trials in individuals with or without prior influenza vaccination shows that use of green tea catechins, either in capsule form or as a gargled liquid, reduces the rate of influenza infections by 33% when compared with control. Also, a meta-analysis of observational research has found that gargling with or consuming green tea containing catechins is associated with a 48% reduced risk of influenza when compared with not taking green tea catechins. More information is needed to compare the efficacy of the different forms of green tea catechins (107152). Some epidemiological research not included in this meta-analysis has found that drinking at least 5 cups of green tea weekly is associated with a 32% reduced odds of developing confirmed influenza when compared with drinking less than one cup weekly. A sub-group analysis suggests that this association is only evident in individuals who had not received the influenza vaccination (104608). Conversely, other preliminary research shows that gargling with green tea at least three times daily for 90 days does not prevent influenza in high school students when compared with water (90150). Green tea has also been evaluated in combination with theanine. One small study shows that taking a combination of green tea catechins (THEA-FLAN 90S, Ito-en Co) 378 mg standardized to 270 mg of epigallocatechin gallate (EGCG) with theanine 210 mg daily for 5 months reduces the risk of developing clinically defined influenza, but not laboratory-confirmed influenza infection, when compared with placebo (54021). Other preliminary clinical research in healthy adults shows that taking two capsules of a specific formulation (ImmuneGuard, Nutraceutical Holdings LLC) containing L-theanine (Suntheanine, Taiyo International) plus EGCG (Sunphenon, Taiyo International) twice daily for 3 months reduces the number of subjects with cold or flu symptoms and the number of days with symptoms when compared with placebo (53754).
• Japanese cedar pollinosis. It is unclear if oral green tea is beneficial for preventing Japanese cedar pollinosis symptoms. Details: In patients with Japanese cedar pollinosis, clinical research shows that drinking Benifuuki green tea drink 350 mL containing O-methylated catechin 34-40 mg daily beginning 6-10 weeks before pollen exposure until the end of pollen season can reduce nasal and ocular symptoms. Clinical research compared the "benifuuki" drink enriched in O-methylated EGCG with that of another green tea "yabukita," containing no O-methylated EGCG (53884,90156).
• Kidney stones (nephrolithiasis). It is unclear if drinking green tea prevents kidney stones. Details: Population research suggests that drinking green tea is associated with a reduced risk of having kidney stones. This risk was 22% lower in males and 16% lower in females when compared with never or former green tea drinkers (104613).
• Leukemia. It is unclear if drinking green tea is beneficial for leukemia prevention. Details: Although some large epidemiological studies suggest that drinking green tea reduces the risk of leukemia by 51% to 80% (53799,90183,102723), a meta-analysis of generally low-quality population research shows a variable association between green tea intake and risk of leukemia (102716).
• Liver cancer. It is unclear if drinking green tea is beneficial for liver cancer prevention. Details: Two meta-analyses of epidemiological research suggest that green tea consumption is associated with a reduced risk of liver cancer (97132,111016). The most recent meta-analysis in approximately 1.5 million adults in Asia, North America, and Europe suggests that the highest intake of green tea is associated with a 20% reduced risk of liver cancer when compared with the lowest. The most benefit was associated with consumption of at least 4 cups daily (111016). Another meta-analysis that included studies conducted in Japan, China, or Singapore suggests that higher green tea consumption is associated with a 12% reduced incidence of liver cancer when compared with the lowest consumption of green tea. However, the benefit appears to be limited to females; green tea consumption was not associated with a reduced risk of liver cancer in males (97132). A large epidemiological study in Chinese females also suggests that green tea consumption is associated with a reduced risk of liver cancer. Consuming a cumulative intake of 30 kg dried green tea leaves is associated with a 46% reduced risk of primary liver cancer over a median of 18 years when compared with never drinking green tea (111030). In contrast, some individual epidemiological studies suggest that green tea consumption is not associated with a reduced risk of liver cancer in Japanese individuals (90181,102716).
• Lung cancer. It is unclear if drinking green tea is beneficial for lung cancer prevention. Details: Individual observational studies and meta-analyses of population research have yielded conflicting evidence about the effects of green tea on lung cancer risk (13190,14498,53829,90177,102716). Although one meta-analysis of population research suggests that the highest intake of green tea does not reduce lung cancer risk when compared to the lowest intakes (102716), other analyses suggest that increasing green tea consumption by two cups daily is associated with an 18% decreased risk of lung cancer, and that drinking 7-10 cups of green tea daily is associated with an 18% to 33% reduced risk of lung cancer when compared with drinking less than one cup daily (53829,90177).
• Mental alertness. It is unclear if oral green tea is beneficial for mental alertness. Details: Green tea contains caffeine. Consumption of caffeinated beverages seems to prevent a decline in alertness and cognitive capacity when consumed throughout the day (4221,4224). Also, combining caffeine with glucose as an "energy drink" seems to improve mental performance better than placebo or either caffeine or glucose alone (13732). However, there is mixed evidence regarding the effects of green tea on mental alertness.
• Metabolic syndrome. It is unclear if oral green tea is beneficial for improving metabolic parameters in people with this condition. Details: Preliminary clinical research shows that taking green tea extract 1000 mg daily or drinking four cups of green tea daily for 8 weeks does not improve metabolic syndrome features, including waist circumference, blood pressure, cholesterol levels, or blood sugar in obese patients with metabolic syndrome when compared to control (53995).
• Multiple myeloma. It is unclear if drinking green tea is beneficial for multiple myeloma prevention. Details: Population research suggests that drinking at least 5 cups of green tea each day is not associated with a reduced risk of multiple myeloma when compared with never drinking green tea (102723).
• Myocardial infarction (MI). It is unclear if drinking green tea prevents MI or if drinking green tea prevents mortality in patients with a previous MI. Details: When compared with drinking less than one cup of green tea daily, epidemiological research in a population at high risk of coronary artery disease has found that drinking more than three cups of green tea daily is associated with a 49% reduced odds of having a past MI as determined by a coronary angiography. A sub-group analysis found that these odds only occurred in individuals consuming both fruits and vegetables more than four times weekly and not in individuals consuming fruits or vegetables less often (104588). In addition, observational research has found that drinking either 1-3 cups or at least 4 cups of green tea daily is associated with 19% and 32% lower odds of MI, respectively, when compared to drinking less than 1 cup daily (97134). In patients with a previous MI, drinking at least 7 cups of green tea daily is associated with a 53% reduced odds of all-cause mortality over a median of 18.5 years when compared with not drinking green tea (107160).
• Nasopharyngeal cancer. It is unclear if drinking green tea is beneficial for nasopharyngeal cancer prevention. Details: A meta-analysis of epidemiological research has found that the highest intake of green tea is associated with a 51% reduced risk of nasopharyngeal cancer when compared with the lowest intake (102716).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral green tea is beneficial for NAFLD. Details: Clinical research shows that drinking green tea 700 mL containing 1080 mg of catechins daily for 12 weeks does not affect body weight or body mass index (BMI), but does reduce body fat percentage from 34% to 32%, when compared with drinking either green tea 700 mL containing 200 mg of catechins or a control tea. Also, the liver-to-spleen attenuation ratio increased by 11% when compared with baseline (90168). Meta-analyses of four studies in patients with NAFLD show that taking green tea extract 500-1000 mg daily or green tea catechins 600 mg daily improves liver function tests when compared with placebo (98459,102720). One meta-analysis also shows that these doses improve BMI, total cholesterol, and low-density lipoprotein (LDL) cholesterol when compared with placebo (98459).
• Non-Hodgkin lymphoma. It is unclear if drinking green tea is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that drinking at least 3.5 cups of green tea daily is not associated with a reduced risk of non-Hodgkin lymphoma when compared with never drinking or drinking less than 1 cup of green tea daily (102005,102723).
• Obesity. Evidence for the use of green tea products for weight loss is conflicting. The conflicting findings may be related to the caffeine and catechin content of the studied products, as well as the physical activity level of the individual. Details: Many clinical studies show that drinking green tea or taking green tea extract that contains caffeine (about 70-200 mg) and high levels of catechins (about 576-886 mg) daily for 12-24 weeks modestly improves weight loss when compared to control in overweight individuals or patients with obesity (8114,37725,53906,90184). A meta-analysis of 25 randomized clinical trials shows that taking green tea extract containing caffeine results in an additional weight loss of 1.8 kg when compared with a control group not taking green tea extract (102719). In addition, a meta-analysis of clinical trials shows that taking green tea reduces body weight by 0.4 kg in mainly overweight individuals with type 2 diabetes (104610). Some research also shows that drinking green tea or taking green tea extract containing high levels of catechins but no caffeine reduces weight and visceral fat in overweight individuals or patients with obesity when used for up to 12 weeks (53994,54039,90184). In these clinical trials, the following doses have been used: two capsules of green tea extract daily standardized to containing 870 mg of catechins (460 mg EGCG) or 4 cups of green tea daily standardized to contain 928 mg of catechins (440 mg EGCG) for 8 weeks (53994); a specific decaffeinated green tea extract (Sunphenon 90LB, Taiyo Kagaku Ltd.) 530 mg twice daily for 6 weeks (54039); catechin-enriched green tea beverages providing 234-886 mg of catechins once or twice daily for approximately 3 months (37705,53906,90184); a specific green tea extract (AR25, Exolise, Arkopharma), taken as four capsules standardized to contain 375 mg of catechins (epigallocatechin gallate 270 mg) in two divided doses daily for 12 weeks (8114). Some research has also shown weight loss benefits of multi-ingredient products or diets containing green tea. Multi-ingredient products have included an herbal mixture of garcinia extract 650 mg, green tea extract 100 mg, coffee extract 75 mg, and banaba extract 25 mg per tablet (IQP-GC-101, InQpharm Europe Ltd.) 30 minutes before meals twice daily for 12 weeks (90137) and a specific product (Sanavita Industry, Piracicaba) containing powdered green tea (40 mg of caffeine), orange pulp, vitamin C, zinc, and selenium, taken as 20 grams in two divided doses daily for 8 weeks (90134). Drinking green tea has also been used as part of a Mediterranean diet also including Wolffia globose (109888). However, many studies show conflicting results (37715,37753,54035,98419,98420,98422). Reasons for these inconsistent findings are not entirely clear, but may relate to the use of decaffeinated green tea products, the use of green tea products containing low catechin amounts, or the presence and type of concomitant exercise. Some research shows that green tea extract containing a lower catechin amount (491 mg daily) or decaffeinated green tea products do not improve weight loss when compared with placebo in patients with obesity (37753,54035,98419). One meta-analysis of 15 clinical studies including about 1240 patients with obesity shows that using green tea products that are decaffeinated does not improve body weight, body mass index, or waist circumference when compared with control, while green tea products containing catechins 576-714 mg daily and caffeine do improve these outcomes (16892). Taking green tea after weight loss does not seem to improve weight maintenance when compared with control (14428,54076). Other clinical research shows that green tea does not improve weight loss in individuals with obesity who are already participating in exercise, such as walking and interval sprinting (37715,98420). In contrast, another small clinical study shows that taking green tea 500 mg daily for 10 weeks while participating in HIIT improves weight, body fat percentage, triglycerides, and low-density lipoprotein (LDL) cholesterol levels when compared with either green tea or HIIT alone. However, it appears that the majority of these improvements are due to participation in HIIT (100201). There is also some limited research in children. One small clinical trial in obese children ages 6-16 years shows that taking green tea providing 576 mg catechins daily for 24 weeks modestly reduces waist circumference, as well as systolic blood pressure and low-density lipoprotein (LDL) cholesterol, when compared with taking green tea providing 75 mg catechins daily. However, there were no significant difference between groups for other anthropometric measures or cardiovascular risk factors (37743). Another clinical trial in obese females ages 6-10 years who were also given diet and exercise advice shows that taking decaffeinated green tea polyphenols 400 mg daily for 12 weeks modestly reduces fat mass, but does not affect other anthropometric measures, when compared with placebo. Also, taking green tea polyphenols modestly reduces ovary volume, but has no effect on other measures of early puberty, such as breast development, uterine volume, or levels of sex hormones (107162).
• Oral cancer. It is unclear if oral green tea is beneficial for oral cancer prevention. Details: Meta-analyses of epidemiological research suggest that the highest intake of green tea is associated with a 20% to 29% reduction in risk of oral cancer when compared with the lowest intake (90180,102716). Also, preliminary clinical research in patients with high-risk oral premalignant lesions shows that taking a green tea extract 500-1000 mg/m2 three times daily after meals for 12 weeks increases the rate of clinical and histological response when compared with placebo (53936).
• Oral leukoplakia. It is unclear if drinking green tea and concomitantly applying topical green tea to lesions is beneficial for oral leukoplakia. Details: Preliminary clinical research in patients with oral leukoplakia shows that drinking 3 grams of a mixed tea product containing green tea daily for 6 months, while also topically applying a 10% mixed tea product in the mouth three times daily, reduces oral lesion size by about 38%, compared with a 3% increase in those taking placebo. It is not clear if this effect is due to green tea, the other ingredients, or the combination (4213).
• Osteopenia. It is unclear if oral green tea is beneficial for preventing osteopenia. Details: Population research suggests that drinking green tea for 10 years is associated with increased bone mineral density (8116). Other population research suggests that drinking less than one cup of green tea daily is associated with an 81% to 85% increased odds of having osteopenia when compared with drinking green tea 1-3 times daily (111026). Preliminary clinical research in postmenopausal adults with osteopenia shows that taking capsules containing green tea polyphenols 500 mg (233 mg as epigallocatechin-3-gallate or EGCG) daily, possibly while practicing tai chi 60 minutes three times weekly, for 24 weeks improves serum markers of bone turnover and muscle strength when compared to baseline (54040). However, the results from this study are limited by a lack of control group and the fact that diagnostic measures of bone health, such as T-score or Z-score, were not assessed.
• Osteoporosis. It is unclear if oral green tea is beneficial for preventing osteoporosis. Details: Population research suggests that drinking green tea for 10 years is associated with increased bone mineral density (8116). Other population research suggests that drinking less than one cup of green tea daily is associated with up to a 91% increased odds of having osteoporosis when compared with drinking green tea 1-3 times daily (111026). More recent clinical research shows that taking decaffeinated green tea extract supplying approximately 1315 mg of catechins (843 mg as EGCG) daily does not improve bone mineral density, T-score, or Z-score in postmenopausal adults (98419).
• Overall mortality. Some population research suggests that drinking green tea may reduce the risk of overall mortality by a small amount. Details: A meta-analysis of population research in Japanese adults found that drinking at least 5 cups of green tea daily is associated with reduced risk of all-cause mortality when compared with drinking less than 1 cup daily (102002). Another meta-analysis of population research found that each one cup per day increase in green tea consumption is associated with a 3% reduced risk of all-cause mortality (102728). However, more recent population research has found that although drinking green tea is associated with reduced risk of all-cause mortality in patients with a previous MI and stroke, drinking as much as 7 cups of green tea daily is not associated with a reduced odds of all-cause mortality over a median of 18.5 years in individuals with no history of stroke or MI when compared with not drinking green tea (107160).
• Pancreatic cancer. It is unclear if drinking green tea is beneficial for pancreatic cancer prevention. Details: A meta-analysis of population research suggests that the highest intake of green tea is not associated with a reduced risk of pancreatic cancer when compared with the lowest intake (102716). However, one epidemiological study suggests that drinking green tea is associated with a reduced risk of pancreatic cancer (54096).
• Parkinson disease. Although consuming caffeinated beverages might reduce the risk of developing Parkinson disease, it is unclear if oral green tea prevents or improves symptoms in people with this condition. Details: There is some evidence from large-scale epidemiological studies that the incidence of Parkinson disease decreases with increased consumption of caffeinated beverages such as coffee, tea, and cola. For men, the effects seem to be dose related. Men consuming a total of 421-2716 mg of caffeine (approximately 5-33 cups of tea) from any source daily seem to have the greatest reduction in risk. However, there seems to be a significant reduction in risk even with consumption of as little as 124-208 mg caffeine daily (approximately one to three cups tea) (6022). In females, the effects do not seem to be dose related. Moderate consumption of approximately 1-4 cups daily seems to provide the most reduction in risk (1238). It is unclear if consuming green tea is more or less effective than other caffeinated beverages for reducing Parkinson disease risk.
• Periodontitis. It is unclear if oral or topical green tea is beneficial for improving oral health or improving periodontal disease. Details: Epidemiological research has found that intake of green tea is inversely associated with symptoms of periodontal disease, including probing depth, attachment loss, and bleeding on probing (53844). A small clinical trial shows that taking green tea extract 1.55% by weight in chewable candy for 28 days appears to reduce plaque accumulation and gingival inflammation (7594). A small clinical trial in patients with chronic periodontitis shows that applying a gel containing green tea extract 1 gram/100 mL into the periodontal pocket as an adjunct to scaling improves gingivitis, periodontal disease, and clinical attachment by 7%, 112%, and 116%, respectively, when compared with placebo gel (90135). A meta-analysis of low-quality clinical research also shows that use of oral or topical products containing green tea modestly improve clinical attachment when compared with control products, including triclosan toothpaste and placebo. Green tea products included gel, paste, and tea (107156).
• Pneumonia. It is unclear if drinking green tea is beneficial for pneumonia prevention. Details: Epidemiological research in Japanese females has found that consuming green tea is associated with a lower risk of death from pneumonia when compared to those who do not drink green tea (53897). However, other epidemiological research in hospitalized elderly Japanese adults has found that there is no association between green tea consumption during the past month and prevalence of pneumonia at time of hospitalization (107161).
• Polycystic ovary syndrome (PCOS). It is unclear if oral green tea is beneficial for PCOS. Details: A meta-analysis of 4 small clinical trials shows that taking green tea modestly reduces weight in patients with PCOS when compared with placebo. However, there was no effect on other endpoints including body mass index (BMI), percent body fat, or waist or hip circumference. Three studies in the meta-analysis used green tea 1000-2000 mg/daily in tablets or capsules; the other study used green tea powder providing epigallocatechin gallate 1620 mg daily (111019). However, the included studies were small and utilized heterogeneous dosing regimens. Subsequently, a moderate-sized clinical study in patients with PCOS shows that taking green tea leaf powder, 500 mg twice daily for 1 week followed by 1500 mg daily for 3 months, improves menstrual cycle regularity, but does not reduce BMI or waist or hip circumference, when compared with metformin or placebo (114894).
• Postoperative pain. It is unclear if rinsing the mouth with green tea is beneficial for postoperative pain associated with molar removal. Details: In patients undergoing third molar extraction, a small clinical trial shows that using 15 mL of a mouthwash containing green tea extract 5 grams/100 mL twice daily, beginning the day after surgical removal of impacted molars and continuing for 7 days thereafter, reduces pain by 60% and analgesic use during the first three days when compared with using a mouthwash that does not contain green tea (90141).
• Prostate cancer. It is unclear if drinking green tea or taking green tea catechins by mouth is beneficial for prostate cancer treatment or prevention. Details: Green tea catechins have been evaluated for reducing prostate cancer risk in high-risk patients (14127,98421,102716). A meta-analysis of results from three clinical trials shows that taking green tea catechins 400-600 mg daily for 12-30 months reduces the risk of prostate cancer by approximately 62% when compared with placebo in high-risk patients (98421). However, another meta-analysis including two of these studies plus one additional does not show that taking green tea catechins reduces the incidence of prostate cancer in high-risk patients (102716). Most population research has found that drinking higher amounts of green tea is not associated with a reduced risk for prostate cancer when compared with those who never or rarely drink green tea (14128,54036,53741,53753,90153,90181,98421). However, one meta-analysis of population research found that people who drink very high amounts of green tea (7-15 cups daily) have a 19% to 44% reduced risk of prostate cancer (98421). Another population study found that higher green tea intake is associated with a reduced risk of advanced, but not overall, prostate cancer risk (53753). In April 2012, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming green tea may reduce the risk of prostate cancer, although the FDA has concluded that there is very little scientific evidence to support this claim (102106). Additionally, most clinical research shows that drinking large amounts of green tea or taking green tea extract does not reduce disease progression in patients with prostate cancer (11366,53726). Green tea and green tea catechins have also been evaluated for reducing prostate specific antigen (PSA) levels. A meta-analysis of clinical research in patients with or at risk of prostate cancer shows that taking green tea or green tea extract for 3 weeks to 12 months does not modify PSA levels when compared with water or placebo. However, sub-analyses suggest that there is significant heterogeneity with respect to findings between geographical locations, with some evidence of benefit in studies conducted in the US (107155).
• Radiation dermatitis. It is unclear if topical green tea is beneficial for preventing radiation dermatitis. Details: Preliminary clinical research in patients undergoing radiotherapy after breast cancer surgery shows that spraying epigallocatechin gallate (EGCG) over the radiation field prevents the development of at least moderate severity radiation dermatitis by 30% when compared with saline as placebo. Also, occurrence of symptoms was delayed by about 2.7 days and symptom severity was reduced. EGCG 660 mcmol/L was sprayed 3 times daily from the first day of radiation until 2 weeks after completion at 0.05 mL per squared cm (111031). The interpretation of these results is limited by the unbalanced treatment groups.
• Radiation-induced diarrhea. It is unclear if oral green tea is beneficial for reducing diarrhea associated with radiotherapy. Details: A small clinical trial shows that taking a green tea tablet (Camgreen, Iran Giahessence Pharmacy Co.) 450 mg daily for 5 weeks during pelvic irradiation reduces the frequency of diarrhea in patients undergoing radiotherapy treatment. In the fifth week of treatment, 19% of patients taking green tea had diarrhea, compared with approximately 62% of those taking placebo (104614).
• Radiation-induced nausea and vomiting. It is unclear if oral green tea is beneficial for reducing vomiting associated with radiotherapy. Details: A small clinical trial shows that taking a green tea tablet (Camgreen, Iran Giahessence Pharmacy Co.) 450 mg daily for 5 weeks during pelvic irradiation does not reduce the frequency of vomiting when compared with placebo in patients undergoing radiotherapy treatment (104614).
• Renal cell carcinoma. It is unclear if oral green tea is beneficial for preventing kidney cancer. Details: Epidemiological research suggests that green tea intake is not associated with risk of kidney cancer over a mean of 19 years in Japanese adults. However, in females, consuming at least 5 cups of green tea daily, but not lesser amounts, is associated with a 55% reduced risk of kidney cancer when compared with rare intake (111022).
• Skin cancer. Although there has been interest in using oral or topical green tea for skin cancer, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Stress. It is unclear if oral green tea is beneficial for stress reduction. Details: Preliminary clinical research shows that taking a specific brand of green tea extract (Teavigo, DSM) 300 mg orally for 7 days reduces stress and increases calmness when compared with placebo in healthy individuals (54055).
• Stretch marks (striae distensae). It is unclear if topical green tea is beneficial for stretch marks. Details: A small clinical study in young adult females shows that applying a green tea extract 3% cream to stretch marks on the leg twice daily for 8 weeks reduces stretch mark severity when compared to baseline (114893). The validity of this study is limited by the lack of a control group.
• Stroke. It is unclear if consumption of green tea is associated with a reduced risk of stroke or with reduced all-cause mortality in patients with a previous stroke. Details: Large-scale population research in Japanese individuals suggests that consuming at least 3-5 cups of green tea daily is associated with a reduced risk of cerebrovascular mortality when compared with drinking less than 1 cup daily. This association appears to be primarily related to a decrease in risk for cerebral infarction or hemorrhage (14498,54080,102002). Other population research suggests that drinking 1-3 cups of green tea daily is associated with a 36% reduced odds of stroke when compared with drinking less than 1 cup daily, while drinking 4 or more cups daily has no effect. Also, green tea consumption was not associated with reduced incidence of cerebral hemorrhage or infarction in this study (97134). Meta-analyses of population research suggest that an increase of 1 cup per day in green tea consumption is associated with a 6% reduced risk of stroke or cerebral hemorrhage (102728,111021). A prospective, observational study also suggests that higher intake of tea, including green and black tea, of at least 2 cups daily is associated with a 16% reduced risk of stroke when compared with not drinking tea. This study also found that drinking 2-3 cups daily of each tea and coffee is associated with a 38% reduced risk of stroke when compared with not drinking tea and coffee. The combination of 0.5-1 cups of coffee and 2-3 cups of tea daily, but not tea alone, was associated with a 50% reduced risk of post-stroke dementia when compared with not drinking tea and coffee (107204). In patients with a previous stroke, drinking at least 3 cups of green tea daily is associated with a 48% to 62% reduced odds of all-cause mortality over a median of 18.5 years when compared with not drinking green tea (107160).
• Sunburn. It is unclear if oral or topical green tea is beneficial for preventing ultraviolet radiation-induced erythema. Details: A meta-analysis of three small clinical trials shows that taking green tea catechins 540-1402 mg daily for 6 to 12 weeks has a small to moderate protective effect against ultraviolet radiation-induced erythema when compared with placebo, especially at lower doses of ultraviolet radiation. A single topical dose of green tea ingredients may also be beneficial, but data is limited (107153).
• Systemic lupus erythematosus (SLE). It is unclear if oral green tea is beneficial for SLE. Details: Preliminary clinical research shows that taking green tea extract 500 mg (containing 22% polyphenols) twice daily for 3 months modestly improves disease activity, general health, and vitality when compared with placebo (97136).
• Tinea pedis. It is unclear if a topical green tea footbath is beneficial for athlete's foot. Details: In bedridden, elderly patients with cognitive deficiency, use of a footbath containing a 0.1% green tea extract for 15 minutes once daily for 12 weeks does not improve symptoms of athlete's foot, but does improve skin condition, when compared with a footbath not containing green tea. The green tea extract Sunphenon BG-3 (Taiyo Kagaku Co. Ltd., Yokkaichi), prepared by dissolving 5 grams of the Sunphenon BG-3 product in 5 liters of water to create a 0.1% green tea solution, was used (90151).
• Tooth extraction. Topical green tea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, split-mouth clinical study in patients undergoing third molar extractions shows that applying a gel containing green tea extract 0.5% and hyaluronic acid into the surgical site immediately after extraction and three times daily for 7 days improves some post-operative outcomes, such as reducing exudate or facial edema when compared with placebo (114895). It is unclear if these effects are due to green tea, hyaluronic acid, or the combination.
• Ulcerative colitis. It is unclear if oral green tea is beneficial for ulcerative colitis. Details: Preliminary clinical research in patients with mild to moderate ulcerative colitis shows that taking a specific green tea product (Polyphenon E, Mitsui-Norin) 200 mg or 400 mg twice daily for 8 weeks may increase the number of people who respond to therapy and achieve remission when compared with placebo. After treatment, 10 of 15 patients in the green tea extract group responded to therapy and 8 of 15 patients achieved remission, compared with 0 in the placebo group (90140).
• Upper respiratory tract infection (URTI). It is unclear if gargling and swallowing green tea is beneficial for reducing URTI symptoms. Details: Preliminary clinical research shows that gargling and swallowing green tea (Morgentau, Ronnefeld KG) 100 mL daily over 4 days is less effective than proprietary labdanum lozenges (CYSTUS052, Dr Pandalis Urheimische Medizin GmbH & Co.) for upper respiratory tract symptoms in patients with URTIs (53867).
• Urinary tract infections (UTIs). It is unclear if oral green tea is beneficial for reducing UTI symptoms. Details: A small clinical study in females with acute uncomplicated cystitis shows that adding green tea 2000 mg daily for 3 days to treatment with trimethoprim-sulfamethoxazole reduces symptoms of cystitis when compared with placebo (99799). This study is limited by its small size and the lack of information on antibiotic resistance in each treatment group.
• Wrinkled skin. It is unclear if oral or topical green tea is beneficial for wrinkles. Details: Some preliminary clinical research shows that taking green tea catechins 175 mg twice daily for two years does not reduce signs of photo-aging of the skin in females with facial photo-aging when compared with placebo (53873). However, using a combination of topical green tea 10% cream and oral green tea extract 300 mg twice daily for 8 weeks seems to improve skin elasticity in females with moderate photo-aging based on microscopic analysis, although the clinical appearance of the skin does not seem to significantly improve (53731). Other preliminary clinical research shows that consuming one liter of a beverage with green tea polyphenols for 12 weeks improves skin elasticity, roughness, and hydration in middle-aged females when compared with placebo (54030). More evidence is needed to rate green tea for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diarrhea. Clinical research in adults with acute diarrhea shows that taking guava leaf extract (QG-5) 500 mg every 8 hours for 3 days in addition to oral rehydration therapy (ORT) does not shorten the duration of diarrhea or improve stool consistency or pain intensity when compared with ORT alone. However, there was a reduction in the number of episodes of abdominal pain after the first day of treatment (70318).
• Dysmenorrhea. Clinical research in young women with dysmenorrhea shows that taking guava leaf extract 1 mg or 2 mg three times daily for 5 days starting 24 hours before menstruation for 3 cycles does not reduce pain when compared with placebo. However, pain was reduced by a small amount in the women with the best compliance (101782).
• Gingivitis. Clinical research in patients with moderate to severe chronic gingivitis shows that using a guava leaf extract 0.15% mouth rinse twice daily with brushing for 30 days is as effective as 0.2% chlorhexidine and more effective than water for reducing gingivitis severity and microbial counts. However, using the guava leaf extract mouth rinse does not appear to improve plaque (101754).
• Hypertension. Preliminary clinical research in patients with essential hypertension shows that eating guava fruit 500-1000 grams daily in place of other foods high in saturated fat and cholesterol for 12 weeks lowers systolic blood pressure by 9.0 mmHg and diastolic blood pressure by 8.0 mmHg compared to usual diet (95562).
• Knee pain. Preliminary clinical research in patients with knee pain shows that taking guava leaf extract 1 gram daily for 12 weeks reduces pain and stiffness by a small amount when compared to placebo. There is no effect on function (101758). This study was small and might not have been adequately powered to detect differences. More evidence is needed to rate guava for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral hawthorn is beneficial in patients with angina. Details: Preliminary clinical research in patients with angina taking chronic beta-adrenergic receptor blockers or ACE inhibitor therapy shows that taking a hawthorn (Crataegus pinnatifada) extract 100 mg orally three times daily for four weeks improves angina and electrocardiogram (ECG) findings and reduces nitroglycerin intake when compared with placebo (19242). Other preliminary clinical research in patients with unstable angina shows that taking hawthorn 10 grams and hu zang 15 grams orally daily for 4 weeks does not reduce the frequency of angina pectoris attacks when compared with control. However, taking hawthorn and hu zang improved some subjective symptom scores and quality of life scores (109610).
• Anxiety. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate generalized anxiety shows that taking a specific product (Sympathyl, not available in the US) containing hawthorn, magnesium, and California poppy for 90 days modestly improves anxiety scores when compared with placebo (12583). Also, a clinical study in adults with adjustment disorder and anxious mood shows that hawthorn, in combination with black horehound, passion flower, valerian, kola nut, and guarana, modestly improves anxiety scores when compared with placebo (6250). It is unclear if these effects are due to hawthorn, other ingredients, or the combination. Another small clinical study in healthy adults shows that taking a combination of herbal extracts containing hawthorn, passionflower, ballota, and valerian root daily for 14 days reduces subjective anxiety and objective sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to hawthorn, other ingredients, or the combination.
• Arrhythmia. Although there has been interest in using oral hawthorn for arrhythmia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Atherosclerosis. Although there has been interest in using oral hawthorn for atherosclerosis, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral hawthorn for CVD, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cognitive function. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, a single dose of 25 drops of a combination product of D-camphor and hawthorn berry extract (Korodin) was superior to placebo for increasing cognitive performance in elderly female patients as measured by visuomotor speed and information processing capacity. The active treatment group showed an improvement in attentional and mental performance (19240,91504).
• Congestive heart failure (CHF). The evidence on the effects of oral hawthorn in patients with CHF is conflicting. Although some older research suggests it may be beneficial, more recent, larger studies suggest it may actually increase the risk for complications. Details: There is contradictory evidence about the effects of hawthorn extract in heart failure patients. Several clinical studies show that taking specific hawthorn leaf and flower extracts (LI 132, Faros 300, Lichtwer Pharma; WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; or HeartCare, Nature's Way) 240-600 mg daily improves ejection fraction and exercise tolerance, reduces subjective symptoms, and decreases the risk of death in patients with New York Heart Association (NYHA) stage II heart failure. In these studies, the maximum effect was usually seen after 6-12 weeks of treatment (8279,8280,11449,19221,19223,19225,19226,19227,19228). Another clinical trial shows that hawthorn extract (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals or HeartCare, Nature's Way) 1800 mg daily, combined with diuretic therapy, improves exercise tolerance and reduces subjective symptoms in NYHA stage III heart failure. In this study, maximum effect was usually seen after 16 weeks of treatment (8281). In another trial, patients with NYHA II heart failure taking either hawthorn (LI 132, Faros) 300 mg three times daily or captopril 12.5 mg three times daily experienced similar improvements in cardiac performance and symptoms (19230). However, other clinical research suggests no benefit and possible harm with hawthorn. A large-scale clinical trial (SPICE) in patients with NYHA stage II or III heart failure shows that taking specific hawthorn extracts (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; HeartCare, Nature's Way) 900 mg daily for 24 months, in combination with conventional treatment, does not decrease hospitalization due to progressive heart failure, non-fatal myocardial infarction, or cardiac death (17203). Another clinical trial in patients with NYHA stage II or III heart failure shows that taking these same specific hawthorn extracts at the same dose for up to 6 months does not slow the progression of heart failure when compared with placebo (19222). In a retrospective analysis of this study, it was shown that heart failure progression was significantly increased in patients taking hawthorn when compared with placebo. The rate of death was also increased by 1.7% over placebo, and heart failure-related hospitalizations increased by 8% over placebo in patients treated with hawthorn (16824).
• Hyperlipidemia. Although there has been interest in using oral hawthorn for hyperlipidemia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Hypertension. It is unclear if oral hawthorn is beneficial for lowering blood pressure. Details: One preliminary clinical trial showed that taking hawthorn standardized extract 1,000-2,500 mg daily for three days does not significantly reduce blood pressure in hypertensive or prehypertensive patients when compared with placebo (19244). However, another study in patients with diabetes and hypertension shows that taking a specific hawthorn extract (LI 132) 1,200mg daily for 16 weeks significantly decreased diastolic, but not systolic, blood pressure when compared with placebo (19245).
• Obesity. Although there has been interest in using oral hawthorn for obesity, there is insufficient reliable information about the clinical effects of hawthorn for this condition.
• Orthostatic hypotension. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults with orthostatic hypotension shows that taking a specific combination product containing hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen) 25 drops orally three times daily for 7 days attenuates the blood pressure reduction upon standing when compared with placebo. Signs and symptoms of orthostatic hypotension such as dizziness, blurry vision, and falls also seem to be reduced when compared with baseline (39614,39617). A meta-analysis of 4 studies shows that giving single doses of 20-25 drops of the same combination product increases systolic and diastolic blood pressure when compared with placebo (103620). However, the studies have methodologic problems and, while 2 were conducted in females with orthostatic hypotension, the others involved health young adults or normotensive elderly subjects. The effect of hawthorn alone for treatment of orthostatic hypotension has not been determined. The combination product used in these studies is not available in the US. More evidence is needed to rate hawthorn for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). It is unclear if oral hemp seed oil is beneficial in patients with eczema. Details: A small preliminary clinical trial in patients with eczema shows that taking hemp seed oil 30 mL daily for 8 weeks improves skin dryness, itchiness, and use of dermal medication when compared with baseline, but not when compared with an olive oil control (101125).
• Constipation. Oral hemp seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with functional constipation shows that taking a proprietary Chinese herbal medicine (Hemp Seed Pill) containing hemp seed, rhubarb root, peony root, apricot kernel, bitter orange fruit, and magnolia bark twice daily for 8 weeks results in a response rate to 43%, compared with 8% in those taking placebo. The response rate was defined as an increase of at least 1 complete spontaneous bowel movement per week. This combination product also improved the responder rate in the 2 weeks after treatment, as well as the overall use of rescue therapy, when compared with placebo (101127). Data from this study pooled with data from another larger study in adults with functional constipation shows that this same product increases the likelihood of complete response, defined as at least 3 complete spontaneous bowel movements per week or an increase over baseline of at least 1 weekly, by 1.43 times when compared with placebo. Complete spontaneous bowel movements per week also increased by 1 when compared with placebo (107319). It is unclear if these effects are due to hemp seed, other ingredients, or the combination.
• Dysmenorrhea. Although there is interest in using oral hemp for dysmenorrhea, there is insufficient reliable information about the clinical effects of oral hemp for this condition.
• Familial hypercholesterolemia. It is unclear if oral hemp seed oil is beneficial in children with this condition. Details: A small preliminary clinical trial shows that taking hemp seed oil (AlfaLife, Freia Farmaceutici Srl) 3 grams daily for 8 weeks does not improve levels of total or low-density lipoprotein (LDL) cholesterol when compared with no treatment in hyperlipidemic children aged 6-16 years who are also following a low-fat diet with high fruit and vegetable intake (101144).
• Hypertension. It is unclear if oral hemp seed protein is beneficial for hypertension. Details: A small clinical trial in adults with hypertension shows that consuming hemp seed protein 45-50 grams, with or without bioactive peptides, daily for 6 weeks reduces 24-hour ambulatory systolic and diastolic blood pressure when compared to casein protein, with greater reduction observed with the addition of bioactive peptides (115745). The validity of these results is limited by the lack of data on patients' hypertension medications, diet, and physical activity.
• Joint pain. Although there is interest in using oral hemp for joint pain, there is insufficient reliable information about the clinical effects of oral hemp for this condition.
• Multiple sclerosis (MS). Oral hemp seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with relapsing-remitting MS shows that taking a combination of hemp seed oil 5.4-6.3 grams and evening primrose oil three times daily for 6 months seems to improve disability scores and relapse rate when compared to baseline. However, the control group in this study ingested olive oil and also experienced notable improvements in disability and relapse rates (88183). This study is limited due to high dropout rate and because there was no statistical comparison between treatment and control groups.
• Obesity. It is unclear if an oral cannabidiol-rich hemp oil extract helps to improve weight loss. Details: A small clinical study in healthy overweight adults shows that taking a specific hemp oil extract (PlusCBD Extra Strength Hemp Extract, CV Sciences) as 60 mg, providing 15 mg cannabidiol, daily for 6 weeks, does not reduce weight or body mass index when compared with placebo (103805). The validity of this study is limited due to its exploratory nature and lack of control for voluntary dietary changes.
• Osteoarthritis. It is unclear if oral hemp seed is beneficial in patients with osteoarthritis. Details: A clinical study in 18 older adults with osteoarthritis undergoing in-hospital rehabilitation following knee or hip arthroplasty shows that consuming pasta enriched with hemp seed flour for 6 weeks improves pain scores by about 3 points, compared with only 1 point in those consuming a regular pasta control (107320). A small clinical study in adults with knee osteoarthritis shows that taking a hemp seed oil supplement 826 mg daily in combination with ginger extract and terpenes such as beta-caryophyllene and myrcene for 45 days reduces patient-reported pain and severity and improves functionality when compared to hemp seed oil alone (115742). However, the clinical significance of these findings is unclear; additionally, it is unclear if these results are due to hemp seed oil, the other ingredients, or the combination.
• Pain (chronic). It is unclear if hemp oil reduces chronic pain. Details: A small clinical study in adults with chronic pain receiving chiropractic care shows that taking a combination supplement containing hemp oil standardized to 15 mg of phytocannabinoids, broccoli extract, and calamari oil daily for 12 weeks decreases pain intensity and interference of pain with general activity, walking, and sleeping when compared with a mineral oil placebo (114971). It is unclear if these effects are due to hemp oil, other ingredients, or the combination.
• Psychological well-being. Although there is interest in using oral hemp for psychological well-being, there is insufficient reliable information about the clinical effects of oral hemp for this condition. More evidence is needed to rate hemp for these uses.

(Read more about HEMP)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. It is unclear if consuming kale in the diet can reduce the risk of bladder cancer. Details: Population research suggests that patients with bladder cancer consumed approximately 0.18 fewer cups of cruciferous vegetables, such as cabbage, Brussels sprout, cauliflower, broccoli, kale, or collards, on a weekly basis in the year prior to diagnosis when compared with people without bladder cancer. The effects of kale, specifically, are unclear (14864). Other population research suggests that eating at least five servings per week of cruciferous vegetables, such as cauliflower, Brussels sprout, cabbage, broccoli, and kale, is associated with a 51% reduction in the risk of developing bladder cancer in males when compared with eating up to one serving per week. However, higher intake of kale alone does not seem to be associated with a reduced risk of bladder cancer (26184).
• Breast cancer. It is unclear if consuming kale in the diet can reduce the risk of breast cancer. Details: Population research suggests that the highest dietary intake of cruciferous vegetables, including broccoli, Brussels sprout, cabbage, cauliflower, collards, and kale, is associated with a slight increase in the risk of breast cancer in premenopausal adults when compared with the lowest intake (26188). Cruciferous vegetables might increase urinary levels of 2-hydroxyestrone, and its ratio to 16-alpha-hydroxyestrone, which could reduce the risk of breast cancer. However, research in pre-menopausal adults shows that taking a dried kale and Brussels sprout supplement, 3.3 grams daily for 8 weeks, or increasing dietary intake of Brussels sprout or broccoli by one 40-gram serving daily, does not increase urinary levels of 2-hydroxyestrone, or its ratio to 16-alpha-hydroxyestrone, when compared with placebo (112086). In postmenopausal adults, the highest intake of cruciferous vegetables appears to be associated with a statistically insignificant reduced risk of breast cancer (26188).
• Inflammatory bowel disease (IBD). Although there is interest in oral kale for IBD, there is insufficient reliable information available about the use of kale for this purpose.
• Menopausal symptoms. Although there is interest in oral kale for reducing menopausal symptoms, there is insufficient reliable information available about the use of kale for this purpose. More evidence is needed to rate kale for these uses.

(Read more about KALE)

EFFECTIVE

• Lactose intolerance. Lactase is effective for reducing gastrointestinal symptoms from consuming lactose in lactose intolerant individuals. Details: Multiple clinical trials show that taking lactase orally is effective for reducing GI symptoms in lactose-intolerant people when used before the consumption of lactose or when added to milk prior to consumption (2371,2372,2373,106669).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Colic. It is unclear if oral lactase is beneficial in infants with colic. Details: Preliminary clinical research in infants with colic shows that supplementing human milk or formula with lactase (Crosscare Ltd) for 10 days reduces breath hydrogen levels, but not time spent crying, when compared with placebo. However, approximately 30% of infants in this study were considered to be noncompliant. When only infants considered to be compliant were included in the analysis, time spent crying during the 10-day treatment period was reduced by about 6 hours in the lactase group when compared with placebo (96347). In two other small trials, giving 5 drops of a specific lactase formulation (Colibid, RG Pharmaceutica or Yamoo, Walter Bushnell) to infants aged 0-6 months with colic before each feed, or 4 times a day, for 2-4 weeks significantly reduces crying time and fussing time when compared with placebo (104107,112190). However, measures of crying time were based on subjective parent recall only.
• Prematurity. It is unclear if oral lactase is beneficial in premature patients. Details: Clinical research shows that giving fortified human milk or preterm formula treated with lactase drops (Lactaid, McNeil Consumer Products Company) to preterm infants does not improve weight gain, feeding tolerance, weekly length gain, or gain in head circumference by 36 weeks' gestational age or discharge from the hospital (whichever comes first) when compared with giving untreated milk or formula (96346). More evidence is needed to rate lactase for these uses.

(Read more about LACTASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

(Read more about LIPASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral maitake mushroom for allergic rhinitis, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Cancer. Although there has been interest in using oral maitake mushroom for cancer, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Chemotherapy-induced anemia. Although there has been interest in using oral maitake mushroom for preventing chemotherapy-induced anemia, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Chemotherapy-induced diarrhea. Although there has been interest in using oral maitake mushroom for preventing chemotherapy-induced diarrhea, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Chemotherapy-related fatigue. Although there has been interest in using oral maitake mushroom for preventing chemotherapy-related fatigue, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Chemotherapy-induced leukopenia. Although there has been interest in using oral maitake mushroom for preventing chemotherapy-induced leukemia, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Chemotherapy-induced nausea and vomiting (CINV). Although there has been interest in using oral maitake mushroom for preventing CINV, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral maitake mushroom for CFS, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Coronavirus disease 2019 (COVID-19). Although there has been interest in using oral maitake mushroom for COVID-19, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Diabetes. Although there has been interest in using oral maitake mushroom for diabetes, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• HIV/AIDS. Although there has been interest in using oral maitake mushroom for HIV/AIDS, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Hyperlipidemia. Although there has been interest in using oral maitake mushroom for hyperlipidemia, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Hypertension. Although there has been interest in using oral maitake mushroom for hypertension, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Laryngeal cancer. It is unclear if maitake mushroom is beneficial for improving quality of life in patients with laryngeal cancer. Details: Clinical research in patients with laryngeal or pharyngeal cancer undergoing chemo-radiation treatment shows that taking maitake mushroom polysaccharides D-fraction 1 gram 3 times daily during treatment modestly improve survival over 5 years and prevents the decline in overall quality of life when compared with taking placebo (111935).
• Myelodysplastic syndromes. Although there has been interest in using oral maitake mushroom for myelodysplastic syndromes, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Obesity. Although there has been interest in using oral maitake mushroom for obesity, there is insufficient reliable information about the clinical effects of maitake mushroom for this purpose.
• Pharyngeal cancer. It is unclear if maitake mushroom is beneficial for improving quality of life in patients with pharyngeal cancer. Details: Clinical research in patients with laryngeal or pharyngeal cancer undergoing chemo-radiation treatment shows that taking maitake mushroom polysaccharides D-fraction 1 gram 3 times daily during treatment modestly improve survival over 5 years and prevents the decline in overall quality of life when compared with taking placebo (111935).
• Polycystic ovary syndrome (PCOS). Maitake mushroom may have some benefit in PCOS, but it does not appear to be as effective as clomiphene. Details: Preliminary clinical research in patients with PCOS shows that taking three tablets of a specific combination product (SX-Fraction, Maitake Products, Inc.), each containing maitake mushroom powder 250 mg plus maitake SX-fraction (a glycoprotein-rich extract) 18 mg, three times daily starting on the first day of menses for up to 28 weeks, can improve ovulation cycle rates, but does not appear to be as effective as clomiphene. After 12 weeks of treatment, patients taking the maitake mushroom product had an ovulatory cycle rate of about 42% compared with about 70% in those taking clomiphene 50 mg daily. However, 13 out of 15 patients who failed monotherapy with maitake mushroom or clomiphene alone ovulated when both maitake mushroom and clomiphene were used for 4 cycles (17131). More evidence is needed to rate the effectiveness of maitake mushroom for these uses.

(Read more about MAITAKE MUSHROOM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral noni for aging, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Asthma. Although there has been interest in using oral noni for asthma, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Atherosclerosis. Although there has been interest in using oral noni for atherosclerosis, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Athletic performance. It is unclear if oral noni juice is beneficial for athletic performance. Details: Preliminary clinical research shows that drinking 100 mL of a specific juice (Tahitian Noni Juice (TNJ), Tahitian Noni International) containing 89% pureed noni in grapefruit and blackberry juices twice daily for 21 days can increase running time-to-fatigue by approximately 21% in trained distance runners when compared with baseline. Runners taking placebo blackberry juice did not demonstrate improved endurance when compared with baseline (65230).
• Burns. Although there has been interest in using topical noni for burns, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cancer. It is unclear if oral noni is beneficial in patients with cancer. Details: Preliminary, low-quality clinical research shows that taking noni fruit extract 2-14 grams daily for 28 days does not improve physical function, fatigue, pain, or tumor growth in patients with various forms of advanced cancer when compared with baseline (65173).
• Cardiovascular disease (CVD). Although there has been interest in using oral noni for CVD, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cataracts. Although there has been interest in using oral noni for cataracts, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cervical spondylosis. It is unclear if oral noni is beneficial in patients with cervical spondylosis. Details: Preliminary clinical research shows that taking oral noni juice 15 mL twice daily in combination with physiotherapy for 4 weeks can improve neck pain and flexibility scores more than physiotherapy alone in patients with cervical spondylosis. Treatment with noni juice alone was not different than physiotherapy alone. However, the study may have been inadequately powered to detect a difference between these groups (65197).
• Colic. Although there has been interest in using oral noni for colic, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Common cold. Although there has been interest in using oral noni for the common cold, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cough. Although there has been interest in using oral noni for cough, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Depression. Although there has been interest in using oral noni for depression, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Diabetes. Although there has been interest in using oral noni for diabetes, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Epilepsy. Although there has been interest in using oral noni for epilepsy, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Headache. Although there has been interest in using oral and topical noni for headache, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Hearing loss. It is unclear if oral noni is beneficial for hearing loss. Details: Preliminary clinical research shows that drinking 4 ounces of noni juice daily for 3 months does not improve hearing at most frequencies in hearing-impaired postmenopausal females (65146).
• HIV/AIDS. Although there has been interest in using oral noni for HIV/AIDS, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Hypertension. It is unclear if oral noni is beneficial in patients with hypertension. Details: Preliminary clinical research shows that drinking 4 ounces of a specific noni juice (Tahitian Noni Juice) daily for one month reduces blood pressure by approximately 8% when compared with baseline in individuals with hypertension (65231). The validity of this finding is limited by the lack of a comparator group.
• Insomnia. Although there has been interest in using oral noni for insomnia, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Leishmania lesions. It is unclear if topical noni is beneficial for improving the severity of leishmania lesions. Details: Preliminary clinical research shows that topical application of an ointment containing noni stem extract 1% three times daily for 6 weeks improves leishmania lesion scores when compared with baseline. A good to excellent response was reported in 80% of patients (65174). However, the validity of this finding is limited by the lack of a comparator group.
• Leprosy. Although there has been interest in using topical noni for leprosy, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Liver disease. Although there has been interest in using oral noni for liver disease, there is insufficient reliable information about the clinical effects of noni for this purpose. Additionally, there is some concern that noni might cause hepatotoxicity in some patients.
• Malaria. Although there has been interest in using oral noni for malaria, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Migraine headache. Although there has been interest in using oral noni for migraine headache, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Osteoarthritis. It is unclear if oral noni is beneficial in patients with osteoarthritis. Details: Preliminary clinical research in patients with knee or hip osteoarthritis shows that drinking 3 ounces of a specific noni juice (Tahitian Noni Juice) daily for 90 days can reduce the need for analgesic medications and improve quality of life parameters, including mobility, joint function, social activity, tension level, mood, and the ability to conduct activities of daily living when compared with baseline (65206). However, the validity of this study is limited by the lack of a comparator group.
• Parturition. Although there has been interest in using oral noni for parturition, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Postoperative nausea and vomiting (PONV). It is unclear if oral noni is beneficial in patients with PONV. Details: Preliminary clinical research shows that taking noni fruit extract 600 mg orally one hour prior to surgery reduces postoperative nausea, but not vomiting, in the first 6 hours after surgery by 40% when compared with placebo. However, taking noni fruit extract did not reduce PONV in the first 6-24 hours after the surgery. Taking noni fruit extract 150-300 mg also did not reduce PONV when compared with placebo (17169).
• Premenstrual syndrome (PMS). Although there has been interest in using oral noni for PMS, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral and topical noni for RA, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Stroke. Although there has been interest in using oral noni for stroke, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Urinary tract infections (UTIs). Oral noni has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some observational research in females with recurrent UTIs has found that taking antibiotics with a combination of noni fruit extract 200 mg, d-mannose 500 mg, and N-acetylcysteine 100 mg orally twice daily for 2 months, then daily for 4 months, may be associated with a lower incidence of recurrent UTI when compared with antibiotics alone. Of patients without a UTI in the first 2 months, 100% of those taking the combination product remained UTI free at 6 months whereas only 6% of those taking antibiotics alone remained UTI free. This combination also seems to improve symptoms of urgency, frequency, and incontinence (97360). It is not clear if these effects are due to noni, other ingredients, or the combination.
• Wound healing. Although there has been interest in using topical noni for wound healing, there is insufficient reliable information about the clinical effects of noni for this purpose. More evidence is needed to rate noni for these uses.

(Read more about NONI)

LIKELY EFFECTIVE

• Coronary heart disease (CHD). A diet high in soluble fiber, such as that found in oats, reduces the risk of CHD. Details: Clinical research shows that a diet containing foods high in fiber, such as oats, oat bran, or whole oat flour, reduces the risk of CHD (2737,4960,4962,4963,4964,4965,4966,4967,4968). In 1993, the US Food and Drug Administration (FDA) approved a health claim stating that consuming at least 3 grams of soluble fiber per day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of CHD (102336). However, clinical studies show that at least 3.6 grams of soluble fiber daily is needed to reduce the risk of CHD (5786,5787,5788,5794,5795,5796).
• Dyslipidemia. A diet rich in soluble fiber, such as that found in oats, can reduce cholesterol by a moderate amount. Details: Oats, oat bran, and other soluble fibers can modestly reduce total and low-density lipoprotein (LDL) cholesterol, especially when consumed as part of a diet low in saturated fat. Consuming 56-150 grams of whole oat products such as oatmeal and oat bran, containing 3.6-10 grams of soluble fiber daily, can significantly lower total and LDL cholesterol levels. For each gram of soluble fiber consumed, total cholesterol decreases by about 1.4 mg/dL and LDL by about 1.2 mg/dL. Eating 3-10 grams of soluble fiber daily can reduce total cholesterol by about 4-14 mg/dL (4976,4977,5786,5788,5792,5794,5795,8521,107749,113488,113495). For example, eating 3 bowls of oatmeal (28 gram servings) daily, providing a total of 3 grams of soluble fiber daily, can decrease total cholesterol by about 5 mg/dL (5788). However, consuming more than 10 grams of soluble fiber daily doesn't seem to increase effectiveness (5788). A meta-analysis comparing the effects of oats and isolated beta-glucans shows that both products similarly impact lipid profiles, suggesting that the bioactive component of oats are beta-glucans (113488). Oat bran products, such as oat bran muffins and oat bran flakes, may vary in their ability to lower cholesterol, depending on the total soluble fiber content and other dietary variables (6188). Whole oat products might be more effective for lowering LDL and total cholesterol than foods containing oat bran plus soluble fiber (10145). Although oats are shown to lower total and LDL cholesterol, a meta-analysis and a small clinical study in adults with and without dyslipidemia shows that consuming oatmeal or oat products does not reduce triglycerides or increase high-density lipoprotein (HDL) cholesterol when compared with controls (113488,113495).

POSSIBLY EFFECTIVE

• Diabetes. A diet rich in whole grains, such as oats, may help prevent diabetes or improve blood glucose control in patients with type 1, type 2, or gestational diabetes. Details: Population research shows that for every 16 gram daily serving of whole grains, including oats, there is a 7% to 11% lower risk of developing type 2 diabetes (100622). There is also evidence that consuming oats can decrease blood glucose and insulin levels, as well as lipid levels, in patients with diabetes. The glycemic effects of oats depend on the level of processing of the oat products. Consuming intact oat kernels or thick-cut oats (>0.6 mm) reduces postprandial blood glucose and insulin, but consuming thin-cut, or "quick", oats has no effect (105536). Clinical research shows that consuming oats and oat bran for 4-8 weeks decreases pre-prandial blood glucose, 24-hour plasma glucose, glycated hemoglobin (HbA1c), insulin levels, and low-density lipoprotein (LDL) cholesterol in people with type 2 diabetes (4980,4982,6266,103345). Various doses have been used, including 3 grams of soluble fiber daily, or bread providing 34 grams of total fiber daily (9 grams of soluble fiber) (4961,4980). Additional clinical research in obese adults with type 2 diabetes shows that eating whole grain oats 50-100 grams daily in place of other carbohydrates reduces postprandial blood glucose by 19-27 mg/dL when compared with other carbohydrates in a healthy diet. After 1 year, the groups consuming 50 grams and 100 grams of oats had an additional 0.48% and 0.64% reduction in HbA1c, respectively, when compared with the regular healthy diet group (97520). There is also some evidence that consuming oats 50 grams daily, containing 25 grams of soluble fiber, might be more effective for improving glycemic control and decreasing hyperinsulinemia than the standard moderate fiber diet recommended by the American Diabetes Association (ADA) (6266). Oats have also been evaluated in adolescents with type 1 diabetes. One very small clinical study shows that taking 50 grams of a specific oat product (Betaglucare), providing beta-glucans 6 grams, in three divided doses daily for one week is beneficial for glycemic control and variability when compared with a standard diet without beta-glucans or with taking only 25 grams of the product daily. Maximal, mean, and pre- and post-meal blood glucose levels were modestly lower, and minimal blood glucose levels were modestly higher. Most measures of glycemic variability were statistically different, although there were no differences in the duration of hypoglycemia or hyperglycemia between groups (105261). Oats have also been evaluated in patients with gestational diabetes. A randomized, controlled trial shows that taking 30 grams of a specific oat bran product (OAB; Golden Light Cup Company) orally twice daily at lunch and dinner for 4 weeks improves mean fasting blood glucose and two-hour postprandial glucose when compared with a control group. After 4 weeks, the mean fasting blood glucose and 2-hour postprandial glucose in the treatment group were 85 mg/dL and 104 mg/dL, respectively, compared with 93 mg/dL and 117 mg/dL, respectively, in the control group (107751). The validity of this study is limited by the short treatment duration and lack of follow-up.
• Gastric cancer. A diet rich in soluble fiber, such as that found in oats, might reduce the risk of gastric cancer. Details: Observational research has found that consuming a diet that includes cereal fiber, such as oats and oat bran, might reduce the incidence of gastric cancer (10435).

POSSIBLY INEFFECTIVE

• Colorectal cancer. Regular consumption of oats does not seem to reduce the risk of colorectal cancer. Details: Observational research has found that consuming oat bran or oats orally doesn't seem to reduce the risk of colon cancer. Additionally, consuming fiber, including oat-bran fiber, is not associated with a reduction in the risk for recurrence of colorectal adenomas (4820,5104).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using topical oats for acne, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Anxiety. Although there is interest in using oral oats for anxiety, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Atopic dermatitis (eczema). Topical colloidal oatmeal cream may be beneficial in patients with atopic dermatitis. Details: Preliminary clinical research shows that applying a cream containing colloidal oatmeal 1% daily for 2 weeks moderately reduces the severity of atopic dermatitis when compared with baseline (103344). The validity of this finding is limited by the lack of a comparator group. Other research suggests that colloidal oatmeal may be beneficial when used in combination with topical steroids. Clinical research shows that the benefits obtained from applying an ointment containing fluocinolone 0.025% to the hands for 2 weeks were better maintained in the patients who also used a cream containing colloidal oatmeal 1% during this time period and for an additional 4 weeks when compared with patients using fluocinolone and the cream base without colloidal oatmeal. Quality of life was also improved in the patients using colloidal oatmeal (103340).
• Breast cancer. Observational research suggests that regular oatmeal intake may be associated with reduced mortality from breast cancer. Details: Population research in postmenopausal patients has found that those who have eaten 50 grams of oatmeal daily prior to a breast cancer diagnosis have a 20% reduced risk of all-cause mortality in the 7 years following the diagnosis when compared with patients who have not eaten oatmeal. However, no benefit was seen when post-diagnostic oatmeal intakes were examined (103343).
• Burns. Although there is interest in using topical oats for burns, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral oats for CFS, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Cognitive function. It is unclear if oral oats are beneficial in healthy adults with mild memory impairment. Details: Preliminary clinical research in healthy middle-aged adults with self-reported memory decline shows that consuming a specific wild green-oats extract (Neuravena, Frutarom) 800 mg as a single dose improves overall speed, but not overall accuracy, of cognitive performance when compared with placebo. However, a higher dose of 1600 mg was ineffective (97519).
• Dry skin. It is unclear if applying lotion containing colloidal oat extract improves dry skin to a greater extent than other lotion products. Details: Preliminary clinical research shows that applying a lotion containing colloidal oat extract (Aveeno Active Naturals Skin Relief 24Hr Moisturizing Lotion, Johnson & Johnson) twice daily for 2 weeks improves itchiness, cracking, scaling, dryness, and roughness when compared to baseline in females with dry skin (91458). Additional preliminary clinical research shows that applying a colloidal oatmeal lotion to the legs twice daily for three weeks reduces skin dryness and improves skin integrity when compared to baseline in adults with dry skin (97518). The validity of these findings is limited by the lack of a comparator group.
• Exercise-induced muscle soreness. It is unclear if oral oats are beneficial for exercise-induced muscle soreness. Details: A small clinical trial shows that eating two cookies containing oat flour 60 grams daily for 8 weeks reduces muscle soreness 48 or 72 hours after downhill running when compared with baseline (103341).
• Fat redistribution syndrome. It is unclear if oral oats are beneficial for fat redistribution syndrome. Details: Consumption of a high fiber diet, including oats, with adequate energy and protein might prevent fat deposition in patients with HIV. A one-gram increase in total dietary fiber may decrease the risk of fat deposition by 7% (12517).
• Gallbladder disease. Although there is interest in using oral oats for gallbladder disease, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Hypertension. It is unclear if oral oats are beneficial for hypertension. Details: A meta-analysis of 21 clinical studies in healthy adults and those with a variety of metabolic conditions including hypertension shows that consumption of oat products reduces systolic blood pressure (SBP) by 3 mmHg but has no effect on diastolic blood pressure (DBP) when compared with control. Subgroup analysis suggests that consuming oat products reduces SBP by 10 mmHg in patients with hypertension at baseline. An additional subgroup analysis suggests that consuming at least 5 grams of beta-glucan-enriched oats daily or consuming oats for a duration at least 8 weeks reduces SBP and DBP (113494). Observational research has found that consumption of oats as oatmeal or oat cereal does not seem to reduce DBPor SBP in males with minor elevations in blood pressure or patients with dyslipidemia (2956,113495). A randomized, controlled trial in patients with stage 1 hypertension receiving dietary guidance shows that taking 30 grams of oat bran, providing 8.9 grams of dietary fiber, once daily with breakfast or in between meals for 3 months improves various blood pressure measures when compared with dietary guidance alone. After 3 months of treatment, 24-hour maximum SBP and DBP decreased by 14 mmHg and 11 mmHg, respectively, and office SBP and DBP decreased by 15 mmHg and 10 mmHg, respectively. Oat consumption may also have impacted antihypertensive medication use. Two patients in the control group increased doses of antihypertensive medications, whereas 6 patients in the treatment group decreased doses and 1 patient discontinued use (107750). The effect of oral oat bran on patients with stage 2 hypertension or pre-hypertension is unknown.
• Irritable bowel syndrome (IBS). Although there is interest in using oral oats for IBS, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Metabolic syndrome. Limited research suggests that oats may not be beneficial for metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that adding oat bran 40 grams daily for 6 weeks to a low-calorie diet does not reduce the incidence of metabolic syndrome. Oat bran also does not improve body weight, blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, or blood glucose levels when compared with a low-calorie diet alone in patients with metabolic syndrome (103342).
• Osteoarthritis. Although there is interest in using oral oats for osteoarthritis, there is insufficient reliable information about the clinical effects of oats for this condition.
• Pruritus. Applying oat lotion topically may improve some types of pruritus. Details: Preliminary clinical research shows that applying an oat lotion (Espanol) twice daily for up to 2 weeks can decrease itching intensity by about 20% when compared to baseline in patients with pruritus associated with chronic kidney disease (uremic pruritus). This decrease is similar to the effects of applying vinegar 5% solution or taking hydroxyzine 10 mg orally. However, applying the oat lotion does not appear to decrease the frequency of itching (91457).
• Psoriasis. Although there is interest in using topical oats for psoriasis, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Rheumatoid arthritis (RA). Although there is interest in using oral oats for RA, there is insufficient reliable information about the clinical effects of oats for this purpose.
• Stroke. It is unclear if oral oats are beneficial for reducing the risk of stroke. Details: Population research suggests that consuming oatmeal for breakfast once weekly might reduce the incidence of stroke by a small amount when compared with consuming white bread or eggs for breakfast (103337).
• Ulcerative colitis. Oral oats have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific oat-based product (Profermin, Nordisk Rebalance) containing fermented oat flour, Lactobacillus plantarum, barley malt flour, and lecithin, 250 mL orally twice daily for 8 weeks, reduces disease activity and increases remission in about two-fold more patients with relapsing ulcerative colitis, when compared with treatment with a specific nutritional beverage (Fresubin Original, Fresenius Kabi) (90271).
• Wound healing. Although there is interest in using topical oats for wound healing, there is insufficient reliable information about the clinical effects of oats for this purpose. More evidence is needed to rate oats for these uses.

(Read more about OATS)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. Although there has been interest in using oral pea protein for diabetes, there is insufficient reliable information about the clinical effects of pea protein for this purpose.
• Exercise-induced muscle damage. It is unclear if oral pea protein is beneficial for exercise-induced muscle damage. Details: A small clinical study in healthy, untrained males shows that taking a specific type of pea protein (Nutralys S85 Plus, Roquette) 0.3 grams/kg 3 times daily for 5 days after a 90-minute whole-body high-intensity eccentric exercise bout does not reduce surrogate markers of exercise-induced muscle damage, including creatine kinase, lactate dehydrogenase, and myoglobin, when compared with whey protein or water (104758). However, the study may have been inadequately powered to detect a difference between groups and is further limited by double-blinding restricted only to the protein supplements. The water control did not match the taste, texture, or calorie content of the protein supplements. Another small clinical trial in healthy, physically active older adults shows that taking pea protein 25 grams daily for 10 days prior to and 3 days after a single 20-30 km endurance walk does not improve markers of muscle damage when compared with placebo and may be less effective when compared with whey protein (111729).
• Exercise-induced muscle soreness. It is unclear if oral pea protein is beneficial for exercise-induced muscle soreness. Details: A small clinical study in healthy, untrained males shows that taking a specific type of pea protein (Nutralys S85 Plus, Roquette) 0.3 grams/kg 3 times daily for 5 days after a 90-minute whole-body high-intensity eccentric exercise bout does not reduce exercise-induced muscle soreness when compared with whey protein or water (104758). However, the study may have been inadequately powered to detect a difference between groups and is further limited by double-blinding restricted only to the protein supplements. The water control did not match the taste, texture, or calorie content of the protein supplements. Another small clinical trial in healthy, physically active older adults shows that taking pea protein 25 grams daily for 10 days prior to and 3 days after a single 20-30 km endurance walk does not improve muscle soreness when compared with whey protein or placebo (111729).
• Hyperlipidemia. Although there has been interest in using oral pea protein for hyperlipidemia, there is insufficient reliable information about the clinical effects of pea protein for this purpose.
• Hypertension. It is unclear if oral pea protein hydrolysate is beneficial for hypertension. Details: A small clinical study in adults with elevated blood pressure shows that taking a pea protein hydrolysate 3 grams daily for 3 weeks reduces systolic blood pressure by 6 mmHg when compared with placebo. Taking the same product at a dose of 1.5 grams daily does not reduce blood pressure (94973).
• Irritable bowel syndrome (IBS). Oral pea protein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small open-label study in patients with diarrhea-predominant IBS shows that taking two tablets of a specific product (Gelsectan, Noventure) containing pea protein, grape seed extract tannins, xyloglucan, and xylo-oligosaccharides (doses unknown) before breakfast and dinner daily for 6 months improves IBS-related symptoms, including diarrhea, pain, bloating, defecatory frequency, stool consistency, and defecatory urgency when compared to baseline (108881). The validity of this study is limited by a lack of placebo control group.
• Muscle strength. Clinical research on the impact of oral pea protein on muscle strength is mixed. Its effects might be similar to whey protein. Pea protein may be more effective in individuals with lower baseline muscle strength. Details: A clinical trial in physically active, but non-resistance trained, young male adults participating in a 12-week upper body resistance training program shows that taking a specific type of pea protein isolate (Nutralys, Roquette) 25 grams twice daily over the training program does not augment training-induced increases in muscle thickness or strength when compared with whey protein or isocaloric placebo. However, a post hoc analysis of participants with the lowest muscle strength at baseline shows that pea protein supplementation increases bicep muscle thickness more than placebo and to a similar degree as whey protein (95426). Additionally, a very small clinical study in trained adults shows that taking pea protein 24 grams twice daily during an 8-week high-intensity functional training program improves muscle strength to a similar degree as whey protein, while neither supplement appears to impact muscle thickness or body mass (102013). The small study size and lack of an isocaloric, protein-free control limits conclusions that can be drawn from this study.
• Obesity. Although there has been interest in using oral pea protein for obesity, there is insufficient reliable information about the clinical effects of pea protein for this purpose.
• Postoperative recovery. Oral pea protein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults undergoing gastrointestinal resection due to cancer shows that consuming a beverage (Providextra, Fresenius Kabi) containing pea protein hydrolysate 11% and carbohydrates 89% the night before (400 mL) and the morning of surgery (200 mL) reduces postoperative hospital stay by almost 2-fold when compared with conventional preoperative fasting (94933). It is unclear if these findings are due to pea protein, carbohydrates, or the combination. More evidence is needed to rate pea protein for these uses.

(Read more about PEA PROTEIN)

EFFECTIVE

• Hypokalemia. Oral or intravenous potassium can treat and prevent hypokalemia. Details: Administering potassium orally or intravenously is effective for treating and preventing hypokalemia (15,107970). Oral potassium 20 mEq (780 mg of elemental potassium) is typically taken once daily to prevent hypokalemia (15,95010). Oral potassium 40-100 mEq (1560-3900 mg of elemental potassium) is typically taken in 2-5 divided doses daily to treat hypokalemia (95010). Doses should be limited to 40 mEq (1560 mg of elemental potassium), and the total dose should not exceed 200 mEq (7800 mg of elemental potassium) in 24 hours (95010). Potassium supplementation and route of administration should be individualized based on serum potassium level and patient status (15,107970).

LIKELY EFFECTIVE

• Hypertension. Oral potassium, via dietary intake or supplementation, reduces blood pressure. Details: Population research has found that higher dietary potassium consumption is associated with a lower risk of developing hypertension (1310,8817,69512). Additionally, most clinical research shows that potassium, taken orally as part of the diet or as a supplement, reduces systolic blood pressure by about 3-9.5 mmHg and diastolic blood pressure by about 2-6.4 mmHg in patients with or without hypertension (3385,92104,92106,95624,107974). In most of these studies, daily intake of potassium typically ranged from about 1500-7800 mg, with the most common intake being about 2340-2540 mg daily (92104,95624). However, some research shows that taking potassium does not lower systolic or diastolic blood pressure (69541,69550,107966). Differences in the patient populations, potassium intake, and salt intake could have contributed to the conflicting results. Potassium seems to be more effective for people with hypertension, low potassium levels, high daily sodium intake, and for Black adults (3384,3385,3386,92104,92106). Some research also shows that the greatest blood pressure-lowering effects of potassium occur at doses of about 3900-7800 mg daily (95624). A meta-analysis of clinical trials using a novel computational technique to assess both potassium intake and excretion suggests that the optimal blood pressure reduction occurs when taking about 1500 mg supplemental potassium daily or an overall intake of 4500-6500 mg potassium daily (105448). This analysis is limited by the heterogeneity and short duration of the included trials. There is also interest in utilizing low-sodium, high-potassium food substitutes to treat hypertension. Research shows that using salt substitutes containing 25% to 30% potassium chloride reduces systolic and diastolic blood pressure by 3-4.6 mmHg and 1 mmHg, respectively, when compared with regular table salt (107971,107976). In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines recommending that patients with hypertension consume 3500-5000 mg of potassium daily (95680). This intake of potassium is expected to lower systolic blood pressure by about 4-5 mmHg in patients with hypertension and by about 2 mmHg in normotensive patients (3385). Although potassium supplements and dietary potassium both seem to be beneficial, the guidelines recommend getting potassium from dietary sources, since potassium-rich diets are usually heart-healthy (95680). Additionally, the US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Kidney stones (nephrolithiasis). Oral prescription potassium citrate reduces the risk of kidney stone recurrence. It is unclear if non-prescription potassium citrate would be beneficial. Details: The American Urological Association (AUA) recommends potassium citrate therapy for patients with recurrent calcium stones and low urinary citrate, those with recurrent calcium or calcium oxalate stones without current metabolic abnormalities, and those with uric acid or cystine stones. The citrate component reduces urine calcium excretion and increases urine citrate and urine pH, which in turn alleviates crystal growth, formation, and aggregation. Sodium citrate may also be used to prevent stone recurrence; however, due to sodium's propensity to increase urine calcium excretion, potassium citrate remains the preferred salt formulation (107972). It is important to note that potassium citrate supplements are not equivalent to prescription potassium citrate products. Dose and duration of treatment is determined by a healthcare professional and individualized based on a patient's urinary citrate levels (107975,107989). Serum potassium levels should be monitored prior to starting potassium citrate, within 2 weeks of treatment initiation, and every 12 months (107975).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Eating foods high in potassium and low in sodium might reduce the risk of cardiovascular disease. It is unclear if taking potassium supplements has the same benefit. Details: Large population studies in adults without prior CVD have found that higher dietary potassium intake is associated with a lower risk of cardiovascular events (109395,109399). One study found that daily potassium intake of about 3300 mg is associated with a 13% reduction in CVD risk when compared with intake of about 1920 mg (109399). The other study found that each additional 1000 mg of daily urinary potassium excretion, which is a marker of dietary intake, is associated with an 18% reduction in CVD risk (109395). Another observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).
• Stroke. Eating foods high in potassium and low in sodium might reduce the risk of stroke. It is unclear if taking potassium supplements has the same benefit. Details: Higher dietary intake of potassium seems to be associated with a lower risk of stroke. Population research has found that increasing dietary potassium intake by 1-1.5 grams daily is associated with up to a 20% reduced risk of stroke (92105,92107). Some population research has found that higher supplemental intake of potassium is associated with a 29% reduced risk of ischemic stroke. However, supplemental potassium intake is not found to be associated with a lower risk of hemorrhagic or total stroke (92107). An observational study in over 15,000 adults with history of stroke or hypertension shows that replacing regular table salt with a substitute product containing 75% sodium chloride and 25% potassium chloride for an average of 5 years decreases the rate of stroke, major cardiovascular events, or death (107976). High quality clinical trials are needed to confirm this association. The US Food and Drug Administration (FDA) has determined that foods containing at least 350 mg potassium and that are low in sodium, saturated fat, and cholesterol can state that "diets containing foods that are good sources of potassium and low in sodium may reduce the risk of high blood pressure and stroke" (1310,8817).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental hypersensitivity. It is unclear if topical potassium improves dental hypersensitivity. Details: One meta-analysis of clinical research shows that using a dentifrice containing 5% potassium nitrite reduces dentin sensitivity when compared with a dentifrice that does not contain potassium nitrite (69549). Other clinical research published in a systematic review shows that potassium-containing toothpastes might reduce dentin sensitivity more than controls that do not contain potassium. However, these toothpastes might be less effective than other active toothpastes, such as those containing sodium monofluorophosphate, and the effect may result from a placebo effect, since the mechanism of action of potassium is unclear (69456).
• Diabetes. It is unclear if increasing dietary potassium reduces the risk of diabetes. Details: A meta-analysis of 7 large population studies has found that consuming dietary potassium 3300-3500 mg daily is associated with a 20% reduction in the risk of diabetes when compared with consumption below 1000 mg daily. Results were similar when studies that measured potassium intake with a dietary questionnaire were analyzed separately from those that measured intake based on urinary potassium excretion (110776). However, the validity of this finding is limited by the heterogeneity of the included studies. Furthermore, despite use of data from various databases, most studies included in the analysis were conducted by the same author.
• Impaired glucose tolerance (prediabetes). It is unclear if oral potassium improves glycemic control in prediabetes. Details: A small clinical study in Black patients with prediabetes shows that taking extended-release potassium (Klor-Con M10, Cardinal Health) 40 mEq daily as potassium chloride for 3 months does not improve glucose tolerance when compared with placebo. Although fasting glucose levels were slightly reduced in the potassium group when compared with placebo, both groups experienced a worsening of glucose intolerance, with no change in insulin levels or glycated hemoglobin (98533).
• Osteoporosis. Although there is interest in using oral potassium for osteoporosis, there is insufficient reliable information about the clinical effects of potassium for this condition.
• Physical performance. It is unclear if oral potassium improves physical performance in older adults. Details: Observational research in older adults has found that decreased dietary potassium intake and increased dietary sodium intake over 5 years is associated with worsened physical performance (105450).
• Systemic lupus erythematosus (SLE). It is unclear if oral potassium is beneficial in patients with SLE. Details: Observational research in patients with SLE has found that increased dietary potassium intake is not associated with improvements in disease activity scores or markers of cardiovascular disease, including lipid levels and blood pressure, when compared with low dietary potassium intake. However, higher potassium intake does seem to reduce the odds of having elevated levels of C-reactive protein, a marker of inflammation, in these patients (109397). More evidence is needed to rate potassium for these uses.

(Read more about POTASSIUM)

Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Obesity. Preliminary clinical research in healthy overweight males shows that consuming a bread providing quinoa flour 20 grams daily for 4 weeks does not affect anthropometric measures, blood pressure, or plasma levels of glucose or cholesterol when compared with consuming a refined wheat bread (99147).
• Postmenopausal conditions. One small clinical study in postmenopausal adults shows that consuming quinoa flakes 25 grams daily for 4 weeks does not improve glycemic or lipid indices or anthropometric measures when compared with consuming corn flakes (99148). More evidence is needed to rate quinoa for these uses.

(Read more about QUINOA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Topical red raspberry leaf has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing red raspberry leaf cell culture extract 0.0005%, vitamin C 20%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Cardiovascular disease (CVD). Although there has been interest in using oral red raspberry leaf for CVD, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Congestive heart failure (CHF). Although there has been interest in using oral red raspberry leaf for CHF, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Diabetes. Although there has been interest in using oral red raspberry leaf for diabetes, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Dysmenorrhea. Although there has been interest in using oral red raspberry leaf for dysmenorrhea, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Hypertension. Although there has been interest in using oral red raspberry leaf for hypertension, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Influenza. Although there has been interest in using oral red raspberry leaf for influenza, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Labor pain. Some research suggests that oral red raspberry leaf does not reduce analgesic use during labor. Details: Clinical research shows that taking red raspberry leaf 2.4 grams daily, beginning at 32 weeks' gestation and continuing until delivery, does not decrease the need for analgesics in the perinatal time period when compared with placebo (9796). A systematic review of retrospective studies also supports these findings, showing no improvement in perineal outcomes in patients consuming red raspberry leaf prior to labor (108005).
• Menorrhagia. Although there has been interest in using oral red raspberry leaf for menorrhagia, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Obesity. It is unclear if oral red raspberry fruit is beneficial in patients with obesity. Details: Preliminary clinical research in overweight and obese adults shows that consuming frozen red raspberry fruit 280 grams daily for 8 weeks does not reduce body mass index or waist circumference when compared with control (105873).
• Osteoarthritis. It is unclear if oral red raspberry leaf extract is beneficial for knee osteoarthritis. Details: A moderate-sized clinical study in patients with knee osteoarthritis shows that taking red raspberry leaf extract 200 or 400 mg once daily for 12 weeks reduces pain at the higher dose when measured by the visual analog scale, but does not improve physical performance, physical activity, walking distance, or Western Ontario McMaster osteoarthritis index (WOMAC) global score or pain, stiffness, and function subscores when compared with placebo (112127).
• Parturition. Some research suggests that oral red raspberry leaf does not shorten the duration of labor. Details: Clinical research shows that taking red raspberry leaf 2.4 grams daily, beginning at 32 weeks' gestation and continuing until delivery, does not reduce the length of labor when compared with placebo (108005). Traditionally, doses of up to 4 grams daily have been recommended for this purpose; however, doses greater than 2.4 grams daily have not been evaluated for safety or efficacy. Further high-quality research is needed to determine the optimal dose, duration, and formulation, if any, of red raspberry leaf for this purpose.
• Pharyngitis. Although there has been interest in using topical red raspberry leaf for pharyngitis, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Pregnancy-induced nausea and vomiting. Although there has been interest in using oral red raspberry leaf for pregnancy-induced nausea and vomiting, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Respiratory tract infections. Although there has been interest in using oral red raspberry leaf for respiratory tract infections, there is insufficient reliable information about the clinical effects of red raspberry for this purpose. More evidence is needed to rate red raspberry leaf for this use.

(Read more about RED RASPBERRY)

POSSIBLY INEFFECTIVE

• Hyperlipidemia. Preliminary clinical studies show that oral reishi mushroom does not improve lipid levels in patients with hyperlipidemia or type 2 diabetes. Details: Preliminary clinical research shows that taking reishi mushroom extract 1440 mg daily for 12 weeks does not significantly improve the lipid profile in patients with hyperlipidemia (70776). Also, a meta-analysis shows that taking reishi mushroom extract 1400-4000 mg daily for 12-16 weeks does not reduce total cholesterol or low-density lipoprotein (LDL) cholesterol in patients with type 2 diabetes (91435).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral reishi mushroom for aging, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Altitude sickness. Although there has been interest in using oral reishi mushroom for altitude sickness, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Alzheimer disease. A small clinical study suggests that oral reishi mushroom does not improve Alzheimer disease symptoms. Details: Preliminary clinical research in patients with Alzheimer disease shows that taking reishi mushroom powder 1000 mg three times daily for 6 weeks does not improve memory, language skills, or quality of life when compared with placebo (97942).
• Asthma. Although there has been interest in using oral reishi mushroom for asthma, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Benign prostatic hyperplasia (BPH). Preliminary clinical research suggests that oral reishi mushroom extract can help reduce some lower urinary tract symptoms in patients with BPH. Details: Clinical research in patients with mild to moderate lower urinary tract symptoms (LUTS) associated with BPH, urinary incontinence, overactive bladder, or other conditions, shows that taking reishi mushroom extract 6 mg orally once daily for up to 12 weeks moderately improves total symptom severity measured on the International Prostate Symptom Score (IPSS) scale, when compared with placebo (91436,91437). A higher dose of 60 mg daily is not more effective than the 6 mg dose, and a lower dose of 0.6 mg daily is not more effective than placebo (91437). Reishi mushroom extract does not improve peak urine flow rate, residual urine volume, prostate volume, or quality of life when compared with placebo (91436,91437). The relevance of these results is unclear since not all of the patients with LUTS had BPH.
• Bronchitis. Although there has been interest in using oral reishi mushroom for bronchitis, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Cancer. It is unclear if oral reishi mushroom is beneficial when used in conjunction with chemotherapy. Details: A meta-analysis of 9 clinical trials using various reishi mushroom products in combination with chemotherapy found that complete and partial responses increased by 30% with combination therapy when compared with chemotherapy alone. However, there was no difference in overall survival (102915). The reliability and applicability of these results are unclear since the trials looked at several different types of cancer, used varying doses and durations of therapy, and were all conducted in China or other Asian countries.
• Cancer-related fatigue. It is unclear if oral reishi mushroom is beneficial in patients with breast cancer and fatigue. Details: Results from a small clinical study in breast cancer patients show that taking reishi mushroom powder 1000 mg orally three times daily for 4 weeks can improve cancer-related fatigue when compared with placebo (91438). However, it is not clear if the improvement is clinically meaningful.
• Cardiovascular disease (CVD). It is unclear if oral reishi mushroom is beneficial for reducing CVD risk factors. Details: A meta-analysis of 5 low-quality studies in adults with diabetes shows that taking reishi mushroom 1400-3000 mg daily for 12-16 weeks does not reduce CVD risk factors, including total and low-density lipoprotein (LDL) cholesterol, triglycerides, blood pressure, and body mass index, when compared with placebo (91435).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral reishi mushroom for CFS, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Chronic kidney disease (CKD). Although there has been interest in using oral reishi mushroom for CKD, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Colorectal adenoma. Limited clinical research suggests that oral reishi mushroom extract may be beneficial for reducing colorectal adenoma size. Details: Preliminary clinical research in patients with colorectal adenomas shows that taking reishi mushroom extract 1500 mg orally in two divided doses daily for 12 months reduces the number and size of adenomas when compared with no treatment (70774).
• Coronary heart disease (CHD). It is unclear if oral reishi mushroom is beneficial for CHD. Details: Preliminary clinical research shows that taking a specific reishi mushroom extract (Ganopoly, Encore International Co.) 1800 mg orally three times daily for 12 weeks reduces symptoms of CHD, such as chest pain, palpitations, and shortness of breath, in a greater percentage of patients when compared with placebo (70800).
• Diabetes. Evidence on the use of oral reishi mushroom in patients with type 2 diabetes is conflicting. Details: A meta-analysis of clinical research in patients with type 2 diabetes shows that taking reishi mushroom extract 1400-4000 mg daily for 12-16 weeks does not reduce glycated hemoglobin (HbA1c) or plasma lipids (91435). However, one preliminary clinical study in patients with type 2 diabetes shows that taking a specific reishi mushroom extract (Ganopoly, Encore International Co.) 1800 mg three times daily for 12 weeks reduces HbA1c, but not fasting blood glucose, when compared with placebo (70801).
• Fibromyalgia. It is unclear if oral reishi mushroom is beneficial for fibromyalgia. Details: A small clinical trial in patients with fibromyalgia shows that taking reishi mushroom (MundoReishi Salud S.L.) powder 3 grams twice daily for 6 weeks does not improve mood, quality of life, anthropometric measures, blood pressure, or glycemic or lipid parameters when compared with placebo (108309,108310). However, the study may have been underpowered to detect any differences between groups.
• Genital herpes. Oral reishi mushroom has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent genital herpes shows that taking 4.4 grams of a mixture of hot water extracts of reishi mushroom, terminalia, Job's tears, Wisteria floribunda, Trapa natans, and Elfvingia applanata orally once daily for 2 days, then 2.2 grams daily thereafter until outbreak resolution, decreases the time to outbreak resolution by 6 days when compared with previous outbreaks (91434).
• Gulf war syndrome. It is unclear if oral reishi mushroom is beneficial for Gulf war syndrome. Details: A very small exploratory clinical trial in adults with Gulf war syndrome shows that taking reishi mushroom extract (JHS Natural Products, Mushroom Science) 1600 mg in two divided doses daily for 30 days does not improve symptoms when compared with placebo. Also, symptoms modestly worsened after an additional 30 days of treatment at a dose of 3200 mg daily (108311).
• Hepatitis B. One small clinical study suggests that a specific reishi mushroom extract may reduce hepatitis B activity and improve liver function. Details: Preliminary clinical research shows that taking a specific reishi mushroom extract (Ganopoly, Encore International Co.) 1800 mg orally three times daily for 12 weeks reduces levels of hepatitis B viral DNA and hepatitis B surface antigen, which are markers of hepatitis B activity, and normalizes aminotransferase levels in a greater percentage of patients when compared with placebo (70799).
• Herpes labialis (cold sores). Oral reishi mushroom has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent herpes labialis shows that taking 4.4 grams of a mixture of hot water extracts of reishi mushroom, terminalia, Job's tears, Wisteria floribunda, Trapa natans, and Elfvingia applanata orally once daily for 2 days, then 2.2 grams daily thereafter until outbreak resolution, decreases the time to outbreak resolution by almost 4 days when compared with previous outbreaks (91434).
• Herpes zoster (shingles). Although there has been interest in using oral reishi mushroom for herpes zoster, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Human papillomavirus (HPV). Oral reishi mushroom has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with oral HPV shows that taking a combination of reishi and coriolus mushroom powders, 400 mg orally daily for 2 months, clears HPV in 88% of patients when compared with baseline (91433). The validity of this finding is limited by the lack of a comparator group.
• Hypertension. Limited research suggests that oral reishi mushroom may be beneficial in some types of hypertension. Details: Preliminary clinical research shows that taking reishi mushroom extract 1440 mg daily for 12 weeks does not lower blood pressure in patients with hypertension (70776). However, in other clinical research, taking reishi mushroom extract 330-1440 mg daily for 1-6 months reduces blood pressure in patients with stage II or essential hypertension, but not in those with mild hypertension or diabetes (70786,70802,91435).
• Influenza. Although there has been interest in using reishi mushroom for influenza, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Insomnia. Although there has been interest in using reishi mushroom for insomnia, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Lung cancer. Small clinical studies suggest that oral reishi mushroom does not reduce the size of lung tumors. Details: A meta-analysis of preliminary clinical research shows that taking reishi mushroom does not reduce the size of lung tumors. However, it may stimulate immune function and improve quality of life in lung cancer patients when compared with control (70779).
• Peptic ulcers. Although there has been interest in using oral reishi mushroom for peptic ulcers, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose.
• Rheumatoid arthritis (RA). Oral reishi mushroom has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with active RA who are taking disease-modifying antirheumatic drugs shows that taking reishi mushroom extract 4 grams in combination with San Miao San (containing 2.4 grams each of atractylodes, phellodendron, and Achyranthes bidentata) daily for 24 weeks does not increase the percentage of patients achieving a 20% response based on the American College of Rheumatology (ACR) criteria or modify blood markers of disease and inflammation when compared with placebo (70767).
• Stress. Although there has been interest in using oral reishi mushroom for stress, there is insufficient reliable information about the clinical effects of reishi mushroom for this purpose. More evidence is needed to rate reishi mushroom for these uses.

(Read more about REISHI MUSHROOM)

POSSIBLY INEFFECTIVE

• Dental Plaque. A solution containing an extract of shiitake mushroom is less effective than fluoride mouthwash for reducing dental plaque. Details: Clinical research shows that rinsing the mouth with a solution containing shiitake mushroom extract does not reduce dental plaque when compared with placebo and appears to be less effective than fluoride mouth rinse (Meridol) (94250).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral shiitake mushroom for aging, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Atherosclerosis. Although there has been interest in using oral shiitake mushroom for atherosclerosis, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Breast cancer. Although there has been interest in using oral shiitake mushroom for breast cancer, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Cancer. It is unclear if oral shiitake mushroom is beneficial in patients with cancer. Details: Although some small clinical studies in patients with gastric or colon cancer have found that patients taking the shiitake mushroom extract AHCC 3-6 grams daily have better survival rates and quality of life when compared with historical population data, other observational research has not found a benefit for patients with head, neck, lung, or breast cancer when compared with baseline (30421,30425,30454). The validity of these studies is limited by lack of a comparator group.
• Chemotherapy-induced anemia. It is unclear if oral shiitake mushroom is beneficial in patients with chemotherapy-induced anemia. Details: A small clinical study in adults receiving chemotherapy for pancreatic cancer shows that taking the shiitake mushroom extract AHCC 6 grams daily for 8-12 weeks does not reduce the rate of grade 2 to 3 anemia when compared with placebo (110131).
• Chemotherapy-induced leukopenia. It is unclear if oral shiitake mushroom is beneficial in patients with chemotherapy-induced leukopenia. Details: Preliminary clinical research in patients with breast cancer receiving chemotherapy shows that taking the shiitake mushroom extract AHCC significantly reduces chemotherapy-related neutrophil events and lipid abnormalities when compared with standard care (94829).Observational research in patients with resectable pancreatic ductal adenocarcinoma has found that taking this product orally 3 grams daily throughout 2 cycles of neoadjuvant gemcitabine improves the neutrophil-to-lymphocyte ratio and nutritional scores when compared with standard of care (106783). In contrast, other clinical research in patients with pancreatic or biliary tract cancer receiving gemcitabine chemotherapy shows that taking AHCC 6 grams daily for two months does not seem to affect neutropenia, thrombocytopenia, or hepatic dysfunction when compared with standard of care. However, taking AHCC did reduce C-reactive protein and increase hemoglobin and albumin when compared to standard of care (30424).
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral shiitake mushroom is beneficial in patients with CINV. Details: Preliminary clinical research in patients being treated for head and neck cancers shows that taking the shiitake mushroom extract AHCC 3 grams daily, beginning 3 days prior to chemotherapy and continuing until one week after chemotherapy, reduces gastric side effects and the need for antiemetic therapy when compared with baseline (30425). The validity of these findings is limited by the lack of a comparator group.
• Chemotherapy-induced taste changes. It is unclear if oral shiitake mushroom is beneficial for the prevention of taste changes due to chemotherapy. Details: A small clinical study in adults receiving chemotherapy for pancreatic cancer shows that taking the shiitake mushroom extract AHCC 6 grams daily for 8-12 weeks reduces the rate of patient-reported taste disorders by 27% when compared with placebo (110131). Although patients in the AHCC group had modest improvements in some nutritional parameters when compared with the placebo group, it is unclear if any changes would be considered clinically significant.
• Common cold. Although there has been interest in using oral shiitake mushroom for the common cold, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Coronavirus disease 2019 (COVID-19). Although there has been interest in using oral shiitake mushroom for COVID-19, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Diabetes. Although there has been interest in using oral shiitake mushroom for diabetes, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Genital herpes. Although there has been interest in using oral shiitake mushroom for genital herpes, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Hepatitis C. It is unclear if oral shiitake mushroom is beneficial in patients with hepatitis C. Details: Preliminary clinical research in adults with chronic hepatitis C shows that taking the shiitake mushroom extract AHCC 6 grams daily for 6 months does not significantly reduce alanine aminotransferase (ALT) or hepatitis C virus RNA levels when compared with placebo (30419).
• HIV/AIDS. Although there has been interest in using oral shiitake mushroom for HIV/AIDS, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Human papillomavirus (HPV). It is unclear if oral shiitake mushroom is beneficial in patients with HPV. Details: A small clinical study in adult females with persistent high-risk HPV shows that taking the shiitake mushroom extract AHCC 3 grams daily leads to clearance of HPV RNA and DNA in 64% of patients after 6 months of treatment, compared to 11% of patients taking placebo (110129). The validity of these findings is limited by lack of statistical comparison between groups.
• Hypercholesterolemia. It is unclear whether oral shiitake mushroom is beneficial for lowering blood lipid levels. Details: Clinical research in adults with borderline high levels of cholesterol or triglycerides shows that consuming bars providing shiitake mushroom for 66 days modestly reduces triglyceride levels, but does not affect levels of low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol, when compared with placebo bars. Each bar provided dried shiitake mushroom 3.5 grams daily and the number of bars consumed daily was based on body mass index (108300). The effect of shiitake mushroom in patients with hypercholesterolemia, specifically, is unclear due to the heterogenous patient population.
• Hypertension. Although there has been interest in using oral shiitake mushroom for hypertension, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Impaired glucose tolerance (prediabetes). Oral shiitake mushroom has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults with prediabetes shows that taking freeze-dried shiitake mushroom 0.96 grams in combination with chokeberry 1.36 grams, Panax ginseng 1.64 grams, and nattokinase 0.8 grams (Chakreis, YD Nutraceuticals Ltd.) twice daily for 12 weeks does not affect glycated hemoglobin, fasting blood glucose, or oral glucose tolerance test results when compared with placebo. However, there were some modest beneficial effects on insulin resistance and fasting insulin and liver transaminase levels (108301).
• Influenza. Although there has been interest in using oral shiitake mushroom for influenza, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Liver cancer. Small, low-quality clinical studies suggest that oral shiitake mushroom extract may improve overall survival in patients with liver cancer. Details: Preliminary clinical research in patients with advanced hepatic cancer shows that taking the shiitake mushroom extract AHCC orally 6 grams daily for a median of 3.5 months along with supportive care increases the median survival time by 2 months when compared with placebo. Taking AHCC also improved quality of life scores when compared with placebo (30359). Population research in patients with hepatocellular carcinoma has also found that taking AHCC 3 grams daily for up to 9 years after surgical resection reduces tumor recurrence and mortality by 48% and 56%, respectively, when compared with control (30353). In another small, open label clinical study of adults with advanced hepatocellular carcinoma, tumor recurrence occurred in 52% of patients who took AHCC 1 gram three times daily for 2 years after surgical resection (110130). The interpretation of these results is limited by the lack of a control group.
• Obesity. Although there has been interest in using oral shiitake mushroom for obesity, there is insufficient reliable information about the clinical effects of shiitake mushroom for this purpose.
• Prostate cancer. It is unclear whether shiitake mushroom has a role in preventing disease progression. Details: Preliminary clinical research shows that taking shiitake mushroom extract does not prevent disease progression, as determined by prostate-specific antigen (PSA) levels, when compared with baseline (10451). More evidence is needed to rate shiitake mushroom for these uses.

(Read more about SHIITAKE MUSHROOM)

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about SODIUM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• HIV/AIDS. Preliminary clinical research in HIV patients using antiretroviral therapy shows that taking a specific product containing sorghum extract and other ingredients (Jobelyn, Health Forever Product Ltd.) orally twice daily for 12 weeks improves CD4+ T cell count when compared with antiretroviral therapy alone. Hemoglobin levels were increased compared with baseline in patients ineligible for antiretrovirals (97674).
• Iron deficiency anemia. Preliminary clinical research shows that taking a specific product containing sorghum extract and other ingredients (Jobelyn, Health Forever Product Ltd.) orally once daily for 3 weeks does not improve red blood cell indices in patients with anemia who were also taking iron 600 mg daily and folic acid 5 mg daily (97675).
• Obesity. Preliminary clinical research in overweight and obese men shows that eating extruded sorghum cereal 40 grams each morning along with a calorie restricted diet for 8 weeks reduces body fat by around 2%, but does not appear to improve body weight, body mass index, or waist circumference, when compared with extruded wheat cereal plus calorie restriction (103898). More evidence is needed to sorghum for these uses.

(Read more about SORGHUM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cognitive function. It is unclear if consuming spinach is beneficial for cognitive function. Details: Preliminary clinical research in healthy adults shows that consuming spinach 200 grams with lunch does not improve attention or memory after 150 minutes when compared with a rice milk control (96852).
• Muscle strength. It is unclear if oral spinach is beneficial for muscle strength. Details: A small, preliminary clinical study in healthy adults over 50 years of age shows that taking an aqueous spinach extract, 1 gram orally twice daily, in conjunction with a moderate-intensity exercise program, 3 sessions per week of 1 hour each for 12 weeks, improves several measures of muscle strength and quality in both sexes, and increases lower leg muscle mass in males, when compared with placebo (109546).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral spinach can reduce the risk of developing NAFLD. Details: A large observational study has found that raw, but not boiled, spinach consumption is inversely associated with the risk of developing NAFLD (106566).
• Obesity. It is unclear if consuming spinach is beneficial for weight loss. Details: Preliminary clinical research in overweight or obese middle-aged and older females shows that taking a specific spinach product (Appethyl, Greenleaf Medical AB) 5 grams daily before breakfast for 12 weeks increases weight loss by an additional 1.5 kg when compared with placebo. However, fat loss, waist circumference, and blood lipids are not improved when compared with placebo (96856,96857).
• Polycystic ovary syndrome (PCOS). It is unclear if oral spinach-derived thylakoids are beneficial for PCOS. Details: A small clinical study in premenopausal adults with PCOS and obesity shows that adding 5 grams orally daily of spinach-derived thylakoids to a low-calorie diet for 12 weeks reduces weight and body mass index (BMI) by 8%, compared with 4% with placebo and the low-calorie diet. Insulin resistance is also improved among those receiving spinach extract. These changes are unlikely to be clinically significant (106568). More evidence is needed to rate spinach for these uses.

(Read more about SPINACH)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). Pooled analyses of clinical research show that taking freeze-dried strawberry powder or eating fresh strawberries for 3-12 weeks can reduce levels of C-reactive protein, a marker of inflammation and risk factor for CVD, by 0.47-0.63 mg/L when compared with placebo. These analyses report conflicting effects on blood pressure and lipid levels (103881,103882), with one analysis reporting small improvements that are not clinically significant (103881). It is unclear whether strawberry can prevent CVD or related outcomes.
• Diabetes. Preliminary clinical research in adults with type 2 diabetes shows that taking freeze-dried strawberry powder 50 grams daily for 6 weeks reduces glycated hemoglobin (HbA1c) by 0.47% compared to an increase of 0.15% with placebo. However, there were no changes in serum glucose, anthropometric measurements, blood lipids, or blood pressure. Also, the short duration of supplementation makes it unclear whether the change in HbA1c was due to strawberry (100113,100119).
• Hyperlipidemia. Data on the effects of strawberry on serum lipids are conflicting. Clinical research in adults with abdominal obesity and elevated serum lipids shows that taking freeze-dried strawberry powder 50 grams daily for 12 weeks reduces total and low-density lipoprotein (LDL) cholesterol when compared with either placebo or taking 25 grams of freeze-dried strawberry daily. In those taking 50 grams daily, levels of LDL cholesterol decreased by approximately 21% from baseline, compared with a 2% reduction in those taking placebo. However, strawberry did not improve levels of high-density lipoprotein (HDL) cholesterol or triglycerides (100109). Another study also reported reduced levels of total and LDL cholesterol (112318), while others report no changes in any lipid levels (112320,112321). In a meta-analysis, strawberry was associated with mean decreases of 11 mg/dL in LDL levels, and 12 mg/dL in total cholesterol, as well as increases in high-density lipoprotein (HDL) cholesterol (112323).
• Hypertension. Preliminary clinical research in postmenopausal women with pre- or stage I hypertension shows that taking freeze-dried strawberry powder 25 or 50 grams daily for 8 weeks does not reduce blood pressure when compared with placebo. However, over 50% of the included women were also taking at least one blood pressure lowering medication (100111).
• Obesity. Clinical research in adults with obesity or abdominal obesity and elevated serum lipids shows that taking freeze-dried strawberry powder 50 grams daily for 12 weeks does not reduce body weight or adiposity when compared with either placebo or freeze-dried strawberries 25 grams daily (100109,100116). Similarly, preliminary clinical research in adults with type 2 diabetes who are overweight or obese shows that taking freeze-dried strawberry powder 50 grams daily for 6 weeks does not improve weight loss when compared with placebo (100113). Evidence from mainly small, lower-quality studies is mixed as to whether taking strawberries has beneficial effects on cardiovascular risk factors when compared to control in obese individuals (100109,100116,100118).
• Osteoarthritis. Preliminary clinical research in obese adults with osteoarthritis shows that taking freeze-dried strawberry powder 50 grams daily for 12 weeks reduces some, but not all, measures of pain by up to 45%, compared to no change in those taking placebo (100116). More evidence is needed to rate strawberry for these uses.

(Read more about STRAWBERRY)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). Although there has been interest in using oral sweet cherry for CVD, there is insufficient reliable information about the clinical effects of sweet cherry for this condition.
• Diabetes. Although there has been interest in using oral sweet cherry for diabetes, there is insufficient reliable information about the clinical effects of sweet cherry for this condition.
• Gout. Although there has been interest in using oral sweet cherry for gout, there is insufficient reliable information about the clinical effects of sweet cherry for this condition.
• Obesity. It is unclear if oral sweet cherry is beneficial for obesity. Details: A small clinical study in adults with obesity shows that consuming sweet cherry juice as 50 mL concentrate and 3-gram powder in 150 mL water twice daily for 30 days modestly lowers blood pressure when compared with placebo. However, sweet cherry does not reduce body weight or body mass index when compared to baseline (111723). The interpretation of these findings is limited by the lack of clarity about the dose of sweet cherry and high rate of patients discontinuing the study.
• Osteoarthritis. Although there has been interest in using oral sweet cherry for osteoarthritis, there is insufficient reliable information about the clinical effects of sweet cherry for this condition. More evidence is needed to rate sweet cherry for these uses.

(Read more about SWEET CHERRY)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. It is unclear if dietary citrus fruits are beneficial in patients with asthma. Details: There is some evidence that consumption of vitamin C-rich citrus fruits, including sweet orange and others, might improve lung function in people with asthma. However, this is controversial. Some studies show that intake of citrus fruits 1-2 times per week produces significant benefit (6049,6055,6056), while other studies have not found this benefit (6057,6058).
• Common cold. It is unclear if drinking sweet orange juice prevents the common cold. Details: Preliminary clinical research in healthy individuals ages 17 to 25 years suggests that drinking sweet orange juice 180 mL daily for 72 days might decrease the risk of developing common cold-related symptoms (15328).
• Constipation. It is unclear if consuming sweet orange juice with orange pomace is beneficial in patients with constipation. Details: A moderate-sized crossover clinical study in healthy adults shows that consuming 16 ounces of sweet orange juice with orange pomace 180 grams daily for 4 weeks does not change the number of bowel movements per week, stool consistency, or ease of stool passage when compared with sweet orange juice alone (114401). Several factors limit the validity or generalizability of these findings, including exclusion of patients with recent constipation and variability of total dietary fiber intake among study participants.
• Depression. It is unclear if drinking sweet orange juice or using sweet orange essential oil as aromatherapy is beneficial for depression. Details: Preliminary clinical research in adults with depression shows that drinking flavonoid-rich sweet orange juice 190 mL three times daily for 8 weeks modestly improves depression scores when compared to baseline, but not when compared with a low-flavonoid orange drink (110045). Sweet orange has also been studied as part of a combination aromatherapy. A very small clinical study in community-dwelling older adults shows that massage therapy to the upper body with sweet orange, lavender, and bergamot oils twice weekly for 8 weeks improves symptoms of depression in 65% of patients when compared with no intervention. Twice weekly inhalation of the same essential oils via nebulizer, without massage, also improves symptoms of depression in 55% of patients when compared with no intervention (98474).
• Hypercholesterolemia. It is unclear if drinking sweet orange juice improves blood lipid levels. Details: A very small clinical study in hypercholesterolemic patients shows that drinking large amounts of sweet orange juice (750 mL daily for four weeks) seems to increase high-density lipoprotein (HDL) cholesterol by 21% and reduce the ratio of low-density lipoprotein (LDL) to HDL cholesterol by 16% when compared to baseline. This effect was not seen with 250-500 mL of sweet orange juice. Because consumption of this large amount of juice daily provides approximately 20% of the daily energy requirement, this regimen may not be practical (3340).
• Insomnia. Sweet orange essential oil as aromatherapy has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: Preliminary clinical research in adults undergoing hemodialysis shows that inhaling aromatherapy with sweet orange and lavender oil nightly before bed for one month improves overall sleep quality by 72% and fatigue by about 78% when compared with no treatment (98508).
• Kidney failure. It is unclear if sweet orange oil massage can improve fatigue or symptoms of restless leg syndrome (RLS) in adults receiving hemodialysis. Details: A small clinical study shows that receiving an 18-minute foot massage with sweet orange oil 1.5% for 3 weeks during hemodialysis sessions modestly improves sleep quality and symptoms of RLS when compared with routine care. However, it does not seem to be more effective than using lavender oil (109859).
• Kidney stones (nephrolithiasis). It is unclear if drinking sweet orange juice is beneficial for preventing kidney stones. Details: Consuming 400 mL of sweet orange juice three times a day, providing a total of 100 mEq of citrate daily, increases urinary pH and urinary citrate levels (15171). Theoretically, this might reduce kidney stone formation in patients with calcium nephrolithiasis. However, this outcome has not been evaluated in clinical research.
• Obesity. It is unclear if drinking sweet orange juice or taking oral sweet orange extract improves weight loss or other metabolic parameters in adults with overweight or obesity. Most studies suggest that any effects are unlikely to be considered clinically relevant. Details: Some preliminary clinical research in adults with overweight or obesity shows that taking a specific sweet orange extract (Morosil, Bionap S.R.L.) 400 mg orally once daily for six months reduces waist circumference, body weight, fat mass, and body mass index (BMI) by 2% to 5% when compared with placebo (110046). However, other preliminary clinical research in this population shows that drinking red sweet orange juice 750 mL daily for 8 weeks does not reduce body weight or BMI when compared with baseline (92309). A meta-analysis of clinical research in adults, most of whom were overweight or obese at baseline, shows that drinking 250-750 mL of various types of sweet orange juice daily for 2-12 weeks does not reduce body weight, BMI, waist circumference, or body fat percentage (BFP) when compared with control groups, which included either no supplementation, pomegranate juice, or exercise (107853). The validity of this meta-analysis is limited due to the population heterogeneity and variety of orange juice formulations and controls utilized. Some clinical studies have also evaluated sweet orange juice for improving cardiovascular risk factors in overweight and obese adults. Although some research has shown benefit, not all research agrees (110046,110047). A meta-analysis of randomized clinical trials in adults with overweight or obesity shows that drinking sweet orange juice 250-600 mL daily for 2-13 weeks modestly increases high-density lipoprotein cholesterol levels and decrease average systolic blood pressure by 1 mmHg when compared with control. However, drinking sweet orange juice does not affect other blood lipid levels, blood glucose levels, or markers of insulin resistance (110048). The validity of this study is limited by high heterogeneity and a small sample size. In addition, these improvements are unlikely to be considered clinically relevant. Sweet orange extract has also been studied in combination with other ingredients. Some clinical research in overweight adults shows that taking a specific combination product (Sinetrol, Fytexia) 450-700 mg twice daily containing sweet orange, blood orange, and grapefruit extracts for 12 weeks reduces body weight, BFP, and BMI when compared with placebo or baseline (95517,95518). It is unclear if these effects are due to sweet orange, other ingredients, or the combination.
• Pre-procedural anxiety. It is unclear if inhaling sweet orange essential oil as aromatherapy reduces anxiety before surgeries or invasive procedures. Details: A small, low-quality study suggests that inhaling the scent from 3 drops of sweet orange essential oil applied to a cotton ball for 5 minutes modesty reduces anxiety and pain scores in patients undergoing needle insertion for hemodialysis when compared with performing a breathing exercise for 3 minutes (105455).
• Prostate cancer. It is unclear if drinking sweet orange juice reduces prostate cancer risk. Details: Observational research has found that increasing dietary intake of sweet orange or sweet orange juice is not associated with a reduced risk of developing prostate cancer (15172).
• Stress. It is unclear if inhaling sweet orange essential oil as aromatherapy is beneficial for stress. Details: Preliminary clinical research shows that using up to 10 drops of sweet orange essential oil as aromatherapy helps prevent some anxiety and tension associated with stressful tasks when compared with control (90505). More evidence is needed to rate sweet orange for these uses.

(Read more about SWEET ORANGE)

POSSIBLY INEFFECTIVE

• Bladder cancer. Consuming tomatoes and tomato-based products does not appear to reduce the risk of bladder cancer. Details: Observational studies have found no association between tomato and tomato-based product intake and the risk of bladder cancer (2407).
• Breast cancer. Consuming tomatoes and tomato-based products does not appear to reduce the risk of breast cancer. Details: Observational studies have found no association between tomato or tomato-based product intake and risk of breast cancer (15747).
• Diabetes. Consuming tomatoes and tomato-based products does not appear to prevent the development of type 2 diabetes or improve glycemic control in patients with type 2 diabetes. Details: Observational studies have found that increasing intake of tomato or tomato-based products does not significantly decrease the risk of developing type 2 diabetes (14004,14361). Additionally, a small clinical study in non-smoking male patients with type 2 diabetes shows that consuming raw tomato 200 grams daily for 8 weeks does not improve plasma glucose levels when compared to baseline (102477). The validity of this finding is limited by the lack of comparator group.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if tomato improves skin appearance. Details: A small study of females aged 35-55 shows that taking a certain tomato pulp product (Lumenato, Lycored) 1 capsule daily for 12 weeks improves patient reported skin appearance scores when compared to baseline (110523). The interpretation of this result is limited by the lack of a placebo group.
• Benign prostatic hyperplasia (BPH). Oral tomato powder has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with BPH shows that taking 5 grams of a whole tomato food supplement consisting of tomato powder and polyphenols extracted from olives daily for 2 months improves quality of life and reduces lower urinary tract symptoms including urinary frequency, urinary urgency, and nocturia when compared to baseline. No improvements in these symptoms were reported with placebo (106656). It is unclear if these findings are due to tomato, olive polyphenols, or the combination.
• Cardiovascular disease (CVD). It is unclear if consuming tomato-based foods reduces the risk of cardiovascular events. Details: Observational research has found that increased consumption of tomato-based foods is associated with an insignificant trend towards a reduced risk of myocardial infarction, stroke, and other cardiovascular events (10418,102178).
• Cataracts. It is unclear if consuming tomatoes reduces the risk of cataracts. Details: Observational research has found that eating more than 3 servings of tomatoes each week may decrease the risk of developing cataracts (9439).
• Cervical cancer. It is unclear if consuming tomatoes reduces the risk of cervical cancer. Details: Observational research has found that increased tomato intake is associated with a decreased risk of cervical cancer (2407).
• Colorectal cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of colorectal cancer is conflicting and limited to observational studies only. Details: Some observational research has found that increasing tomato or tomato-based product intake is associated with a reduced risk of colorectal cancer (2404,2407). However, higher quality observational research has found that tomato-based product intake is not associated with risk of colorectal cancer (15747).
• Exercise-induced asthma. It is unclear if oral tomato extract is beneficial in patients with exercise-induced asthma. Details: A small clinical study in patients with exercise-induced asthma shows that taking a specific tomato extract (Lyc-O-Mato, LycoRed Ltd) 30 mg daily for 1 week seems to reduce exercise-induced asthma when compared with placebo. The tomato extract seems to prevent decreases in forced expiratory volume (FEV1) in response to exercise (7898).
• Gastric cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of gastric cancer is conflicting and limited to observational studies only. Details: Some observational studies have found that increasing tomato or tomato-based product intake is associated with a reduced risk of gastric cancer in some subgroups of patients (2407,15747,102480). However, other observational research has found that tomato-based product intake is not associated with risk of gastric cancer (15747). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding tomatoes and gastric cancer risk. However, the FDA concludes that it is highly unlikely that tomatoes reduce the risk of gastric cancer (102375).
• Hyperlipidemia. Small clinical studies suggest that consuming tomato sauce or semi-dried tomatoes may modestly reduce low-density lipoprotein (LDL) cholesterol levels in patients with hyperlipidemia. Details: One small, open-label clinical trial in patients with hyperlipidemia shows that consuming a specific vine-ripened tomato sauce (OsteoCol, C.G. Food, SRL) 150 mL daily for 6 weeks reduces total cholesterol and LDL cholesterol levels when compared to baseline. Patients adherent to the tomato sauce regimen showed an 11 mg/dL and 12 mg/dL reduction in total and LDL cholesterol, respectively, while those consuming a sterol-enriched yogurt saw total and LDL cholesterol levels decrease by 18 mg/dL and 16 mg/dL, respectively. Patients with a baseline LDL cholesterol level of greater than 152 mg/dL saw the greatest benefit from this tomato sauce (106653). Another small clinical study in Japanese patients with borderline high cholesterol shows that taking 50 grams of a semi-dried tomato containing lycopene 22-27.8 mg daily for 12 weeks modestly reduces LDL cholesterol levels but does not affect high-density lipoprotein (HDL) cholesterol levels when compared with taking 50 grams of a tomato without lycopene (102180). This suggests that any benefit of tomato on blood lipid levels is likely due to its lycopene content.
• Hypertension. Small clinical studies and observational research suggest that oral tomato extract or dietary tomato consumption may modestly reduce blood pressure in patients with hypertension. Details: Several small clinical trials in patients with hypertension show that taking a specific tomato extract product (Lyc-O-Mato, LycoRed, Ltd.), providing lycopene 15-30 mg daily, for 6-8 weeks, reduces systolic blood pressure by around 7-13 mmHg and diastolic blood pressure by around 4-6 mmHg when compared to baseline (14287,60415,102182). The validity of these findings is limited by the lack of a comparator group. Additionally, a large observational study, conducted over 3 years, suggests that moderate consumption of tomato-based products (i.e., 44-82 grams daily) is associated with marginally lower blood pressure when compared with higher and lower consumption in older adults with grade 1 hypertension. However, this association is not seen in patients with grade 2 or 3 hypertension (113145). Interpretation of these results is limited by self-reported data and lack of generalizability outside of confounders relating to a Mediterranean lifestyle. Evidence on the use of tomato in patients with pre-hypertension is mixed. One small clinical study in patients with pre-hypertension shows that taking a specific tomato extract (Fruitflow, Provexis Plc, UK.) 150 mg as a single dose seems to modestly reduce blood pressure over a 24-hour period when compared with placebo (102478). This study is limited by its small size and short duration. Another small clinical study in pre-hypertensive patients shows that taking a specific tomato extract (Lyc-o-Mato, LycoRed Ltd) containing lycopene 15 mg daily for 8 weeks does not reduce blood pressure when compared with placebo (42079). The impact of dietary tomato consumption on preventing hypertension has also been evaluated. A large prospective observational study in Chinese adults without a history of smoking or myocardial infarction suggests moderate dietary intake of tomatoes (i.e. up to 33.3 grams daily) is associated with a 49-58% reduction in the risk of developing new onset hypertension when compared with no consumption after about 6 years' follow up. However, the associated risk reduction was less with higher consumption (110525). These results may not apply to patients in countries where dietary trends are different, and the validity of these findings is limited by the potential for confounding. Another large observational study, conducted over 3 years in older adults at high cardiovascular risk, suggests that higher consumption (i.e., at least 1 large-sized tomato daily) is associated with reduced risk of hypertension by 36% when compared with moderate and lower consumption (113145). However, interpretation of these results is limited by self-reported data, and lack of generalizability outside of confounders relating to a Mediterranean lifestyle.
• Lung cancer. It is unclear if consuming tomatoes reduces the risk of lung cancer; the available research is conflicting. Details: Some observational studies have found an association between increased tomato and tomato-based product consumption and a reduced risk of lung cancer; however, many of these studies were not stratified based on the patient's smoking status. Higher quality, large-scale observational studies have not found any association between tomato product intake and lung cancer risk (15747).
• Muscle strength. It is unclear if consuming tomatoes improves muscle strength or attenuates declines in muscle strength. Details: A small observational study in Japanese adults 22-68 years of age found that more frequent tomato consumption (2 or more times weekly) is associated with an attenuated rate of handgrip strength decline over 3 years when compared with less frequent tomato consumption (102473).
• Ovarian cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of ovarian cancer is conflicting and limited to observational studies only. Details: Some observational research has found that increased tomato or tomato juice intake is not associated with risk of ovarian cancer; however, consuming tomato sauce two or more times weekly is associated with a decreased risk (2407). Other observational research has found that increased dietary intake of lycopene, particularly from tomato sauce, is associated with a reduced risk of ovarian cancer in premenopausal patients (10133). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding tomato sauce and ovarian cancer risk. However, the FDA concludes that it is highly uncertain that tomato sauce reduces the risk of ovarian cancer (102375).
• Pancreatic cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of pancreatic cancer is conflicting and limited to observational studies only. Details: A large-scale observational study have found that that tomato or tomato-based product intake is not associated with a decreased risk of pancreatic cancer (15747). However, other observational studies have found that raw tomato intake, and high tomato intake in general, is associated with a reduced risk of pancreatic cancer (2407,15747,15750). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding tomatoes and pancreatic cancer risk. However, the FDA concludes that it is highly unlikely that tomatoes reduce the risk of pancreatic cancer (102375).
• Prostate cancer. Consuming tomatoes or tomato-based products may slightly lower the risk of prostate cancer; however, observational research is mixed and high-quality clinical trials addressing tomato intake and prostate cancer risk are lacking. Details: Some observational studies have found that consuming tomato products, including tomatoes, tomato sauce, pizza, or tomato juice, one time or more per week, is associated with a modest reduction in the risk of prostate cancer (2406,7772,7895,12878,15747,102476). However, other observational research has found that tomato consumption is not associated with a reduced risk of prostate cancer (14125,15172,15747,92171). One small clinical study in patients with high-grade prostatic intraepithelial neoplasia shows that taking tomato extract capsules containing lycopene 30 mg daily for 6 months does not impact benign tissue endpoints when compared with placebo (102471). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that one-half to one cup of tomatoes or tomato sauce weekly may reduce the risk of prostate cancer. However, the FDA concludes that there is little scientific evidence to support this claim (102375).
• Radiation dermatitis. It is unclear if drinking tomato juice is beneficial in patients with radiation dermatitis. Details: One small, uncontrolled clinical trial in patients undergoing radiotherapy for breast cancer shows that drinking tomato juice 160 mg daily for 6 months after radiotherapy improves the severity of dermatitis within 1 month of treatment when compared to baseline (106654). The lack of a comparator group limits the validity of these findings; it is unclear how tomato juice consumption compared with the natural resolution of radiation dermatitis. More evidence is needed to rate tomato for these uses.

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EFFECTIVE

• Vitamin A deficiency. Oral vitamin A is effective for treatment and prevention of vitamin A deficiency. Details: Clinical and observational research in children shows that taking vitamin A orally is effective for preventing and improving symptoms of vitamin A deficiency, including xerophthalmia, night blindness, and Bitot's spots (82329,82689,82710,90773). Vitamin A deficiency can occur due to abnormal storage and transport of vitamin A in people with abetalipoproteinemia, protein deficiency, diabetes mellitus, hyperthyroidism, fever, liver disease, and cystic fibrosis (7135). However, research suggests that supplementation with vitamin A may not be necessary for most newborns with vitamin A deficiency. An observational study in newborns with vitamin A levels of 0.43-0.59 mcmol/L or >0.59 mcmol/L found that vitamin A levels increased naturally over the first six months of life, regardless of oral vitamin A supplementation. However, in infants with very low vitamin A levels (<0.43 mcmol/L), vitamin A supplementation was associated with significant increases in vitamin A levels at 6 months of age when compared with no supplementation, suggesting that only newborns with very low vitamin A levels should receive oral vitamin A (107298).

POSSIBLY EFFECTIVE

• Aging skin. Topical vitamin A (retinol) formulations seem to improve symptoms of aging skin, such as wrinkles and mottled pigmentation. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of aging facial skin (103711). However, this drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Although research evaluating non-prescription topical vitamin A shows benefit for reducing wrinkles, most studies have been small and used different formulations. One small study in adults over 40 years of age shows that applying a pea size amount of 0.075% retinol cream to the face daily for 26 weeks seems to reduce deep and fine wrinkling when compared with placebo. Applying a lower dose of 0.04% retinol cream for 13 weeks seems to reduce fine wrinkling to a lesser degree, with no effect on deep wrinkles, when compared with placebo cream (104458). Another small clinical study in adults over 80 years of age shows that applying 2 mL of retinol 0.4% lotion to the upper arm up to 3 times weekly for 24 weeks reduces visible wrinkles when compared with placebo (94683). Two small studies in females ages 33 to 65 show that applying retinol 0.15%, 0.3% and 0.5% in liquid crystal formulation once daily to the face for 2-3 months improves skin pigmentation, elasticity, and wrinkles when compared with baseline (103680,104464). The validity of these two studies is limited by the lack of a comparator treatment. Topical vitamin A is frequently combined with other ingredients in commercial formulations; however these combinations have rarely been studied. A small clinical study in adults over 35 years with skin aging shows that applying a cream containing retinol 0.5%, niacinamide, resveratrol, and hexylresorcinol seems to improve wrinkling and skin tone when compared with baseline (104455). Another small preliminary clinical trial in adults ages 35-65 years with periorbital lines and wrinkles shows that applying a cream containing retinol modestly improves dryness, puffiness, redness, and darkness when compared with baseline. The retinol was conjugated with lactic acid, and the cream contained other nutrient and herbal ingredients It was applied around the eyes each evening, sometimes used in combination with another product each morning (109747).
• Bronchopulmonary dysplasia. Intramuscular vitamin A may reduce the risk of bronchopulmonary dysplasia (BPD) in very low birth weight infants when given at a dose of 5000 IU three times weekly for 28 days. Lower doses do not seem to be effective. It is unclear if enteral vitamin A is beneficial for BPD. Details: A meta-analysis of 6 clinical trials in premature infants shows that intramuscular administration of vitamin A every other day or three times weekly for 28 days reduces the risk of BPD by around 33% when compared with control (107297). The results from this meta-analysis are primarily driven by a modestly sized clinical trial in very low birth weight infants which shows that intramuscular administration of vitamin A 5000 IU three times weekly for 28 days reduces the risk of BPD by 15% when compared with a sham control (82195). A subgroup analysis of this trial suggests that infants with the lowest BPD risk estimate based on gestational age, birth weight, sex, ethnicity, and oxygen levels 24 hours after birth appear to benefit more from vitamin A therapy than those with higher BPD risk estimates (107296). Previous research in this area utilized a lower dose of only 2000 IU every other day for 28 days, and showed no significant improvement in the rate of BPD (82331,82613). The evaluation of a higher dose was prompted by research noting that the lower doses evaluated in these earlier studies were unable to achieve serum retinol concentrations above 25 mcg/dL, while doses at or above 5000 IU three times weekly could reach this level (82731). Enteral vitamin A has also been investigated. Meta-analyses of two clinical trials show that supplementation with vitamin A at an average of 5,000 IU daily, staring within four days of birth, does not reduce the incidence of BPD when compared with placebo (109750,109753).
• Diarrhea. Vitamin A seems to reduce the incidence of diarrhea in young children. However, it is unclear if oral vitamin A while breastfeeding is beneficial for preventing diarrhea in nursing infants. Details: A meta-analysis of clinical research in children up to age 5 shows that vitamin A supplementation reduces the incidence of diarrhea by 15% and mortality related to diarrhea by 12% when compared with control, usually placebo or no supplementation (109755). However, one small clinical trial in breastfeeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of diarrhea in the nursing infants when compared with placebo (107293).
• Measles. High-dose vitamin A, at recommended age-specific doses, seems to reduce mortality in children with measles under 2 years of age. Additionally, vitamin A may reduce the incidence of measles in children up to 5 years of age who are at risk for vitamin A deficiency. Details: Vitamin A deficiency is a known risk factor for severe measles, as well as measles-related morbidity and mortality. The use of vitamin A supplementation for the treatment of measles has been studied mostly in resource-limited countries with increased risk for vitamin A deficiency. However, measles infection has also been shown to deplete vitamin A stores, leading to recommendations for vitamin A supplementation in acute measles, regardless of geographic location (115976). Meta-analyses of clinical research show that taking vitamin A does not reduce mortality in children with measles when all ages and/or doses are considered (82373,82502). However, a sub-analysis of 3 studies that utilized a higher dose of 200,000 IU orally daily for two days, in children under 2 years of age who were hospitalized with measles, shows that this dosing regimen reduces the relative risk of mortality by about 60% when compared with placebo (82373,82502). Additionally, vitamin A supplementation in children with measles may reduce the risk of some complications, such as croup (82373). Most studies in these analyses were conducted in regions with high measles case-fatality rates; the benefit of vitamin A supplementation in regions with lower case-fatality rates, such as the United States, is unclear. Based on these data, the World Health Organization (WHO) recommends treatment with vitamin A, using age-specific doses, for all children with acute measles (115966). The American Academy of Pediatrics (AAP) also recommends the administration of age-specific doses to all children with measles, regardless of severity, as follows: 200,000 IU daily for 2 days in children at least one year of age, 100,000 IU daily for 2 days in children 6-12 months of age, and 50,000 IU daily for 2 days in children under 6 months old. In children with clinical symptoms of vitamin A deficiency, an additional age-specific dose is recommended 2-6 weeks later (115977). Vitamin A supplementation has also been studied in apparently healthy children living in regions at high risk for vitamin A deficiency. A meta-analysis of 6 clinical studies shows that taking vitamin A reduces the incidence of measles in children ages 6 months to 5 years. These studies provided vitamin A supplementation either as a single high dose or as three high doses over one year. In 3 studies, vitamin A was given in conjunction with measles vaccination; vaccination status was not provided for the other studies (109755). The WHO and AAP do not recommend the use of vitamin A for measles prevention. Instead, routine measles vaccination is recommended. Additionally, for people over 6 months of age with recent measles exposure who are unimmunized or insufficiently immunized, immediate measles vaccination is recommended (115966,115977).
• Night vision. Oral vitamin A as retinyl palmitate seems to reduce night blindness during pregnancy in malnourished patients. Details: Clinical research shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related night blindness by 37% in malnourished patients (6154). Some evidence suggests that zinc supplements might potentiate the effects of vitamin A in restoring sight in zinc-deficient pregnant patients affected by night blindness (8630).
• Oral leukoplakia. High-dose oral vitamin A seems to reduce oral leukoplakia lesions in patients that chew tobacco and/or betel nut. Details: Clinical research in patients with tobacco and/or betel nut chewing habits shows that taking oral vitamin A 200,000-300,000 IU weekly for 6-12 months seems to result in remission of leukoplakia lesions in over 50% of participants when compared with placebo (34674,82617). However, it is unknown if vitamin A prevents the development of oral cancer from oral leukoplakia lesions.
• Overall mortality. In children at risk for vitamin A deficiency, oral vitamin A seems to reduce mortality. However, it does not seem to reduce mortality in healthy adults. Details: Despite previous debate on whether the programs supplying high-dose vitamin A in low- and middle-income countries with prevalent vitamin A deficiency are safe and effective for reducing child mortality, most experts, including World Health Organization, recommend high-dose vitamin A supplementation for those children (95055,95724,97170,109755). Meta-analyses including 8-18 clinical studies show that vitamin A supplementation reduces all-cause mortality by about 12%-26% in children 6 months to 5 years of age (82559,95055,115748), but does not seem to reduce mortality in neonates or children 1-6 months of age (115748). Notably, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which involved one million preschool children and was included in one of the previously discussed meta-analyses, suggests that high-dose vitamin A supplementation does not reduce mortality (90773). However, this trial was limited due to under-resourcing and undetermined patient consent and treatment compliance (90773). Adult mortality is not reduced by vitamin A supplementation. In fact, some evidence even shows that vitamin A supplementation increases mortality when administered to healthy adult patients or those with a stabilized disease (15305,34622,90775).
• Postpartum complications. Oral vitamin A seems to reduce postpartum diarrhea and mortality in malnourished patients. Details: A large clinical study in malnourished pregnant patients in Nepal shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before, during, and after pregnancy reduces the occurrence of blood and mucus in the stool by 93% and the occurrence of diarrhea by up to 90% during the first 6 months postpartum when compared with placebo (2581). Another clinical study in the same population shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related mortality by 40% when compared with placebo (6153).
• Retinitis pigmentosa. Oral vitamin A supplementation in children with retinitis pigmentosa seems to slow retinal function decline. Details: Observational and clinical research in children with retinitis pigmentosa shows that taking an age-adjusted dose of vitamin A, up to a maximum dose of 15,000 IU daily, modestly attenuates the decline in retinal function when compared with control (83,97167,103677).
• Ulcerative colitis. Oral vitamin A supplementation in patients with ulcerative colitis seems to improve clinical response and mucosal healing. Details: A clinical study in adults with symptomatic ulcerative colitis despite treatment with 5-aminosalicylic acid shows that taking vitamin A 25,000 IU daily for 2 months reduces disease severity and increases the rate of clinical response and mucosal healing when compared with placebo. The number needed to treat (NNT) for clinical response is 3; the NNT for mucosal healing is 5 (100329).
• Wrinkled skin. Topical vitamin A (retinol) formulations seem to improve photodamage and wrinkles. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of facial skin (103711). This drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Some research in females ages 35-65 with moderately wrinkled and photoaged skin suggests that commercially available retinol formulations might reduce wrinkles and skin roughness similarly to tretinoin. One study used retinol serum starting at a concentration of 0.25% and increased to 1% over 3 months, compared with tretinoin cream 0.025% gradually increased to 0.1% (103671), while another study compared a gradual release tri-retinol 1.1% cream applied daily for 3 months to tretinoin 0.025% cream (104456). Commercial retinol also seems to be beneficial when compared with placebo. A meta-analysis of 6 clinical studies including a total of 352 females over 30 years of age with mild to moderate photodamage shows that applying stabilized retinol 0.1% to the face once or twice daily for 8-12 weeks reduces overall photodamage when compared with placebo. Retinol also reduced uneven skin tone, brown spots, wrinkles and fine lines on the forehead, cheek, and undereye, and crow's feet. Five of the six studies used a split-face design, with each participant serving as their own control. Skin assessments were performed by a single dermatologist in all six studies (114500).

POSSIBLY INEFFECTIVE

• Atopic disease. Supplementation with oral vitamin A does not seem to reduce the risk of atopy. Details: Clinical research in infants born in Guinea-Bissau shows that a single dose of vitamin A does not reduce the incidence of atopy when compared with placebo (90779,90780). Furthermore, giving a single dose of vitamin A to some infants, such as low birth weight infants and infants given Bacille Calmette-Guerin (BCG) vaccination, was associated with increased atopy and wheeze (90779).
• Fetal and premature infant mortality. Giving oral vitamin A to malnourished adults during pregnancy and postpartum does not seem to reduce fetal, early infant, or first year mortality. Giving oral or intramuscular vitamin A to the infant also does not seem to reduce mortality in most patients. Details: Most meta-analyses of clinical research in malnourished patients suggest that vitamin A supplementation during pregnancy or postpartum does not reduce fetal, early infant, or first year mortality (6152,34601,34602,34627,82479,82566,82567,90774,90776,90782,90784,95057,109750,109753). Also, giving vitamin A supplements or intramuscular vitamin A to low birth weight infants does not appear to reduce mortality in these patients (82195,82431,82498,90778,90781,95053,107296,107297). Furthermore, vitamin A supplementation in term infants from low or middle income countries also does not appear to reduce the risk of mortality at 6 or 12 months of age when compared with placebo (95054,103674). Some evidence from a meta-analysis of clinical research shows that vitamin A supplementation may reduce the risk of mortality at 6 months in Asian infants, although it appears to increase the risk of mortality at 6 months in studies conducted in Africa. It also appears to increase the risk of mortality in female term infants by 12 months (95054).
• Intestinal parasite infection. Oral high-dose vitamin A does not seem to prevent reinfection with intestinal parasites. Details: Clinical research in children living in Malaysia that were given albendazole 400 mg daily for 3-4 days for parasitic worms, shows that adding a single dose of vitamin A 200,000 IU does not help to prevent reinfection when compared with placebo (90772).
• Melanoma. Oral vitamin A in patients with resected melanoma does not seem to improve survival and disease recurrence. Details: A clinical study in patients with completely resected melanoma shows that taking vitamin A 100,000 IU daily for 18 months does not increase disease-free survival when compared with no supplementation (82670).
• Miscarriage. Oral vitamin A given to the mother does not prevent miscarriage or stillbirth. Details: A meta-analysis of clinical research shows that maternal supplementation with oral vitamin A, either alone or in combination with other vitamins, prior to or during early pregnancy does not reduce the risk of miscarriage or stillbirth when compared with control (104462).
• Sepsis. Most research shows that oral vitamin A does not reduce the risk of sepsis in premature infants. Details: A meta-analysis of three clinical trials in premature infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the incidence of sepsis when compared with placebo (109753).
• Tuberculosis. Oral vitamin A does not seem to improve tuberculosis disease duration or mortality. Details: Low levels of vitamin A are common in patients with tuberculosis. However, taking vitamin A 2000 IU to 200,000 IU by mouth for 2-24 months does not improve symptoms, decrease disease duration, or reduce mortality when compared with placebo in these patients (82570,103668,109754). This may be due to the fact that vitamin A levels may normalize following the initiation of tuberculosis treatment, even without additional vitamin A supplementation.